Kidney Disease and Diabetes

Summary

Persons with diabetes make up the largest single group of kidney failure patients requiring dialysis or transplant in the United States. The high count reflects the growth in diabetes prevalence and increased access to dialysis and transplantation. Kidney failure affects about 1% of persons with diabetes in the United States; a considerably higher proportion, about 40%, have less severe kidney disease. Based on data from the National Health and Nutrition Examination Surveys 2017–March 2020, 14% of adults age ≥20 years or an estimated 35.5 million individuals had chronic kidney disease (CKD), and 38.7% of adults with diabetes had CKD-defined single measurements of albuminuria and serum creatinine.

Improvements in the management of persons with diabetes and CKD have extended the time course from onset of severe albuminuria to kidney failure and reduced the occurrence of cardiovascular events. Newer antihyperglycemic treatment strategies with sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and the newer mineralocorticoid receptor antagonists (MRAs) have shown efficacy in slowing kidney disease progression and reducing cardiovascular outcomes, without increasing the risk of hypoglycemia. In addition, landmark studies have shown that persons with kidney disease associated with diabetes require multidisciplinary management involving a combination of treatments and behavioral adjustments to delay progression of CKD and to prevent the associated complications.

Introduction

Important progress has been made since Diabetes in America, 3rd edition, was published in understanding the course and determinants of diabetes-related kidney disease (DKD) and its treatment (1). A new equation was developed for estimating glomerular filtration rate (GFR) that does not include a race term (2,3). Our understanding of glomerular hemodynamics and how it affects DKD progression has evolved (4,5). The management of DKD in type 2 diabetes was revolutionized by new medication classes, including sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), and newer mineralocorticoid receptor antagonists (MRAs), which are effective at slowing kidney disease progression in diabetes (6,7,8,9). Newly updated guidelines were published that considered these findings, as well as emerging data on the role of multidisciplinary approaches in the management of DKD (10).

Nevertheless, kidney disease remains a major cause of morbidity and mortality in persons with diabetes, as indicated by the dramatic increase in the number of persons receiving renal replacement therapy since the 1980s. Increased availability of dialysis and transplant and the rising prevalence of diabetes are primarily responsible for this trend. For 2022, approximately 25% of U.S. health expenditures, or $503.4 billion, were incurred by people with diabetes; 32% of the diabetes cost was attributable to associated chronic kidney disease (CKD) (11). Because kidney disease in diabetes is strongly associated with cardiovascular disease (CVD) and the development of kidney failure, the combined cost incurred by CKD and diabetes is associated with a greater percentage of the Medicare budget than that associated with congestive heart failure, another common and costly condition (12). People with diabetes and kidney disease represent 4.6% of the overall Medicare population and incur 7.5% of annual Medicare spending (12).

Projected increases in diabetes prevalence and the increasing frequency of both type 1 and type 2 diabetes in young people threaten to reverse the modest progress achieved with available treatments (13). Not only is the course of kidney disease in youth-onset type 2 diabetes more aggressive than in type 1 diabetes (14,15), but the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study suggests it may also be more treatment resistant than kidney disease in adults with type 2 diabetes (16). Although the development of new therapeutic options is essential for improving the management of this complex disease, diabetes prevention may ultimately offer the greatest benefit for stemming the rising tide of DKD.

This review has been updated to incorporate the substantial advances made in the past 6 years in understanding the pathogenesis, course, and management of CKD in persons with diabetes. It draws from recent publications, including large clinical trials and reflects the opinions of the authors.

Sources and Limitations of National Data on Kidney Disease and Diabetes

The National Health and Nutrition Examination Survey (NHANES) is a cross-sectional, national probability sample that has been conducted periodically since 1971 and continuously since 1999. NHANES data collected from individuals for the period 1988–2020 were used to assess CKD among a nationally representative U.S. sample. Participants self-reported diagnosed diabetes status, based on the question of “Other than during pregnancy, have you ever been told by a doctor or health professional that you have diabetes or sugar diabetes?” An advantage of the NHANES is that the survey includes a health exam in a mobile examination center where laboratory measures are collected. Thus, the NHANES has laboratory information on glycated hemoglobin (A1C) and fasting plasma glucose, so persons with undiagnosed diabetes can also be assessed. Participants self-reported demographic characteristics, CVD, and prescription medications. During the exam component, blood pressure was taken by a trained interviewer.

Definition, Measurements, and Classification

Although CKD in people with diabetes is heterogeneous, clinically it is usually attributed to diabetes, unless biomarker or biopsy information indicates otherwise (10). In recognition of this limitation, this article will use the term diabetes-related CKD (DKD). Irrespective of etiology, CKD is defined by reduced kidney function or the presence of kidney damage for at least 3 months, regardless of kidney function (10). Kidney damage is ascertained by increased urinary markers, such as albuminuria, or by abnormal urinary sediment, abnormal imaging studies, or kidney biopsy (10). The clinical diagnosis of DKD is based largely on the finding of elevated excretion of urinary albumin in a person with diabetes in the absence of other kidney disease.

Persons are classified as having elevated albuminuria if the albumin-to-creatinine ratio (ACR) in at least two urine samples collected within 3–6 months is ≥30 mg/g in the absence of clinical or laboratory evidence of urinary tract infection (10). Elevated albuminuria, the earliest marker of diabetic kidney damage, is frequently associated with a progressive decline in kidney function and a high risk for kidney failure and CVD. Although albuminuria is a continuous risk factor, it is often arbitrarily divided into moderately increased albuminuria (ACR 30–299 mg/g)—generally characterized by stable kidney function and a greater risk for higher levels of albuminuria than an ACR <30 mg/g—and severely increased albuminuria (ACR ≥300 mg/g), associated with arterial hypertension and a high risk of kidney failure (Table 1) (10). Because albuminuria occurs as a continuum, the American Diabetes Association (ADA) recommends simply using the term albuminuria for an ACR ≥30 mg/g (17). Urinary albumin excretion can be determined from 24-hour, overnight, or shorter urine collection periods; however, urinary ACR measured in a first morning void specimen is highly correlated with the 24-hour albumin excretion rate (AER) and is therefore an established and recommended way to assess urinary albumin excretion. Differences in methods of urine collection, albumin and creatinine measurements, reporting of results, and lack of standardized reference intervals for ACR often make comparisons between studies difficult.

TABLE 1.

Albuminuria Categories According to KDIGO Classification

Reduced kidney function is defined by GFR <60 mL/min/1.73 m², and kidney failure by GFR <15 mL/min/1.73 m² (Table 2) (10). Accurate determination of GFR is best achieved by infusing special markers into the bloodstream that are filtered at the glomerulus, but not secreted or reabsorbed by the tubules (e.g., inulin, iothalamate, iohexol, or ⁵¹Cr-EDTA), and measuring their disappearance from the blood or their appearance in the urine. Because such testing is laborious and expensive to use in large populations, the National Kidney Foundation (NKF) now recommends using the new CKD-EPI creatinine equation refit without the race variable to calculate the estimated GFR (eGFR) (2,3). An equation based on serum cystatin C, an endogenous filtration marker that is less influenced than serum creatinine by variations in muscle mass, diet, and tubular secretion or an equation that includes both serum creatinine and serum cystatin C may also be useful first-line tests (2,3). Regardless of etiology, CKD is classified based on both albuminuria and eGFR categories. Figure 1 shows the risk stratification of these stages for mortality, kidney, and cardiovascular outcomes (10).

TABLE 2.

Kidney Function Categories According to KDIGO Classification

FIGURE 1.

Classification of Chronic Kidney Disease to Indicate Prognosis Based on the Combined Measures of Albuminuria and Estimated Glomerular Filtration Rate. CKD stages based on both albuminuria and GFR levels are indicated in each cell. Symbols rank adjusted (more...)

In persons with diabetes, CKD may or may not be caused by diabetes alone. In those with type 1 diabetes of ≥10 years duration, CKD should be attributed to diabetes in the absence of other documented causes of kidney disease (10). Among persons with type 2 diabetes in particular, an eye examination is a useful, simple, and noninvasive test for differentiating between CKD caused by diabetes or other causes (18,19). A meta-analysis of 2,012 pooled patients with diabetes and CKD indicated that diabetic retinopathy has a sensitivity of 0.65 (95% confidence interval [CI] 0.62–0.68) and specificity of 0.75 (95% CI 0.73–0.78) for CKD due to diabetes (18). The presence of diabetic retinopathy in those with severe albuminuria is strongly suggestive of diabetes as cause of CKD, whereas the absence of diabetic retinopathy in those with normal or moderate albuminuria and an eGFR <60 mL/min/1.73 m² suggests DKD due to other causes (18,20). Clinical biopsy studies show that nondiabetic morphologic changes are present in 3%–69.5% of patients with DKD, depending on the population characteristics and clinical profile, as elaborated below.

Figure 1 illustrates the Kidney Disease: Improving Global Outcomes (KDIGO) CKD classification that reflects prognosis based on the combined measures of eGFR and albuminuria (10). The risk associations of GFR and albuminuria categories with renal, cardiovascular, and all-cause mortality outcomes are reviewed in the following sections. For screening and management of kidney disease in persons with diabetes, the NKF and ADA recommend annual ACR screening starting at 5 years duration of type 1 diabetes and at diagnosis of type 2 diabetes (10,17). Serum creatinine measurements and eGFR assessment are recommended at least annually in adults with diabetes, regardless of ACR level.

Pathophysiology and Clinical Course

DKD typically progresses through a number of phases in which albumin or protein excretion increases, and GFR may rise and subsequently fall, sometimes culminating in kidney failure (Figure 2) (21,22). A diagram of the clinical progression of DKD and some of the factors contributing to it is shown in Figure 3 (1,23,24,25,26,27,28,29). The clinical manifestations of kidney disease are similar in both type 1 and type 2 diabetes. The major histologic changes of DKD and their relationships with kidney disease progression are discussed in detail in the Morphometry section.

FIGURE 2.

Outline of the Natural History of Diabetic Kidney Disease in Persons With Type 1 Diabetes. The figure is based on data from 20 men, all of whom developed nephropathy. The time between the first examination and follow-up averaged 12±3 years; not (more...)

FIGURE 3.

Risk Factors For and Clinical Course of Kidney Disease in Diabetes. The thick horizontal arrows represent the reversibility of albuminuria with progressive kidney disease. BMI, body mass index; BP, blood pressure; ESKD, end-stage kidney disease; GFR, (more...)

Glomerular Hemodynamic Function

In healthy adults, the eGFR ranges from 90 to 140 mL/min/1.73 m², is stable through mid-adult life, and declines by approximately 1 mL/min/year after age 50 years, with the onset of global kidney sclerosis (49,50,51,52). The onset of diabetes is associated with hemodynamic changes in the kidney circulation that lead to increased renal plasma flow, glomerular capillary hyperperfusion, and an increased glomerular transcapillary hydraulic pressure gradient (Figures 4 and 5) (53,54,55,56,57,58,59).

FIGURE 4.

Mean Glomerular Filtration Rate in Men With Newly Diagnosed Type 1 Diabetes and Without Diabetes. Subjects were 31 nondiabetic men and 11 men with newly diagnosed and untreated type 1 diabetes; horizontal lines are mean ± standard deviation. The (more...)

FIGURE 5.

Glomerular Filtration Rate and Renal Plasma Flow in Persons With Type 2 Diabetes and Without Diabetes. GFR and effective renal plasma flow were measured in 110 persons with type 2 diabetes and 32 persons without diabetes; mean values are shown for each (more...)

Glomerular capillary hypertension and the ensuing increase in filtration pressure are partly responsible for the elevation of the eGFR, but various other glomerular and tubular factors also influence the magnitude of the hyperfiltration (60,61,62). The prevalence of hyperfiltration, generally defined as an eGFR of at least two standard deviations above the age- and sex-specific mean eGFR in persons with normal glucose tolerance, varies from 40% to 60% in persons with type 1 diabetes and from 7% to 73% in those with type 2 diabetes (26,63,64,65,66,67). The large variations in these estimates are attributed to differences in age, race and ethnicity, body size, glycemic control (with hyperglycemia increasing glycosuria and hyperfiltration), duration of diabetes, absence of diet standardization, and methodologies used to measure and report kidney function among different populations. In addition, simple single compartment models of plasma disappearance curves will overestimate GFR, and other methods are needed to accurately measure GFR and define its normal range. Accordingly, the definition of whole-kidney hyperfiltration is arbitrary, since whole-kidney eGFR is a product of single nephron filtration and nephron mass, and the latter varies significantly among people (68). More recently, filtration fractions or peak GFRs are explored in longitudinal studies to better ascertain hyperfiltration.

Several investigators have reported a relationship between hyperfiltration and the subsequent development of moderate albuminuria and progressive DKD (69,70,71), but others have not (24,25,72). Hyperfiltration may also reflect a generalized vascular dysfunction related to diabetes that in turn predisposes to DKD (73,74). Innovative analyses have revealed distinct molecular pathomechanisms contributing to the development of hyperfiltration, such as putative ligand-receptor pairs and downstream intracellular targets linked to cellular crosstalk between endothelial and mesangial cells (10).

After the initial elevation at onset of diabetes, the eGFR decreases to a near-normal range in response to metabolic control in both type 1 and type 2 diabetes (75,76,77,78) but usually not to levels found in persons without diabetes (55,78,79,80). In some, this reversal could reflect the initiation of progressive kidney disease, as suggested by the appearance of global glomerular sclerosis and the fall in single-nephron filtration coefficient (81). In others, it could represent a purely functional change in kidney hemodynamics associated with improvement in diabetes control or simply the intrinsic variability in the eGFR in the absence of significant histopathologic changes (82). Distinguishing between these two potential causes of eGFR decline requires either observation of the eGFR over a long period of time to determine whether it plateaus, reverses direction, or continues to decline to pathologic levels, or attention to other biomarkers, including albuminuria.

Coincident with the initial elevation of the eGFR at the diagnosis of diabetes is a slightly elevated urinary albumin excretion, although levels in the moderate albuminuria range or above are usually seen only after several years of diabetes (83). The eGFR in persons with moderate albuminuria is higher on average than in those with normal urinary albumin excretion (84,85). In those with severe albuminuria, it is lower, although in persons with type 2 diabetes, the eGFR may still be within the normal range (86,87). Cross-sectional data suggest that eGFR declines in persons with severe albuminuria, reflecting progressive glomerulosclerosis and loss of filtration surface area. Longitudinal studies confirm this hypothesis (88,89). The absence of albuminuria, however, does not preclude the presence of progressive kidney damage (see the Incidence of Elevated Albuminuria section) (90).

Kidney hemodynamic alterations induced by hyperglycemia and hypertension are believed to cause mechanical stretch and shear stress on endothelial cells and the mesangium, activating complex biochemical pathways that increase extracellular matrix production, hyperglycemia-induced injury, and podocyte damage and loss. These alterations ultimately lead to defects in selective glomerular capillary permeability, albuminuria, protein extravasation into the glomerular mesangium, expansion of mesangial matrix, and glomerulosclerosis (91,92,93,94,95,96,97,98). Trajectories of specific intraglomerular parameters estimated with the Gomez equation (99,100), namely the balance in vascular resistance between the afferent and efferent arterioles and the intraglomerular pressure, each predict incident kidney failure after adjusting for kidney function and both parameters correlate with mesangial fractional volume, a structural predictor of progressive DKD (4,101). Integration of long-term eGFR trajectories with morphometric and molecular analyses of research kidney biopsies identified an endothelial stress response with concomitant activation of downstream mesangial cell pathways associated with hyperfiltration providing a potential link between hyperfiltration and molecular pathways in the kidneys that lead to structural injury and progressive DKD (5).

Morphometry

The histologic changes in the kidneys of persons with type 1 diabetes and CKD are well described, typically homogenous, and predict development of elevated albuminuria, kidney failure, and cardiovascular death (102,103,104). On the other hand, the kidney lesions underlying CKD in type 2 diabetes are more heterogeneous (105,106). Longitudinal studies suggest a relationship between kidney lesions and eGFR decline (107,108). This section reviews the morphometric characteristics of DKD.

To appear in the urine, albumin must cross each layer of the glomerular filtration barrier consisting of the endothelial surface layer, fenestrated endothelial cells, glomerular basement membrane, and the glomerular epithelial cells or podocytes. Elevated albuminuria is an early clinical indicator of the destruction of the endothelial surface layer at the glomerular level (109,110,111,112), reduction in size and density of endothelial cell fenestrations (113,114,115), and thickening of the basement membranes. Subsequent expansion of the mesangium, consisting of mesangial cells and mesangial matrix, and podocyte injury and detachment further increase albuminuria, decreasing the available capillary filtration surface and leading to glomerulosclerosis. In addition to the glomerular morphologic lesions, diabetes progressively affects the kidney tubules, interstitium, and arterioles.

Glomerular basement membrane thickening strongly associates with albuminuria and eGFR impairment, suggesting that it is a good marker of early DKD. This alteration is followed by an increase in the mesangial volume per glomerulus (fractional mesangial volume), which is correlated inversely with eGFR, and positively with albuminuria and hypertension (65,116,117), and is therefore a strong predictor of progressive kidney dysfunction (Figure 6) (118). Virtually all persons with type 1 diabetes and advanced kidney disease have markedly thickened glomerular basement membrane and diffuse mesangial expansion. About 25% of persons with >10 years of diabetes duration present with Kimmelstiel-Wilson nodules, which are rounded, paucicellular, lamellated accumulations of mesangial matrix at the periphery of the glomerulus (119,120). Kimmelstiel-Wilson lesions associate with longer diabetes duration, higher serum creatinine, and more severe diabetic retinopathy (121). Mesangial expansion changes the architecture of the glomerular tuft, restricts the cellular component, distorts and occludes glomerular capillaries, decreasing the available capillary filtration surface and contributing to the decline in kidney function. Glomerular hypertrophy may compensate for the loss of filtration surface area, providing a means by which the eGFR is maintained in progressive kidney disease (122).

FIGURE 6.

Glomerular Basement Membrane and Fractional Mesangial Volume by Albuminuria in Persons With Type 1 Diabetes. GBM width and Vv(Mes/glom) in 88 normoalbuminuric (NA), 17 moderately albuminuric (MA), and 19 proteinuric (P) persons with type 1 diabetes. Normoalbuminuria (more...)

Podocyte injury appears to play an essential role in the progression of DKD. The podocyte, with its extended foot processes, provides structural support for the glomerular capillaries, as well as hydraulic resistance, and prevents the escape of proteins into the urinary space (123). With glomerular hypertrophy, the podocytes, which have a limited proliferative potential (124,125,126,127), stretch their foot processes more broadly to maintain coverage of the expanded glomerular basement membrane, a compensatory mechanism believed to influence their functional integrity (128). In addition, glomerular endothelial cell dysfunction, which precedes podocyte injury (121), appears to contribute to the latter through several mechanisms, including protein overload and toxicity at the podocyte level due to saturation of clearance mechanisms (129), increased shear stress (110), decreased endothelial nitric oxide synthase (eNOS) expression and activity (130,131), and production of cytokines, proteoglycans, and growth factors (113). Podocytes are known to absorb excess albumin arriving in the surrounding urinary space, and this increased workload may initiate inflammatory signaling and contribute to changes in podocyte-associated molecules and foot process effacement (132,133). Sustained mechanical stress and glomerular hypertension may ultimately lead to podocyte detachment and loss in the urine, leaving areas of bare glomerular basement membrane that further enhance loss of protein (Figure 7) (115). These denuded areas may initiate glomerular-tubular junction abnormalities and focal or global glomerular sclerosis (134). In persons with either type 1 (135) or type 2 (115,136) diabetes, podocyte changes may occur even before the increase in ACR, suggesting that diabetes itself may induce podocyte alterations. In a study of persons with type 2 diabetes, moderate albuminuria was associated with 20% and severe albuminuria with 40% podocyte loss relative to normal albuminuria (128). Moreover, individuals with moderate albuminuria had a 35% decline in the number of podocytes per glomerulus, and one-half of them progressed to severe albuminuria during 4 years of follow-up (81). Similarly, a lower number of podocytes and changes in the shape of the remaining podocytes were found in persons with type 2 diabetes and elevated albuminuria when compared with those with normal levels of albuminuria and similar fractional mesangial volume, indicating that changes in podocyte structure and density occur early during DKD and contribute to albuminuria. Other cross-sectional and experimental studies have reported similar findings (126,137). Some data suggest a repair mechanism via recruitment of parietal epithelial cells that is overwhelmed when podocyte loss exceeds a modest threshold (138,139,140). Consequently, significant damage to the podocytes is a potential starting point for irreversible glomerular injury in DKD.

FIGURE 7.

Peripheral Glomerular Capillaries From Pima Indians With Type 2 Diabetes. Transmission electron microscopy, x 11,280. Panel A: Intact podocyte foot processes (P) attached to glomerular basement membrane (GBM). Panel B: Local podocyte detachment (PD) and (more...)

In contrast with mesangial expansion, expansion of the interstitium, i.e., the intertubular, extraglomerular, extravascular space of the kidneys, primarily involves a cellular component represented by T lymphocytes and macrophages that infiltrate the interstitium, with subsequent fibrosis and declining kidney function (141,142). Efferent and afferent arteriolar hyalinosis, consisting of intramural accumulations of plasma proteins and lipids within kidney arterioles, may occur within a few years of diabetes onset (116,143,144). Although afferent arteriolar hyalinosis is a less specific diabetic lesion, both lesions are associated with elevated albuminuria and progression of kidney disease. Similar exudative lesions may occur in the glomerular capillaries (hyalinosis), Bowman’s capsule (capsular drops) (145,146), or proximal convoluted tubules and are generally associated with advanced DKD (116).

Advanced DKD is characterized by a marked reduction in the number of functioning glomeruli and further compensatory enlargement of those that remain functional. This stage is associated with a markedly reduced eGFR.

The intra- and extraglomerular morphologic changes described in this section progress at variable rates. Nonetheless, in one study, glomerular structural lesions explained 95% of the variability in albuminuria and 78% of eGFR variability (118,147). The latter percentage increased to 92% by adding indices of glomerular-tubular junction abnormalities and interstitial expansion to the regression models (147).

Albuminuria, however, is neither a sensitive nor specific early biomarker of progression to kidney failure, and the absence of albuminuria does not exclude the presence of relatively advanced diabetic kidney lesions and progressive kidney damage (148,149,150,151,152,153,154,155,156). New biomarkers of DKD appear to have additional prognostic information beyond that provided by albuminuria. These markers include kidney injury molecule 1 (KIM-1), liver fatty acid-binding protein (L-FABP), N-acetyl-β-D-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL) (157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173), β-trace protein, β₂-microglobulin (174,175,176), and tumor necrosis factor receptors 1 and 2 (177,178,179,180,181,182,183,184). Tumor necrosis factor-alpha receptor 1 and receptor 2 consistently enhance the discrimination of the survival models for kidney failure beyond that achievable by the clinically recognized risk factors in persons with type 1 or type 2 diabetes (177,178,179,180,181,182,183,184). Evaluation of other biomarkers in relation to DKD often shows conflicting results (157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173). This may be due to differences in study design, inclusion of persons without diabetes, use of surrogate or composite outcomes, or incomplete covariate adjustment in risk models (173). Nevertheless, combinations of biomarkers may enhance our ability to predict progressive DKD. A signature of 17 circulating inflammatory proteins enriched in tumor necrosis factor-receptor superfamily members, for example, was strongly associated with the 10-year risk of kidney failure in both type 1 and type 2 diabetes and in those with early and advanced stages of DKD (185).

Selective Glomerular Permeability

The glomerular capillary wall serves as a filter that discriminates among molecules on the basis of size, electrical charge, and configuration. Studies of glomerular filtrate collected by micropuncture or narrow size fractioning of exogenous polymers, such as dextran, indicate that albuminuria is primarily the result of impairment of the electrostatic barrier within the glomerulus, consequent to a decrease in endothelial cell glycocalyx (186,187) and heparan sulfate content of the glomerular basement membrane (188,189), and by changes in size selectivity across the glomerular capillary wall (Figure 8) (64,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206).

FIGURE 8.

Fractional Dextran Clearance Profile in Pima Indians With and Without Type 2 Diabetes. The figure compares the fractional dextran clearance profile in persons with type 2 diabetes and those with normal glucose tolerance. Fractional dextran clearances (more...)

A comparison of the mean dextran sieving profiles in 43 Pima Indians with type 2 diabetes and initially moderate albuminuria, who were followed for up to 8 years, showed no difference in the size selectivity of the glomerular filtration barrier between participants with moderate albuminuria and participants with long-term normal albuminuria (207). However, participants with severe albuminuria after 4 years of follow-up had a significantly higher fractional clearance of the large-radius test molecules than normoalbuminuric controls, with a reduction at the low-radius end, as shown in Figure 9. When the macromolecular shunt was analyzed as a function of albuminuria, an abrupt transition was apparent at an ACR of approximately 3,000 mg/g (Figure 10), whereas the contribution of the shunt in the moderate albuminuria range was very modest. These data suggest that permselectivity defects in the glomerular filtration barrier have little or no role in the development of moderate albuminuria. By contrast, a primary contributor to severe albuminuria is the shunt resulting from the presence of large pores within the glomerular capillary wall through which plasma proteins can easily pass (208,209,210,211). Morphometric data in participants with severe albuminuria identified a significant correlation between the shunt magnitude and podocyte foot process width (Figure 11) (207), which was not discernible in participants with moderate albuminuria. A similar size-selectivity defect has been reported in type 1 diabetes (203,208). These findings are consistent with the view that permselectivity defects responsible for increased albumin excretion may be focal and likely due to podocyte foot process effacement and simplification and, possibly, to defective intercellular junctions (212).

FIGURE 9.

Dextran Sieving Curves in Pima Indians With Type 2 Diabetes. Sieving coefficients were measured in 31 persons with diabetes and severe albuminuria at 48 months follow-up (▵) and 11 controls with diabetes and long-term normoalbuminuria (○). (more...)

FIGURE 10.

Graph of the Shunt Magnitude as a Function of Albuminuria. The shunt magnitude parameter (ω₀) as a function of albuminuria, as reflected by (Panel A) the fractional clearance of albumin and (Panel B) the urinary albumin-to-creatinine ratio (A/C), (more...)

FIGURE 11.

Relationship Between Shunt Magnitude and Mean Podocyte Foot Process Width. Shunt magnitude (ω₀) and mean foot process width in 10 persons with severe albuminuria who had kidney biopsies.

Subsequent studies using high-quality imaging techniques confirm that glomerular filtration barrier permeability to macromolecules is largely restricted to areas of podocyte damage (213,214,215).

Elevated Albuminuria

As noted earlier in this review, urinary albumin excretion is often increased at diagnosis of both types of diabetes but frequently returns to normal with the institution of glycemic control (22,32,33,34). Persistent albuminuria at the onset of type 2 diabetes, however, may reflect diabetes that has remained undiagnosed for years (34) or the presence of kidney disease unrelated to diabetes, since other kidney diseases are common at the ages when type 2 diabetes typically develops. On the other hand, elevated albuminuria is found in persons with impaired glucose tolerance (216,217,218), raising the possibility that hyperglycemia, even at levels below those diagnostic of diabetes, is sometimes associated with kidney abnormalities. Treatment with ACE inhibitors or ARBs at the highest tolerated dose is recommended in individuals with albuminuria, diabetes, and hypertension to slow decline in kidney function. The addition of SGLT2 inhibitors is also recommended in patients with type 2 diabetes, DKD, and an eGFR ≥20 mL/min/1.73 m². MRAs in addition to ACE/ARBs and SGLT2 inhibitors further reduce albuminuria and kidney disease progression, as discussed in the Treatment of Diabetes-Related Kidney Disease section of this review (10).

Prevalence of Elevated Albuminuria

The prevalence of elevated albuminuria defined as ACR ≥30 mg/g in the U.S. adult population age ≥20 years with self-reported diabetes was 35.5%, 32.7%, 30.4%, 27.9%, and 31.5% based on one-time random spot urine measurements collected for the NHANES 1988–1994, 1999–2004, 2005–2010, 2011–2016, and 2017–2020, respectively (Table 3). When measured in a first morning void sample, the prevalence of ACR ≥30 mg/g in NHANES 2009–2010 participants with self-reported diabetes was 15.7% (95% CI 12.3%–19.0%) (219), prevalence of moderate albuminuria (ACR 30–299 mg/g) was 11.9% (95% CI 9.7%–14.4%), and the prevalence of severe albuminuria (ACR ≥300 mg/g) was 3.8% (95% CI 2.2%–6.4%). These estimates were significantly lower than the 24.1% prevalence (95% CI 19.8%–28.2%) of ACR ≥30 mg/g obtained from a random spot urine in the same population (prevalence of moderate albuminuria 19.3%, 95% CI 16.0%–23.1%, and severe albuminuria 4.8%, 95% CI 3.1%–7.4%). Prevalence of elevated ACR was significantly lower in the NHANES 2009–2010 population without diabetes (6.2%, 95% CI 4.9%–7.5%, in random urine samples; 3.7%, 95% CI 2.9%–4.5%, in first morning voids) (219). As mentioned in the Definition, Measurements, and Classification section, ACR measurement in first morning urine is a more reliable indicator of albumin excretion, since it correlates better with the 24-hour AER than the ACR measured in random spot urine. This finding suggests that ACR measurements based on single random spot urine specimens—the standard measurement in the NHANES—likely overestimate the frequency of elevated ACR in the general population (220,221,222).

TABLE 3.

Prevalence of Chronic Kidney Disease (eGFR and ACR) in Adults Age ≥20 Years, by Age, Sex, Race and Ethnicity, and Risk Factor Categories, U.S., 1988–2020

Because of the high intraindividual variation of ACR, both NKF and ADA guidelines (10,17) recommend confirmation of elevated albuminuria in a repeat measurement—either first morning void or random urine sample. The prevalence of persistent albuminuria, defined as elevated ACR in two consecutive random urine measurements within 2 weeks, was 15.9% in adults with diabetes (defined by A1C ≥6.5% [≥48 mmol/mol] or use of glucose-lowering medicines) in the NHANES 2009–2014, lower than the 20.8% prevalence in the NHANES III (1988–1994) (age, sex, and race and ethnicity adjusted prevalence ratio 0.76, 95% CI 0.65–0.89) (223). This overall change was due to lower albuminuria prevalence in adults age <65 years and non-Hispanic White adults over time. By contrast, the prevalence of a low eGFR increased during the same time in the overall population with diabetes. Updated trends in albuminuria and an eGFR <60 mL/min/1.73 m² in the general U.S. population with diabetes are shown by age group in Table 4 and by race and ethnicity in Table 5. Based on the race-agnostic eGFR, the prevalence of a low eGFR in the U.S. population with diabetes has increased over time among non-Hispanic White adults. Compared with non-Hispanic White adults, the prevalence of a low eGFR was higher among non-Hispanic Black adults and lower among Mexican American adults but remained level in these two populations during the same time period (Table 5).

TABLE 4.

Prevalence of Albuminuria and Decreased Glomerular Filtration Rate in Adults Age ≥20 Years With Diabetes, by Age and Time Period, U.S., 1988–2020

TABLE 5.

Prevalence of Albuminuria and Decreased Glomerular Filtration Rate in Adults Age ≥20 Years With Diabetes, by Race and Ethnicity and Time Period, U.S., 1988–2020

By design, the NHANES does not differentiate the type of diabetes, and results in the adult population with self-reported diabetes largely reflect the experience of persons with type 2 diabetes. In a new analysis of NHANES 2011–2020 data conducted for Diabetes in America, the prevalence of DKD by type of diabetes was estimated using a published algorithm (224) to define persons with type 1 diabetes (Table 6). Results showed a higher prevalence of DKD in those with type 2 diabetes than in those with type 1 diabetes, regardless of sex or race and ethnicity. For both type 1 and type 2 diabetes, DKD prevalence was higher with age and was higher in non-Hispanic Black than in non-Hispanic White persons. DKD was also more frequent in persons with hypertension or CVD, regardless of type of diabetes.

TABLE 6.

Crude Prevalence of Chronic Kidney Disease in Adults Age ≥20 Years, by Type of Diabetes, U.S., 2011–2020

A cross-sectional, clinic-based study of 24,151 patients from 33 countries worldwide with type 2 diabetes, mean diabetes duration of 8 years, and without previously known albuminuria found overall prevalences of moderate and severe albuminuria of 39% and 10%, respectively (225). Compared with White patients, who had the lowest prevalence of albuminuria, Asian and Hispanic patients had nearly twice the odds of albuminuria (adjusted odds ratios [OR] 1.8, 95% CI 1.59–1.97, and OR 1.7, 95% CI 1.47–1.94, respectively). African patients were younger and had shorter known duration of diabetes than other racial and ethnic groups, but the odds of albuminuria were 1.5-fold higher than in White patients (95% CI 1.20–1.83), who had the lowest A1C levels and the highest frequency of antihypertensive, lipid-lowering, and anticoagulant or antiplatelet medication usage. Among Pima Indians with type 2 diabetes (217), 26% had moderate albuminuria and 21% had severe albuminuria, and in the population on the Western Pacific island of Nauru (218), 41% had moderate albuminuria and 31% had severe albuminuria. In an observational cohort in Japan, 25% had moderate albuminuria and 5% had severe albuminuria (226), while among primary care patients with type 2 diabetes in Singapore, 14.2% had moderate albuminuria and 5.7% had severe albuminuria (227). Figure 12 shows the prevalence of moderate and severe albuminuria in Pima Indians according to duration of diabetes (217). Although different methods and definitions of albuminuria were employed in these studies, other factors must be invoked to explain the large differences in the prevalence of elevated albuminuria in these different groups, including access to care, delays in the diagnosis of diabetes, differences in blood pressure and metabolic control, diet, and perhaps genetic susceptibility to DKD.

FIGURE 12.

Prevalence of Elevated Urinary Albumin Excretion in Pima Indians, by Duration of Diabetes, 1982–1988. Moderate albuminuria is defined as 31–299 mg/24 hours and severe albuminuria as ≥300 mg/24 hours.

Incidence of Elevated Albuminuria

Moderate albuminuria predicts the development of severe albuminuria in persons with type 1 (228,229,230,231,232) or type 2 (233,234,235,236) diabetes. In persons with type 1 diabetes, persistent albuminuria rarely develops in the first 10 years after diagnosis (237,238,239). The rate of progression to severe albuminuria is highest between 10 and 20 years duration of diabetes, and subsequently, the incidence rate declines (142,240,241). In the Diabetes Control and Complications Trial (DCCT), the cumulative incidence of persistent moderate albuminuria was 14%, 33%, and 38% at 10-, 20-, and 30-years duration of diabetes, respectively, among persons assigned to conventional treatment (mean A1C 9.6% [81 mmol/mol] at the time of incident albuminuria), which was higher than among those in the intensive treatment arm (10%, 21%, 25%, respectively; mean A1C 8.9% [74 mmol/mol] at the time of incident albuminuria). In 325 participants with incident moderate albuminuria who were followed for up to 23 years, the 10-year cumulative incidence was 28% for severe albuminuria, 15% for impaired eGFR (<60 mL/min/1.73 m² at two consecutive study visits), and 4% for kidney failure (initiation of dialysis or kidney transplant) (35). The 10-year cumulative incidence of regression from persistent microalbuminuria to normoalbuminuria was also common, at 40%. Lower levels of A1C, blood pressure, low-density lipoprotein (LDL) cholesterol, and triglycerides and absence of retinopathy were associated with reduced risk of kidney disease progression.

In persons with type 2 diabetes, the incidence of albuminuria in relation to diabetes duration is more difficult to characterize because of the uncertainty in dating the true onset of diabetes in most studies. No relationship between duration of type 2 diabetes and the incidence of proteinuria was found in the Mayo Clinic population in Rochester, Minnesota (242), whereas in Wisconsin (243), a relationship between diabetes duration and incidence of proteinuria was stronger in persons who received insulin than in those who did not. In Pima Indians, in whom the duration of type 2 diabetes is known with greater accuracy because of systematic periodic oral glucose tolerance testing in the population, the age-sex-adjusted incidence of proteinuria, defined as urinary protein-to-creatinine ratio ≥0.5 g/g, was strongly related to duration of diabetes (244).

A secular decline in the incidence of DKD has been described in type 1 diabetes (245,246,247,248,249,250,251). In the Pittsburgh Epidemiology of Diabetes Complications (EDC) study (247), the cumulative incidence of DKD after 20 years of diabetes, defined as persistent AER >200 µg/min in timed urine collections, was 37% lower in the 179 participants diagnosed with diabetes in 1975–1980 than in the 339 participants diagnosed in 1965–1974. Among those with >25 years of diabetes duration, the declining trend was not statistically significant; Figure 13 shows a comparison of the EDC study (247) with data from the Steno study in Denmark (246). Nevertheless, significant reductions in both mortality and kidney failure rates in this population suggest a slower progression to kidney failure with improved management of diabetes complications. Comparable data have been reported for persons with type 1 diabetes in Sweden (248), where the cumulative incidence of persistent albuminuria (≥1 positive test by Albustix) after 20 years of diabetes decreased from 28% in persons diagnosed with type 1 diabetes in 1961–1965 to 6% in those diagnosed in 1971–1975. Furthermore, none of the 51 persons in whom type 1 diabetes was diagnosed in 1976–1980 developed persistent albuminuria during 12–16 years of follow-up. Figure 14 shows the cumulative incidence of persistent albuminuria in these cohorts according to the calendar year of diagnosis of diabetes. The decline in the cumulative incidence coincided with improvement in glycemic control comparable to that in the intensively treated group in the DCCT study (252). These findings were replicated in the Steno Diabetes Center cohort from Denmark (249,250). The cumulative incidence of DKD, defined as persistent albuminuria, after 20 years of diabetes duration declined from 31.1% in those with onset of type 1 diabetes in 1965–1969 to 13.7% in those with onset of diabetes in 1979–1984, with the most significant decline occurring in the most recent cohort (Figure 15) (250). This change paralleled a significant trend for earlier initiation of antihypertensive treatment following the onset of diabetes, increase in renin-angiotensin-aldosterone system (RAAS) inhibitor usage, and sustained improvement in mean blood pressure.

FIGURE 13.

Incidence of Kidney Disease in Persons With Type 1 Diabetes, Pittsburgh Epidemiology of Diabetes Complications Study, 1986–2000, and Steno Clinic Population, 1933–1984. Kidney disease is defined as an albumin excretion rate >200 µg/min (more...)

FIGURE 14.

Cumulative Incidence of Persistent Albuminuria in Persons With Type 1 Diabetes Diagnosed Before Age 15 Years, by Duration of Diabetes. Persistent albuminuria is defined as ≥1 positive test by Albustix. Subjects are divided into four groups based (more...)

FIGURE 15.

Cumulative Incidence of Diabetic Nephropathy by Period of Onset of Type 1 Diabetes Diagnosed Before Age 15 Years, by Duration of Diabetes.

In contrast with type 1 diabetes, no secular decline in the incidence of proteinuria has been reported in type 2 diabetes. The 10-year cumulative incidence of persistent proteinuria in the predominantly Caucasian population age ≥40 years of Rochester, Minnesota, remained 12% in those diagnosed with type 2 diabetes in 1970–1979 (n=483) and those diagnosed in 1980–1989 (n=680) (253). The 20-year cumulative incidence of proteinuria reported in this study, however, was 41%, higher than the 25% cumulative incidence reported in an earlier Rochester study of individuals diagnosed with diabetes in 1945–1969 (242). These secular differences may be related in part to differences in age distributions and in diabetes diagnosis criteria between the studies. In the Pima Indian longitudinal study, in which the population was screened approximately every 2 years using 2-hour oral glucose tolerance testing, the incidence of proteinuria rose between 1967 and 2002 in response to the longer average duration of diabetes in this population in recent years (Table 7) (254).

TABLE 7.

Incidence of Proteinuria in Three Independent Time Periods Among Pima Indians With Type 2 Diabetes, by Diabetes Duration and Proportion of Person-Years Accumulating in Short and Long Duration Categories, 1967–2002

The progression of kidney disease in persons with newly diagnosed type 2 diabetes in the United Kingdom Prospective Diabetes Study (UKPDS) is presented in Figure 16 (255,256). The rate of progression to the next level of kidney disease severity (moderate albuminuria, severe albuminuria, or elevated plasma creatinine or renal replacement therapy) was 2%–2.8% per year; the risk of death grew with increasing severity of kidney disease, with an annual rate of 1.4% for subjects with no nephropathy, 3.0% for those with moderate albuminuria, 4.6% for those with severe albuminuria, and 19.2% with elevated plasma creatinine or renal replacement therapy. Individuals with severe albuminuria were more likely to die in any year than to develop kidney failure. Progression from no nephropathy to severe albuminuria or more advanced kidney disease was low (0.1%), as was progression from moderate albuminuria to elevated plasma creatinine or renal replacement therapy.

FIGURE 16.

Chronic Kidney Disease Progression in Persons With New-Onset Type 2 Diabetes, United Kingdom Prospective Diabetes Study, 1977–1997. Percentages represent annual rates with 95% confidence intervals.

Although moderate albuminuria was associated historically with an inexorable progression to severe albuminuria and kidney failure (257,258), a substantial proportion of persons with type 1 or type 2 diabetes and moderate albuminuria spontaneously regress to normoalbuminuria. This observation suggests that moderate albuminuria represents reversible kidney injury rather than the onset of an inevitable progression to kidney failure. On the other hand, other causes of transitory elevation in albuminuria need to be considered and excluded, such as orthostatic (postural) proteinuria, intercurrent illness, or exercise. In a prospective observational study of persons with type 1 diabetes, baseline diabetes duration of about 18 years, and moderate albuminuria, only 19% developed severe albuminuria, whereas 59% regressed to normal albuminuria after 6 years of follow-up (38). The incidence of albuminuria reported in predominantly White populations with type 1 diabetes is lower and the rate of regression higher than those reported in Black persons with type 1 diabetes for a similar follow-up time (259,260). In 473 Black persons with type 1 diabetes and baseline mean diabetes duration of 10.4 years, the 6-year cumulative incidence of moderate and severe albuminuria was 26.0% (95% CI 20.9%–31.6%) and 16.9% (95% CI 12.6%–21.8%), respectively, with an overall incidence of elevated albuminuria of 42.9% (95% CI 36.9%–50.0%). Incidence of any proteinuria in this population was positively associated with diabetes duration at baseline in men, whereas in women, it declined after 10 years duration of diabetes (Figure 17) (259). Among the 370 Black persons with moderate albuminuria at baseline, 23.5% (95% CI 19.3%–28.2%) progressed to severe albuminuria. Overall, 33.5% progressed to a worse albuminuria category, and 8.5% improved either spontaneously or due to treatment with ACE inhibitors or other antihypertensive medicines.

FIGURE 17.

Six-Year Incidence of Any Proteinuria in African American Men and Women With Type 1 Diabetes, by Duration of Diabetes at the Baseline Examination, New Jersey 725 Study, 1993–1998.

In general, the proportion of persons with type 2 diabetes who regress from moderately increased albuminuria to normoalbuminuria is 30%–54%, while the frequency of progression to overt proteinuria is 12%–36% (261,262,263). Moderate albuminuria of short duration, use of RAAS inhibitors, lower A1C (<6.9% [<52 mmol/mol]), and systolic blood pressure <129 mmHg are independently associated with albuminuria regression. Among 750 American Indians from Arizona, Oklahoma, and North and South Dakota age 45–74 years in the Strong Heart Study, albuminuria was measured in 1989–1991 (baseline), 1993–1995 (second examination), and 1997–1999 (third examination) (264). Among those with normal ACR at baseline, 67% remained so and 33% developed elevated albuminuria (29% moderate albuminuria and 4% severe albuminuria) by the second examination. More participants with normal albuminuria at the second examination remained normoalbuminuric (77%), and 23% developed elevated albuminuria (19% moderate albuminuria and 4% severe albuminuria) by the third examination, suggesting a decline in onset of kidney disease in the later years. Risk factors for onset of elevated albuminuria were higher A1C, higher systolic blood pressure, higher baseline ACR, smoking, glucose-lowering treatment, and longer diabetes duration. Participants with a baseline ACR between 10 and 30 mg/g had nearly threefold higher risk of elevated ACR over a 4-year period (OR 2.7, 95% CI 1.9–3.9) than those with baseline ACR <5 mg/g (264). The cumulative incidence of elevated ACR increased with duration of diabetes (p<0.01) and was similar in men and women in the three study centers (Figure 18). Although elevated albuminuria generally precedes the decline in kidney function, in youth-onset type 1 diabetes and in adults with type 2 diabetes, the latter may occur without evidence of albuminuria (265,266). However, this phenomenon has not been described in youth-onset type 2 diabetes. A higher prevalence of albuminuria and more rapid progression to kidney disease in youth-onset type 2 diabetes compared with youth-onset type 1 diabetes have been reported (265,266).

FIGURE 18.

Four-Year Cumulative Incidence of Elevated Albuminuria in American Indians, by Duration of Diabetes, Sex, and Study Site, Strong Heart Study. ACR, albumin-to-creatinine ratio.

While elevated albuminuria occurs earlier during type 2 than type 1 diabetes, sustained control of A1C and systolic blood pressure associate with higher likelihood of regression to lower or normal levels regardless of type of diabetes. To date, secular declines in the incidence of albuminuria are reported in type 1 diabetes only. Some studies in persons with diabetes report declines in the eGFR without preceding albuminuria; however, whether lack of albuminuria was due to RAAS treatments or infrequent follow-up remains unclear.

Diabetes-Related Kidney Disease as a Risk Factor for Kidney Failure, Cardiovascular Disease, and Death

A new analysis of the NHANES 1999–2018 conducted for Diabetes in America shows cardiovascular mortality, cancer-related mortality, and all-cause mortality among persons with DKD, defined by albuminuria or low GFR (Table 8). For albuminuria, these associations are a continuum, starting at levels well below the 30 mg/g threshold that defines moderate albuminuria (267,268,269,270). Among American Indians age 45–74 years in the Strong Heart Study (267) who were free of CVD at baseline, high-normal ACR level was a strong and independent predictor of all cardiovascular events, including nonfatal and fatal CVD, and these associations were similar in individuals with or without diabetes. In those with diabetes, the adjusted risks for all, nonfatal, and fatal CVD events increased by 20% (hazard ratio [HR] 1.20, 95% CI 1.07–1.34), 13% (HR 1.13, 95% CI 0.99–1.28), and 48% (HR 1.48, 95% CI 1.17–1.87), respectively, for each doubling of ACR within the normal range.

TABLE 8.

Crude All-Cause and Cause-Specific Death Rates in Adults With Diabetes and Chronic Kidney Disease, U.S., 1999–2018

Among persons with diabetes participating in the NHANES III, those with the highest ACR levels (≥300 mg/g) and lowest eGFR (15–59 mL/min/1.73 m²) had a 2.7-fold higher risk for cardiovascular mortality and a 2.5-fold higher risk for all-cause mortality, relative to those with normal ACR and an eGFR ≥90 mL/min/1.73 m² (271). Similar associations were found in participants without diabetes; however, those with diabetes had greater absolute risks for these outcomes. Adjustments for diabetes duration and cardiovascular risk factors did not change the significance of these associations, suggesting that CKD is a risk amplifier, with much of the excess CVD in diabetes occurring in persons with DKD.

Nearly all of the excess mortality associated with either type of diabetes is found in persons with severe albuminuria (37,272,273), primarily from kidney disease or CVD in persons with type 1 diabetes (272,274), from CVD in White persons with type 2 diabetes (275), and from CVD or kidney disease in Pima Indians with type 2 diabetes (273,276). Among individuals with type 1 diabetes in the EDC study, those who maintained normal levels of albumin excretion had the lowest standardized mortality ratio at 10- and 20-year follow-up, and they were more likely to die from nondiabetes-related causes than individuals who had elevated albuminuria (AER ≥20 μg/min) (277). Other studies in persons with more than 30 years duration of type 1 diabetes show similar associations (278,279).

An analysis of secular trends in the incidence of kidney failure and mortality in patients with type 1 diabetes and severe albuminuria from the Joslin Clinic, however, found no significant decline in pre-kidney failure death rate, progression to kidney failure, or post-kidney failure death rate from 1991 to 2004, despite both widespread adoption of kidney protective treatments during the same period and significant improvements in blood pressure and total serum cholesterol concentration (280,281). Sixty-nine percent of either pre- or post-kidney failure excess mortality was attributable to CVD. Moderate and severe albuminuria independently predicted all-cause mortality in a monotonic fashion in the Finnish Diabetic Nephropathy study (FinnDiane) cohort, which represented 16% of the population with type 1 diabetes in Finland (282). During 7 years of follow-up, the overall death rate in persons with moderate albuminuria was nearly three times that observed in the general Finnish population (adjusted standardized mortality ratio [SMR] 2.8, 95% CI 2.0–4.2), with CVD representing 56% of these deaths. Severe albuminuria was associated with nine times the death rate observed in the age- and sex-matched general population (adjusted SMR 9.2, 95% CI 8.1–10.5), of which 45% was caused by CVD. Indeed, the impact of albuminuria level on mortality risk was equivalent to that of preexisting macrovascular disease, as defined by a history of myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, stroke, carotid surgery, peripheral revascularization, or amputation for critical limb ischemia. Other major causes of death included infections and cancer. By contrast, overall death rates in persons with normal ACR were equivalent to those in the general population (adjusted SMR 0.8, 95% CI 0.5–1.1), regardless of diabetes duration, indicating that DKD is a major driver of excess mortality in type 1 diabetes.

Irrespective of albuminuria level, the eGFR was independently associated with mortality, but in a U-shaped fashion, as shown in Figure 19 (282), possibly reflecting confounding from other morbid conditions unrelated to kidney disease at high eGFR levels, such as serum creatinine confounding due to reduced muscle mass, increased tubular secretion, and extrarenal elimination of creatinine. Moreover, measurement imprecision is greater at lower concentrations of serum creatinine, compounding the difficulty of interpreting serum creatinine levels in those with a normal or high-normal eGFR (283).

FIGURE 19.

Risk of Death Associated With Estimated Glomerular Filtration Rate in Type 1 Diabetes. Relative hazard computed in persons with type 1 diabetes: (Panel A) without end-stage renal disease, (Panel B) with normoalbuminuria, (Panel C) with moderate albuminuria, (more...)

In type 2 diabetes, death rates due to both overall and cardiovascular causes are greatly increased with advancing kidney disease (284,285,286,287). Among 1,993 Pima Indians (55.9% with type 2 diabetes, the only type of diabetes occurring in this population, even at young ages) followed for a median of 11 years, death rates from natural causes increased with worsening kidney function in persons without or with diabetes (Figure 20) (276). Death rates in persons without kidney disease were virtually identical without or with diabetes and increased similarly with worsening kidney disease in both groups, suggesting that kidney disease rather than diabetes per se is the major determinant of increased mortality among the population with diabetes. The higher overall mortality in those with longer duration of diabetes is due primarily to the greater proportion of person-years of follow-up falling in the categories of worse kidney function (Figure 20C). The presence of kidney disease was associated with excess mortality from DKD, CVD, infections, and malignancy in the Pima Indians with diabetes and from infections in those without diabetes. Among 4,081 American Indians, 45% with diabetes, a reduced eGFR (<90 mL/min/1.73 m²) was associated with increased risk of CVD events, including coronary heart disease, stroke, and heart failure during a median follow-up of 15 years (288). The associations between eGFR measure and CVD events were attenuated after adjusting for albuminuria.

FIGURE 20.

Trends in Age-Sex-Adjusted Death Rates From Natural Causes and Cardiovascular Disease in American Indians With and Without Diabetes, by Severity of Kidney Disease. Trends in age- and sex-adjusted death rates from (Panel A) natural causes and (Panel B) (more...)

Fewer studies have focused on the noncardiovascular mortality associated with DKD. Regardless of the presence of diabetes, persons with kidney disease are three to four times more likely to have a poor prognosis after acquiring infections than those without kidney disease (289,290,291). Persons with diabetes have a higher risk of community-acquired lower respiratory tract infection, pneumonia, and sepsis with a declining eGFR and increasing ACR, independent of age, sex, smoking status, and comorbid conditions of diabetes. Although some reports suggest that kidney disease, particularly kidney failure, increases the risk of death from several types of cancer, e.g., bladder and kidney cancers (292,293,294), this is not a uniform finding (292,295,296,297).

Quantitative information about ACR adds significant predictive value to the eGFR about the risk of death or kidney failure, and therefore, using both ACR and the eGFR is significantly better for predicting these outcomes than using either measure alone (298,299,300). An analysis conducted in 10,640 persons with type 2 diabetes enrolled in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial showed similar contributions of high ACR and a low eGFR to cardiovascular and kidney events (Figure 21) (299). These findings concur with those from a systematic review of the association between microvascular and macrovascular disease in type 2 diabetes (301), which showed an approximately twofold increased risk for cardiovascular events associated with albuminuria or a reduced eGFR (Table 9) (268,301,302,303,304,305,306,307,308,309,310,311,312,313,314). The strength of these associations remained after adjustments for multiple confounders, suggesting that microvascular and macrovascular disease in type 2 diabetes may share similar pathophysiologic mechanisms. A meta-analysis of 1,024,977 participants (nearly 13% with diabetes) from 30 general population and high-risk cardiovascular cohorts and 13 CKD cohorts indicated that while the absolute risks for all-cause and cardiovascular mortality are higher in the presence of diabetes, the relative risks of kidney failure or death by eGFR and ACR are similar with or without diabetes (315). These findings underscore the importance of kidney disease per se as a predictor of important clinical outcomes, regardless of the underlying cause of kidney disease.

FIGURE 21.

Association of (A) Urinary Albumin-to-Creatinine Ratio and (B) Estimated Glomerular Filtration Rate Levels During Follow-Up With the Risk for Cardiovascular Events. Closed and open squares represent hazard ratios (HRs) in subgroups for eGFR <60 (more...)

TABLE 9.

Prospective Studies With at Least 200 Type 2 Diabetes Subjects That Evaluated Hard Cardiovascular Endpoints

Kidney Failure

Prevalence of Diabetes-Related Kidney Failure (End-Stage Kidney Disease)

Kidney failure, or stage 5 CKD, is the most advanced stage of CKD, requiring renal replacement therapy, such as dialysis or kidney transplant, for survival. Since 1988, all persons receiving treatment for kidney failure, regardless of age and insurance coverage, are included in the United States Renal Data System (USRDS) registry (12). Consequently, the annual data report published by the USRDS contains the most complete and reliable information on treated kidney failure in the United States.

Table 10 summarizes the incidence and prevalence of treated kidney failure according to demographic characteristics, primary diagnosis, and treatment modality in the United States in 2020 (12). In that year, 130,522 new cases of dialysis and transplant were added to the national registry, of which 59,474 (46%) had kidney disease attributed to diabetes.

TABLE 10.

Summary Statistics on Reported Kidney Failure Treatment, by Age, Sex, Race and Ethnicity, and Primary Diagnosis, U.S. Renal Data System, 2020

Diabetes and hypertension represent the leading causes of kidney failure in the United States (Figure 22) (12). In 1985, the adjusted prevalence of treated kidney failure attributed to diabetes was 103 cases per million population; these patients accounted for 19% of prevalent treated kidney failure in the United States. By 2020, the prevalence had risen to 859.7 cases per million population, representing 38% of prevalent treated kidney failure in the United States (45.5% of dialysis patients and 21.6% of kidney transplant patients) (Table 10) (12). An increasing prevalence of diabetes and improved CVD survival are responsible, in part, for this growth (Figure 23) (316). About 30% of persons with type 1 diabetes and 10%–40% of those with type 2 diabetes eventually develop kidney failure. Because type 2 is the predominant type of diabetes, it also far exceeds type 1 diabetes as a cause of diabetes-related kidney failure. Of 309,017 prevalent cases of treated kidney failure with diabetes at the end of 2020, type 2 diabetes was responsible for 269,980 (87%; Table 11) (12).

FIGURE 22.

Trends in Incident End-Stage Kidney Disease Cases and Incident Rate, by Primary Diagnosis of End-Stage Kidney Disease, U.S. Renal Data System, 2000–2020. Data are adjusted for age, sex, and race and ethnicity; unknown sex and other or unknown (more...)

FIGURE 23.

Incident ESKD Cases (Line) and Increase in ESKD Attributable to Increased Prevalence of Diabetes, Improved Survival Following Myocardial Infarction and Stroke, and U.S. Population Growth in 1991 (Bars). ESKD, end-stage kidney disease.

TABLE 11.

Prevalence of Reported End-Stage Kidney Disease, by Primary Diagnosis, Sex, and Race and Ethnicity, U.S. Renal Data System, 2020

Incidence of Diabetes-Related Treated Kidney Failure

In 1985, the adjusted incidence of kidney failure attributable to diabetes, treated with renal replacement, was 45 cases per million population. The rate increased to 170 per million by 2005 and leveled off thereafter (12). The increasing prevalence of diabetes and more inclusive criteria for initiating renal replacement therapy contributed to higher incidence rates of diabetes-related kidney failure over time.

Trends in the incidence of treated kidney failure due to diabetes differ broadly by age and race and ethnicity (Table 12). The adjusted incidence of treated kidney failure decreased between 2000 and 2020 by 7%, 24%, and 30% in White, Black, and Hispanic persons, respectively, but remains threefold and twofold higher in Black and Hispanic, respectively, compared with White persons with diabetes (12). Among American Indian/Alaska Native populations, incidence of treated kidney failure due to diabetes declined by 53% between 2000 and 2016, more than for any other racial and ethnic group, while it remained relatively stable in the Asian population (317). A study of 452,238 commercially insured and Medicare Advantage patients with CKD found that compared with White patients, Asian, Black, and Hispanic patients were more likely to receive guideline-recommended care in 2012–2019, including treatment with an ACE inhibitor, ARB, or statin, referral to a nephrologist, albuminuria monitoring, and long-term prescription NSAID avoidance, but were similarly or less likely to achieve blood pressure and diabetes control for slowing CKD progression (318). Racial differences in the incidence of treated kidney failure in persons with type 2 diabetes are also attributable in part to differences in the duration of diabetes (319,320,321,322,323,324,325,326). A shift towards a younger age at onset of type 2 diabetes among some minority populations may be partly responsible for the secular trends in kidney failure incidence observed in the younger groups, as illustrated by studies in Pima Indians (327,328). Whereas the incidence of diabetic kidney failure in Pima Indians age ≥45 years declined after 1990, those age <45 years experienced no such decline. The lack of decline in the younger Pima Indians was associated with a lower percentage of RAAS inhibitor usage than in older subjects. Women of childbearing age were least likely to receive RAAS inhibitors, presumably because of concerns about their use in pregnancy.

TABLE 12.

Incidence Rates of Reported End-Stage Kidney Disease Due to Diabetes, by Age, Sex, and Race and Ethnicity, U.S. Renal Data System, 2000–2020

Epidemiologic data on racial and ethnic differences in the incidence of treated kidney failure in type 1 diabetes are sparse, in part because type 1 diabetes is less frequent, particularly among minority populations, and in part due to uncertainties related to diagnosis; young persons or those who are treated with insulin are often misclassified as having type 1 diabetes. According to USRDS data, of all new cases of treated kidney failure due to diabetes between 2016 and 2020, 91% were attributable to type 2 diabetes (Table 13) (12).

TABLE 13.

Incidence of Reported End-Stage Kidney Disease, by Primary Diagnosis, Sex, and Race and Ethnicity, U.S. Renal Data System, 2016–2020

Survival of Persons With Treated Diabetes-Related Kidney Failure

Persons with a primary diagnosis of diabetes treated for kidney failure have lower survival relative to other causes of kidney failure (12), primarily due to CVD (329,330,331,332), which continues to advance during the course of renal replacement therapy. While survival on dialysis has slowly improved across modalities since 2000 (Figure 24), it remains reduced in persons with diabetes, more than half of whom die within 5 years of beginning dialysis in the United States (Figure 25) (12). Among incident treated kidney failure patients with a primary diagnosis of type 1 diabetes in 2017–2021, 14.6% died during the first year, while the proportion of those receiving a kidney transplant in the first year was 6% (12).

FIGURE 24.

Survival Probabilities Among Incident End-Stage Kidney Disease Patients With Diabetes, by Treatment Modality, U.S. Renal Data System, 2000–2015. Data are adjusted for age, sex, race and ethnicity, and primary cause of end-stage kidney disease. (more...)

FIGURE 25.

Survival Probabilities Among Incident Dialysis Patients, by Cause of End-Stage Kidney Disease, U.S. Renal Data System, 2000–2015. Data are adjusted for age, sex, race and ethnicity, and primary cause of end-stage kidney disease. GN, glomerulonephritis; (more...)

Black (333,334), Hispanic (335), Asian (12), and American Indian (12,336) patients treated for diabetes-related kidney failure generally have a lower adjusted risk of death compared with White patients. In 2020, White patients with diabetes had the lowest expected remaining years of life on dialysis, and Asian patients had the highest expected survival (Figure 26) (12). Data from the USRDS also indicate that Asian patients with kidney transplant due to diabetes had the longest survival, whereas American Indians had the lowest number of expected remaining years of life. Among patients on hemodialysis due to DKD, the risk of death was 31% lower in American Indian, Black, or Hispanic patients and 38% lower in Asian patients compared with White patients. In 1995–2010, among American Indians, those with 100% Indian ancestry had the lowest adjusted risk of death compared with White patients (HR 0.58, 95% CI 0.55–0.61) (Figure 27) (337). The risk of death increased to 0.95 (95% CI 0.82–1.11) in those with less than one-quarter American Indian ancestry (337), suggesting that hereditary factors play a role in how patients respond to dialysis treatment. Kidney transplant recipients with diabetes have much better survival than those on dialysis, as shown in Figure 24 (12).

FIGURE 26.

Expected Remaining Years of Life Among Prevalent Dialysis Patients With Diabetes, U.S. Renal Data System, 2020. SOURCE: Reference (12)

FIGURE 27.

Hazard Ratios for Death From Any Cause Among Non-Hispanic American Indians With Diabetes at Initiation of Hemodialysis, by Degree of American Indian Ancestry, 1995–2010. Information on American Indian ancestry was obtained from the IHS patient database. (more...)

Risk Factors for Diabetes-Related Kidney Disease

Numerous risk factors have been identified for the development and progression of DKD. In this section, the evidence for some of the more prominent factors is reviewed.

Hyperglycemia

Increased blood glucose concentration is a major risk factor for the development and progression of moderate albuminuria in both types of diabetes (106,237,241,242,243,244,338,351,352,353,354,355,356,357,358,359,360,361,362,363) but may have a lesser influence on progression of more advanced kidney dysfunction (353,364), when hypertension, hypercholesterolemia, and genetic factors play a greater role in shaping the outcome (38,352). In the EDC study, participants with type 1 diabetes and A1C >10% (>86 mmol/mol) had a 3.6-fold higher risk of developing moderate albuminuria than those with lower A1C levels. Glycemic control was the only predictor of moderate albuminuria in both men and women, regardless of diabetes duration (352). Higher 2-hour post-load plasma glucose concentration (Figure 28), fasting plasma glucose, and A1C in Pima Indians with type 2 diabetes were associated with a higher incidence of elevated ACR after adjustment for age, sex, and duration of diabetes (244,354). Similarly, among American Indians age 45–74 years with type 2 diabetes from Arizona, Oklahoma, and North and South Dakota, higher fasting plasma glucose and A1C among those with normal baseline ACR and serum creatinine were associated with increased risk of elevated albuminuria (264).

FIGURE 28.

Incidence of Proteinuria in Pima Indians With Type 2 Diabetes, by OGTT Glucose Level and Diabetes Duration. Incidence of proteinuria (protein-to-creatinine ratio ≥1.0 g/g) by duration of diabetes in 480 Pima Indians with type 2 diabetes, according (more...)

Hyperglycemia induces hyperfiltration, a predictor of progressive kidney disease (67,69,70,365,366). In humans, therapeutic interventions that improve glycemic control reduce hyperfiltration in both type 1 and type 2 diabetes (96,367).

Evidence for the role of hyperglycemia in the development of diabetic glomerular lesions comes from biopsy studies in identical twins discordant for type 1 diabetes (368) and from morphologic studies before and after pancreas transplantation (369). Glomerular changes, including widened glomerular and tubular basement membranes and increased mesangial fraction, were identified only in the diabetic member of twin pairs (Figure 29), suggesting that metabolic status, and not genetic predisposition, is responsible for the development of diabetic kidney lesions (368). Prolonged normoglycemia following pancreas transplant in persons with type 1 diabetes and established DKD promotes virtually complete reversal of glomerular and tubular basement membrane thickness and of increases in mesangial and interstitial volumes (Figure 30) (369).

FIGURE 29.

Morphometric Measurements in Kidney and Skeletal Muscle From Identical Twins Discordant for Type 1 Diabetes. Panel A: basement membrane width (nm). Panel B: fractional volume of the mesangium (%). Values for twins without diabetes (●) are linked to (more...)

FIGURE 30.

Renal Histologic Changes at Baseline and 5 and 10 Years After Pancreas Transplantation. Thickness of the GBM (Panel A), thickness of the TBM (Panel B), mesangial fractional volume (Panel C), and mesangial matrix fractional volume (Panel D) are shown before (more...)

Hypertension

High blood pressure is related to DKD in many cross-sectional and longitudinal studies of both type 1 and type 2 diabetes. In type 1 diabetes, this relationship frequently reflects elevation of blood pressure in response to kidney disease (370,371,372,373). In type 2 diabetes, the onset of hypertension generally precedes DKD and is often associated with obesity. The risk of kidney disease is three times as high in persons with type 1 diabetes who have a hypertensive parent as in those whose parents are not hypertensive (Figure 31) (374). In addition, those with kidney disease have a higher prevalence of parental hypertension and a higher mean arterial blood pressure during adolescence (375). Increased blood pressure during sleep may herald the development of moderate albuminuria in adolescents and young adults with type 1 diabetes, as shown in Figure 32 (376). In that study, blood pressure was monitored at 2-year intervals for up to 9 years or as long as the ACR was in the normal range; a ratio of ≤0.9 between the mean nighttime systolic pressure and the mean daytime systolic pressure defined the dipping during sleep. Moderate albuminuria did not develop in those with poor metabolic control in whom blood pressure remained normal, suggesting that nocturnal elevation in blood pressure may identify those with type 1 diabetes who are most susceptible to progression of kidney disease. Prolonged hypertension may lead to kidney damage through multiple mechanisms (377), including hardening and narrowing of the renal arterioles with reduction in renal perfusion volume. Damage to the endothelium can reduce the synthesis of nitric oxide, leading to further vascular damage. Podocyte dysfunction may also ensue, due to maladaptive responses from cell injury and mechanical stress from increased intraglomerular pressure.

FIGURE 31.

Mean Blood Pressure in Parents of Persons With Type 1 Diabetes and With or Without Proteinuria. Family study of diabetes, including 26 surviving parents of 17 persons with type 1 diabetes and proteinuria and parents of 17 matched persons without diabetes (more...)

FIGURE 32.

Nocturnal Systolic Blood Pressure According to Albuminuria and Level of Glycated Hemoglobin (A1C) in Type 1 Diabetes. Panel A: Nocturnal systolic blood pressure in 14 subjects who subsequently developed moderate albuminuria (microalbuminuria) and in 61 subjects (more...)

In Pima Indian offspring with type 2 diabetes, the prevalence of proteinuria was similar if neither parent or only one parent had hypertension (8.9% and 9.4%, respectively) but was significantly higher if both parents had hypertension (18.8%), after adjustment for age, sex, duration of diabetes, and 2-hour post-load plasma glucose concentration in the offspring and diabetes in the parents (378). The odds for proteinuria in the offspring when both parents had hypertension was 2.2 times (95% CI 1.2–4.2) that when only one parent had hypertension. This relationship was present even when controlled for the effects of blood pressure and its treatment in the offspring. In addition, higher blood pressure before the onset of type 2 diabetes was related to a higher prevalence of elevated albuminuria after the onset of diabetes, suggesting that blood pressure plays a causal role in the development of DKD (Figure 33) (379).

FIGURE 33.

Prevalence of Elevated Albuminuria in Pima Indians After Diagnosis of Type 2 Diabetes, by Blood Pressure Before Onset of Diabetes. Elevated albuminuria is defined by urinary albumin-to-creatinine (ACR) ratio ≥100 mg/g. Participants with the highest (more...)

Sodium-lithium countertransport activity, a genetically influenced trait, is often higher in persons with essential hypertension and in those whose parents have essential hypertension (380,381,382,383). In type 1 diabetes, elevated rates of countertransport activity are reported in persons with moderate albuminuria or proteinuria (Figure 34) (384,385,386,387), elevated GFR (388), and proliferative retinopathy (389). These findings suggest that persons with diabetes and hypertension and with elevated sodium-lithium countertransport activity are at greater risk for DKD and possibly other microvascular complications, although these findings have not been uniformly confirmed (387,390,391). Few studies assessed this relationship in those with type 2 diabetes; some found an association between higher sodium-lithium countertransport activity and albuminuria (392,393,394), and others did not (395,396).

FIGURE 34.

Correlation of Sodium-Lithium Countertransport Activity With Nephropathy. Sodium-lithium (Na-Li) countertransport activity was measured in 21 persons with type 1 diabetes and normoalbuminuric matched controls. Diabetic nephropathy is defined by a urinary (more...)

Lipids

Many of the abnormalities in plasma lipoproteins associated with kidney disease are sequelae of kidney dysfunction, yet dyslipidemia may also play a role in the pathogenesis of glomerular injury (397,398,399). Persons with pre-dialysis DKD typically have significant hypertriglyceridemia, elevated LDL, and low high-density lipoprotein (HDL) cholesterol concentrations. These abnormalities are more pronounced in persons with severe albuminuria than those with moderate albuminuria (35,400,401,402) but tend to subside with progression to uremia and dialysis (Table 14) (403). Besides quantitative changes, lipid particles in people with diabetes change qualitatively; LDL and HDL particles tend to be smaller and denser with advancing CKD (402,404).

TABLE 14.

Changes in Lipids, Lipoproteins, ApoA, and ApoB, by Stage of Chronic Kidney Disease

In a study of persons with type 1 diabetes, LDL cholesterol predicted progression of DKD as defined by a doubling of albuminuria or a decline in creatinine clearance in excess of 3 mL/min/year (405). In that study, LDL cholesterol was associated with elevated albuminuria after nearly 9 years of follow-up; a higher triglyceride content of very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) particles predicted worsening of moderate albuminuria, whereas smaller LDL size was associated with declining kidney function in persons with severe baseline albuminuria. These findings suggest that specific lipids or lipid profiles may influence the onset or progression of DKD, although the findings have not been consistently observed (352,406,407,408).

In type 2 diabetes, prospective studies with long follow-up found that LDL cholesterol increases the risk for severe albuminuria (409) and kidney failure (410). In a post hoc analysis of 1,061 persons with type 2 diabetes included in the Reduction of Endpoints in Non-insulin dependent diabetes with the Angiotensin II Antagonist Losartan (RENAAL) study, the risk of kidney failure was 32% higher for each 50 mg/dL (1.30 mmol/L) increase in LDL cholesterol concentration and 67% higher for each 100 mg/dL (2.59 mmol/L) increase in total cholesterol concentration; lowering LDL cholesterol concentrations with a statin reduced the 1-year risk of kidney failure, although concurrent treatment with losartan, an ARB, likely contributed to improving this outcome by ACR (410). Elevated plasma triglycerides are associated with increased risk for both moderate and severe albuminuria (409) and with kidney failure in type 2 diabetes (411). In addition, low concentrations of HDL cholesterol predict increased risk of albuminuria progression in persons with type 2 diabetes and moderate albuminuria (412,413). In the UKPDS, each mmol/L decline in HDL cholesterol was associated with nearly threefold risk of doubling of serum creatinine concentration (HR 2.78, 95% CI 1.01–7.68) 15 years after the diagnosis of type 2 diabetes (409). The Strong Heart Study examined the relationship between plasma lipoprotein concentrations and the risk of elevated albuminuria in 671 American Indians with type 2 diabetes who were followed for a mean of 3.9 years (414). A low HDL cholesterol concentration was associated with elevated ACR in women only (OR 0.56, 95% CI 0.32–0.98) after adjustment for age, duration of diabetes, hypoglycemic treatment, A1C, study site, degree of Indian ancestry, mean arterial blood pressure, baseline albumin excretion, insulin concentration, body mass index (BMI), alcohol consumption, and physical activity. The association between HDL cholesterol and increased ACR in women was largely explained by a HDL cholesterol concentration <0.9 mmol/L, with little additional effect at higher HDL concentrations (Figure 35) (414). No other lipids were found to increase the risk of incident albuminuria; high levels of total and VLDL triglycerides and small LDL size were positively, but not significantly, associated with abnormal albuminuria. In the absence of a standard measure of insulin resistance, however, the study could not determine whether low HDL cholesterol itself, insulin resistance, or other correlated variables were most prominently increasing the risk of nephropathy (414).

FIGURE 35.

Effect of Serum HDL Cholesterol Concentration on the Incidence of Albuminuria in American Indians With Type 2 Diabetes, Strong Heart Study, 1989–1996. Effect of HDL cholesterol concentration on the incidence of albuminuria (ACR ≥30 mg/g) (more...)

Dyslipidemia may contribute to onset and progression of DKD through mechanisms similar to those responsible for arterial atherogenesis (398,415,416). Hypercholesterolemia may impair the kidney’s hemodynamic responses and tubular function by decreasing nitric oxide production and/or increasing superoxide activity in the kidney (417,418,419,420,421), with resulting antidiuretic and antinatriuretic effects (422). Although not directly affecting GFR, these actions may play a role in the development of systemic hypertension associated with diabetes (422). Oxidized LDL and free fatty acids can cause structural and functional damage to podocytes by inducing mitochondrial dysfunction and accumulation of reactive oxygen species (423), suggesting a direct causal role in the development and progression of proteinuria. Experimental rodent models of type 1 and type 2 diabetes indicate that down-regulation of glomerular ATP-binding cassette transporter (ABCA1) expression can lead to excessive cholesterol accumulation in podocytes (424,425). Under normal conditions, ABCA1 mediates the efflux of cholesterol to lipid-poor apolipoproteins (primarily Apo A1) to form HDLs. This mechanism has also been demonstrated in glomerular transcripts from persons with DKD when compared with living normal controls (426,427). Nevertheless, a definitive role for dyslipidemia in the development and progression of DKD in humans remains to be established.

Smoking

A cross-sectional analysis of 61,675 participants in the NKF’s Kidney Early Evaluation Program (KEEP), 27.1% of whom had CKD, identified smoking along with obesity, diabetes, hypertension, and CVD as significant factors associated with CKD (443). Similarly, in 14,632 participants in the NHANES 1999–2004, 15.3% of whom had CKD, current smoking increased the odds of CKD by 31% (443).

In a large population-based study, maternal smoking during pregnancy increased the odds of albuminuria in the full-term offspring who later developed type 1 diabetes by threefold, independent of low birth weight or blood pressure levels (444). In young persons with type 1 diabetes who smoked, the risk of albuminuria was nearly threefold higher than in nonsmokers (445). Likewise, the frequency of proteinuria (>500 mg/24 hours) was twice as high in smokers as in nonsmokers of similar age, duration of type 1 diabetes, A1C, and prevalence of hypertension (446). On the other hand, no relationship was observed between smoking and GFR decline in a longitudinal study of persons with type 1 diabetes with albuminuria and serial ⁵¹Cr-EDTA GFR measurements over a median follow-up of 7 years (Figure 36) (447), although other smaller studies identified an association (448,449,450).

FIGURE 36.

Impact of Smoking Habit on Kidney Function, Adjusted for Difference in Blood Pressure Between Groups, Steno Clinic, 1983–1997. GFR was measured yearly by the ⁵¹Cr-EDTA plasma clearance technique. In 301 persons with type 1 diabetes and severe (more...)

In men with type 2 diabetes, cigarette smoking was associated with higher A1C and ACR levels in a dose-dependent fashion (451), with nearly one-half of the heavy smokers having A1C >9% (>75 mmol/mol) and ACR ≥30 mg/g. The odds of elevated ACR were 2.8–3.2 times as high in those smoking more than 15 pack-years than in nonsmokers, regardless of age, blood pressure control, or diabetes duration. This and other studies in type 2 diabetes suggest that smoking is associated with kidney damage regardless of blood pressure control and treatment with RAAS inhibitors (452,453). Smoking also increased the risk of moderate or severe albuminuria (adjusted OR 1.50, 95% CI 1.21–1.86) after 5 years of follow-up in a large population-based study of persons with type 2 diabetes and no kidney disease at baseline from the Swedish National Diabetes Registry, although no association was found with the rate of kidney function decline (454).

In addition to nicotine, mainstream cigarette combustion produces more than 4,000 compounds, including reactive oxygen species, carbon monoxide, nitric oxide, toxic metals, and polycyclic aromatic hydrocarbons, which may add to an already increased susceptibility to DKD (455). Although the precise mechanisms are unclear, tobacco smoking is known to cause vasoconstriction, impair platelet function and coagulation, and alter blood pressure (456,457). Given that persons with diabetes already have widespread vascular damage as a consequence of their diabetes (458), smoking may accelerate the process.

Obesity

Obesity is a major risk factor for diabetes, hypertension, and CVD, all of which increase the risk for kidney disease. It increasingly affects young people, particularly among Hispanic, Black, and American Indian populations (459), leading to an earlier onset of diabetes and its major complications, including kidney disease (460). In a simulation study using data from the NHANES, lifetime risk of any-stage kidney disease has been estimated at 32.5% for individuals with normal weight, 37.6% with overweight, and 41.0% with obesity (461). The longitudinal population-based study in the Pima Indians showed that between 1965 and 2003, BMI increased in all age groups, including children. During the same time period, the incidence of diabetes increased nearly sixfold among those age <15 years, without a similar trend in the older ages. These findings suggest that the increasing prevalence and degree of obesity in youth combined with a nearly fourfold increase in the frequency of exposure to diabetes in utero have shifted the onset of diabetes to younger ages (462). For any diabetes duration, participants with youth-onset type 2 diabetes had a lower risk of kidney failure (p=0.007) than those with older-onset diabetes (Figure 37). Because of the longer duration of diabetes by mid-life, however, the incidence of kidney failure was higher between ages 25 and 54 years in those with youth-onset diabetes than in those with adult-onset diabetes (p<0.001) (Figure 37) (327). Given the continued increase in obesity, the experience in the Pima Indians may be relevant to other populations at high risk for diabetes.

FIGURE 37.

Effect of Youth-Onset Type 2 Diabetes on Incidence of End-Stage Kidney Disease in Pima Indians, by Diabetes Duration and Age, 1965–2002. Participants were observed from onset of diabetes to outcome or December 2002. Youth-onset type 2 diabetes (more...)

Animal and human kidney biopsy studies describe obesity-associated adaptive increases in GFR and renal plasma flow, resulting from both proximal salt reabsorption and elevated angiotensin II, as well as structural changes, such as glomerular hypertrophy and focal segmental glomerulosclerosis (463). A retrospective clinical and histopathologic study of 6,818 native kidney biopsies found diabetes-like lesions in 45% of persons with obesity-related glomerulopathy (464). Further, the prevalence of obesity-related glomerulopathy, defined as glomerulomegaly with or without focal segmental glomerulosclerosis, increased tenfold over a 15-year period (from 0.2% in 1986–1990 to 2.0% in 1996–2000) (464). As the authors excluded other causes of focal segmental glomerulosclerosis, this increase was largely attributed to the rising prevalence of obesity in the general population. Notably, five individuals who lost significant weight experienced a 50%–75% decline in proteinuria, and their kidney function remained stable.

Other Risk Factors for DKD

Drug and Iodinated Contrast-Associated Nephrotoxicity

Cumulative toxicity from prolonged exposure to NSAIDs is a cause of CKD, particularly among the elderly and those with diabetes, underlying volume depletion, heart failure, or preexisting kidney dysfunction (473,474,475,476,477).

A variety of commonly used or prescribed medicines have been associated with tubulointerstitial and glomerular lesions, including hydralazine, levamisole, and antithyroid drugs (478). Two main mechanisms of interaction with kidney structures have been described: direct cellular toxicity and immune-mediated injury (479). These injuries and the related clinical parameters are generally reversible after withdrawing the offending drug. Nonetheless, establishing a causal link between drug exposure and the development of renal pathology is often difficult, due to lack of specific markers, recall bias, underlying diseases, heterogeneity of symptoms, and physicians’ unfamiliarity with the renal effects caused by certain drugs.

Iodinated contrast-induced nephropathy is one of the most commonly reported causes of acute kidney failure in hospitalized patients. Those with diabetes and an eGFR <60 mL/min/1.73 m² are at particularly increased risk for contrast-induced nephropathy, especially with use of high-osmolar iodinated contrast media (480).

Autonomic Neuropathy

In the United States, between 25% and 28% of adults age ≥40 years with diabetes have peripheral neuropathy (481). Autonomic neuropathy with ensuing alteration of glomerular vascular resistance may hasten deterioration of kidney function in persons with type 1 diabetes (482). Whether autonomic neuropathy per se is part of the pathogenic process leading to DKD or is a reflection of the severity of diabetes is unclear (482,483,484). Nonetheless, the two microvascular complications of diabetes occur together frequently. One study reported that half of the deaths in those with type 1 diabetes and autonomic neuropathy were attributed to DKD (485).

Pregnancy

Among women with normal kidney function, regardless of the presence of diabetes, pregnancy is associated with a rise in the eGFR of about 50% that persists through the 37th week of gestation (283,486) and is accompanied by a moderate increase in urinary protein excretion (283,487). Table 15 summarizes ACR and kidney function characteristic of nondiabetic and diabetic pregnancies (488). Most women with DKD have successful pregnancy outcomes despite increased risk. Those with advanced kidney disease, poor glycemic control, or hypertension, however, are at increased risk of pregnancy complications and subsequent deterioration in kidney function (486).

TABLE 15.

Kidney Function During and After Pregnancy, by Presence or Absence of Diabetes

Although neither pregnancy nor parity adversely affects the course of early DKD (489), the few available studies suggest that women with more severe kidney impairment may be at greater risk of kidney disease progression later in life. In a retrospective review of pregnant women with type 1 diabetes, a creatinine clearance <90 mL/min or a urinary protein excretion >1g/day during the first 20 weeks of gestation was associated with a greater decline in kidney function at approximately 3 years after delivery than in those with less severe DKD during early pregnancy (490). On average, creatinine clearance declined from 120 mL/min in the first weeks of pregnancy to 78 mL/min at the 3-year follow-up (p=0.01), even as changes in proteinuria remained nonsignificant from the initial measurement during pregnancy (2.94±4.26 g/24 hours vs. 1.74±1.33 g/24 hours, p=0.25) (Table 16) (490). Mothers with advanced kidney disease were more likely to experience preeclampsia and have offspring with low birth weight. Worsening of preexisting DKD was also reported among women with type 1 diabetes who were followed for up to 26 years (491). In this study, morbidity and mortality remained higher in women with pregnancies 10 years after their last delivery than in those without pregnancies (491). Preeclampsia is more frequent in women with diabetes and is associated with 7.7-fold higher odds of subsequent DKD compared with those with normotensive pregnancies (492).

TABLE 16.

Serial Creatinine Clearance and 24-Hour Proteinuria Measurements During and After Pregnancy in Participants With Type 1 Diabetes, 1988–1994

Intrauterine Factors

Clinical studies indicate that exposure to a diabetic intrauterine environment increases the risk of kidney disease later in life, perhaps as a consequence of reduced nephron formation during fetal development (493,494,495). Individuals with reduced nephron endowment are also prone to develop hypertension and CVD. These conditions may be triggered or hastened by exposure to additional kidney insults, such as high-salt diet, obesity, and diabetes (493,494,496). Moreover, impaired nephrogenesis and hypertension may be passed to the next generation through changes in epigenetic gene regulation (497,498,499). Consistent quantitative information about this risk comes from longitudinal studies in Pima Indians. Exposure to diabetes in utero among Pima Indians increased nearly fourfold over a 30-year period, paralleled by a doubling in the prevalence of children with diabetes attributable to this exposure (500). Intrauterine exposure to diabetes was associated with a fourfold increase in the age-sex-adjusted incidence of kidney failure in young adults with type 2 diabetes, mediated largely by the younger age at onset of diabetes (Figure 38) (328). A study exploring the impact of intrauterine exposure to diabetes compared renal vascular resistance in 19 adult nondiabetic offspring of mothers with type 1 diabetes with 18 offspring of fathers with type 1 diabetes as control subjects (501). At baseline, exposed and control subjects had similar age (median 24 and 25 years, respectively), BMI, age at delivery, glucose concentrations, blood pressure, kidney size, and ⁵¹Cr-EDTA-measured GFR. Kidney vasodilatation induced with amino acid infusion was associated with significantly less increase in GFR and effective renal plasma flow and less decline in mean arterial pressure in offspring of mothers with type 1 diabetes, suggesting a reduced kidney functional reserve, possibly due to low nephron number and compensatory permanent single nephron hyperfiltration. A proposed explanation for these observations is that exposure to a diabetic intrauterine environment causes differential apoptosis during nephrogenesis via increased intrarenal renin-angiotensin system activation and nuclear factor (NF)-kappaB signaling (502,503).

FIGURE 38.

Cumulative Incidence of Diabetic End-Stage Kidney Disease Among Pima Indians, by Offspring’s Age and Duration of Diabetes, According to Exposure to Diabetes in Utero, 1965–2006.

A critical shortage of maternal fuels during pregnancy may manifest as intrauterine growth retardation, defined as birth weight below the 10th percentile for gestational age. Low birth weight is frequent in minority populations, in populations undergoing rapid transition from traditional to modern lifestyle, and in those with low socioeconomic status, as well as in pregnancies associated with inadequate maternal weight gain, poor antenatal care, maternal hypertension, or smoking (504). In 12,364 adults with a history of diabetes or hypertension screened by the NKF’s KEEP, 15% of whom reported birth weight <2,500 g, a U-shaped relationship was found between birth weight and CKD among White men (505). Similarly, in a population-based, case-control study using 1987–2008 birth certificates from Washington state, low birth weight (defined as 400–2,499 g) was associated with a twofold higher risk of CKD in the offspring (OR 2.41, 95% CI 2.08–2.80) compared with those of normal birth weight (defined as 2,500–3,999 g); the higher odds persisted after adjustment for maternal diabetes, BMI, and smoking (OR 2.88, 95% CI 2.28–3.63) (Figure 39) (506). The same study found that children with CKD were more likely to be born to mothers with overweight or obesity (OR 1.25, 95% CI 1.10–1.41), regardless of maternal diabetes, gestational hypertension, and smoking (506).

FIGURE 39.

Association Between Birth Weight and Chronic Kidney Disease. The horizontal dashed line represents the reference birth weight (defined as 2,500–3,999 g). Birth weight is based on Washington state birth records from 1987–2008. Chronic kidney (more...)

Familial and Genetic Factors

Familial aggregation of DKD and racial and ethnic differences in disease susceptibility suggest a genetic predisposition to DKD. Three initial studies reported familial clustering of DKD (507,508,509). In one study, DKD was reported in 83% (24 of 29) of the siblings of probands with type 1 diabetes and kidney disease but in only 17% (2 of 12) of the siblings of probands with type 1 diabetes without kidney disease (Figure 40) (507). Moreover, 41% of the affected siblings of persons with DKD had kidney failure. A similar study in persons with type 1 diabetes found DKD in 33% of the siblings of persons with DKD but in only 10% of the siblings of persons without DKD (508). Familial clustering is also found in type 2 diabetes. In two generations of Pima Indians with type 2 diabetes, the frequency of proteinuria in the offspring with diabetes was higher if both parents with diabetes had proteinuria than if neither did; if one parent had proteinuria, the prevalence was intermediate (Figure 41) (509).

FIGURE 40.

Kidney Status of Siblings of Type 1 Diabetes Probands, by Diabetic Nephropathy. Probands with diabetic nephropathy were persons with kidney transplant for diabetic ESKD; probands without diabetic nephropathy were persons with albumin excretion rate <45 (more...)

FIGURE 41.

Prevalence of Proteinuria in Offspring, by Number of Parents With Proteinuria, Pima Indians. Proteinuria is defined as urinary protein excretion ≥1g protein/24 hours. Data are adjusted for age, systolic blood pressure, diabetes duration, and glucose (more...)

A number of candidate genes have been identified that may be related to DKD. In Pima Indians, a potential susceptibility locus for kidney failure was found within the plasmacytoma variant 1 (PVT1) gene (510), which was confirmed in subjects of European descent with type 1 diabetes (511). Genome-wide association studies of subjects with type 1 diabetes in the Genetics of Kidneys in Diabetes (GoKinD) study (512) found single nucleotide polymorphisms (SNPs) in the FERM domain-containing protein 3 (FRMD3) gene and near the cysteinyl-tRNA synthetase (CARS) gene associated with DKD, defined by overt proteinuria or kidney failure. These associations were confirmed in the DCCT/Epidemiology of Diabetes Interventions and Complications (EDIC) prospective study of type 1 diabetes (513), and susceptibility loci near CARS were found to be common to both types of diabetes in another study (514). Engulfment and cell motility 1 (ELMO1) loci were associated with DKD in European (515) and Japanese (516) persons with type 1 diabetes and in Black persons with kidney failure due to type 2 diabetes (517). The Family Investigation of Nephropathy and Diabetes (FIND) study (518) collected DNA and cell lines from European American, Black, American Indian, and Hispanic American families in whom type 2 diabetes was the predominant cause of kidney disease. For all ethnicities combined, the strongest evidence for linkage to DKD was on the long arm of chromosomes 7, 14, 18, and on the short arm of chromosome 10; to ACR on the long arm of chromosomes 2, 7, and 15; and to the eGFR on the long arm of chromosomes 1, 7, and 8 (519,520).

A meta-analysis assessing the effects of all genetic variants associated with severe albuminuria or kidney failure found 24 reproducible genetic variants associated with DKD (Figure 42) (521). These genetic variants are involved in the renin-angiotensin system, polyol, oxidative stress, inflammation, angiogenesis, glomerular filtration barrier defects, cell growth, differentiation, and apoptosis pathways, supporting their roles in the pathogenesis of DKD (521). Another meta-analysis identified additional variants, primarily involved in kidney DNA methylation, that were associated with kidney disease (522). Albuminuria and, to a greater degree, GFR are heritable (523), but the actual genes responsible for DKD remain elusive. Although these findings are not universal, they do suggest that genetic factors may predispose some individuals to a higher risk of DKD than others.

FIGURE 42.

Genetic Variants Reproducibly Associated With Diabetic Nephropathy. Panel A: All genetic variants in or near a gene that were reproduced in an independent study and significantly associated with diabetic nephropathy after meta-analysis. Panel B: All genetic (more...)

In addition to specific genetic factors, the multifaceted cross-talk between genes and environmental factors can induce tissue-specific epigenetic changes, i.e., heritable changes in gene expression without alterations in the DNA sequence that can lead to aberrant gene regulation expressed as pathologic phenotype. Epigenetic changes include DNA cytosine methylation, histone posttranslational modifications in chromatin, and noncoding RNAs—all of which can modulate diabetes complications through alterations in gene expression (Figure 43) (524). Through epigenetic mechanisms, for example, cells acquire metabolic memory of prior hyperglycemic exposure that appears to mediate the development and progression of DKD (525,526). Hyperglycemia-induced epigenetic aberrations alter transcription factors involved in the expression of genes mediating the pathogenesis of DKD (Figure 43) (524). Several microRNAs and certain long noncoding RNAs also have regulatory roles in DKD, including promoting/modulating fibrotic gene expression in renal cells by targeting transcription repressors (525). Although the mechanisms of such cellular memory are not entirely elucidated, its presence is supported by the regression of morphologic lesions in diabetic kidneys after a long period of normoglycemia following pancreas transplantation (369). Similarly, the long-lasting effects of previous strict glycemic control observed in persons with type 1 diabetes in the DCCT or type 2 diabetes in the UKPDS could be attributed to cellular metabolic memory. Therapeutic approaches targeting transforming growth factor beta (TGF-β), angiotensin II type 1 receptor, or microRNAs can block some of the events involved in the pathogenesis of DKD, suggesting the need for novel therapies.

FIGURE 43.

Signaling and Epigenetic Networks Involved in the Pathogenesis of Diabetic Complications and Metabolic Memory. Metabolic and hemodynamic disorders associated with diabetes can upregulate growth factors and lipids that trigger signaling pathways, transcription (more...)

Treatment of Diabetes-Related Kidney Disease

Large, well-designed clinical trials have examined the effects of treatments on the onset and progression of kidney disease in persons with diabetes. The results of these trials helped inform and refine clinical practice guidelines for the management of persons with diabetes and kidney disease. This section summarizes the current understanding of kidney protective treatments in those with diabetes.

Glycemic Control

Hyperglycemia plays a fundamental role in the development of DKD, as discussed previously in this review. Many clinical trials have examined the effect of glycemic control on the course of DKD (250,513,527,528,529,530,531,532,533,534,535,536,537,538,539,540,541,542).

In type 1 diabetes, the DCCT and its long-term follow-up, the EDIC observational study, demonstrated that intensive treatment of hyperglycemia prevents the development of albuminuria and slows its progression (513,543). In the DCCT, 1,441 persons with type 1 diabetes were randomly divided into two groups, half receiving intensive insulin therapy and the other half receiving conventional insulin therapy. Participants were followed for a mean of 6.5 years (252). Intensive insulin therapy reduced the risks of moderate albuminuria (≥40 mg/24 hours) and severe albuminuria (≥300 mg/24 hours) by 39% and 54%, respectively. In both the primary and secondary prevention cohorts, intensive therapy reduced the proportion of participants developing moderate or severe albuminuria more than conventional treatment (Figure 44). At the end of the randomization period, both treatment groups were offered intensive therapy and followed during the EDIC study to determine the longer-term effects of prior intensive treatment on kidney disease (513). Despite the fact that the difference in A1C levels achieved during the DCCT (7.4% [57 mmol/mol] in the intensive treatment group vs. 9.1% [76 mmol/mol] in the conventional treatment group, p<0.01) disappeared promptly during the EDIC study, the beneficial effect of early intensive insulin treatment persisted for 8 years after the end of randomization, with 57% lower adjusted risk for moderate albuminuria and 84% lower risk for severe albuminuria in the former intensively treated group compared with the former conventionally treated group (Figure 45) (513). In later analyses, although the risk of treated kidney failure did not differ significantly between treatment groups during 22 years of combined follow-up (0.5 cases/1,000 person-years in the intensive treatment group vs. 1.1 cases/1,000 person-years in the conventional treatment group, p=0.10), intensive early glycemic control reduced the risk of a sustained eGFR <60 mL/min/1.73 m² by 50% (95% CI 18%–69%, p=0.006) (532). Intensive metabolic control also reduced CVD outcomes by 42%, with a specific 57% decrease in myocardial infarction, stroke, or death from CVD; these effects were partly mediated by the reduced incidence of DKD (533).

FIGURE 44.

Cumulative Incidence of Moderately Elevated and Severe Albuminuria in Participants With Type 1 Diabetes, Diabetes Control and Complications Trial. Moderate albuminuria is defined as an albumin excretion rate ≥40 mg/24 hours; severe albuminuria (more...)

FIGURE 45.

Differences in Glycated Hemoglobin (A1C) Level and Prevalence and Incidence of Moderate and Severe Albuminuria, by Randomized Treatment Group at the End of the Diabetes Control and Complications Trial and Each Year in the Epidemiology of Diabetes Interventions (more...)

The long-term positive effect of intensive glycemic control—“metabolic memory” or the glycemic “legacy effect”—observed in persons with type 1 diabetes followed in the DCCT/EDIC study (533) has also been observed in persons with type 2 diabetes. The UKPDS was the first large-scale clinical trial to evaluate the effects of intensive glycemic control versus conventional therapy with diet alone on long-term diabetes complications in individuals with newly diagnosed type 2 diabetes and overweight or obesity. No differences in the relative risk for kidney outcomes (renal death or kidney failure) were seen between the intensive and conventional therapy groups after 10 years (544). The level of glycemic control achieved in the UKPDS was similar to that achieved in the DCCT.

Subsequent randomized controlled trials explored the effect of even more intensive glycemic control on microvascular and macrovascular outcomes in type 2 diabetes. A meta-analysis of these trials (537) indicated that even more intensive glucose lowering was associated with a significant reduction in the rate of moderate albuminuria (risk ratio 0.90, 95% CI 0.85–0.96) but had no effects on mortality, kidney failure, or other vascular outcomes. Baseline characteristics and mean A1C levels achieved during standard and intensive glycemic therapy in these clinical trials are shown in Table 17 (537,538,539,540,541,542,545). The modest gains in intermediate outcomes across these studies were counterbalanced by a twofold to threefold higher risk of severe hypoglycemia that required the intervention of another person in the intensive treatment arms of the Action to Control Cardiovascular Risk in Diabetes (ACCORD), ADVANCE, and Veterans Affairs Diabetes Trial (VADT) (Table 18) (541,542,545). The ACCORD trial, targeting an A1C <6.0% (<42 mmol/mol) in the intensive intervention arm, reported an increased risk of cardiovascular death for intensive versus conventional glycemic control, although it remains unclear whether this effect was related to more hypoglycemic episodes, the use of additional hypoglycemic medicines, or to the target glycemic level itself. Significant weight gain in those receiving intensive treatment also might have offset the beneficial effects of lower A1C levels.

TABLE 17.

Characteristics of Persons With Type 2 Diabetes Included in Randomized Controlled Studies of Intensive Versus Conventional Glycemic Treatment

TABLE 18.

Effect of Intensive Versus Conventional Glycemic Control on Kidney Outcomes in Type 2 Diabetes

Persons with advanced kidney disease experience reduced renal gluconeogenesis and impaired kidney clearance of insulin and certain oral hypoglycemic drugs (546), potentially increasing the likelihood of severe hypoglycemia, particularly when associated with inadequate nutrition. Furthermore, because A1C may underestimate the level of glycemia in uremic patients, due to the shortened lifespan of red blood cells and treatment with erythropoietin, establishing an optimal target A1C in uremic patients remains challenging (547,548). Persons with DKD often have higher glycemic levels than expected for a given A1C, albeit with a wide variation in the glucose/A1C relationship (549,550,551,552,553,554). The Dialysis Outcomes and Practice Patterns Study (DOPPS) (555) found a U-shaped association between A1C and all-cause mortality in hemodialysis patients with type 1 or type 2 diabetes. The lowest death rates were associated with A1C levels of 7.0%–7.9% (53–63 mmol/mol), comparable to those found in a population-based study of patients with diabetes and an eGFR <60 mL/min/1.73 m² who were not on dialysis (556). Another study using time-dependent modeling of A1C values in patients with diabetes on dialysis found similar nonlinear associations with mortality (557). Nevertheless, A1C remains the best clinical marker of long-term glycemic control in persons with DKD, particularly if combined with self-monitoring or continuous monitoring of blood glucose (10). The clinical value of alternative glycemic biomarkers to A1C, including measurement of glycated albumin and fructosamine, is still being explored.

Glucagon-Like Peptide-1 Receptor Agonists

GLP-1 RAs are increasingly used for glycemic management in persons with type 2 diabetes. GLP-1 RAs act at the level of the seven-transmembrane G protein-coupled GLP-1 receptor to activate adenylate cyclase and stimulate a cascade resulting in the postprandial release of insulin, as well as numerous additional downstream effects, including increased beta cell proliferation, somatostatin release, natriuresis and diuresis, glucose uptake in the muscle and adipose tissue, skeletal muscle perfusion, lipolysis, and satiety, and decreased beta cell apoptosis, glucagon secretion, gastric emptying, gastrointestinal motility, gluconeogenesis, steatosis, and generalized inflammation (562).

As a drug class, GLP-1 RAs undergo renal clearance; thus, kidney effects of GLP-1 RAs are difficult to evaluate, and studies are largely limited to intermediate health outcomes, including changes in the eGFR or albuminuria (563,564,565), presence of new-onset severe albuminuria (566,567), time to new-onset severe albuminuria (568), or persistent severe albuminuria (9).

Most existing data regarding kidney outcomes in GLP-1 RA studies come from large, placebo-controlled safety and cardiovascular outcomes trials in adults with type 2 diabetes who either have preexisting CVD or are at high risk for CVD (Table 19) (8,9,567,569,570,571,572,573). Both the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with type 2 diabetes (SUSTAIN-6) and the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial enrolled individuals with type 2 diabetes and prevalent CVD and showed significantly lower risk for new or worsening DKD with semaglutide (HR 0.64, 95% CI 0.46–0.88, p=0.005) or liraglutide (-22%, HR 0.74, 95% CI 0.60–0.91) versus placebo (8,9). However, both the SUSTAIN-6 and LEADER trials used a prespecified composite kidney outcome, including persistent doubling of serum creatinine concentration, new onset of persistent macroalbuminuria, an eGFR ≤45 mL/min/1.73 m², need for continuous kidney replacement therapy, and death from kidney disease (8,9), rather than direct assessments of kidney function. The Exenatide Study of Cardiovascular Event Lowering (EXSCEL) also used a composite score, including 40% eGFR decline, use of kidney replacement therapy, kidney death, or new macroalbuminuria, to evaluate the effects of a median of 3.2 years of treatment with extended-release exenatide versus placebo in people with type 2 diabetes. EXSCEL found nonsignificant improvement in the composite kidney outcome with GLP-1 RA therapy (HR 0.88, 95% CI 0.76–1.01, p=0.065) and a similar effect on worsening kidney function (HR 0.88, 95% CI 0.74–1.05, p=0.16) (570,571).

TABLE 19.

Characteristics of Participants in Studies Assessing Kidney Outcomes and Use of Glucagon-Like Peptide-1 Receptor Agonists, Sodium-Glucose Cotransporter-2 Inhibitors, and Dipeptidyl Peptidase-4 Inhibitors

Dedicated kidney outcomes trials, particularly in individuals with known kidney disease, are limited but have confirmed the positive effects of GLP-1 RAs seen in safety and efficacy trials. In the Study Comparing Dulaglutide with Insulin Glargine on Glycemic Control in Participants with Type 2 Diabetes and Moderate or Severe Chronic Kidney Disease (AWARD-7), dulaglutide reduced severe albuminuria by 29% (95% CI 11.5%–43.0%) and attenuated eGFR decline versus insulin glargine alone in adults with type 2 diabetes and moderate to severe CKD (564). In the Evaluate Renal Function with Semaglutide Once Weekly (FLOW) trial, patients with type 2 diabetes and CKD (defined by an eGFR 50–75 mL/min/1.73 m² and urinary ACR 300–5,000 mg/g or an eGFR 25–<50 mL/min/1.73 m² and urinary ACR 100–5,000 mg/g) randomized to semaglutide had a 21% lower risk for the composite kidney-specific outcomes (HR 0.79, 95% CI 0.66–0.94) and a 29% lower risk for cardiovascular death (HR 0.71, 95% CI 0.56–0.89) compared with placebo (573).

These trials confirm the favorable effects of GLP-1 RAs on kidney, cardiovascular, and survival outcomes in high-risk populations with type 2 diabetes, although gastrointestinal disorders are common causes of treatment discontinuation.

Blood Pressure Control

Blood pressure control, particularly with RAAS inhibitors, significantly decreases the risk of progression from moderate albuminuria to severe albuminuria, increases the rate of regression from moderate albuminuria to normoalbuminuria, and decreases the risk of heart failure and overall cardiovascular outcomes in persons with DKD, regardless of type of diabetes (599,600,601). Although several types of antihypertensive drugs are effective in ameliorating the course of DKD, including beta blockers, non-dihydropyridine calcium channel blockers, diuretics, and RAAS inhibitors, the purported relationship between increased intraglomerular pressure and proteinuria that is mediated by RAAS components, as well as their association with virtually every aspect of kidney disease progression, has been borne out by evidence that RAAS inhibitors, including primarily ACE inhibitors and ARBs, prevent progression of DKD.

A landmark study of 409 mostly hypertensive persons with type 1 diabetes and urinary protein excretion ≥500 mg/24 hours, who were randomized to receive either captopril (an ACE inhibitor) or placebo, found a 48% lower risk of doubling of serum creatinine concentration in the captopril group compared to the placebo group after a median follow-up of 3 years (Figure 46) (602). The risk of the combined endpoints of death, dialysis, or transplantation was 50% lower (Figure 46). A significant renoprotective effect of captopril, however, was limited to those with baseline serum creatinine concentrations ≥1.5 mg/dL. No long-term studies have examined the renoprotective efficacy of ARBs in type 1 diabetes and advanced kidney disease. In persons with type 1 diabetes and lower levels of ACR, with or without hypertension, randomized controlled studies demonstrate that RAAS inhibitors do not prevent increases in ACR, serum creatinine, or kidney failure during up to 5 years of follow-up (Table 20) (542,602,603,604,605,606,607,608,609,610,611,612,613,614,615,616,617,618,619). Moreover, when given to normoalbuminuric, normotensive persons with type 1 diabetes, these treatments do not reduce the rate of expansion of the fractional mesangial volume over a period of 4–5 years (603).

FIGURE 46.

Effect of Captopril on Incidence of Kidney Disease in Persons With Type 1 Diabetes and Proteinuria, 1987–1992. The Collaborative Study included 409 subjects with type 1 diabetes and urinary protein excretion ≥500 mg/24 hours, who were (more...)

TABLE 20.

Randomized Controlled Studies of Renin-Angiotensin System Inhibitors

In hypertensive persons with type 2 diabetes and severe albuminuria, the RENAAL study (612) and the Irbesartan Diabetic Nephropathy Trial (IDNT) (613) reported results that were similar to those in persons with type 1 diabetes and severe albuminuria (Table 20) (602). Both studies reported lower risks of doubling of serum creatinine and kidney failure compared with placebo; the IDNT found a 39% lower risk of doubling of serum creatinine compared with amlodipine. The Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria (IRMA 2) study found that high-dose irbesartan prevented progression to severe albuminuria in hypertensive persons (611). Although none of these three ARB trials found significant reductions in kidney failure incidence during the intervention periods, several cost-benefit analyses based on the IDNT and the cost of medicine and kidney failure treatment specific to the United States, Canada, and several European countries consistently predicted both long-term survival advantage and higher cost-effectiveness with ARB than with other treatments (620). These benefits might be due in part to less comorbidity associated with RAAS treatment, such as heart failure and retinopathy, and in part to lower kidney failure incidence when longer time periods are considered. No long-term studies have examined the renoprotective efficacy of ACE inhibitors in persons with type 2 diabetes and ACR ≥300 mg/g.

Dual RAAS blockade is as effective as monotherapy in reducing blood pressure and albuminuria in persons with diabetes (616,621,622), but it does not offer benefit and has more adverse effects, so it is not recommended (614). The Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) (619) and Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial (623) found an excess risk of acute kidney injury and hyperkalemia with dual RAAS therapy, without a significant cardiovascular and renal benefit. Further, even after 5 years of treatment, albuminuria increased to pretreatment levels soon after the withdrawal of these drugs (603,604,605). This observation suggests the need for longer periods of normalization of both ACR and glycemic levels to achieve a durable treatment effect on underlying disease processes or more sensitive early markers of kidney disease progression. Adding the direct renin inhibitor aliskiren to an ARB (losartan) in persons with type 2 diabetes, hypertension, and ACR ≥300 mg/g more effectively reduced mean urinary ACR than losartan alone (20%, 95% CI 9%–30%, p<0.001) (624); the mean eGFR decline during the 24-week study period also tended to be lower in the aliskiren group (2.4 mL/min/1.73 m² vs. 3.8 mL/min/1.73 m² in the placebo group, p=0.07). The Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE), a subsequent, larger study in persons with type 2 diabetes, CKD, and high cardiovascular risk, was stopped early due to therapeutic futility and increased risk of stroke and other adverse events (625). Neither ALTITUDE nor VA NEPHRON-D was continued long enough to establish efficacy, and the trials remained underpowered for their primary CVD and renal outcomes. Based on their other findings, however, dual RAAS blockade is contraindicated due to safety concerns (10).

In a meta-analysis exploring the benefit of intensive (achieved systolic blood pressure ≤135 mmHg) versus standard (achieved systolic blood pressure ≤140 mmHg) blood pressure targets in subjects with type 2 diabetes, the former was associated with significant 17% and 27% reductions in the odds for moderate and severe albuminuria, respectively (626). For persons with severe albuminuria (>3 g/24 hours), a post hoc analysis from the MDRD study indicated better kidney outcomes with a lower blood pressure goal (<130/80 mmHg) (627). Whereas stringent blood pressure targets lowered the risk for stroke and death, the few studies reporting kidney failure or doubling of serum creatinine showed no benefits for these outcomes, suggesting the importance of individualizing blood pressure goals in persons with diabetes to account for the presence and severity of CKD, age, and associated cardiovascular risk. Moreover, ACE inhibitors and beta blockers may be less effective in controlling blood pressure and reducing albuminuria in Black than in White persons (628,629,630), suggesting that different drug combinations may be more effective in slowing progression of kidney disease in Black persons (631,632).

Table 21 shows the Eighth Joint National Committee’s (JNC 8) recommendations for management of hypertension in the population with diabetes and CKD in comparison with other guidelines (17,632,633,634,635). The thresholds and goals recommended by the guideline-writing groups differ within a narrow range, with 2014–2015 JNC 8 recommendations endorsing less intensive and more individualized blood pressure targets for diabetes and CKD than more recent guidelines. In elderly persons, in particular, antihypertensive treatment should be individualized, taking into consideration such factors as frailty, comorbidities, and albuminuria (Figure 47) (632). There is consensus on the initial use of RAAS treatment in persons with albuminuria, but not for those without elevated albuminuria.

TABLE 21.

Guideline Comparisons of Blood Pressure Goals and Drug Therapy for Adults With Hypertension

FIGURE 47.

2014 Hypertension Guideline Management Algorithm, Eighth Joint National Committee. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; CKD, chronic kidney disease; DBP, diastolic blood pressure; (more...)

Dietary Modification

In animals with experimental diabetes, reduced protein intake protects against hyperfiltration and progressive sclerosis of functioning glomeruli (649,650). In persons with type 1 diabetes and normal urinary albumin excretion, short-term dietary protein restriction favorably modifies glomerular hemodynamic function, and in those with moderate albuminuria, it also reduces urinary albumin excretion (651,652,653,654,655). Similar effects have been found in persons with clinical proteinuria (Table 22) (656,657,658,659). The largest study (660) randomized 82 persons with type 1 diabetes, severe albuminuria, and prerandomization eGFR decline of 7.1 mL/min/year to usual-protein diet (1.02 g/kg/day, 95% CI 0.95–1.10) or reduced-protein diet (0.89 g/kg/day, 95% CI 0.83–0.95) (p=0.005) for a period of 4 years. At the end of the study, the CVD-adjusted risk of kidney failure or death was 0.23 (95% CI 0.07–0.72, p=0.01) in the group receiving the reduced-protein diet compared with the group receiving the usual diet (Figure 48), suggesting that even moderate protein restriction, which moves intakes from excess toward the norm, provides benefits beyond conventional drug therapy in these persons.

TABLE 22.

Clinical Trials of the Effect of Dietary Protein Reduction on the Course of Diabetic Nephropathy in Persons With Type 1 Diabetes and Severe Albuminuria

FIGURE 48.

Cumulative Incidence of End-Stage Kidney Disease or Death in Persons With Type 1 Diabetes, by Protein Intake. Eighty-two persons with type 1 diabetes and severe albuminuria were randomized to usual-protein diet and low-protein diet. The numbers at the (more...)

Fewer studies are available in persons with type 2 diabetes. A study of the efficacy of dietary protein restriction in 160 persons with type 2 diabetes and moderate albuminuria or ≥5 years duration of diabetes found no beneficial effect of protein restriction on albuminuria or the eGFR during a mean follow-up of 28 months (661). In fact, a protein intake restricted to 0.8 g/kg/day could not be effectively achieved beyond the first 6 months of the study, reflecting the inconvenience associated with a strict dietary regimen that may outweigh the benefits of such therapy.

A systematic review of randomized studies (662) concluded that a reduced-protein diet in persons with CKD associated with either type of diabetes had no significant effect on kidney function relative to normal protein consumption, despite improvements in proteinuria and A1C, and that dietary protein restriction may significantly increase the risk for malnutrition in those with more advanced CKD (663). On the other hand, studies evaluating a reduction or alteration of protein intake in persons with DKD are generally small (under 100 subjects), of short duration (<2 years), have limited documentation on the quality of protein (animal or vegetable), fat and carbohydrate intake, and evaluate intermediate outcomes, i.e., albuminuria and the eGFR, rather than major health outcomes. Because the low quality of evidence precludes a recommendation, KDIGO suggests maintaining 0.8 g/kg/day dietary protein intake for persons with DKD not treated with dialysis (10).

Sodium intake is a major contributor to blood pressure increase. According to the Institute of Medicine (664), about 75% of dietary sodium intake is obtained from preprocessed foods or is added to restaurant food during preparation, and only about 25% comes from natural sources or is added by the consumer. The Dietary Guidelines for Americans (665) recommend that persons age ≥51 years, Black persons, and persons with hypertension, diabetes, or CKD limit their sodium intake to 1,500 mg daily. In the NHANES 2005–2008, virtually all (99.4%) of those encouraged to limit their sodium intake exceeded the recommended limit on a daily basis (666).

Although sodium reduction has a positive impact on blood pressure in persons with diabetes (667), its long-term effect on kidney outcomes remains unclear. Most individuals may benefit from a Dietary Approaches to Stop Hypertension (DASH) diet, a reduced-sodium diet emphasizing fruits, vegetables, low-fat dairy foods, whole grains, nuts, poultry, fish, and smaller amounts of red meat and refined sugars than the typical diet in the United States (668). The DASH diet reflects a shift towards whole-diet approaches to the management of DKD that integrate multiple healthful eating goals simultaneously, without a focus on single nutrients. In addition to lowering blood pressure, a DASH-type diet was associated with preserved kidney function over 11 years in women from the Nurses’ Health Study with a mildly decreased eGFR, an effect primarily associated with reduced red meat intake (669). Nonetheless, the DASH diet may not be suitable, without modification, for persons with an eGFR <60 mL/min/1.73 m² because of its high content of potassium (4.5 g/day), phosphorus (1.7 g/day), and protein (1.4 g/kg/day).

Other Kidney Diseases Associated With Infections in Persons With Diabetes

Urinary Tract Infections

Persons with diabetes may be more susceptible to infections of the urinary tract. Autopsy studies from the pre-antibiotic era (688,689,690,691,692) reported 10%–20% prevalence of histologic pyelonephritis in persons with diabetes, five times that in persons without diabetes. Not only was the frequency of urinary tract infection greater in those with diabetes at that time, but the infections were often more serious and protracted (689). With the introduction of effective antimicrobial therapy, the frequency and severity of urinary tract infections may have diminished (693).

Table 23 presents the prevalence of asymptomatic bacteriuria in persons with and without diabetes from several different clinic- or hospital-based populations (694,695,696,697,698,699,700,701,702,703,704,705,706,707,708,709,710,711). In a systematic review and meta-analysis of published data since 1966 (694), women with diabetes have about three times the frequency of bacteriuria as women without diabetes (OR 2.6, 95% CI 1.6–4.1), and men with diabetes have about four times the frequency of bacteriuria as healthy control subjects (OR 3.7, 95% CI 1.3–10.2) (694,699,700,704,712,713,714,715,716,717,718,719). Some studies have reported a longer duration of diabetes in women with asymptomatic bacteriuria than in those without (pooled difference 0.17 years, 95% CI 0.03–0.31, p=0.01), but the same review found no difference in A1C (694). Some studies have shown a relationship between asymptomatic bacteriuria in persons with diabetes and more frequent development of genitourinary tract infections (711,720,721,722,723), but others have not found a relationship (693,724). In most studies, the microorganisms causing asymptomatic bacteriuria in persons with diabetes are similar to those causing bacteriuria in persons without diabetes (693), but a survey of 514 persons with diabetes and 405 persons without diabetes found that nearly one-half of those with diabetes and bacteriuria were infected by bacteria other than E. coli, whereas all but one case of bacteriuria in persons without diabetes were caused by E. coli (713). The prevalence of asymptomatic bacteriuria is not influenced by the type of diabetes (693,694).

TABLE 23.

Prevalence of Asymptomatic Bacteriuria in Populations With and Without Diabetes

The reported prevalences of cystitis and pyelonephritis in 550 women with type 1 diabetes in the UroEDIC study of EDIC year 10 subjects surveyed for urologic complications of type 1 diabetes were 15% and 3%, respectively, during the preceding 12 months (725). Table 24 presents risk factors for urinary tract infections in this cohort. The prevalence of cystitis in women in the UroEDIC was similar to that in White women without diabetes age 20–59 years from the NHANES III. Among men in the UroEDIC, the prevalence of urinary tract infections was 4% for cystitis and 0% for pyelonephritis, too low to be included in the risk factor evaluation.

TABLE 24.

Adjusted Odds Ratios for Cystitis or Pyelonephritis in Women With Type 1 Diabetes Participating in the Uro-EDIC Survey, 2002–2004

HIV

Diabetes and hypertension associated with human immunodeficiency virus (HIV) infection are described as risk factors for the development of HIV-associated immune complex kidney disease (726,727,728). While hypertension may be a consequence of HIV-related kidney disease, the association with diabetes appears to be mediated by postinfectious glomerulonephritis (726,729). A cross-sectional comparison of persons with type 2 diabetes with and without HIV and persons with HIV only is presented in Table 25 (730). Among the 73 persons with HIV and type 2 diabetes, the combination of diabetes, higher HIV viral load, and antiretroviral treatment with abacavir was a significant predictor of ACR ≥30 mg/g. Antiretroviral therapy has nephrotoxic effects, including tubulointerstitial nephropathies, proximal tubular dysfunction, Fanconi’s syndrome, and nephrogenic diabetes insipidus (731).

TABLE 25.

Demographic and Clinical Characteristics of Subjects With HIV, Diabetes, and Both HIV and Diabetes, 2007–2009

Conclusions

CKD is a public health problem that affects nearly 14% of the U.S. population and is disproportionately distributed among minority and disadvantaged groups. Most risk factors for CKD are modifiable; therefore, public health strategies targeting these factors may significantly reduce the disease burden.

Diabetes is the leading cause of CKD, and the increasing prevalence of diabetes together with improved availability of dialysis and transplants have sustained a continued rise in the proportion of CKD attributable to diabetes since the 1980s. In persons with type 1 diabetes, the incidence of CKD has declined in parallel with a significant trend for earlier initiation of antihypertensive treatment following the onset of diabetes, expansion of RAAS inhibitor usage, and sustained improvements in glycemic control. On the other hand, in persons with type 2 diabetes, the incidence of CKD does not appear to be declining, possibly due to the higher number and prevalence of CKD risk factors associated with type 2 diabetes that outweigh current treatment options or their effectiveness. An ever-increasing number of persons with diabetes, 91% of whom have type 2 diabetes, require renal replacement therapy, at enormous cost to patients, their families, and society.

Improved management of hyperglycemia, hypertension, hyperlipidemia, and albuminuria have dramatically slowed progression to kidney failure, as illustrated by a decreased incidence of kidney failure attributed to diabetes since 2005. Trends in the incidence of kidney failure due to diabetes, however, differ broadly by age and race and ethnicity. At the national level, the incidence of kidney failure in persons with a primary diagnosis of diabetes remains higher in Black, Mexican American, Asian, and American Indian persons than in White persons, with the highest rates being found in Black and American Indian persons.

List of Abbreviations

A1C

glycated hemoglobin

ACCORD

Action to Control Cardiovascular Risk in Diabetes

ACE

angiotensin-converting enzyme

ACR

albumin-to-creatinine ratio

ADA

American Diabetes Association

ADVANCE

Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation

AER

albumin excretion rate

ARB

angiotensin receptor blocker

BMI

body mass index

CI

confidence interval

CKD

chronic kidney disease

COVID-19

coronavirus disease of 2019

CVD

cardiovascular disease

DASH

Dietary Approaches to Stop Hypertension

DCCT

Diabetes Control and Complications Trial

DKD

diabetes-related kidney disease

DNA

deoxyribonucleic acid

EDC

Epidemiology of Diabetes Complications study

EDIC

Epidemiology of Diabetes Interventions and Complications study

EDTA

ethylenediaminetetraacetic acid

eGFR

estimated glomerular filtration rate

ERA

endothelin receptor antagonist

GFR

glomerular filtration rate

GLP-1

glucagon-like peptide-1

GLP-1 RA

glucagon-like peptide-1 receptor agonist

HDL

high-density lipoprotein

HIV

human immunodeficiency virus

HR

hazard ratio

IDNT

Irbesartan Diabetic Nephropathy Trial

KDIGO

Kidney Disease: Improving Global Outcomes

KEEP

Kidney Early Evaluation Program

LDL

low-density lipoprotein

MDRD

Modification of Diet in Renal Disease study

MR

mineralocorticoid receptor

MRA

mineralocorticoid receptor antagonist

NHANES

National Health and Nutrition Examination Survey

NKF

National Kidney Foundation

NSAID

nonsteroidal anti-inflammatory drug

OR

odds ratio

RAAS

renin-angiotensin-aldosterone system

RENAAL

Reduction of Endpoints in Non-insulin dependent diabetes with the Angiotensin II Antagonist Losartan

SGLT2

sodium-glucose cotransporter-2

SMR

standardized mortality ratio

TGF-β

transforming growth factor beta

TODAY

Treatment Options for Type 2 Diabetes in Adolescents and Youth trial

UKPDS

United Kingdom Prospective Diabetes Study

UroEDIC

ancillary study of urologic complications in the DCCT/EDIC cohort

USRDS

United States Renal Data System

VLDL

very low-density lipoprotein

Conversions

A1C: (% x 10.93) - 23.50 = mmol/mol

Albumin-to-creatinine ratio: mg/g x 0.113 = mg/mmol

Cholesterol: mg/dL x 0.0259 = mmol/L

Glucose: mg/dL x 0.0555 = mmol/L

Triglycerides: mg/dL x 0.0113 = mmol/L

Acknowledgment

This is an update of: Pavkov ME, Collins AJ, Coresh J, Nelson RG: Kidney Disease in Diabetes. Chapter 22 in Diabetes in America, 3rd ed. Cowie CC, Casagrande SS, Menke A, Cissell MA, Eberhardt MS, Meigs JB, Gregg EW, Knowler WC, Barrett-Connor E, Becker DJ, Brancati FL, Boyko EJ, Herman WH, Howard BV, Narayan KMV, Rewers M, Fradkin JE, Eds. Bethesda, MD, National Institutes of Health, NIH Pub No. 17-1468, 2018, p. 22.1–22.84.

Article History

Received in final form on June 6, 2024.

Disclaimer

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the National Institutes of Health nor the Centers for Disease Control and Prevention.

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Drs. Pavkov, Koyama, and Nelson reported no conflicts of interest. Dr. Bjornstad reported serving or having served as a consultant for AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, LG Chemistry, Sanofi, Novo Nordisk, and Horizon Pharma; he also serves or has served on the advisory boards and/or steering committees of AstraZeneca, Bayer, Boehringer Ingelheim, Novo Nordisk, and XORTX.