Diabetic Microvascular Disease: An Endocrine Society Scientific Statement

Eugene J. Barrett; Zhenqi Liu; Mogher Khamaisi; George L. King; Ronald Klein; Barbara E. K. Klein; Timothy M. Hughes; Suzanne Craft; Barry I. Freedman; Donald W. Bowden; Aaron I. Vinik; Carolina M. Casellini

Disclosures

J Clin Endocrinol Metab. 2017;102(12):4343-4410. 

In This Article

Microvascular Disease in the Kidney

Introduction

Microvascular renal disease is part of the classical triopathy of diabetes complications. It is a major contributor to the development of ESKD in the developed world. In addition to the morbidity/mortality provoked by DN per se, it associates strongly with CVD progression and mortality. In this study, we review the epidemiology of DN, its pathogenesis, and evolving information on genetic factors that either enhance or diminish the risk for development or progression of DN in diabetic patients. We also briefly highlight aspects of current treatment.

Epidemiology

Determining precise incidence and prevalence rates for KD in subjects with diabetes depends on the definition applied. Excessive albuminuria and/or reduced estimated GFRs (eGFRs) in subjects with diabetes are associated with diabetic KD (DKD), but also to nondiabetic KD, particularly in those with T2DM who have atypical clinical courses (short disease duration, severe hypertension, rapidly changing kidney function, or absence of DR). Between 2005 and 2010, National Health and Nutrition Examination Survey data revealed high rates of nephropathy among subjects with diabetes—19.3% had an eGFR <60 mL/min/1.73 m2 (using the Chronic Kidney Disease Epidemiology Collaboration formula), 29.9% an elevated urine albumin: creatinine ratio ≥30 mg/g, and 8.6% had both albuminuria and low eGFR.[525] Based on these definitions, similar high rates of KD are present in patients with undiagnosed diabetes,[526] and 17.7% of patients with prediabetes have KD.[527] The incidence rate of CKD was significantly higher among those with metabolic syndrome (but lacking diabetes) in the Atherosclerosis Risk In Communities study, relative to those without metabolic syndrome.[528] These studies demonstrate that hyperglycemia can lead to reduced kidney function and albuminuria prior to the onset of frank diabetes.

The incidence rate of diabetes-attributed nephropathy in the US diabetes population has been stable for the past 2 decades.[526,529] This is concerning because it occurred despite marked reductions in HbA1c and systemic BPs, a >10-fold increase in prescription of statins (with a mean 32 mg/dL reduction in LDL cholesterol), and a nearly fourfold increase in use of renin-angiotensin aldosterone system (RAAS) inhibitors during this period. Thus, these stable rates of diabetic patients developing DKD will continue to translate into increasing patient numbers with nephropathy due to rising rates of diabetes and obesity. The prevalence of DKD in the US population was estimated at 2.2% between 1988 and 1994 (95% CI: 1.8%to 2.6%), with significant increases to 2.8% (95% CI: 2.4% to 3.4%) between 1999 and 2004, and 3.3% (95% CI: 2.8% to 3.7%) between 2005 and 2008 (P < 0.001 for trend).[525] Much of the excess morbidity and mortality in subjects with diabetes appear to relate to the presence of KD.[530,531]

The annual incidence rate of ESKD cases attributed to DKD has also been relatively stable at 152 per million population between 2000 and 2010, although dramatic differences occur based on age and ethnicity.[525] The gender-adjusted incident rate for diabetes-attributed ESKD in European Americans aged 30 to 39 years fell by1%from 2000 to 2010 (to 35.4 cases/million in 2010). In contrast, African Americans, Native Americans, and Asian Americans in this age range saw their incidence rates increase by 69%, 30.1%, and 100% (133.8, 116, and 32.6 million) during this period, respectively. The rate of incident ESKD attributed to diabetes fell by 3.6% between 2000 and 2010 in European Americans 60 to 69 years old, whereas it rose by 29% in those >70 years. Between 2000 and 2010, the incidence rate of diabetes-attributed ESKD in African Americans, Native Americans, and Hispanic Americans aged 60 to 69 fell by 17.2%, 40.4%, and 15.7%, respectively.

Clinical Presentation

Our understanding of the natural history of DKD has evolved. Although best evaluated in T1DM with a clear date of disease onset, the histologic and clinical courses of DKD appear similar in T1DM and T2DM. In subjects with hyperglycemia, we do not uniformly see the assumed progression from preglomerular afferent arteriolar vasodilation to high renal blood flows, elevated intraglomerular pressures, and intermittent then fixed microalbuminuria with subsequent macroalbuminuria and declining GFR. Approximately 10% of subjects with T1DM will manifest steadily declining eGFR in the absence of heavy proteinuria.[129] Albuminuria and loss of kidney function (declining eGFR) are independent processes with different genetic bases.[532]

Current levels of albuminuria divide into three categories: normoalbuminuria (urine albumin:creatinine ratio <30 mg/g), often further divided to highnormal >15 mg/g, which extends into the previously normal range; microalbuminuria (30 to 300 mg/g); and macroalbuminuria (>300 mg/g), also known as overt proteinuria.

Higher risk for CVD events is associated with higher levels of albuminuria.[533,534] UKPDS[195] participants with T2DM and microalbuminuria had equivalent rates of progressing to macroalbuminuria and death.[195] In those with macroalbuminuria, the risk of death far exceeded the risk for developing progressive loss of eGFR or initiating renal replacement therapy. The urine albumin:creatinine ratio can vary by up to 40% on repeat testing, and T1DMpatients with effective glycemic, lipid, and BP control frequently experience microalbuminuria remission.[529,531] Therefore, an abnormal urine albumin:creatinine ratio may not be reflective of a risk for progression in DKD.

During prolonged follow-up of T1DM subjects with an initially normal eGFR (>60 mL/min), ~two-thirds of patients with microalbuminuria and one-third with overt proteinuria demonstrated stable renal function with low risk for subsequent progression to ESKD.[535,536] In contrast, one-third of those with microalbuminuria and two-thirds with overt proteinuria had declining kidney function and were at high risk for subsequent ESKD. The rates of decline were variable between patients, but remained relatively consistent in each individual. Early eGFR slope appears predictive of a future rate of progression in DKD.[536] In addition, researchers evaluated the relatively frequent failure of ACE inhibitors (ACEi) to halt progression of early T1DM KD. Although precise mechanisms are unclear, poor glycemic control and hypercholesterolemia are most likely involved.[535]

These data suggest independence between the development and progression of pathologic changes in the glomerular and interstitial renal compartments in DKD. The glomerulus appears primarily responsible for proteinuria. However, interstitial changes better predict subsequent declines in kidney function, as in other forms of nephropathy. In a study of RAAS-blocking agents in the primary prevention of DKD, glomerular mesangial fractional volumes (and other glomerular parameters) were not appreciably different in normoalbuminuric T1DM patients after 5 years of treatment with an ACEi, ARB, or placebo.[100] Additionally, interstitial changes were not different between these treatment groups, suggesting that RAAS blockers are not suitable for the primary prevention of DKD, despite lowering systemic BPs.

Although many patients with progressive DKD and falling eGFR have proteinuria, urine albumin:creatinine ratios better predict CVD events and CVD mortality, relative to the progression of KD.[195] Damage to the systemic vasculature, including in the glomerulus, relates to endothelial dysfunction from hyperglycemia and most likely contributes to albumin leakage into the urine. This may not reflect diabetic glomerular changes, but contributes to the high rates of CVD and death. Once on renal replacement therapy, death rates from CVD remain high in subjects with DKD. Adjusted 5-year survival on dialysis was 32% in subjects with DKD through December 2010.[525]

Non-DN is frequently present and often misdiagnosed as DKD in proteinuric patients with T2DM and brief diabetes durations who have severe hypertension or rapid loss of eGFR. Several studies report 50% or more of proteinuric patients with T2DM undergoing renal biopsy had nondiabetic CKD.[423,537,538] Immunoglobulin A nephropathy frequently coexists with DKD in Asian and American Indian populations, as well.[539] These factors contribute to errors in calculating the true incidence and prevalence of DKD and hamper treatment trials in DKD by including cases with non-DKD. This is further supported by the identification of two coding nephropathy risk variants in the apolipoprotein L1 (APOL1) gene that contribute to African-ancestry populations having the majority of nondiabetic CKD cases.

APOL1 is strongly associated with a spectrum of proteinuric KDs related to focal segmental glomerulosclerosis, including HIV-associated nephropathy and focal global glomerulosclerosis, which was erroneously attributed to hypertension in African Americans.[540–547] The APOL1 family of nondiabetic KDs accounts for up to 40% of ESKD in African Americans. T2DM and focal segmental glomerulosclerosis are common in African ancestry populations and frequently coexist. It is difficult to accurately determine the cause of nephropathy in those with proteinuria and T2DM without a kidney biopsy, a procedure not commonly performed in patients with longstanding diabetes. APOL1 genotyping may provide a noninvasive tool for identifying CKD that is unrelated to diabetes in individuals of African ancestry.[548] As discussed later, partitioning for APOL1 in African Americans with clinically diagnosed DKD replicated the FERMdomain-containing 3 (FRMD3) gene association with DKD, an effect not possible prior to accounting for APOL1.[548–550]

A Genetic Component to Diabetic KD Risk

In addition to lifestyle and environment, genetic heritage is widely accepted as a contributor to the complex phenotype of DKD. An improved understanding of the genetic contributors to DKD has the potential to play a significant role in early prediction, prevention, and efforts to halt disease progression. For example, if genetic predictions using a combination of genetic variants that are proven to predict higher DKD risk (i.e., a genetic risk score) could identify patients at high risk for DKD, these individuals could undergo active surveillance (with early initiation of antihypertensive, blood sugar, and lipidlowering treatment) when diabetes is initially diagnosed. The potential of this form of personalized medicine for patients with diabetes has not yet been translated into practice. There is little doubt that genetic variations contribute to DKD risk, supported by a wide range of studies in both T1DM and T2DM in multiple ethnicities. As outlined previously, ethnic disparities in DKD prevalence suggest that the different natural histories of human populations have resulted in genetic architectures that confer different DKD risks. Familial clustering and aggregation of DKD have been documented for discrete definitions of DKD (i.e., ESKD in T1DM-affected European Americans and Europeans)[551–553] and in diverse T2DM populations, such as African Americans,[554,555] European Americans,[554] Canadians,[556] Native Americans,[557] Europeans,[558] East Asians,[559] Brazilians,[560] and South Asians.[561] In addition, familial aggregation in the form of heritability of quantitative measures of renal function (e.g., urinary protein excretion and eGFR) has been widely reported,[562–564] and segregation analyses in European American[565] and Pima[566] diabetes families suggest that genetics significantly influence variations in urinary protein excretion.

The search for diabetic KD susceptibility genes. The broad acceptance that DKD has a significant genetic component has motivated increasingly sophisticated efforts to identify specific genetic polymorphisms associated with DKD. A widely used approach is the comparison of allele frequencies between DKD cases and non-DKD controls, with KD defined as a dichotomous trait (either affected or unaffected). The simplest approach has been candidate gene analysis, which entails the assessment of genetic variations in one or more genes with plausible physiological links to DKD. Candidate gene studies continue to be reported in large numbers and in diverse ethnicities. These studies are frequently based on small numbers of cases and controls and often on small numbers of genetic polymorphisms. Thus, they have limited power and do not comprehensively test the gene in question. Such studies, however, can contribute to larger, better-powered meta-analysis efforts. Metaanalyses, although better powered, also have limitations, such as focusing on a limited number of genetic variants and including diverse study samples that were not collected in a uniform fashion.

Two large meta-analyses have evaluated the angiotensin 1–convertingACEinsertion–deletion polymorphism in diverse samples of T1DM and T2DM cases and control subjects.[567,568] These studies concluded that the ACE D allele was associated with DN risk with ORs in the range of 1.1 to 1.3, an effect similar to many common variant associations with complex diseases. Mooyaart et al.[569] combined bioinformatic and meta-analysis methods to evaluate evidence for genetic associations with DKD. They reported that of 671 genetic association studies investigating DKD, researchers identified 34 replicated genetic variants; 21 of these remained significantly associated with DKD in a random–effects meta-analysis. Genetic variants in the PKCβ1 gene (PRKCB1) were associated with T2DM KD in a carefully performed candidate gene study from Hong Kong, with replication.[32] However, results of these studies have not yet been translated into practice. This may prove difficult, given the variations between the many studies of T1DM KD and T2DM KD and variations in sample sizes and ethnic origins. For example, many genes associated with DKD failed to replicate when tested in European-derived samples with T1DM KD.[570]

Early studies using classical family-based linkage analysis showed great promise. Vardarli et al.[571] performed a genome linkage scan in Turkish kindreds with multiple DKD-affected individuals. They observed a major linkage peak on chromosome 18 [logarithm of odds score 6.6 (i.e., odds of 106.6:1) for linkage], revealing evidence for a novel DKD gene. Analysis of this locus in the Pima Indian population provided some evidence of confirmation.[572] The carnosinase 1 gene (CNDP1) was ultimately implicated as the likely cause of DKD on 18q.[573]CNDP1 is expressed in the brain and kidney, and carnosine is a scavenger of oxygen-free radicals and may inhibit the formation of advanced glycosylation end products. A polymorphic trinucleotide repeat in exon 2 of CNDP1 coding for a leucine repeat in the leader peptide of the carnosinase-1 precursor was associated with DKD. There are additional studies in both T1DM and T2DM from multiple ethnic groups that include several study designs (family based and case control). The CNDP1 association was replicated in European Americans with T2DM KD,[574] but an analysis of European Americans only nominally associated CNDP1 with T1DM KD.[575] Studies have extended the evaluation of CNDP1 to test other genetic variations in the region, including the neighboring CNDP2 gene. McDonough et al.[576] performed a detailed resequencing and analysis of variants in the CNDP1 and CNDP2 genes in European Americans and African Americans. DKD protection was not observed in African Americans, suggesting that the protection afforded by the CNDP1 was masked by additional CNDP1 and CNDP2 risk haplotypes, defined by specific combinations of single-nucleotide polymorphisms (SNPs). Analysis of this locus continues to be of interest.[577,578]

There are a number of other family-based linkage studies that include, in some cases, complementary association analyses.[579,580] The Family Investigation of Nephropathy and Diabetes study[581] included 11 US clinical centers and nearly 10,000 European Americans, African Americans, Mexican Americans, and American Indians with T2DM KD. Initial analyses targeted the relationship of both quantitative albuminuria and GFR with DKD.[582–584] In spite of these efforts, the significance and impact of family-based linkage studies remain unclear to human geneticists, with only a few examples of linkage studies leading to the identification of genes underlying complex traits such as DKD. Even in successful cases, such as CNDP1, the overall clinical implications remain uncertain.

Smaller and less comprehensive efforts are now transitioning to larger, better-powered studies with more comprehensive genetic analyses in DKD, including genome-wide association studies (GWAS). In many cases, this new generation of studies has multiple collaborating research groups. For example, McKnight et al.[585] initiated a new level of rigor in study design in their analysis of the Warren 3/UK Genetics of Kidneys in Diabetes Study Group cohort of T1DM patients, with replication testing and meta-analysis of samples from the Finnish Diabetic Nephropathy study. In total, McKnight et al. evaluated >3400 samples with moderate evidence for association (allelic P value 0.006, OR 1.27).

Initial GWAS in Japanese and Pima Indians suggested an association between T2DM KD susceptibility and the engulfment and cell motility 1 gene and the plasmacytoma variant translocation gene, respectively.[586,587]

Recent extensions of the earlier GWAS work reported results for two genes, acetyl-coenzyme A carboxylase β (ACACB) and FRMD3. A report by Maeda et al.[588] identified SNPs in the ACACB gene associated with proteinuria in T2DM, and these explorations have been extended to multiple ethnic populations, with an associated SNP being consistently more frequent in DKD cases compared with controls.[589] Additional in vitro functional analysis further supports a role for ACACB,[588] and Murea et al.[590] have proposed that genes involved in lipid metabolism, such as ACACB, could influence DKD. Similarly, Pezzolesi et al.[549] performed a GWAS for T1DMKD in a Genetics of Kidneys in Diabetes sample and carried out a replication analysis in DCCT and EDIC participants. Noteworthy was the identification of association between DKD and the FRMD3 gene. Importantly, follow-up analyses in multiple populations, including both T1DM and T2DM KD cases, have also reported evidence for the association of FRMD3 with DKD.[548,591] A recent mechanistic study proposed a pathway by which FRMD3 variants could influence the risk of DKD based on transcriptional regulation of bone morphogenetic protein pathway genes.[592]

A new generation of better-powered GWAS with increasingly larger sample sizes is now appearing. One of these is an African American T2DM-ESKD study encompassing >5800 African Americans,[550] and another is an analysis of high-density GWAS data from the Family Investigation of Nephropathy and Diabetes consortium withmultiethnic samples. Although McDonough et al.[550] detected no genome-wide significant associations with T2DM-ESKD (P ≤5 × 10−8, multiple variants in RNF185, LIMK2, SFI1, APOL3, and MYH9 demonstrated strong evidence of association with allcause ESKD, including advanced KD attributed to diabetes and nondiabetic etiologies. Strikingly, the majority of these associations were based on the contribution of protection from nephropathy, rather than risk. Sandholm et al.[593] recently performed an analysis of T1DM KD in subjects from both the Genetics of Nephropathy: an International Effort cohort (including subjects from the United Kingdom-Republic of Ireland, Finnish Diabetic Nephropathy study) and the Genetics of Kidneys in Diabetes cohort (including >6500 European DNA samples). The analysis revealed several variants with strong evidence of association with T1DM KD in the AFF3 (AF4/FMR2 family, member 3) gene (P = 1.26 × 10−8, OR = 1.26) and an intergenic SNP on chromosome 15q26 (P = 2.0 × 10−9, OR = 1.80). An important addition to this study was functional data suggesting that AFF3 is involved in renal tubule fibrosis through the TGF-β1 pathway. The strongest genetic association with DKD was in the Genetics of Nephropathy: an International Effort study observed using T1DM-ESKD as the phenotype. With these encouraging new results from GWAS studies, optimism should be guarded; replication in other large studies remains necessary.

Genetics of diabetic KD now and in the future. The search for genes associated with common and complex diseases has been driven by technical developments such as the GWAS method. Even with continuing innovations, researchers have made limited progress in both T1DM KD and T2DM KD in all ethnic groups. Given that DKD is a common disorder with high public health impact, it is surprising that the sample sizes for contemporary studies of DKD are small and powered only to detect major genetic effects. In the future, researchers and funding agencies should consider expanding available study populations to enhance the power for gene detection.

Several research questions remain. Despite shared chronic hyperglycemia, it is uncertain whether shared genetic contributors in DKD exist for T1DM and T2DM. Although there are several studies of DKD in T1DM and T2DM that have identified genes (such as CNDP1, ACACB, FRMD3, and ELMO1) that are shared across populations,[586,594–596] the results are not compelling. It is also unclear whether DKD genes will translate their impact across ethnic differences within human populations. It is striking that mutations in the APOL1 gene are powerfully associated (OR 7.3 to 29)[540,547] with non-DKDforms of severe nephropathy in African Americans, and yet, these APOL1 risk variants are virtually absent in European-derived populations.[540,597] The discovery of APOL1 is also in striking contrast to the apparent heterogeneous genetic architecture of DKD. Although we do not have a complete picture of DKD, there is clearly no genetic contributor to DKD remotely as powerful as APOL1 is in non-DKD. In sum, the goal of creating genetic risk scores (i.e., combinations of genetic variants that will aid in the prediction of DKD risk) remains a work in progress.

This does not mean that creating genetic tools for DKD that have clinical value will be beyond reach. As outlined previously, the cornerstone of genetic research to date has been the GWAS method, which is limited to common variations and frequently captures information primarily from noncoding variants in the genome. New technical innovations have facilitated the creation of large and growing databases of coding variants (both low frequency and rare) through next-generation sequencing of complete sets of exons from individual DNAs (exome sequencing). Researchers are actively making use of these resources to test for the impact of low-frequency coding variants on DKD, and efforts are underway to perform exome sequencing in DNAs from DKD-affected individuals. For example, the T2DM-Genes Consortium sponsored exome sequencing for >1000 of the DKD cases and controls from the African American T2DMESKD GWAS.[550] Equally, epigenetic mechanisms (such as posttranslational methylation or demethylation and histone acetylation to alter the expression of genes) represent an attractive potential mechanism by which the hyperglycemic environment could mediate renal failure.[83] Initial reports on epigenetic studies are now appearing.[598] These many paths of investigation will undoubtedly reveal new insights into the genetic contributors to DKD in the near future.

Current Treatment

Therapies to prevent or slow the development of DKD are multifactorial and include lowering blood sugar levels with medications, diet, and exercise, as well as treating hypertension and hyperlipidemia. As previously discussed, an early decline in the eGFR slope best correlated with subsequent risk of ESKD.[535,536] Maintaining eGFR remains the primary focus for preventing advanced DKD and slowing the progression to ESKD. Intensive glycemic control in patients with T1DM and T2DM prevents or delays the development of microvascular complications and reduces the rate of development of overt proteinuria. However, limited data exist on whether improving glycemic control prevents low eGFR and diabetic ESKD. Reducing albuminuria through improved glycemic control and other treatments is expected to lower CVD event rates but requires evaluation regarding how it affects the rate of eGFR loss. It is expected that reducing early-stage DKD, particularly overt proteinuria, will translate into fewer cases of diabetic ESKD in the future.[599]

Improving glycemic control remains the mainstay of preventing and delaying DKD and other microvascular complications, as has been shown in longitudinal studies of T1DM and T2DM. The DCCT and subsequent EDIC trial[600] demonstrated that intensive glucose control in T1DM delayed the development and progression of microalbuminuria.[601,602] The UKPDS reached similar conclusions in patients with T2DM, reporting that improved glycemic control (metabolic memory) produced prolonged delays or reductions in microvascular complications, which are potentially linked to epigenetic factors.[197,603] The more recent ADVANCE, ACCORD, and Veterans Affairs Diabetes trials extended this finding, all demonstrating significant reductions in microalbuminuria and overt proteinuria with intensive glycemic control.[196,199,604] Improving blood sugar control in subjects with the more advanced stages of DKD will most likely reduce the rate of eGFR loss, as has been shown in UKPDS and DCCT/EDIC.[197,600] However, this may be less effective in halting the progression to ESKD once critical reductions in nephron mass develop. Based on these studies, and considering risks of hypoglycemia, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative Guidelines recommend a target HbA1c of ~7% (and not treating to <7%) to prevent or delay progression of diabetic microvascular complications, including DKD. A target HbA1c >7% is recommended in those with comorbidities or limited life expectancy and at risk for hypoglycemia.[599]

It is important to appreciate that kidney function can impact the metabolism and safety of several blood sugar–lowering medications. National Kidney Foundation Kidney Disease Outcomes Quality Initiative Guidelines suggest avoiding first-generation sulfonylureas when eGFR is <60 mL/min/1.73 m2. Instead, the guidelines prefer second-generation glipizide to reduce the risk of prolonged hypoglycemia.[599] Caution is urged when initiating meglitinides when eGFR is <30 mL/min/1.73 m2. US Food and Drug Administration guidelines recommend patients avoid metformin when eGFR is <30 mL/min/1.73 m2 and avoid starting metformin when eGFR is <45 mL/min/1.73 m2. Clinicians should closely follow people on metformin whose GFR is between 30 and 45 mL/min/1.73 m2 and assess them for risk factors for adverse effects ofmetformin. Japanese and British guidelines also suggest withdrawal when eGFR is <30 mL/min/1.73 m2. Data suggest additional dose adjustments (or avoidance) of diabetes medications in patients with advanced nephropathy for α-glucosidase inhibitors, DPP4 inhibitors, SGLT-2 inhibitors, incretin mimetics, and IAPP analogs.[599]

Lowering systemic BPs with antihypertensive medications and dietary modification slows the development and progression of DKD, although patients most likely need to maintain lower BPs to sustain this benefit.[603,605] The Joint National Commission 7 recommends RAAS-blocking agents. However, these agents appear to be most effective at slowing DKD in patients with high levels of proteinuria.[606] Although RAAS blockers often slow DKD progression, they do not reliably halt the progression to ESKD. Cessation of RAAS blockers may eventually become necessary in patients with stage-4 and stage-5 CKD because of the excessive lowering of eGFR due to reversible hemodynamic effects and hyperkalemia. Studies attempting greater RAAS blockade by combining two agents (ACEi and ARBs) carry greater risks for adverse events and hyperkalemia and should be avoided.[607,608]

It was disappointing that RAAS blockers proved to be ineffective for the primary prevention of the earliest renal histologic lesions of DKD.[100] In a longitudinal kidney biopsy trial, patients receiving an ARB ultimately had higher levels of albuminuria than those on placebo (however, both ACEi and ARBs reduced DR, relative to placebo). Although RAAS blockers are first-line therapies for hypertension in subjects with diabetes, they are not likely to markedly reduce the subsequent development of DKD. National Kidney Foundation Kidney Disease Outcomes Quality Initiative Guidelines do not recommend the routine use of RAAS-blocking agents in normotensive normoalbuminuric subjects with diabetes, although ACEi and ARBs are recommended in normotensive diabetic patients with a urine albumin:creatinine ratio >30 mg/g who are believed to be at risk for future DKD.[599]

Anecdotal evidence suggests that statin therapy for hyperlipidemia may slow nephropathy progression in DKD. However, RCTs with statistically significant results are lacking.[609] Statins often reduce CVD rates in patients with and at risk for DKD. However, trials using statins to lower LDL cholesterol have not demonstrated reduced mortality in patients with diabetes and ESKD on hemodialysis.[610,611] Difficulties controlling blood sugars and the fact that RAAS inhibition was ineffective at primary prevention led to studies testing novel medications for DKD, including inhibitors of advanced glycation end-product formation and agents to reduce oxidative stress and inflammation. To date, these agents have not proven safe and effective for renal protection.[142,612]

Because glycemic control remains the mainstay for preventing DKD and slowing progression, it is critical to appreciate the effect that advanced stages of DKD have on the accuracy of tests used to assess glycemic control, especially the HbA1c. Because hemoglobin resides in red blood cells, HbA1c assesses glycemic control over the preceding 120 days (the life span of a normal red blood cell). In the late stages of DKD and ESKD, red blood cell survival drops, and clinicians often prescribe medications to treat anemia (erythropoietin). For given degrees of glycemic control, HbA1c levels are markedly reduced in patients with eGFR <30 mL/min/1.73 m2 or those on peritoneal dialysis or hemodialysis, relative to subjects with normal kidney function.[613,614] Inaccurately low HbA1c values provide a false sense of security to clinicians and patients.[615] Interpretation of HbA1c in patients with ESKD requires complex statistical adjustment to better reflect ambient blood sugars. Markedly high and low adjusted HbA1c values predict poorer outcomes on dialysis.[616,617] Frequent serum glucose monitoring or novel assays (glycated albumin and continuous glucose monitoring) may more accurately reflect glycemia in patients with advanced DKD.

Summary

Renal microvascular dysfunction, which is common in individuals with diabetes, is characterized by strong but incompletely understood genetic predisposition. Its development and progression are clearly affected by clinical variables, including control of blood glucose and BP. The success in controlling these variables achieved in the past several decades along with other progress with risk factor management are gratifying in that they have lessened progression to ESKD. However, the increased prevalence of diabetes significantly offsets this progress. Consequently, diabetes remains a major contributor to renal failure and the associated increased mortality from CVD seen with ESRD. Developing a more complete understanding of the genetic/molecular factors contributing to initiation and progression of microvascular disease will hopefully lead to even more successful preventive strategies.

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