Diabetic Kidney Disease

Abstract

Diabetic kidney disease (DKD) continues to be a chronic and devastating complication of diabetes. Despite improvements in glycemic control and lower blood pressure targets, the incidence of DKD has not declined substantially. Standards of care for persons with diabetes include screening for kidney complications and close follow-up. Preventive measures continue to rely on glucose and blood pressure control. However, additional measures to slow the progression of kidney damage are under investigation.

Introduction

In the United States, DKD is the leading cause of kidney failure. In 2008, the Centers for Disease Control and Prevention reported that approximately 44 percent of all new cases of kidney failure requiring renal replacement therapy were caused by diabetes mellitus¹. The overall prevalence of micro- and macroalbuminuria is nearly 35 percent of persons with both types of diabetes¹. Among patients with type 2 diabetes (T2D), chronic kidney disease is the only complication for which the incidence has not decreased despite improvement in diabetes control over the past 20 years². Native Americans, Hispanics (especially Mexican-Americans), and African Americans have a higher risk of developing end stage renal disease than non-Hispanic whites with T2D. In addition to kidney failure, DKD is a strong independent risk factor for cardiovascular disease. The combination of diabetes and nephropathy increases cardiovascular disease risk by 20–40-fold, greatly increasing morbidity and mortality in patients with diabetes³. Thus, the presence of microalbuminuria is an indication for surveillance and management of cardiovascular risk factors.

Screening

The 2007 Kidney Disease Outcomes Quality Initiative (KDOQI) Clinical Practice Guidelines for Diabetes and chronic kidney disease (CKD) recommend that initial screening for DKD should start five years after the diagnosis of type 1 diabetes (T1D) and at diagnosis in persons with T2D. Follow-up testing should be done yearly thereafter. Screening should include measurement of urinary albumin-creatinine ratio (UACR) on a spot urine sample and a serum creatinine (sCr). Elevated UACR should be confirmed in the absence of infection with two additional first void specimens collected over the next three to six months⁴. Lack of retinopathy, lack of autonomic neuropathy, and presence of albuminuria at the time of the diagnosis of diabetes all suggest a non-diabetic etiology for persistent albuminuria⁵. Also, exercise, heart failure, fever, menstruation, marked hyperglycemia and hypertension may elevate UACR independent of kidney damage. Microalbuminuria is diagnosed when UACR is between 30 – 300mg/g, whereas higher levels are considered to be in the macroalbuminuric range. Some authors have recommended changing the nomenclature from microalbuminuria to moderately increased albuminuria and from macroalbuminuria to severely increased albuminuria, arguing that the term microalbuminuria could be interpreted as a finding of minimal clinical importance⁶. The American Diabetes Association (ADA) continues to use the traditional nomenclature, which is what we use for this article.

Measuring sCr is also essential in the diagnosis and follow-up of CKD in patients with diabetes. The sCr should be used to estimate the glomerular filtration rate (eGFR). Most laboratories report eGFR using the Modification of Diet in Renal Disease (MDRD) formula, which has excellent correlation with more invasive measures of GFR in patients with impaired kidney function manifesting as GFR <60 ml/min/1.73m²,⁷. Higher levels of eGFR are reported as >60 ml/min/1.73m2 without providing an actual eGFR value. The Chronic Kidney Disease Epidemiology Collaboration (CKD – EPI) formula, which was developed after the MDRD equation, provides greater accuracy for eGFR calculations >60 ml/min/1.73m², and is the preferred method for calculating eGFR in this range⁸. The National Kidney Foundation 2003 guidelines define CKD as either the presence of kidney damage or GFR less than 60 mL/min/1.73m² for three or more months. Kidney damage is defined as pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies⁹. The presence of albumin in the urine is a well-established marker of kidney damage.

Progression of DKD has historically been taught as a multi-stepwise process with the initial step being the appearance of urinary microalbuminuria, followed by progressive increase in proteinuria that is accompanied by declining kidney function. The result is end stage renal disease (ESRD) with or without antecedent CV disease. However, approximately 30% of patients with DKD do not have albuminuria¹⁰. Recent studies have shown that in T1D, reduced eGFR can be observed before albuminuria appears⁷. Women with T1D, reduced eGFR and normoalbuminuria who underwent kidney biopsies had more advanced glomerular lesions than normoalbuminuric women with normal eGFR¹¹. Also, advanced glomerulosclerosis has been reported in kidney biopsies from patients with T2D without albuminuria or proteinuria¹². This suggests eGFR, and in particular decline in eGFR, is an important component of both the diagnosis and follow-up of DKD with or without the presence of albuminuria (See Figure 1).¹³

Figure 1.

Categories of albuminuria and GFR in CKD, and their relationship to risk of progression to end-stage kidney disease. Reprinted with permission, Kidney International.¹³

There is clearly a need to identify biomarkers of DKD that would precede the appearance of albuminuria. Biomarkers currently under investigation include kidney injury molecule 1(KIM-1), serum cystatin C and neutrophil gelatinase-associated lipocalin (NGAL)^14,15. Cystatin C has been investigated as a more sensitive marker of GFR, but it has not been adopted for widespread clinical use¹⁵.

Pathogenesis of Diabetic Kidney Disease

The renin-angiotensin system (RAS) is the single most significant contributor to the pathogenesis of diabetic kidney disease^16,17. This is due to upregulation of local intrarenal RAS¹⁸ that ultimately results in increased sodium reabsorption¹⁹, preferential efferent arteriolar vasoconstriction and increased glomerular capillary pressure and permeability²⁰.

Hyperglycemia also plays a key pathogenic role. The effects of hyperglycemia are mediated through multiple pathways that result in oxidative stress²¹, as well as release of proinflammatory²² and profibrotic mediators²³. Elevated glucose and critical changes in intrarenal hemodynamics cause alterations in glomerular permeability, glomerular hyperfiltration, glomerular basement thickening, mesangial matrix synthesis and ultimately glomerulosclerosis and interstitial fibrosis²⁴. In addition, excess glucose combines with free amino acids on circulating or tissue proteins to generate advanced glycation end products (AGEs). These products may cause renal and microvascular complications through accumulation in tissues and crosslinking with collagen²⁵.

Another factor contributing to the pathogenesis of DKD may be endothelin-1. In rats with diabetes, the gene expression of endothelin-1 is increased in the kidney²⁶, which results in renal cellular proliferation, podocyte damage, matrix accumulation and fibrosis²⁷.

The predominant structural changes associated with diabetic kidney disease include mesangial expansion, glomerular basement membrane thickening and glomerular sclerosis²⁸. The progression of DKD depends on many factors, and histologic patterns may be important²⁹.

Management of DKD

The primary treatment goal is prevention of DKD, but once DKD is diagnosed, the goal is to slow or prevent progression to ESRD. The mainstays of treatment have traditionally included glycemic and blood pressure control, with dietary therapy as a less established intervention. Additional measures should include avoidance of renal toxins and management of CV risk factors. Without specific interventions, about 80% of T1D patients who develop sustained microalbuminuria will experience an increase in urinary albumin excretion at a rate of 10–20% per year to the stage of overt nephropathy or macroalbuminuria over a period of 10–15 years³⁰. Studies have shown that early decline of eGFR that exceeds 3 ml/min/1.73m² is predictive of progression to ESRD³¹. Early declines in eGFR will be missed if providers delay tracking until the eGFR is <60 ml/min/1.73m², thus the need to utilize the CKD-EPI formula for patients with stage 2 CKD. Higher levels of albuminuria and lower eGFR are risk factors for progression to ESRD, as shown in Figure 1.

Intensive glycemic control was compared to standard control in three large randomized controlled trials. Each found a reduction in progression to macroalbuminuria with intensive control. However, intensive control was associated with increased hypoglycemia. The renal endpoints of doubling of creatinine and progression to ESRD were too few to reach significance in early intervention studies^32–34. The KDOQI guidelines recommend a target hemoglobin A1c (HbA1c) of 7.0%, but with possible adjustment to higher A1c goals for patients with co-morbidities, limited life expectancy or risk of hypoglycemia⁴.

Hypertension in DKD is defined as a systolic blood pressure ≥ 130 mmHg or a diastolic blood pressure ≥ 80 mmHg. Hypertension in both T1D and T2D is caused mainly by volume expansion due to increased sodium reabsorption in the kidneys, low renin activity and peripheral vasoconstriction from dysregulation of factors that control peripheral vascular resistance³⁵. Observational studies have shown that eGFR declines at a rate >10 mL/min/1.73m²/yr in patients with DKD, poorly controlled hypertension and macroalbuminuria, but only 1–4 mL/min/1.73m²/yr in those with well controlled blood pressure⁴. Treatment with angiotension-converting enzyme inhibitors (ACEi) or angiotension receptor blockers (ARB) is more effective in reducing the progression of DKD than treatment with other antihypertensive medications³⁶. In addition, ACEi have been shown to reduce major CVD events in patients with DKD. Mann et al reported that in a large randomized trial of patients with diabetes, end-organ damage and atherosclerosis, ACEi and ARBs were equally effective in preventing progression of DKD. If sufficient blood pressure reduction is not achieved after 4–6 weeks of ACEi/ARB therapy, additional drug therapy is indicated³⁰. The combination of the ACEi and ARB however, did not provide additional benefit and led to higher sCr levels, more hyperkalemia and increased rates of dialysis³⁷. Currently, the American Diabetes Association (ADA) does not recommend the combined use of ACEi and ARBs³⁸. The KDOQI guidelines recommend against the use of ACEi or ARBs for the primary prevention of DKD in normotensive normoalbuminuria patients with diabetes. However, they should be used in patients with albuminuria >30mg/g even if they are normotensive⁴. ACEi should be discontinued if the creatinine level increases by 30 percent above baseline in the first two months of therapy or if hyperkalemia (greater than 5.6mEq/L) occurs. Combined treatment with a mineralocorticoid receptor blocker has also been shown to reduce albuminuria by 23 to 61% compared with standard treatment. However, an increase in hyperkalemia with combined treatment raised the dropout rate to 17%³⁹. Non-dihydropyridine calcium channel blockers have been found to reduce the level of albuminuria but no studies have demonstrated a reduction in rate of fall of GFR with their use⁴⁰. In patients unable to tolerate ACEi or ARBs or whose blood pressure is not at goal on maximum doses of ACEi or ARB, blood pressure goals can be pursued with diuretics, calcium channel blockers, beta blockers and mineralocorticoid receptor blockers.

A low protein diet is also commonly advised in patients with CKD. In the Modification of Diet in Renal Disease (MDRD) Study, the mean change in GFR over three years was not significantly affected with dietary protein restriction (0.58 g/kg/day, versus a usual-protein diet of 1.3 g/kg/day)⁴¹ in patients with baseline GFR 25 to 55 mL/min per 1.73 m². However, in secondary analyses, patients with advanced renal disease (baseline GFR, 13 to 24 mL/min per 1.73 m²) a lowprotein diet (<0.6 g/kg/day) slowed the GFR decline and reduced proteinuria⁴¹. The ADA recommends that dietary protein intake should be limited to 0.8g/kg per day in patients with rapidly progressive DKD³⁸. A very-low-protein diet (<0.3g/kg/day) has been associated with increased mortality over the long term⁴². Higher levels of protein intake have been associated with worsening albuminuria, more rapid decline in GFR and CVD mortality^43,44. High protein foods and dark sodas contribute to excessive phosphate and organic acid intakes that may be reflected in higher phosphate and lower bicarbonate levels in patients with advanced CKD⁴⁵.

Due to a higher risk of CVD in patients with DKD, statin therapy should be initiated in those with hyperlipidemia including patients with a kidney transplant. In addition to lowering cardiovascular risk, atorvastatin has been found to significantly reduce serum levels of AGEs in type 2 diabetic patients in a cholesterol lowering independent manner⁴⁶. KDOQI guidelines do not recommend a statin in patients with ESRD on dialysis⁴.

Patients with T2D and eGFR <60 ml/min/1.73m² may require adjustment of their anti-diabetes therapy. Metformin use can be associated with lactic acidosis, but the FDA has recently modified its recommendations to indicate that metformin may be safely used in patients with mild to moderate renal impairment. However, metformin should not be used in patients with an eGFR ≤30 ml/min/1.73m², and should not be started in patients with an eGFR between 30–45 ml/min/1.73m². Exenatide-based GLP receptor agonists should be discontinued when the sCr is ≥2 mg/dL. The same approach should be followed for alpha-glucosidase inhibitors. All of the dipeptidyl peptidase inhibitors (DPP4i) require dose adjustments at various eGFR cut-offs with the exception of linagliptin, which can be used in patients with any level of kidney dysfunction without dose adjustment. The GLP receptor agonists liraglutide, dulaglutide and albiglutide are not renally excreted, and may be used in patients with impaired kidney function, but side effects of nausea and vomiting may be limiting. The sodium-glucose co-transport inhibitors require dose adjustments at eGFRs of either 60 ml/min/1.73m² or 45 ml/min/1.73m² due to reduced efficacy and increased side effects. Sulfonylureas should be used with caution, especially glyburide, due to renal excretion that may cause higher drug levels in patients with stage 3 and more advanced CKD. Shorter acting sulfonylureas are preferred in these patients to limit the risk of hypoglycemia. While insulin is absolutely required in patients with T1D regardless of kidney function, it is often necessary in patients with T2D. Renal disease in both forms of diabetes increases risk of hypoglycemia due to reduced gluconeogenesis and reduced breakdown of insulin. More intense glucose monitoring and insulin dose adjustments may be needed as kidney function declines.

When should referral to a nephrologist be considered? Patients with atypical features, such as macroproteinuria in the absence of retinopathy may have another etiology for their kidney disease. Other reasons to refer include very heavy proteinuria, an active urine sediment and a rapid decline in GFR. Patients with eGFR <60 ml/min/1.73m2 are at risk for complications of CKD such as renal osteodystrophy, anemia, hyperkalemia, hyperuricemia and rarely systemic acidosis. Nephrology referral may be needed to manage difficult to control hypertension, hyperkalemia or the secondary manifestations of CKD. Patients with DKD should also be referred once they are in stage 4 CKD to improve quality of care and perhaps delay dialysis⁴⁸.

Conclusions

DKD remains a common and devastating complication of both T1D and T2D. Albuminuria at any level is an independent predictor of cardiovascular^33,49 and renal risk⁴⁹ in patients with diabetes. Health care providers should both screen and follow patients with annual measurements of both UACR and sCr. Optimal glucose control and blood pressure management with ACEi or ARB are the mainstays of treatment. CV risk reduction with statins is appropriate in patients with stage 2 and 3 CKD. Treatment of complications of CKD may help to slow progression and improve quality of life. Additional interventions are under investigation, but thus far no specific strategies have been shown to improve outcomes in patients with DKD.

Biography

Victoria E. Bouhairie, MD, (left), is a Clinical Fellow and Janet B. McGill, MD, (right), is a Professor, Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis.

Contact: jmcgill@dom.wustl.edu