DIABETIC NEPHROPATHY


Screening--see "Management of Type 2 Diabetes"

I. Nomenclature

  1. "Microalbuminuria" = 30-299mg/24h albumin excretion
  2. "Albuminuria" aka "Macroalbuminuria" = > 300mg/24h albumin excretion (some sources define as >500mg/24h)

II. Epidemiology and differential diagnosis

  1. 40% of type I and 20% of type II diabetics will develop clinically significant nephropathy
  2. Greater risk for African-Americans and Mexican-Americans than for whites with NIDDM
  3. Risk factors for development of microalbuminuria in a pateint with diabetes:
    1. Hypertension
    2. Hyperglycemia
    3. Dyslipidemia
    4. Smoking
  4. Microalbuminuria and macroalbuminuria are  both associated with higher risk of major cardiovascular events and overall mortality

  5. Differential diagnosis of albuminuria
    1. Diabetic nephropathy 
    2. Heart failureRecent exercise
    3. Hypertensive nephropathy 
    4. Severe hyperglycemia 
    5. Other intrinsic renal disease

III. Pathophysiology

  1. Early DM nephropathy is associated with increased GFR (type I > type II) resulting from:
  1. Increased plasma flow to kidney
  2. Increased transcapillary hydrostatic pressure, possibly due to decreased tone in afferent arteriole (poss. due to hyperglycemia) and/or systemic HTN
  3. It is not associated with a change in Kf (ultrafiltration coefficient)
  4. Increase in GFR and CRF avoided in animals by low protein diet & in humans by
  1. BP control
  2. ACEI's
  3. Glycemic control (possibly)-seems more associated with hyperglycemia than with hypoinsulinemia per se
  1. n.b. GFR = renal plasma flow x ultrafiltration coefficient (Kf) x (hydrostatic pressure gradient - oncotic gradient)
  1. Renal plasma flow is maintained by dilation of afferent arteriole
  2. Kf is a function of glomerular permeability and glomerular surface area
  1. Early DM nephropathy also associated with increased renal size and microalbuminuria (30-300mg/24h) and generally takes 10-15y to progress to "Overt Nephropathy," defined as nephropathy with macroalbuminuria
  1. Overt (aka "Late") DM nephropathy
  1. Mesangial expansion, replacing filtration area ("Kimmelstel-Wilson" glomerulosclerosis)
  2. Glomerular basement membrane thickening with albumin & IgG
  3. Glomerulosclerosis
  4. Macroalbuminuria
  5. Progresses steadily to decreased renal function and ESRD
    1. Rate of progression much lower in Type 2 than Type 1 DM (though data may be biased by higher risk of death from non-renal causes in Type 2 diabetics)
  6. Almost always accompanied by retinopathy

IV. Prevention & management of DM nephropathy

  1. Control of BP and glucose are essential
  2. Prevention in Type 1 DM
  1. 409 pts with IDDM and microalbuminuria (>500 mg/d) & serum Cr <2.5 randomized to captopril vs. placebo. Dose of captopril was titrated to BP; unsure what lowest dose was. Major endpoint was doubling of serum Cr; this occurred in 25 pts on captopril vs. 43 on placebo; also stat. sig. slower decline in CrCl on captopril. Risk reduction for all was greatest for those with Cr >2.0. Captopril overall ass'd with 50% risk red. in risk of (death or dialysis or transplantation) (NEJM 329:1456, 1993)
  2. 143 non-hypertensive pts with IDDM and microalbuminuria (30-300mg/24h) randomized to captopril 50mg BID vs. placebo over 2y. Captopril group had 6% progression to "clinical proteinuria" & stable CrCl; placebo group had 19% progression to "clinical proteinuria" and a sig. decrease in CrCl (Am. J. Med. 99:497, 1995)
  3. In a study of 285 normotensive pts with type 1 DM and normal urine albumin levels (most with minimal or no retinopathy) randomized to enalapril 20mg/d, losartan 100mg/d, or placebo, over 5y f/u, there was no sig. diff. in incidence of new-onset nephropathy or change in GFR; however, incidence of microalbuminuria onset was sig. higher in losartan group (17%) than enalapril or placebo groups (4% and 6% respectively).  However, retinopathy progression was sig. more common among placebo recipients (38%) than enalapril (25%) or losartan (21%) recipients. (NEJM 361:40, 2009-JW)
  4. In a study in 3,326 pts < 55yo with type 1 DM without micro- or macro-albuminuria and without HTN randomized to candesartan vs. placebo x 5y; no sig. diff. between the groups in incidence of microalbuminuria (Ann. Int. Med. 151:11, 2009-JW)
  1. Prevention in Type 2 DM
  1. With microalbuminuria
    1. Confirm microalbuminuria with 24h timed urine collection
    2. Check serum Cr and estimate GFR 
    3. Consider renal ultrasound to distinguish potentially reversible causes of renal disease 
    4. Consider renal biopsy if have microalbuminuria without retinopathy (uncommon)
    5. Limit protein intake to 0.8-1.0g/kg/d in early kidney disease, and to 0.8g/kg/d in later stages.
    6. Screen for secondary anemia (due to renal insufficiency)
    7. Close attention to glycemic and BP control.
    8. Prescribe an ACEI or ARB to reduce risk of progression even if not hypertensive (combining ACEIs + ARBs likely has no benefit and may be associated with harm).  In patients who are hypertensive, ACEI + HCTZ may further decrease the risk of macroalbuminuria.
      1. Enalapril 10mg QD vs. placebo in a double-blind study of 94 normotensive type II diabetics with microalbuminuria (30-300mg/24h) but normal renal function (Cr < 1.4). Avg. age 47; avg. duration DM 6-7y; about 60% male.
    1. Enalapril group had sig. slowing of increase in microalbuminuria and creatinine over 5y; 30% risk reduction of development of "overt proteinuria (>300mg/24h). (Ann. Int. Med 118:577, 1993)
    2. Subsequent 2yr open-label tx among pts who wanted it (about 50%) showed continued benefit to continued tx with enalapril and decline in renal function & rise in albuminuria in those who declined continued enalapril. 42% overall risk reduction for nephropathy over 7-yr period in those who got enalapril (Arch. Int. Med 156:286, 1996)
    1. Enalapril 10mg/d vs. placebo (randomized, single-blind study) in 103 nonobese, normotensive pts with type II DM with baseline albuminuria about 80mg/24h, followed for 5y; placebo group had increase in albumin excretion while enalapril recipients had decrease; at 5y; 23.5% of placebo group vs. 7.7% of enalapril group had progressed to frank albuminuria (>290mg/24h) (Diab. Care 20:1576, 1997--AFP)
    2. In a randomized trial in 590 pts with type 2 DM, HTN, serum Cr < 1.6 for men and < 1.2 for women, and albumin exrection 20-200ug/min (200ug/min = 288mg/d), randomized to irbesartan 150-300mg/d vs. placebo, over 2y f/u, sig. fewer 300mg/d irbesartan pts had progression of albuminuria (5.2% vs. 14.9%); the 150mg/d irbesartan group had intermediate incidence of this endpoint (9.7%).  Both irbesartan groups had significantly lower BP’s than placebo group, but diffs persisted after adjustment for BP differences. (Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (“IPDM”) study--NEJM 345:870, 2001)
    3. 4,912 pts > 50yo with type 2 DM and microalbuminuria randomized to Ramipril 1.25mg vs. placebo; over median 4y f/u, no sig. diff. in incidence of (cardiovascular death, MI, CVA, CHF, or ESRD) (BMJ 328:495, 2004--JW)
    4. Comparisons of ACEIs vs. ARBs
      1. In a study in 250 pts with HTN and type 2 DM and "early nephropathy" (82% with microalbuminuria, 18% with macroalbuminuria, all with serum Cr < 1.6mg/dL and GFR > 70mL/min/1.73m2) randomized to enalapril (up to 20mg/d) vs. telmisartan (up to 80mg/d), over 5y f/u, there was no sig. diff. between the groups in mean decline in BP control, GFR, degree of albuminuria, and incidence of ESRD and cardiovascular events (NEJM 351:1952, 2004--JW)
  1. Without microalbuminuria
    1. 156 pts 40-60yo with type 2 DM dx'd < 10y before, normal BP (mean BP at entry of < 107mm Hg), 24h albumin excretion < 30mg/24h, and normal serum Cr randomized to enalapril 10mg QD vs. placebo; if SBP went < 100mm Hg, enalapril dose reduced by 50%. Over 6y of f/u, sig. less risk of development of microalbuminuria and sig. less decrease in CrCl in the enalapril group (6.5% vs. 19%). Also, risk of development of retinopathy was sig. less in enalapril group (7.8% vs. 19%) (Ann. Int. med. 128:982, 1998)
    2. In a study of 1,204 hypertensive pts with type 2 DM but no microalbuminuria and serum Cr < 1.6mg/dL randomized to trandolapril, verapamil, both, or placebo; other meds added as needed to control BP.  Over median 3.6y f/u, incidence of microalbuminuria was sig. lower in pts randomized to trandolapril or trandolapril + verapamil than verapamil alone or placebo; no diff. between trandolapril monotherapy and verapamil monotherapy; no sig. diff. among groups in BP (NEJM 351:1941, 2004--JW)
    3. In a study in 1,905 pts < 75yo with type 2 DM without micro- or macro-albuminuria and without uncontrolled HTN randomized to candesartan vs. placebo x 5y; no sig. diff. between the groups in incidence of microalbuminuria (Ann. Int. Med. 151:11, 2009-JW)
    4. In a study in 4,400 pts with type 2 DM and no microalbuminuria randomized to olmesartan 40mg/d vs. placebo, over median 3.2y f/u, there was no sig. diff. in overall incidence of microalbuminuria between the two groups, but mean time to onset was sig. later in olmesartan group (722d vs. 576d); however, mean GFR declined more with olmesartan vs. placebo (5ml/min/1.73m2 vs. 1ml/min/1.73m2) and CV mortality was sig. higher in olmesartan recipients (0.7% vs. 0.1%) (NEJM 364:907, 2011-JW)
  1. Studies looking at pts both with and without microalbuminuria
    1. Lisinopril 10QD (dose subsequently adjusted) vs. placebo in 530 normotensive pts aged 20-59yo with "IDDM" and microalbuminuria (15% of pts) or normoalbuminuria; at 2y, albumin excretion was 19% lower in pts on lisinopril; most pronounced in pts with microalbuminuria. Among pts who finished the 2y study (418), the change in albuminuria reached statistical significance only for those with microalbuminura at baseline (Lancet 349:1787, 1997-JW)
    2. In a meta-analysis of 43 trials of ACEIs and/or ARBs vs. placebo or each other in pts with diabetic nephropathy, ACEIs and ARBs had similar effects on renal outcomes. However, ACEIs were ass'd with sig. reduced overall mortality c/w placebo (RR 0.79); no such reduction with ARBs (BMJ 329:828, 2004--JW)
  1. Combination lisinopril + verapamil may slow progression of DM nephropathy better than either alone (Kidney Int. 41:912, 1992; n=30)
  2. Low protein diet (0.6-0.89g/kg/d) may slow progression of early nephropathy in Type 2 DM
  1. Stabilizes CrCl (Arch. Int. Med. 147:492, 1987; Kidney Int. 29:572, 1986; both cited in NEJM article)
  2. Slowed decrease in GFR over 2-3y in crossover study (Lancet 2:1411, 1989; cited in NEJM article)
  3. ADA recommends < 0.8g/kg of ideal body wt/d
  1. Treatment of overt albuminuria & beyond
    1. ACEI's probably protective against ESRD
    2. ARB's may be useful too
      1. Losartan 100mg/d as effective as Enalapril 20mg/d at reducing albuminuria in a randomized crossover trial of 16 pts with Type 1 DM, macroalbuminuria, and normal GFR (Kidney Int. 57:601, 2000--JW)
      2. In trial in 1,715 pts with Type 2 DM, urinary protein excretion > 900mg/d, serum Cr 1-3mg/dL, and BP > 135/85, randomized to irbesartan, amlodipine, or placebo, over avg. 2.6y f/u, incidence of combined endpoint of (doubling of serum Cr or ESRD or death from any cause) was sig. lower in irbesartan pts than amlodipine or placebo pts (33% vs. 41% & 39%, respectively) (Irbesartan Diabetic Nephropathy Trial (“IDNT”)--NEJM 345:851, 2001)
      3. In a study with similar enrollment criteria in 1,513 pts randomized to losartan vs. placebo, over avg. 3.4y f/u, only slight diffs were seen in BP, but the same composite endpoint was sig. less common in losartan pts (RR 0.88).  There was no sig. diffs. In incidence of CV events.  (Reduction of Endpoints in NIDDM with Angiotensin II Antagonist Losartan (“RENAAL”) study--NEJM 345:861, 2001)
      4. 24 type 1 diabetics with albuminuria > 300mg/d and retinopathy randomized to irbesartan 300mg QD vs. placebo; all also on enalapril 40mg QD. Dual-tx pts had sig. greater reduction in albumin excretion (Kidney Int. 63:1874, 2003--JW)
    3. ACEIs and ARBs have been used in combination
    4. Spironolactone
      1. In a study of 21 pts with type 2 diabetes, albuminuria, and HTN but CrCl > 30mL/min/1.73m2 randomized to spironolactone 25mg/d vs. placebo x 8wks; at 8wks, spironolactone recipients had sig. greater decrease in mean albuminuria.  Note that the pts in this study were on ACEIs, which may have the side effect of fatal hyperkalemia when used in combination with spironolactone. (Diab. Care 28:2106, 2005--JW)
    5. Ruboxistaurin
      1. A protein kinase C beta inhibitor
      2. Associated with improved albuminuria and renal function c/w placebo in eary trials (Reported in Family Practice News, 7/2005)
    6. Continue aggressive glycemic and BP control
    7. Dietary protein restriction 
      1. ADA (1998) recommends to < 0.8g/kg/d for overt albuminuria; once GFR starts to fall, go down to 0.6mg/kg/d
    8. Dialysis when necessary
    9. B vitamins-May actually accelerate progression
      1. In a study in 238 pts with type 1 or 2 DM and diabetic nephropathy randomized to (folate 2.5g + vit. B6 25mg + vitamin B12 1mg) QD vs. placebo, at 36mos, mean GFR decrease was sig. worse in active-treatment group as was the incidence of a composite outcome of (MI, CVA, revascularization, or all-cause mortality-RR 2.0) ; no sig. diff. in incidence of requiring dialysis ("Diabetic Intervention with Vitamins to Improve Nephropathy" ("DIVINe") Trial; JAMA 303:1603, 2010-abst)

(Sources include Core Content Review of Family Medicine, 2012, "Diabetic Nephropathy"; Upjohn monograph, 1989)