1. Define the terms diabetic nephropathy (DN) and diabetic kidney disease (DKD).

The terms DN and DKD are used interchangeably to describe a set of characteristic clinical and pathologic findings. The main clinical findings of DKD are the presence of albuminuria, progressive chronic kidney disease (CKD), and less commonly microscopic hematuria. Diabetes is the most common cause of the nephrotic syndrome. Proteinuria is first detected by screening for albumin in the urine. A normal urine albumin level is less than 30 mg/day. Abnormal urine protein is defined in two stages. Moderately increased albuminuria (formerly known as microalbuminuria) is defined as 30 to 300 mg/day. Severely increased albuminuria (formerly known as macroalbuminuria) is defined as greater than 300 mg/day and is also known as overt proteinuria or overt nephropathy. The pathologic features of DKD are outlined in question 4.

2. How is DN from type 1 diabetes mellitus (DM) similar/different from type 2 DM?

See Table 31.1 . Of note, young adults diagnosed with type 2 DM before the age of 20 are at a higher risk for DN, retinopathy, peripheral neuropathy, and hypertension than patients with type 1 DM who are diagnosed at the same age.

3. What is the natural history of the progression of DN to end-stage renal disease (ESRD)?

This question is most clearly answered in patients with nephropathy from type 1 DM, given the readily identifiable onset of DM. The earliest change of kidney function in DM is kidney hypertrophy and glomerular hyperfiltration occurring in the first 1 to 2 years after diagnosis. The degree of hyperfiltration correlates with the risk of developing nephropathy. The onset of albuminuria is on average 15 years after the diagnosis of DM and increases in severity over time. Patients with type 1 DM who have not developed nephropathy after 25 years have a very low risk of developing nephropathy. End-stage kidney disease (ESKD) occurs 20 to 30 years after the onset of diabetes.

Due in part to the unknown time of onset for patients with type 2 DM, moderately increased albuminuria can be seen as early as at the time of diagnosis. In addition, it does not always progress as it does in type 1 DM, because some patients develop diabetes-related loss of kidney function without albuminuria. Patients with DN and type 2 DM are at increased risk of both ESKD and death from cardiovascular disease. Due to increased comorbidities, most patients will die before reaching the need for dialysis.

4. How and when should physicians screen for DKD?

After DM is diagnosed, consideration for screening of DKD must commence. Screening consists of annual measurements of creatinine and urine albumin-to-creatinine ratio (ACR). It should begin 5 years after diagnosis in type 1 DM and at the time of diagnosis in type 2 DM. Moderately increased albuminuria (ACR between 30 mg/g and 300 mg/g) that persists for more than 3 months means the patient is at risk for progression to overt nephropathy.

5. What are the findings seen on kidney biopsy in DN?

Three classic features seen on kidney biopsy:

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  Mesangial expansion leading to wide-appearing glomeruli

  
  
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  Thickening of the glomerular basement membrane (GBM) with the notable absence of GBM deposits

  
  
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  Nodular glomerulosclerosis. Nodular glomerulosclerosis typically presents as rounded tufts of acellular matrix in the mesangium. These are called Kimmelstiel-Wilson nodules.

Other findings include hyaline deposition within Bowman capsule and the afferent and efferent arterioles. This arteriolar deposition can distinguish DN from hypertensive nephropathy, in which hyalinosis is limited to the afferent arteriole.

Although nodular glomerulosclerosis is typically found in diabetic patients, it can also be seen in monoclonal immunoglobulin deposition disease, amyloidosis, membranoproliferative glomerulonephritis, and in idiopathic nodular sclerosis, a disease of older Caucasian patients with history of hypertension and tobacco use.

6. Is a kidney biopsy indicated in the diagnosis of DN?

The presence of proteinuria in a patient with DM does not necessarily equate with a diagnosis of DN and could in fact represent another glomerular disease. Major clues that suggest another cause of proteinuria include:

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  Signs of another systemic disease

  
  
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  Onset of proteinuria less than 5 years after diagnosis of type 1 DM

  
  
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  Absence of retinopathy in a patient with type 1 DM

  
  
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  Rapid deterioration of kidney function or sudden increases in proteinuria

  
  
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  Presence of hematuria, red or white blood cell urine casts, pyuria, or abnormal protein chains in the urine

A study by Mazzucco et al. found that using restrictive criteria such as these to determine the need for a kidney biopsy may lead to more than 50% of kidney biopsies having another glomerular disease present.

7. What is the role of glycemic control in the treatment of DN?

Type 1 DM and type 2 DM have a different pathogenesis, but both are associated with hyperglycemia. Hyperglycemia activates the intrarenal renin-angiotensin system that plays an important role in the development of DN. However, the role of glycemic control in treatment of established DN is controversial.

The best evidence for preventing DN is in patients with type 1 DM. Tight glycemic control in patients with type 1 DM decreases the risk of development of albuminuria. In individuals with type 1 DM and moderately increased albuminuria, tight glycemic control also reduces the risk of progression to nephropathy. In addition, once severely increased albuminuria is present, small studies have found that return to euglycemia by performing a pancreas transplant led to improvement of biopsy findings 10 years post transplant.

In type 2 DM the data is less certain. Tight glycemic control appears to decrease the risk for development of moderately and severely increased albuminuria but does not decrease the risk for doubling of serum of creatinine or of renal death. In addition, tight blood glucose control to a hemoglobin A1c (HbA1C) less than 6.5% resulted in increased mortality. The current goal HbA1c in patients with DKD is less than 7%, with liberalized goals for elderly patients or those prone to hypoglycemia.

8. What is the current treatment of DN?

In addition to glycemic control as noted previously, inhibition of the renin-angiotensin-aldosterone system, sodium restriction, and blood pressure control are important parts of treating DN.

Renin-Angiotensin System (RAS) Inhibition: Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have been a critical component of treating DN for more than 2 decades. Intrarenal RAS activation plays a major role in the pathogenesis and progression of DN. ACE inhibitors have been studied both early and late in the course of type 1 DN and have been shown to slow the rate of estimated glomerular filtration rate (eGFR) decline and decrease the risk of ESKD. Both ARBs and ACE inhibitors have been shown to do the same in patients with type 2 DN. In addition, since the importance of RAS inhibition in treatment of DN was discovered, there appears to be a slowing of the incidence of ESKD from DN in multiple regions of the world.

Sodium Restriction: High dietary sodium intake can cause hypervolemia and hypertension, leading to adverse cardiovascular outcomes. In addition, sodium restriction has been found to enhance the antiproteinuric effects of RAS inhibition.

Blood Pressure Control: Lowering blood pressure, even without using RAS inhibition, has been shown to decrease the rate of albumin excretion. Current guidelines from the 2017 American College of Cardiology/American Heart Association (ACC/AHA) Task Force suggest a goal blood pressure of less than 130/80 mm Hg for diabetic patients. This recommendation is based on the assumption that the vast majority of adults with DM (and CKD) have a 10-year atherosclerotic cardiovascular disease (ASCVD) risk ≥ 10%. This is a departure from the 2014 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) which recommended a goal blood pressure of less than 140/90 mm Hg.