Diabetic Nephropathy

Etiology

Thirty to 40 percent of patients with diabetes mellitus (DM)develop diabetic nephropathy.[3] The exact cause of diabetic nephropathy remains unknown, but insulin resistance, genetics, hyperglycemia, and an autoimmune process may be the causes.

Epidemiology

While patients with type 2 diabetes mellitus may present with albuminuria at the time the diabetes is detected, diabetic nephropathy develops in type 1 diabetes 15 to 20 years later. This difference is mainly because the precise onset of type 2 diabetes is difficult to discern. Structural and functional changes occur in the kidney on account of diabetes and result in proteinuria, hypertension, and progressive reduction of kidney function, which is the hallmark of diabetic nephropathy.

Certain racial groups like African Americans, Native Americans, and Mexican Americans are at high risk of developing diabetic nephropathy. Studies have noted familial clustering, hinting that genetics plays a part in the risk of developing nephropathy.

Pathophysiology

Hyperglycemia leads to the production of reactive oxygen species and activation of pathways, including protein kinase C, polyol, hexosamine, and advanced glycation end products (AGE). A significant feature is marked inflammation manifested by an increase in cytokines and chemokines, including IL-6, MCP-1, TGF-beta (transforming growth factor-beta), and VEGF (vascular endothelial growth factor), causing inflammation fibrosis and increased vascular permeability. A podocytopathy ensues, resulting in albuminuria. The resulting systemic and intraglomerular hypertension results in proteinuria. Proteinuria causes epithelial-mesenchymal cell transformation leading to fibroblasts and chronic tubular injury.

Histopathology

Kimmelstiel-Wilson nodules, glomerular basement membrane thickening, and glomerular sclerosis, inflammation are the common pathologies seen in diabetic nephropathy.

History and Physical

Increasing duration of DM, poor glycemic control, and uncontrolled hypertension are strong risk factors for the development of diabetic nephropathy (DN). A family history of hypertension and cardiovascular events in first-degree relatives is also a strong risk factor for developing diabetic nephropathy. Obesity, smoking, and hyperlipidemia are risk factors for DN. This, along with family clustering, suggests genetic factors could also be at play. Several genes, including polymorphisms in angiotensin-converting enzyme (ACE) and angiotensin receptor, are being studied. Males are at higher risk of developing diabetic nephropathy.

Diabetic nephropathy is diagnosed by persistent albuminuria on two or more occasions, separated at least by three months on early morning urine samples. Persistent albuminuria is greater than 300 mg over 24 hours or greater than 200 micrograms per minute. Moderately increased albuminuria is when the urine albumin excretion rate is between 30 to 300 mg over 24 hours and is a marker of early DN. It is critical to exclude a urinary tract infection as the cause of albuminuria by a urinalysis. 

Early in the course of the disease, patients are often asymptomatic and are diagnosed during screening with levels of 30 to 300 mg/g creatinine. Once nephropathy sets in, patients present with fatigue, foamy urine (urine protein greater than 3.5 g per day), and pedal edema due to hypoalbuminemia and nephrotic syndrome. They may also have associated peripheral vascular disease, hypertension, coronary artery disease, and diabetic retinopathy.

Evaluation

Proteinuria is the hallmark of diabetic nephropathy. The absence of retinopathy makes diabetic nephropathy less likely in T1DM.

The scenario is more difficult in T2DM than with T1DM. The exact time of the onset of T2DM is unclear in most patients. History and physical exam play a crucial role in diagnosing diabetic nephropathy in T2DM.

The criteria for diagnosis include:

• Elevated blood pressure
• Progressive decline in glomerular filtration rate (GFR)
• Persistent albuminuria (greater than 300 mg/d) on at least two visits 3-6 months apart. 

Urine analysis is used to quantify urea, creatinine, and protein. Microscopy is done to rule out a nephritic cause. Serum and urine electrophoresis is done to rule out multiple myeloma, and renal ultrasound is done to assess the kidney size. A renal biopsy is done when the diagnosis is not clear.

Treatment / Management

Treatment of diabetic nephropathy targets four areas: cardiovascular risk reduction, glycemic control, control of blood pressure, and inhibition of the renin-angiotensin system (RAS).

Risk-factor modification, including tobacco cessation and optimal lipid control strategies, are crucial for cardiovascular risk reduction.

Studies have shown a significant reduction in the risk of developing proteinuria and microalbuminuria with intensive diabetes control in T1DM.[4] These studies include DCCT (Diabetes Control and Complications Trial) and EDIC (Epidemiology of Diabetes Interventions and Complications study). The benefits of good glycemic control early in the onset of disease carried over even after a long time, despite glycemic control being similar in both groups on longer follow up. This effect is "metabolic memory," a term coined by DCCT/EDIC investigators.(A1)

In T2DM, UKPDS (United Kingdom Prospective Diabetes Study) showed that targeting an HbA1C of 7% led to a lower risk of microvascular complications, including nephropathy.[5] However, blood pressure (BP) control also led to a decrease in cardiovascular mortality.(A1)

Studies have shown the benefit of ARBs (angiotensin receptor blockers) in delaying the progression of kidney disease.[6][7] These include studies like RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study) and IDNT (Irbesartan Diabetes Nephropathy Trial), which also showed that the BP achieved, better-predicted kidney outcome rather than BP at entry, emphasizing the need for BP control. UKPDS showed the benefit of BP control on any DM-related complication such as death, adverse cardiovascular events, and the composite of microvascular events. However, aggressive control of systolic BP to less than 120 mm Hg, as opposed to standard therapy (less than 140 mm Hg systolic), found no difference in cardiovascular outcome or end-stage renal disease. The Eighth Joint National Committee (JNC 8) guidelines recommend a goal BP less than 140/90 mm Hg for most patients with T2DM and diabetic nephropathy, but with individualization.[8] Recent diabetic society guidelines suggest goals of 130/80 for people with diabetes.(A1)

While RAS blockade is crucial to prevent the development of diabetic nephropathy, multiple studies show that early therapy in patients with T1DM is ineffective in preventing the development of microalbuminuria. However, studies, including ROADMAP (Randomized Olmesartan and Diabetes Microalbuminuria Prevention), have shown that RAS blockade can prevent the development of microalbuminuria in T2DM.[9](B2)

Studies like IRMA2 (Irbesartan in Microalbuminuria, Type 2 Diabetic Nephropathy Trial) have shown the benefit of ARB in preventing proteinuria in patients with microalbuminuria.[10] Studies in patients with T1DM and overt proteinuria have also shown that ACE inhibitors slow the progress of diabetic nephropathy. The IDNT and RENAAL studies have shown similar benefits in T2DM patients. These studies provide clear evidence of the benefit of RAS-blocking medication on slowing progression of diabetic nephropathy, independent of their effect on BP. However, the use of more than one RAS-blocking agents resulted in multiple adverse outcomes, including acute renal failure, and has fallen out of favor.(A1)

Newer drugs like a third-generation mineralocorticoid receptor antagonist, finerenone, has shown albuminuria reduction in diabetic nephropathy at 90 days, on patients already on ARB.[11] The EMPAREG and CANVAS studies showed that SGLT2 (sodium-glucose co-transporter 2) inhibitors that prevent reabsorption of glucose via the renal tubules reduced cardiovascular mortality.[12] In these cardiovascular outcome trials, the SGLT2 inhibitors had positive effects on kidney outcomes, namely albuminuria reduction and a reduction in the occurrence of a composite renal outcome. However, since these are secondary outcomes of trials designed to test cardiovascular benefit, many studies are now underway to test the actual potential of this group of drugs to prevent the progression of diabetic nephropathy.(A1)

Renal Replacement

Once the end-stage renal disease develops with a GFR of 10-15 ml/min, renal replacement therapy may be required. There are several options for dialysis, including peritoneal, hemodialysis, and renal transplant. Renal transplant is considered the best option, and this alternative must be discussed early with the family.

Differential Diagnosis

• Multiple myeloma
• Nephrotic syndrome
• Renal artery stenosis
• Tubulointerstitial nephritis

Toxicity and Adverse Effect Management

Effect of CKD on Diabetes Drugs

The kidneys play a crucial role in clearing insulin from the body.  When the kidney fails, insulin remains for longer periods in the body, and this warrants dose reduction of insulin to prevent hypoglycemia. This principle also is true for most oral antidiabetic medications that are cleared from the kidney.

Metformin is contraindicated in patients with eGFR less than 30 mL/min/1.73 m2, due to the likelihood of lactic acidosis. With most oral drugs, the physician needs to be cautious when the eGFR is less than 45 mL per minute and especially below 30 mL per minute.

Patients with diabetic nephropathy are at risk of developing acute kidney injury (AKI) and, one must exercise extreme caution with the use of nephrotoxic medications like NSAID, intravenous contrast, among others.

Staging

Current Guidelines

• Optimize blood glucose control
• Optimize blood pressure control with ACE inhibitors or ARBs
• Limit protein intake to 0.8 g/kg body weight
• Monitor serum creatinine and BUN
• Monitor urine albumin - creatinine ratio
• ACE inhibitors or ARB are not recommended in patients with normal BP, normal GFR and normal urinary albumin to creatinine ratio
• when GFR falls below 60 ml/min, assess for complications of chronic kidney disease
• If GFR is below 30 ml/min, refer to a nephrologist for renal replacement
• Always refer to a nephrologist to manage chronic kidney disease

Prognosis

Diabetic nephropathy carries high morbidity and mortality. Microalbuminuria is an independent risk factor for cardiovascular mortality. The majority of patients die from end-stage renal disease. In addition, diabetic retinopathy is associated with diabetic nephropathy.