Diabetic Kidney Disease

Kidney disease remains a leading cause of mortality in patients with diabetes

Diabetes is pandemic. Globally, diabetes affects up to half a billion people. In the US, one in 10 people have diabetes. Moreover, for Americans born in the year 2000, the lifetime risk of diabetes is a staggering 25% to 45%.

Diabetes care has significantly improved over the past few decades. Patient education, support, provider role changes, and telemedicine are consistently shown to improve glycemic indices. In response to the diabetes epidemic, the rate of diabetes drug approvals has accelerated. Since January 2013, nine new diabetes products have been approved, including a new inhaled insulin (Afrezza); a new DPP4 inhibitor, alogliptin (Nesina, Kazano, and Oseni); new inhibitors of the sodium glucose transporter 2 (SGLT2) transporter canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance); and a glucagon-like peptide 1 (GLP-1) receptor agonist, albiglutide (Tanzeum).

Despite improvements in diabetes care, the American Diabetes Association estimates that a person diagnosed with diabetes mellitus at age 50 years old dies 6 years earlier than a person without diabetes. Kidney disease shows the strongest correlation with mortality. During the past 20 years, kidney disease incidence only declined by 28% compared with a dramatic more than 70% decline in cardiovascular mortality. Better understanding of diabetic kidney disease (DKD) (1) will likely be essential to decrease not only the number of ESRD patients but also diabetes-associated mortality (2).

We need clarity in diagnosis and better prognostic markers for DKD

The gold standard diagnosis of DKD still relies on comprehensive histopathologic analysis of kidney biopsy samples. Recently, the American Renal Pathology Society (RPS) recommended a histopathologic-based staging (RPS classification) of DKD. The diagnosis is on the basis of the presence of glomerular basement membrane thickening (>395 nm in women and >430 nm in men). Greater than 25% expansion of the mesangial space is the most commonly used criterion to define class II disease according to this RPS classification. Nodular sclerosis is a highly specific but not very sensitive criterion to represent class III lesions. Finally, global sclerosis or class IV is mostly seen in patients with advanced disease (3).

Although biopsy remains the gold standard and the only specific criterion for diagnosis, in practice, DKD remains a clinical diagnosis. Most practitioners use the Kidney Disease Outcomes Quality Initiative guidelines: “In most people with diabetes, CKD should be attributable to DKD in the presence of: 1) macroalbuminuria (i.e., albumin to creatinine ratio [ACR] > 300) or microalbuminuria plus retinopathy, and 2) in people with type 1 diabetes, in the presence of microalbuminuria plus duration of diabetes longer than 10 years” (4). This recommendation is on the basis of old observational studies of patients with type 1 diabetes, in whom microalbuminuria preceded macroalbuminuria followed by functional decline, chronic kidney disease (CKD), and ESRD development. Although patients with type 2 diabetes show much greater heterogeneity in their clinical manifestation, the same paradigm has been used to describe their disease manifestation.

Reports originating from the 1990s began to indicate that the clinical manifestation of DKD is more complex. Large numbers of patients with type 2 diabetes and microalbuminuria, even those with biopsy-proven DKD, actually revert to normoalbuminuria. Moreover, this observation has been made independent of renin-angiotensin-aldosterone system (RAAS) blockade (5). As a consequence, it is being increasingly recognized that albuminuria and GFR decline might be complementary manifestations of DKD. Although some subjects manifest with albuminuria, often followed by GFR decline, other patients with diabetes only manifest with low GFR. This has led several investigators to advocate screening for both GFR and albuminuria to diagnose DKD.

There are significant regional differences in clinical practice patterns with regard to kidney biopsy for patients with diabetes. Studies from the Columbia Pathology Group indicate that urine sediment and serologies are actually poor predictors of histologic manifestations of DKD on biopsy (6). I believe that, until we develop better clarity of the clinical manifestations and markers of DKD, it is probably best to increase reliance on renal biopsies.

RAAS blockade and glucose control remain the mainstays of DKD therapeutics, but targets remain unclear

Hyperglycemia plays a key role in DKD development. Early studies from the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study indicated that early tight glucose control decreases the incidence of diabetic nephropathy in patients with types 1 and 2 diabetes. We also learned that DKD can be reversed in select patients who undergo pancreatic transplantation. This critical observation translated to the recommendations to normalize serum glucose levels in patients with diabetes.

Despite this clear rationale, multiple large trials (the VA-DT, ACCORD, and ADVANCE trials) have now established that intensive glycemic control (to the level of almost normalization of glycohemoglobin levels) does not improve cardiovascular and renal outcomes (7). In these studies, targeting glycohemoglobin levels of 6.5% did not improve survival in patients with type 2 diabetes. A secondary analysis indicated a potential minor benefit for young and relatively healthy individuals. It remains unclear why improved glycemic control did not lead to improved outcomes. Many have speculated that diabetes induces an irreversible change at the cellular level, so-called metabolic memory, which leads to disease development.

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Overall, most guidelines recommend keeping hemoglobin A1c (HbA1c) levels around 7%. Making matters more complicated, HbA1c measurements in patients with CKD are less precise owing to decreased red blood cell half-life in individuals with CKD.

In addition to glycemic control, inhibition of the RAAS remains the mainstay of DKD therapy. Both angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) effectively and significantly reduce albuminuria and slow the progression of DKD. However, combined therapies failed to show reductions in doubling of serum creatinine, dialysis, or death. This may be, in part, due to increased adverse effects, such as hyperkalemia, in patients who are on double therapy.

BP reduction is just one critical mechanism of action whereby ACEis and ARBs slow kidney disease progression. The usual goal is 130/80 mg Hg; unfortunately, there remains a lack of consensus among policy organizations regarding BP targets. In addition, results from several recent hypertension studies have shown improved outcomes with intensive BP control. These results may influence future organization and expert guideline recommendations for DKD BP goals.

The future could be bright: new therapies with promising outcomes

The year 2016 seemed to be a paradigm shift in DKD therapeutics. Several trials have shown positive outcomes using various newer diabetes drugs (Table 1). The LEADER Trial (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) investigated the effects of liraglutide, a glucagon-like peptide-1 (GLP-1) analogue shown to improve glycemic control in patients with diabetes (8). The trial was a double-blind, placebo-controlled study that included subjects with high cardiovascular risk. Results showed that fewer patients died from cardiovascular causes in the liraglutide group (hazard ratio = 0.78). Nephropathy was analyzed as the secondary end point in this study. Kidney disease development was significantly lower (hazard ratio = 0.78) in the liraglutide-treated group compared with the placebo group, indicating a likely benefit of GLP-1 analogues in DKD. Further studies are needed to determine the effect and role of GLP-1 analogues in DKD, but these results are very encouraging.

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More great news came with the positive outcome of two trials using newly registered drugs, empagliflozin and canagliflozin, which are inhibitors of the renal-specific SGLT2. SGLT2 is expressed in the proximal tubules, and genetic deletion of the transporter causes renal glucosuria without any other systemic effect. SGLT2 inhibitors block both glucose and sodium reabsorption in the proximal tubule and thereby result in significant weight loss as well as reduction of systemic BP. Further studies are needed to understand the mechanism of action of SGLT1 in renal physiology. However, one postulated mechanism is attributed to the tubule-glomerular feedback mechanism. Decreased proximal tubule reabsorption of sodium leads to increased distal tubule sodium delivery, resulting in increased GFR. Side effects of the drugs include urinary infection and ketoacidosis. Further studies are needed to clarify its benefits.

The first trial, the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG), investigated the effect of empagliflozin on hard DKD outcomes (9, 10). Remarkably, the EMPA-REG trial reported a statistically significant difference in doubling of serum creatinine, dialysis, and even death in patients treated with empagliflozin compared with controls. Patients treated with empagliflozin were 38% less likely to die from cardiovascular-related events. Interestingly, empagliflozin is a derivative of phlorizin, a dietary constituent found in a number of fruit trees.

Finally, Heerspink et al. (11) compared canagliflozin with glimepiride in a randomized, double-blind trial. They showed that patients receiving canagliflozin showed significantly slower GFR decline and decreased albuminuria (in patients with ACR ≥ 30 mg/g), which were independent of improved glycemic control. Stay tuned for results from the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation Trial, which is aimed at answering whether this drug prevents ESRD and cardiovascular death.

July 2017 (Vol. 9, Number 6)

References

1. Reidy K, et al. Molecular mechanisms of diabetic kidney disease. J Clin Invest 2014; 124:2333–2340.

2. Gregg EW, Williams DE, Geiss L. Changes in diabetes-related complications in the United States. N Engl J Med 2014; 371:286–287.

3. Tervaert TW, et al. Pathologic classification of diabetic nephropathy. J Am Soc Nephrol 2010; 21:556–563.

4. National Kidney Foundation. KDOQI clinical practice guideline for hemodialysis adequacy: 2015 Update. Am J Kidney Dis 2015; 66:884–930.

5. Perkins BA, et al. Regression of microalbuminuria in type 1 diabetes. N Engl J Med 2003; 348:2285–2293.

6. Sharma SG, et al. The modern spectrum of renal biopsy findings in patients with diabetes. Clin J Am Soc Nephrol 2013; 8:1718–1724.

7. Handelsman Y, et al. American Association of Clinical Endocrinologists and American College of Endocrinology—clinical practice guidelines for developing a diabetes mellitus comprehensive care plan—2015. Endocr Pract 2015; 21[Suppl 1]:1–87.

8. Marso SP, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375:311–322.

9. Wanner C, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016; 375:323–334.

10. Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373:2117–2128.

11. Heerspink HJ, et al. Canagliflozin slows progression of renal function decline independently of glycemic effects. J Am Soc Nephrol 2017; 28(1):368–375.