NEPHROPATHY

1. NEPHROPATHY 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada

2. INTRODUCTION • Diabetic nephropathy is the most common cause of renal failure in Canada. • Diabetic nephropathy progresses from subclinical disease, through the earliest clinically detectable stage characterized by microalbuminuria (urine albumin 30 - 300 mg/day), to overt nephropathy with macroalbuminuria (urine albumin > 300 mg/day). This can progress over time to end-stage renal disease.

3. SCREENING • Detection of microalbuminuria identifies individuals at high risk of progression to later stages of kidney disease, cardiovascular events and death. • Screening for microalbuminuria should be performed using a random urine for albumin to creatinine ratio (ACR). • The specimen should also undergo a urine dipstick test as a screen for nondiabetic renal disease.

4. SCREENING • Patients with overt nephropathy (urinary albumin > 300 mg/day, ACR > 20 mg/mmol in men, ACR > 28 mg/mmol in women) typically progress over time to more severe stages of nephropathy and rarely have normalization of urinary protein without directed therapy. • Patients with microalbuminuria (urinary albumin 30 - 300 mg/day, ACR 2.0 - 20 mg/mmol in men, ACR 2.8 - 28 mg/mmol in women) have a variable course.

5. STAGES OF DIABETICNEPHROPATHY

6. NONDIABETIC RENAL DISEASE • Conditions, besides diabetic nephropathy, that can elevate ACR include: recent exercise, fever, urinary tract infection, menstruation, acute elevated BP and congestive heart failure. • Indicators of possible nondiabetic causes for renal disease in patients with diabetes include: lack of retinopathy or neuropathy, persistent hematuria, signs or symptoms of systemic disease, rapidly rising creatinine, high creatinine with little or no proteinuria, family history of nondiabetic renal disease and short duration of diabetes.

7. CREATININE CLEARANCE • Creatinine clearance, an estimate of the kidney’s ability to filter toxins from the blood, should be determined by the Cockcroft-Gault formula rather than by serum creatinine. Serum creatinine alone may falsely indicate that a person’s kidney function is normal. Individuals can lose as much as 50% of their creatinine clearance before serum creatinine levels rise into the abnormal range. • The identification of subclinical renal dysfunction may have management consequences (e.g. drug selection and dosing, use of contrast dye during radiological investigations).

8. CREATININE CLEARANCE • Creatinine clearance should be checked annually in those without known nephropathy and at least every 6 months in those with nephropathy. Cockcroft-Gault formula: Creatinine clearance (mL/min) = • (140 - age in years) x actual weight (kg) • serum creatinine (µmol) • Multiply the result by 1.2 for men. • Normal range is > 90 mL/min, > 1.5 mL/s

9. SCREENING FOR NEPHROPATHY WHEN: Type 1 - annually after puberty and 5 years of DM Type 2 - at diagnosis and then annually WHAT: random urine ACR; and random urine dipstick Suspicion of nondiabetic renal disease? Yes Workup or referral for nondiabetic renal disease No Normal < 2.0 mg/mmol men < 2.8 mg/mmol women Rescreen in 1 year Macroalbuminuria > 20 mg/mmol men > 28 mg/mmol women Diabetic nephropathy diagnosed Check ACR results Microalbuminuria 2.0 - 20 mg/mmol men 2.8 - 28 mg/mmol women Any 2 abnormal out of 3 ACRs: Diabetic nephropathy diagnosed Only 1 abnormal ACR: Repeat screen in 1 year Up to 2 repeat random urine ACRs performed 1 week to 2 months apart

10. PRIORITIES FOR VASCULAR AND RENAL PROTECTION

11. TREATMENT OF NEPHROPATHY • Once nephropathy is diagnosed, intensive glucose control and optimization of blood pressure will help prevent its progression. • Blood pressure goals are the same as for any patient with diabetes and hypertension: < 130/80 mm Hg. • Disruption of the renin-angiotensin system by angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor II antagonists (ARBs) is the preferred method of protecting kidney function in diabetes, even in the absence of hypertension.

12. TREATMENT OF NEPHROPATHY • Patients starting therapy with an ACE inhibitor or ARB should be monitored at 1 to 2 weeks for significant worsening of kidney function or the development of significant hyperkalemia. Serum creatinine typically rises up to 30% above baseline after initiating an ACE inhibitor or ARB, and usually stabilizes after 2 to 4 weeks. • Patients who develop mild to moderate hyperkalemia should receive nutritional counselling regarding a potassium-sparing diet and consideration should be given to the use of non-potassium-sparing diuretics.

13. TREATMENT • Second-line renal protective agents (non-dihydropyridine calcium channel blockers) can be considered in those unable to tolerate an ACE inhibitor or an ARB.

14. TREATMENT OF NEPHROPATHY Choose 2nd line therapy: ACE + ARB or add non-DHP CCB or referral Monitor renal status longitudinally YES Already on ACE inhibitor? NO YES On first-line nephropathy drug? YES First line drug at maximum dose? NO NO NO Add first-line drug; Recheck ACR in 2 weeks to 2 months Titrate up; recheck ACR in 2 weeks to 2 months ACR normal? Yes Remeasure ACR in 1 year First line drugs: Type 1- ACE inhibitor Type 2 with Cr Cl > 60 mL/min - ACE inhibitor or ARB Type 2 with Cr Cl  60 mL/min - ARB

15. NEPHROPATHY- RECOMMENDATIONS • The best possible glycemic control and, if necessary, intensive diabetes management should be instituted in people with type 1 or type 2 diabetes for the prevention, onset and delay in progression of early nephropathy [Grade A, Level 1A]. • Screening for diabetic nephropathy should be conducted using a random urine ACR [Grade D, Consensus]. Postpubertal individuals with type 1 diabetes of  5 years’ duration should be screened annually. Individuals with type 2 diabetes should be screened at diagnosis of diabetes and yearly thereafter [Grade D, Consensus].

16. NEPHROPATHY- RECOMMENDATIONS • Serum creatinine levels should be measured and creatinine clearance estimated annually in those patients with diabetes without albuminuria and at least every 6 months in those with albuminuria [Grade D, Consensus].

17. NEPHROPATHY- RECOMMENDATIONS • Individuals with albuminuria should receive treatment to protect renal function, even in the absence of hypertension: • In people with type 1 diabetes and albuminuria, an ACE inhibitor should be given to reduce urinary albumin and prevent progression of nephropathy [Grade A, Level 1A]. An ARB should be considered in patients unable to tolerate an ACE inhibitor [Grade D, Consensus]. • In people with type 2 diabetes, albuminuria and creatinine clearance > 60 mL/min, an ACE inhibitor or an ARB [Grade A, Level 1A] should be given to reduce urinary albumin and prevent progression of nephropathy. • In people with type 2 diabetes, albuminuria and creatinine clearance  60 mL/min, an ARB should be given to prevent progression of nephropathy [Grade A, Level 1A].

18. NEPHROPATHY- RECOMMENDATIONS • Patients placed on an ACE inhibitor or an ARB should have their serum creatinine and potassium checked within 2 weeks of initiation of therapy and periodically thereafter [Grade D, Consensus].

19. NEPHROPATHY- RECOMMENDATIONS • The use of nondihydropyridine CCBs (diltiazem, verapamil) may be considered to reduce urinary albumin excretion in proteinuric hypertensive patients [Grade B, Level 2]. • A referral to a nephrologist or internist with an expertise in diabetic nephropathy should be considered if the ACR is > 75 mg/mmol, there is persistent hyperkalemia, there is a > 30% increase in serum creatinine within 3 months of starting an ACE inhibitor or ARB, or the creatinine clearance is < 60 mL/min [Grade D, Consensus].