Diabetic Nephropathy

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Contents 1 Introduction 2 Epidemiology 3 Pathology 4 Genetics 5 Laboratory 6 Management 7 More General Terms 8 Additional Terms 9 References

Introduction

• Stages of diabetic nephropathy:
• Stage 1

• hyperfiltration
• glomerular filtration rate 20-50% above normal
• microalbuminuria (30-300 mg/24h)

• Stage 2

• normalization of glomerular filtration rate
• early structural damage

• Stage 3

• early hypertension

• Stage 4

• progression to proteinuria > 0.5 g/day
• hypertension
• declining glomerular filtration rate ( GFR)
• stage 4 lasts 3-15 years

• Stage 5

• progression to end-stage renal disease ( ESRD)
• heavy proteinuria persists
• stage 5 lasts 1-7 years

Epidemiology

• 30-40% of insulin-dependent (type-1) diabetics; develops after 10-20 years
• 10-30% of non- insulin-dependent (type-2) diabetics; develops after 5-10 years
• 30% of hospitalized patients with ESRD
• most common cause of ESRD in the USA
• Native Americans, blacks & hispanics especially at risk

Pathology

• non-enzymatic glycosylation
• renal hemodynamic changes
• hypertension
• thickening of the glomerular basement membrane, glomerulosclerosis or Kimmelstiel-Wilson change
• mesangial expansion
• nodular & diffuse glomerular scarring or sclerosis ( Kimmelstiel-Wilson nodules)
• capsular drop lesions ( pathognomonic)
• fibrin cap lesions ( pathognomonic)
• microaneurysms of the glomerular capillaries
• other pathologic manifestations of diabetic nephropathy

• interstitial fibrosis
• tubular atrophy
• papillary necrosis
• perinephric abscess
• acute pyelonephritis
• neurogenic bladder
• hydronephrosis
• functional obstruction
• cystitis

• may be role for AKR1B1 ( aldehyde reductase)

Genetics

• susceptibility to diabetic nephropathy associated with defects in HFE protein

Laboratory

• urine albumin, urine creatinine ( microalbuminuria)

• primary predictor of renal disease
• proteinuria precedes decline in glomerular filtration

• urine albumin/creatinine ratio at least annually
• bacteruria is not uncommon
• low plasma renin

Management

• tight glycemic control

• does not reverse diabetic nephropathy
• delays onset of nephropathy
• prevents progression of microalbuminuria
• not effective when overt nephropathy is present

• ACE inhibitors

• diminish transglomerular capillary hydrostatic pressure
• slow progression from microalbuminuria to overt proteinuria & decrease degree of microalbuminuria or proteinuria when present
• ACE inhibitors or ARBs do not prevent of slow progression of diabetic nephropathy in normotensive diabetics with microalbuminuria, but may be a good choice for diabetics with hypertension [9]
• ACE inhibitors do slow progression of diabetic nephropathy in patients with macroalbuminuria [9]
• tend to decrease increasing creatinine

• angiotensin 2 receptor antagonists ( ARB)

• when ACE inhibitor is not tolerated
• do not prevent microalbuminuria or progression of microalbuminuria to proteinuria [6,9]

• olmesartan may be exception [8] (see microalbuminuria)

• avoid combination of ACE inhibitor with ARB
• combination of ARB & direct renin antagonist aliskiren may reduce proteinuria [5]

• non-dihydropyridine Ca+2 channel blockers ( diltiazem, verapamil)

• do not prevent microalbuminuria [5]
• may slow progression from microalbuminuria to overt proteinuria

• paricalcitol ( Zemplar) reduces albuminuria [7]
• dietary protein restriction (0.8 g/kg/day)
• aggressive control of blood pressure ( BP)

• ACE inhibitors
• non-dihydropyridine Ca+2 channel blockers

• diltiazem
• verapamil

• may be of benefit in limiting progression of diabetic nephropathy in patients with overt proteinuria
• decreased sodium intake to < 2 g/day
• restrict alcohol intake & encourage weight loss
• goals:

• BP < 130/80 ( mean < 100) or < 125/75 mm Hg
• systolic hypertension: goal is < 160 mm Hg

• kidney or kidney- pancreas transplantation should be considered when creatinine rises above 4 mg/dL
• reduction of formation of advanced glycosylation endproducts ( AGE) pigments may be of some benefit

• aldose reductase inhibitors
• inhibitors of nonenzymatic glycosylation

• refer to nephrologist when creatinine > 2 mg/dL

More General Terms

• chronic kidney disease (CKD)

Additional Terms

• diabetes mellitus
• glomerulonephropathy

References

1. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 608-609
2. Medical Knowledge Self Assessment Program (MKSAP) 11, 15, American College of Physicians, Philadelphia 1998, 2009
3. Prescriber's Letter 10(5):26 2003
4. Journal Watch 24(23):174, 2004 Ruggenenti P, Fassi A, Ilieva AP, Bruno S, Iliev IP, Brusegan V, Rubis N, Gherardi G, Arnoldi F, Ganeva M, Ene-Iordache B, Gaspari F, Perna A, Bossi A, Trevisan R, Dodesini AR, Remuzzi G; Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) Investigators. Preventing microalbuminuria in type 2 diabetes. N Engl J Med. 2004 Nov 4;351(19):1941-51. Epub 2004 Oct 31. PMID: &dopt=Abstract
5. Parving H-H et al, Aliskiren combined with losartan type 2 diabetes and nephropathy. N Engl J Med 2008, 358:2433 PMID: [1]
   - Ingelfinger JR Aliskiren and dual therapy in type 2 diabetes N Engl J Med 2008, 358:2503 PMID: [2]
6. Mann JFE et al Effect of telmisartan on renal outcomes: A randomized trial. Ann Intern Med 2009 Jul 7; 151:1 PMID: [3]
   - Bilous R et al. Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: Three randomized trials. Ann Intern Med 2009 Jul 7; 151:11. PMID: [4]
   - Parfrey PS Angiotensin-receptor blockers in the prevention or treatment of microalbuminuria. Ann Intern Med 2009 Jul 7; 151:63. PMID: [5]
7. de Zeeuw D et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): A randomised controlled trial. Lancet 2010 Nov 6; 376:1543 PMID: [6]
8. Haller H et al Olmesartan for the Delay or Prevention of Microalbuminuria in Type 2 Diabetes N Engl J Med 2011; 364:907-917March 10, 2011 <PubMed> PMID: [7] <Internet> [8]
9. Prescriber's Letter 19(4): 2012 COMMENTARY: Treating Microalbuminuria CHART: Antihypertensive Combinations Detail-Document#: [9] (subscription needed) [10]
10. Prescriber's Letter 19(4): 2012 COMMENTARY: Treating Microalbuminuria CHART: Antihypertensive Combinations Detail-Document#: [11] (subscription needed) [12]
11. Kidney Disease of Diabetes [13]
    - Diabetic Kidney Problems: NIH Institute and Center Resources [14]
12. National Guideline Clearinghouse
    - ACE inhibitor treatment in diabetic nephropathy Caring for Australasians with Renal Impairment ngc-guideline: [15]
    - Angiotensin II antagonists. Caring for Australasians with Renal Impairment ngc-guideline: [16]
    - Antihypertensive therapy in diabetic nephropathy. Caring for Australasians with Renal Impairment ngc-guideline: [17]
    - Control of hypercholesterolaemia and progression of diabetic nephropathy. Caring for Australasians with Renal Impairment ngc-guideline: [18]
    - Glucose control and progression of diabetic nephropathy. Caring for Australasians with Renal Impairment ngc-guideline: [19]
    - Multifactorial therapy and the progression of diabetic nephropathy. Caring for Australasians with Renal Impairment ngc-guideline: [20]
    - Protein restriction to prevent the progression of diabetic nephropathy. Caring for Australasians with Renal Impairment ngc-guideline: [21]
    - Smoking and the progression of diabetic nephropathy. Caring for Australasians with Renal Impairment ngc-guideline: [22]
    - Specific effects of calcium channel blockers in diabetic nephropathy. Caring for Australasians with Renal Impairment ngc-guideline: [23]

diabetic nephropathy (diabetic glomerulosclerosis, DMN)