Are You Sure the Patient Has Diabetic Nephropathy?

Definition: Diabetic nephropathy (DN) is a clinical syndrome characterized by persistent albuminuria, a relentless decline in the glomerular filtration rate (GFR) and raised arterial blood pressure (BP). Persistent albuminuria (>300 mg/24 hr or >200 µg/min) in at least two of three consecutive nonketotic urine samples is the hallmark of diabetic nephropathy.

Epidemiology: About 20% to 30% of patients with type 1 or type 2 diabetes develop nephropathy, but in type 2 diabetes, a considerably smaller fraction progress to end-stage renal disease (ESRD). However, because of the much greater prevalence of type 2 diabetes, such patients constitute over half of the patients starting dialysis. Overall, DN occurs in almost 30% of all diabetics and is the leading cause of ESRD in the U.S. and Europe. Early diagnosis of diabetes and early intervention are critical in preventing the normal progression to renal failure seen in many type 1 and a significant percentage of type 2 diabetics.

In the United Kingdom Prospective Diabetes Study (UKPDS), the risk of a patient with type 2 diabetes progressing from normoalbuminuria to microalbuminuria was 2% per year, risk of progressing to macroalbuminuria was 2.8% per year, and the risk of macroalbuminuria to elevated creatinine level was 2.3% per year. However, in that study, the competing risk of death exceeded the risk of progression once macroalbuminuria had developed. Risk of death was 0.7% per year for normoalbuminuric patients, 3.5% per year for macroalbuminuric patients, and 12.1% per year for patients with elevated level of serum creatinine. There is considerable racial/ethnic variability in this regard, with native Americans; Hispanics, especially Mexican Americans; and African Americans having a much higher risk of developing ESRD than non-Hispanic whites with type 2 diabetes.

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Signs/symptoms of diabetic nephropathy

Albuminuria: Screening for microalbuminuria and an estimated glomerular filtration rate (eGFR) should be performed annually in type 1 diabetics with diabetes of duration >5 years, in all type 2 diabetics starting at diagnosis, and all patients with diabetes and hypertension.

Urinary albumin can be checked by three methods:

  • Albumin-to-creatinine ratio on a spot urine sample

  • 24-hour urine collection

  • Timed urine collections

Normal albumin excretion on a spot collection should be <30 µg/mg of creatinine. Microalbuminuria is 30 to 299 µg/mg creatinine, while macro(clinical)-albuminuria is >300 µg/mg creatinine. Measuring timed or 24 hour urine collections is burdensome and adds little to the predictive value or accuracy of the spot sample.

Transient elevations in urinary albumin excretion can be seen in hyperglycemia, exercise, urinary tract infections (UTIs), marked hypertension, heart failure, and acute febrile illness.

Hypertension: In patients with type 1 diabetes, hypertension is usually caused by underlying diabetic nephropathy and typically becomes manifest around development of microalbuminuria. In patients with type 2 diabetes, hypertension is present at the time of diagnosis in about one-third of patients as part of the metabolic syndrome.

The mechanism of hypertension in DN is complex; it is not completely understood and involves excess sodium retention, activation of the sympathetic nervous system, renin-angiotensin-aldosterone system (RAAS), endothelial cell dysfunction, and increased oxidative stress. It is usually associated with an expanded plasma volume, increased peripheral vascular resistance, and low renin activity. At any given level of GFR, BP tends to be higher in diabetic than nondiabetic patients with renal disease.

Other signs/symptoms of diabetic nephropathy

Peripheral edema may be the first symptom of diabetic nephropathy. Fluid retention may be present even with preserved renal function and a slight reduction in serum albumin.

There is usually a relentless, often linear but variable decline in GFR, ranging from 2 to 20 ml/min/yr.

What Else Could the Patient Have?

The differential diagnosis nephropathy in a patient with diabetes who had albuminuria and/or renal dysfunction should include:

  • Nephrosclerosis

  • Renal artery stenosis with/without renovascular hypertension

  • Primary or secondary glomerular disease

  • Interstitial nephritis

  • Amyloidosis

  • Chronic urinary obstruction

Key Laboratory and Imaging Tests

Diagnosis

Diagnosis of diabetic nephropathy is based on detection of proteinuria. In addition, many patients will also have hypertension and retinopathy. The main diagnostic procedures to establish diagnosis are:

  • Determination of albuminuria or proteinuria

  • Measurement of BP which should be measured at every routine visit

  • Measurement of serum creatinine concentration and eGFR.

  • Renal ultrasound

  • Ophthalmologic examination

If proteinuria is found on urine analysis, it is important to rule out the various causes that can cause false-positive results, such as UTI.

This proteinuria, if confirmed, needs to be quantitated by one of the three methods mentioned in the albuminuria section. If the patient has typical diabetic nephropathy (i.e., type 1 diabetes for >10 years, retinopathy, prior microalbuminuria, no hematuria or red cell casts, and normal renal ultrasound), then no further workup is required. However, if the patient has no retinopathy, and has nephrotic range proteinuria without progression through microalbuminuria or has macroscopic hematuria or red cell casts, the patient needs to be evaluated further. It has to be noted that microscopic hematuria may be found in a third of patients with diabetic nephropathy, but red cell casts are very uncommon. Biopsies in such patients reveal nondiabetic renal disease in at least half of them.

Imaging studies

A renal ultrasound is usually obtained to evaluate for kidney size. In earlier stages on DN, the kidney may be enlarged because of hyperfiltration. With progression of diabetic renal disease, the kidney size often but not always decreases because of glomerulosclerosis. Also, chronic kidney/medical disease can be detected on renal ultrasound by assessing for hyperechogenicity. Ultrasound also helps in ruling out outlet obstruction as a cause of renal dysfunction.

Proteinuria in diabetes is occasionally due to a glomerular disease other than diabetic nephropathy. Patients with diabetes most often develop nephrotic-range proteinuria (>3.5 g/24 hr), but typically only after long-standing diabetes. A bland urine sediment supports the diagnosis of diabetes, although it is not uncommon to have some microscopic hematuria with advanced diabetic nephropathy.

Major clinical clues suggesting nondiabetic glomerular disease as etiology of proteinuria are:

  • Significant proteinuria without a long history of diabetes

  • No signs of other end-organ damage such as retinopathy or neuropathy (in type 1 diabetes). Although the presence of retinopathy supports diabetes as a cause of the proteinuria, lack of retinopathy does not rule out diabetes as the underlying etiology. This is especially true in patients with type 2 diabetes.

  • Acute onset of renal disease or of nephrotic syndrome

  • Presence of active urinary sediment containing red cells and cellular casts

  • Rapidly rising urinary protein level, or rapidly declining GFR

Indications for renal biopsy in diabetic patient

  • If retinopathy is not present in the type 1 diabetic patient (absence of retinopathy does not rule out DN in type 2 diabetes)

  • If onset of proteinuria is sudden or rapid, especially if in type 1 diabetic and duration of disease is <5 years or if evolution is atypical (without transitioning through usual stages of overt proteinuria)

  • If active urinary sediment (red cell casts or acanthocytes) or macroscopic hematuria is found

  • If decline of renal function is exceptionally rapid or if renal dysfunction is found without significant proteinuria

When a diabetic patient with impaired renal function is seen:

  • Assess the cause of renal failure

  • Assess the rate of progression and magnitude of proteinuria

  • Assess presence of microvascular and macrovascular complications of diabetes

Pathophysiology and natural history

As mentioned before, microalbuminuria is usually the first manifestation of DN. It is also called early or incipient nephropathy. It usually progresses to overt nephropathy in two-thirds of the patients. Natural history of DN is a process that progresses gradually over years.

Early DN is evidenced by glomerular hyperfiltration and an increase in GFR. This is believed to be related to changes in hemodynamics in renal microvasculature and increased cell growth and expansion of the kidneys, possibly secondary to hyperglycemia and its effects on insulin-like growth factor (IGF). Microalbuminuria typically occurs after 5 years in type 1 diabetes. Overt nephropathy, with urinary protein excretion >300 mg/day often develops after 10 to 15 years. However, type 2 diabetes has a more variable course. Patients often present at diagnosis with microalbuminuria; 40-60% of these patients will progress to overt nephropathy.

Long-standing hyperglycemia is a significant risk factor for development of DN. It may directly result in mesangial expansion and injury. The mesangium expands initially by cell proliferation and later by cell hypertrophy. Transforming growth factor (TGF-beta) is especially important in mediation of this expansion and later fibrosis via collagen and fibronectin deposition. Advanced glycosylation end products (AGEs) can be formed by the binding of glucose to proteins in kidneys and in the circulation. AGEs can form cross-links over years of hyperglycemia and can contribute to renal damage by stimulation of growth and fibrotic factors, as well as increasing oxidative stress. There can also be increased levels of mediators of proliferation and expansion, such as platelet derived growth factor, vascular endothelial growth factor (VEGF), and TGF-beta, and reduction in renal nitric oxide levels all of which can contribute to further renal and microvascular complications.

There is also activation of the renin-angiotensin system in the proximal tubular cells, podocytes, and mesangial cells. Angiotensin II (Ang II) is stimulated in diabetes. Even though the levels of plasma renin activity are suppressed in diabetics, as compared to controls, there is evidence that intrarenal levels of Ang II are increased.

Ang II preferentially constricts the efferent arteriole in the glomeruli, leading to higher intraglomerular pressure. Ang II also stimulates renal growth and fibrosis. It is because of this reason, pharmacologic interventions that inhibit production of Ang II or block ATI receptors that target RAAS are a cornerstone in the treatment of hypertension in DN patients. In addition stimulation of aldosterone by Ang II is also considered important in the pathogenesis.

Management and Treatment of Diabetic Nephropathy

Despite significant progress has been made in recent years in the understanding of the pathophysiology, prevention, and treatment of DN, we are far from optimal therapy. Both glycemic control and rigorous BP control have significant impact on prevention and progression of DN.

Studies in both type 1 and 2 diabetes patients have shown that use of angiotensin-converting enzyme (ACE) inhibitors leads to decreased albumin excretion and may postpone or even prevent overt nephropathy. Once overt nephropathy is present, progression cannot be halted, but only be slowed.

Lifestyle modifications: Should have a central role in managing these patients.

  • Smoking: Smoking increases risk and progression of DN. In the Appropriate BP in Diabetes Trial, 61% of enrollees were smokers. Analysis of a number of risk factors showed a 1.6 fold increased risk of DN among smokers.

  • Hyperlipidemia: common in diabetics. Aggressive lipid lowering is important, since diabetes is considered a coronary artery disease equivalent.

  • Weight reduction: marked decrease in proteinuria may be seen in diabetic patients who lose weight. Maintain body mass index (BMI) of 18.5 to 24.9 kg/m2.

  • Adopt DASH style diet eating plan: Diet rich in fruits, vegetables, and low fat dairy products.

  • Physical activity: regular aerobic physical activity at least 30 minutes per day, most days of the week

  • Dietary sodium reduction: to less than 2.4 g (100 mmol/day) sodium or 6 g sodium chloride.

Effect of glycemic control

The Diabetes Control and Complications Trial(DCCT) and United Kingdom Prospective Diabetes Study(UKPDS) have shown that intensive diabetes can significantly reduce the risk of development of microalbuminuria and overt macroalbuminuria. A Hb A1C of <7 is recommended by ADA guidelines, though AACE recommends Hb A1C <6.5%.

Close monitoring of glucose is required, as certain opposing influences may make glycemia control difficult to predict. On the one hand, renal failure can cause insulin resistance by accumulation of a (hypothetical) circulating factor interfering with the action of insulin leading to impaired glucose tolerance. On the other hand, the half-life of insulin is prolonged, causing the tendency to develop hypoglycemic episodes. Most sulfonylurea compounds accumulate in renal failure, except glimepiride and gliquidone. Glinides and glitazones do not accumulate. Hence any of these drugs that do not accumulate should be considered for use as oral hypoglycemics, once renal failure develops.

It had been the practice to discontinue Metformin when the creatinine is >1.5 mg/dl in males and >1.4 mg/dl in females. The FDA, based on its review of the literature, have recommended the eGFR be used to assess the suitability for use in patients with renal impairment. An eGFR should be obtained prior to initiating metformin. Metformin is contraindicated in patients with an eGFR < 30 ml/minute/1.73 M2 and is not recommended to be started in patients with an eGFR between 30-45 ml/minute/1.73 M2. In patients who are taking metformin and their eGFR falls between 30-45 ml/minute/1.73 M2 consideration of the risks and benefits of continuing or stopping metformin should be undertaken. However, there is an ongoing investigation to evaluate the benefits of continuing metformin in patients with advanced CKD.

Management of hypertension in DN

Target BP in DN

The American Diabetes Association guidelines recommend that most patients with diabetes and hypertension should be treated to achieve a blood pressure of < 140/90.

Current KDOQI guidelines recommend a BP of <130/80 mm Hg in patients with DN. Studies have shown that it takes an average of 2.9 appropriately dosed antihypertensive drugs to achieve BP control below target in diabetic patients with hypertension. If a patient has hypertension, diabetes, and renal disease, this average increases to about 3.5 medications.

However, the published guidelines from the Joint National Committee of Hypertension Management (JNC 8 published in 2014) recommends a target blood pressure of 140/90 mm/Hg in patients with diabetes based on the fact that none of the published major clinical trials including ACCORD-BP, UKPDS, or HOT have shown conclusive benefit in the outcomes by lowering BP to less than 140/90 mm/Hg. The ACCORD-BP study did not demonstrate a difference in outcomes in the primary prespecified endpoint between targeting a systolic blood pressure of <120 vs. <140. The SPRINT study, that used the same targets as in the ACCORD- BP study, demonstrated in high-risk hypertensive patients that targeting a systolic BP < 120. Both studies demonstrated increased adverse events and use of anti-hypertensive medications in the systolic BP <120 treatment arms. Additional studies may need to be performed to address the optimal lower systolic BP in patients with diabetes mellitus.

The essential goal of therapy is treatment of hypertension and reduction of proteinuria. Several studies have demonstrated the critical role of using drugs that block the RAAS in further slowing down the progression of DN. Use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blocker (ARB) has become the standard of care in patients with DN.

Antihypertensive Medications

In addition to lifestyle measures, all patients with diabetes and BP >140/90 mm Hg should be started on once daily RAAS blocker and the dose maximized within the first month of treatment if BP is not <130/80 mm/Hg. If the BP is >160/100, two pharmacologic agents should be initiated and titrated in addition to lifestyle measures. If BP is >20/10 mm Hg above goal, then combination therapy with RAAS blocker and either a diuretic (thiazide diuretic if GFR >30 ml/min or loop diuretic if GFR is lower) or a dihydropyridine calcium channel blocker (CCB) started.

When choosing an ACEI or ARB, the dose should be titrated to the maximally tolerated dose necessary to reach goal BP.

If an ACEI is started and the adverse effect of cough appears, treatment should be changed to an appropriate dose of an ARB.

If within a month of monotherapy titration the BP goal is not achieved, then either a low-dose thiazide diuretic such as 12.5 mg chlorthalidone or hydrochlorothiazide or CCB should be added. In patients with a GFR < 30ml/min, replace the thiazide diuretic with a loop diuretic.

If potassium levels are elevated (>5 mEq/L) before initiating RAAS blocking drugs, a review of all high potassium containing foods and substances, and drugs such as NSAIDS should be discussed with the patient. If potassium levels stay elevated, use of a loop diuretic twice or thrice daily maybe appropriate to allow use of the RAAS blocker. If hyperkalemia persists, replace ACEI with ARMs and if this does not lower potassium, discontinue ARBs.

Minimizing the number of antihypertensives improves patient adherence. Therefore, fixed drug combinations may be used.

If after 2 to 4 weeks of adding a diuretic or CCB, BP is still not at goal, titrate diuretic and/ or CCB to maximum tolerated dose. However, in at least 20% of the remaining cases, a fourth and possibly a fifth agent will be needed. If blood pressure is uncontrolled after administering 3 agents of which one is a diuretic, an evaluation for secondary causes of hypertension should be considered.

Inhibition of the RAAS: ACEI or ARB as monotherapy

Current recommendations are to use an ACEI or ARB as a first-line option in treating hypertension in patients with DN. The classic study with captopril published in the early 1990s showed that ACEI slow down the decline in GFR and prevent increases in albuminuria in patients with type 1 diabetes and DN. The Irbesartan in Diabetic Nephropathy Trial (IDNT) and Reduction in Endpoints in NIDDM with Angiotensin Antagonist Losartan (RENAAL) studies were sentinel studies establishing the efficacy of ARBs in patients with type 2 DM and nephropathy.

The IRbesartan in MicroalbuminuriA (IRMA) study demonstrated progression to macroalbuminuria was significantly reduced by Irbesartan in type 2 diabetics. The Diabetics Exposed to Telmisartan and Enalapril (DETAIL) study demonstrated that ARBs are noninferior to ACEIs in patients with type 2 diabetes and microalbuminuria on the basis of the outcome of GFR decline.

Thus these studies indicate that administration of an ACEI or ARB can be used as first-line therapy options for hypertension in patients with DN without evidence suggesting superior efficacy of active drugs to one another.

Inhibition of the RAAS: ACEI or ARB as dual therapy

Because ACEI or ARB are individually renoprotective, questions arose regarding the utility of combination therapy with ACEI and ARB. The concept behind this was more complete inhibition of Ang II, which can be produced through non-ACE pathways. Prior studies using combination therapy in patients with type 1 and 2 diabetes, showed significant reductions in albuminuria and/or BP and was generally well tolerated. Concerns about this strategy arose with the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), which found no difference in primary endpoint of stroke, MI, and sudden cardiac death between groups. However, those in the combination group had higher rates of renal impairment and hyperkalemia. An ongoing multicenter study, VA NEPHRON-D Study (VA Nephropathy in Diabetes) is testing the efficacy and safety of an ACEI (lisinopril) + ARB (losartan) in reduction in GFR to >30 ml/min or >50%, ESRD, or death in DM2 and nephropathy. The results of the study were published in November 2013 and concluded that combination therapy resulted in increased risk of adverse events among patients with diabetic nephropathy.

Based on the ONTARGET results, it is better to avoid combination ACEI and ARB therapy.

Direct renin inhibitors (DRI) in DN

Renin levels are elevated with either ACEI or ARB and may produce Ang II through non-ACE pathways. Aliskiren is a direct renin inhibitor that lowers BP and albuminuria in patients with DN. Its utility as an add-on therapy is being investigated in the Aliskiren Trial in type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (ALTITUDE) where an ACEI or an ARB + DRI are being tested. The trial was stopped early by the data monitoring committee due to increased rate of adverse events, such as nonfatal stroke, hyperkalemia, and hypotension. The committee also stated that it was unlikely there would be a benefit to the use of aliskiren in the trial. At this time there is no recommendation to use aliskiren in patients with diabetes. Further studies will be needed to demonstrate the benefits.

Mineralocorticoid receptor antagonists in DN

With both ACEI and ARB, plasma aldosterone levels are expected to decrease. In some patients on maintenance therapy with these drugs, aldosterone levels increase to pretreatment levels through the phenomenon of “aldosterone escape.” This may be seen in up to 40% of patients on either ACEIs or ARBs and may contribute to local renal damage, albuminuria, and possible systemic hypertension. A few studies have shown a small reduction in albuminuria but increased risk of hyperkalemia, especially in those with decreased renal function.

Renal Replacement Therapy Options

When GFR falls below 10 to 12 ml/min/1.73 m2, or signs and symptoms of volume overload or uremia develop, patients may need to be on some form of renal replacement therapy (RRT). The three forms of RRT are: hemodialysis, peritoneal dialysis, and renal transplant. Referral for evaluation for RRT should occur when the eGFR is <30 ml/min/1.73 m2.

Dialysis: Survival analysis shows that the two modalities (hemodialysis and peritoneal dialysis) are comparable with regard to patient outcomes. However, when compared to nondiabetics, diabetic patients on dialysis do much worse, with a 5-year survival rate as low as 5% in elderly type 2 diabetics. This survival can improve to 58% at 3 years, with meticulous management.

Issues that can decrease survival time in these patients can include: Cardiovascular disease, peripheral vascular disease, malnutrition, or access related infections.

Renal transplant: By far the best treatment for ESRD is a kidney transplant. This can be done alone or with a combined kidney-pancreas transplant. Patient survival time is much greater after transplant when compared to remaining on dialysis. Data from the Organ Procurement and Transplantation Network reported a 1-, 3-, and 5-year survival rate for transplanted diabetics of 90%, 79%, and 66%, respectively. This, compared to a 2-year survival rate of patients on hemodialysis of 58%, looks more promising. The renal transplant can come from a living donor or a deceased donor. Three-year allograft survival is better for the living donor than the deceased donor transplant. Preemptive transplant is an even better option as it offers a survival advantage over patients receiving a transplant while on dialysis.

Diabetic ketoacidosis (DKA) in ESRD patients

Development of DKA is not very common in ESRD patients. Some of the reasons for this are: Glycemic control may get better as renal function worsens, since insulin metabolism is decreased. Also, since many dialysis patients are anuric, fluid and electrolyte losses may be lesser due to lack of glycosuria and osmotic diuresis. On the other hand, hyperkalemia, metabolic acidosis and volume overload are more common.

Management of DKA in ESRD patients

Potassium supplementation should be avoided, since despite the hypokalemia seen on labs, the total body potassium stores may be high. However, if clinical suspicion or electrocardiographic findings of hyperkalemia are present, immediate potassium lowering therapies should be initiated, including emergent hemodialysis.

Dialysis dependent patients with DKA often present with profound metabolic acidosis, since the anuric kidneys cannot manage the increased acid loading secondary to ketogenesis. Aggressive fluid resuscitation to increase acid excretion is not a safe choice in anuric patients if they are not volume depleted. Bicarbonate therapy is usually not very effective in this patient population. If metabolic acidosis is very severe, emergent hemodialysis may be used to correct it.

If fluid resuscitation is required for a volume depleted patient, who is dialysis dependent, it should be done in small aliquots, with constant reevaluation for volume overload.

The most common indications for dialysis in a dialysis-dependent patient, presenting with DKA are: hyperkalemia, severe metabolic acidosis, and volume overload.

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