Diabetic Nephropathy

Diabetic kidney disease is the most common cause of kidney failure.

20-40% of diabetics get diabetic kidney disease.  It typically occurs after 5 years of diabetes.  Remember that the true duration of diabetes is often not known in patients with type 2 as the patient may have had the condition undiagnosed for a period of time.

Diabetic nephropathy is a microvascular complication.  Other microvascular complications are retinopathy and neuropathy.

Macrovascular complications include coronary artery disease and peripheral arterial disease.

What happens:  The pathophysiologic process

Hyperfiltration

The diabetic state initially causes an increase in glomerular filtration rate (GFR).  This is referred to as hyperfiltration.  This turns out to be bad for the kidney as it leads to increased glomerular pressure.

Silent Disease – Early pathologic changes

Mesangial Matrix deposition in the glomeruli and basement membrane thickening. These pathologic findings occur before clinical manifestations (GFR and urine albumin creatinine ratio remain normal).

Incipient Diabetic Nephropathy

This is manifest by microalbuminuria (microalbumin creatinine ratio 30-300 micrograms per milligram

Overt proteinuria

(Microalbumin creatinine ratio > 300), which may be in the nephrotic range.  Predictive of kidney failure.

Decrease in GFR

This is associated with a specific finding on kidney biopsy – nodular glomerulosclerosis.  This is referred to as the Kimmelstiel-Wilson (KW) lesion (or KW disease)

This is the classic progression observed in patients with type 1 diabetes.  In type 2 diabetes a decrease in eGFR may occur without significant albuminuria.  Biopsy in these cases often shows pathology of diabetic nodular glomerulosclerosis.

Diagnosis

Although diabetic nephropathy has the distinct pathology of nodular glomerulosclerosis, kidney biopsy typically is not performed and the diagnosis is presumptive.  2 questions should be asked to make the presumptive diagnosis:

1. Is the clinical picture characteristic of diabetic nephropathy?
2. Are there findings that suggest an alternative or additional diagnosis?  (Remember there may be background diabetic nephropathy on biopsy with an additional glomerular disease causing the clinical presentation).
3. Is the clinical picture characteristic of diabetic nephropathy?  What are the clinical characteristics?
   1. Duration of diabetes > 5 years
   2. Other associated microvascular complications.  (Specifically diabetic retinopathy)
   3. Presence of albuminuria.  Typically overt albuminuria ( albumin creatinine ratio > 300 microgram per milligram).  This typically occurs prior to decrease in GFR.
4. Findings suggestive of an alternative diagnoses.
   1. Active urine sediment such as glomerular hematuria (dysmorphic red blood cells) or the presence of casts.  (Patients with diabetic nephropathy may have microscopic hematuria, although dysmorphic RBC are uncommon).
   2. Rapidly worsening albuminuria or nephrotic syndrome. (Increase by more than 5-10 fold over less than 1-2 years)
   3. Rapidly worsening kidney function (decrease in GFR > 5 ml/min per year).
   4. Other systemic disease associated with kidney disease.

If the patient does not have the typical clinical characteristics listed in 1 or has any of the findings listed in 2 consider the possibility of another kidney disease.  This means consider a kidney biopsy.

What happens in real life?  My approach.

Patient presents with severe proteinuria (protein creatinine ratio > 1000 mg/gram) or nephrotic range proteinuria (protein creatinine ratio > 3500 mg/gram), with or without a decrease in GFR.

In these cases I take the following steps:

1. Serologic evaluation for nephrotic glomerular disease (link) – Causes of Nephrotic Syndrome, Evaluation of Nephrotic Proteinuria | BCNephro
   1. ANA
   2. Complements (C3 and C4)
   3. Hepatitis B surface antigen and Hepatitis C antibody
   4. HIV
   5. Phospholipase A2 receptor antibody
   6. Serum free light chains (kappa and lambda)

1. Consideration of renal biopsy.  I use the following factors in deciding to perform a biopsy:
   1. Positive serology suggestive of an alternative diagnosis
   2. Age of patient (more likely to perform in a younger patient)
   3. Rapidly decreasing kidney function/GFR
   4. Presence of full blown nephrotic syndrome (edema, hypoalbuminemia, hyperlipidemia)
   5. Lack of significant improvement in proteinuria with medical management including BP controlled to target (<130/80), RAS blocker (ACE-I or ARB), SGLT2 inhibitor and/or mineralocorticoid receptor antagonist .

There is also the possibility of a patient with diabetes presenting with a decrease in GFR without significant albuminuria.  In this case a kidney biopsy may also be considered.

Kidney Biopsy:  The kidney biopsy shows the lesion of nodular glomerulosclerosis.  This is also called Kimmelstiel-Wilson (KW) disease.  However, this pathologic lesion can be found in other conditions.

• Diabetes with decreased GFR without significant albuminuria
• Non diabetics with significant albuminuria (particularly smokers)
• Light Chain Deposition Disease. A monoclonal paraproteinemia typically with kappa light chain restriction.

Treatment

• Diabetic control
• BP control
• Proteinuria

Diabetic control

Is obviously important:

• Metformin – (eGFR > 30)
  • Many (especially patients) believe metformin is contraindicated in advanced CKD because it is nephrotoxic. It is not nephrotoxic.  The reason it is contraindicated is because of an increased risk of metformin induced lactic acidosis in patients with low eGFR.
• SGLT 2 inhibitor – (eGFR > 20)
• GLP agonist – (if HgA1c not at target)

Hypertension control

You get more bang for your buck by controlling blood pressure than for  blood glucose.  Target BP is < 130/80

Proteinuria

Controlling BP helps control proteinuria.  Recommended medications are:

• Renin Angiotensin System (RAS) Blockers (Angiotensin Converting Enzyme (ACE) inhibitors of Angiotensin Receptor BLockers (ARB)
  • Hypertension
  • Albumin creatinine ratio > 30

RAS blockers have been shown to:

• Decrease progression from microalbuminuria to macroalbuminuria link

https://www.nejm.org/doi/10.1056/NEJMoa011489?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200www.ncbi.nlm.nih.gov

• Decrease risk of death, end stage kidney disease or doubling of creatinine in patients with overt albuminuria link https://www.nejm.org/doi/10.1056/NEJMoa011303?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200www.ncbi.nlm.nih.gov

• SGLT 2 inhibitor: Add on to RAS blocker if:
  • Albuminuria (albumin creatinine ratio > 200) and eGFR > 20 and/or
  • Diabetes not at target and already on (or cannot take) metformin and
  • No contraindication ( Urinary tract infections, risk for Fournier’s gangrene)

SGLT 2 inhibitors have been shown to decrease the risk of cardiac or renal death, end stage kidney disease or decrease in eGFR by 50% in patients on an RAS blocker and albumin creatinine ratio of 200-5000 mg/gram. (Subgroup of microalbuminuria < 300 mg/gram was not analyzed) link

Dapagliflozin in Patients with Chronic Kidney Disease | NEJM

• Mineralocorticoid Receptor Antagonist (MRA) –
  • Non steroidal MRA: Finerenone if:
    • Unable to use SGLT2 inhibitor
    • Persistent albuminuria despite RAS blocker and SGLT2 inhibitor.

Finerenone has been shown to decrease incidence of renal death, kidney failure, or decrease in eGFR by 40% in patients with overt albuminuria or microalbuminuria with retinopathy already on RAS blockers. Link

Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes | NEJM

• Spironolactone/ Eplerenone
• Hypertension not controlled to target despite RAS blocker.

Summary – My Approach

1. Diabetic patient with albuminuria (> 30 mg/gram) or HTN – Treat with maximally tolerated dose of RAS blocker (ACE-I or ARB).
2. If blood pressure is not at target (<130/80) on maximal dose of RAS blocker (or intolerant of RAS blocker) look at potassium.
   1. Potassium high or high normal add diuretic (typically chlorthalidone).
   2. Potassium low or low normal add spironolactone.
3. If blood pressure is not at target after step 2 add agent not used in step 2.
4. If overt albuminuria (>300 mg/gram) with blood pressure controlled to target add SGLT2 inhibitor (unless contraindication)
5. If overt albuminuria (>300 mg/gram) with blood pressure controlled to target and contraindication to or intolerance of SGLT2 inhibitor and contraindication to spironolactone (or spironolactone not required for BP control) add Finerenone.