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diabetic nephropathy; diabetic glomerulosclerosis; Kimmelstiel-Wilson disease (DMN)

Stages of diabetic nephropathy: 1) Stage 1 a) hyperfiltration b) glomerular filtration rate 20-50% above normal c) microalbuminuria (30-300 mg/24h) 2) Stage 2 a) normalization of glomerular filtration rate b) early structural damage 3) Stage 3 - early hypertension 4) Stage 4 a) progression to proteinuria > 0.5 g/day b) hypertension c) declining glomerular filtration rate (GFR) d) stage 4 lasts 3-15 years 5) Stage 5 a) progression to end-stage renal disease (ESRD) b) heavy proteinuria persists c) stage 5 lasts 1-7 years Epidemiology: 1) 30-40% of insulin-dependent (type-1) diabetics; develops after 10-20 years 2) 10-30% of non-insulin-dependent (type-2) diabetics; develops after 5-10 years 3) 30% of hospitalized patients with ESRD 4) most common cause of ESRD in the USA 5) most common cause of overall cause of nephrotic syndrome in adults 5) Native Americans, blacks & hispanics especially at risk Pathology: 1) non-enzymatic glycosylation 2) renal hemodynamic changes 3) hypertension 4) thickening of the glomerular basement membrane, glomerulosclerosis or Kimmelstiel-Wilson change 5) mesangial expansion 6) nodular & diffuse glomerular scarring or sclerosis (Kimmelstiel-Wilson nodules) 7) capsular drop lesions (pathognomonic) 8) fibrin cap lesions (pathognomonic) 9) microaneurysms of the glomerular capillaries 10) other pathologic manifestations of diabetic nephropathy a) interstitial fibrosis b) tubular atrophy c) papillary necrosis d) perinephric abscess e) acute pyelonephritis f) neurogenic bladder g) hydronephrosis h) functional obstruction i) cystitis 11) may be role for AKR1B1 (aldehyde reductase) Genetics: - susceptibility to diabetic nephropathy associated with defects in HFE protein Clinical manifestations: - diabetes mellitus of long duration - evidence of microvascular disease (retinopathy) - evidence of macrovascular disease (cardiovascular disease) Laboratory: 1) urine albumin, urine creatinine (microalbuminuria) a) primary predictor of renal disease b) proteinuria precedes decline in glomerular filtration 2) urine albumin/creatinine ratio at least annually a) starting with time of diagnosis type 2 diabetes b) start witin 5 years of onset for type 1 diabetes [2] 3) serum creatinine - decline in GFR < 16 mL/min/1.73 m2 [2] 4) bacteriuria is not uncommon 5) low plasma renin Management: 1) tight glycemic control a) delays onset of nephropathy b) prevents progression of microalbuminuria c) does not reverse diabetic nephropathy d) not effective when overt nephropathy is present e) HgbA1c < 6% or > 9% associated with excess mortality [16] - progression to ESRD not associated with glycemic control [16] f) target hemoglobin A1c of 6.5-8.0% when eGFR > 29 mL/min [21] 2) aggressive control of blood pressure (BP) a) ACE inhibitors vs ARBs - ACE inhibitors & ARBs slow progression of diabetic nephropathy [2] - ACE inhibitors or ARBs do not prevent or slow progression of diabetic nephropathy in normotensive diabetics with microalbuminuria, but may be a good choice for diabetics with hypertension [9,10] - only ARBs better than placebo for preventing ESRD [15] - adequate BP control & use of an ACE inhibitor or ARB slows progression of diabetic nephropathy [2] b) non-dihydropyridine Ca+2 channel blockers 1] diltiazem 2] verapamil c) no drug better than placebo in terms of survival [15] d) may be of benefit in limiting progression of diabetic nephropathy in patients with overt proteinuria e) decreased sodium intake to < 2 g/day f) restrict alcohol intake & encourage weight loss g) goals: 1] BP < 130/80 (mean < 100), < 140/70 mm Hg 2] systolic hypertension: goal is < 160 mm Hg 3) ACE inhibitors a) diminish transglomerular capillary hydrostatic pressure b) slow progression from microalbuminuria to overt proteinuria & decrease degree of microalbuminuria or proteinuria when present c) ACE inhibitors do slow progression of diabetic nephropathy in patients with macroalbuminuria [9,10] d) tend to decrease increasing creatinine 4) angiotensin 2 receptor antagonists (ARB) a) when ACE inhibitor is not tolerated b) do not prevent microalbuminuria or progression of microalbuminuria to proteinuria [6,9,10] - olmesartan may be exception [8] (see microalbuminuria) c) avoid combination of ACE inhibitor with ARB d) combination of ARB & direct renin antagonist aliskiren may reduce proteinuria [5] 5) GLP-1 agonists & SGLT-2 inhibitors diminish risk of hyperkalemia in patients taking ACE-inhibitors or ARBs [31] 6) non-dihydropyridine Ca+2 channel blockers (diltiazem, verapamil) a) do not prevent microalbuminuria [5] b) may slow progression from microalbuminuria to overt proteinuria 7) paricalcitol (Zemplar) reduces albuminuria [7] 8) aldosterone receptor antagonist finerenone may slow decline in renal function [24] - recommended for patients with type 2 diabetes & CKD with eGFR >= 25 mL/min & albuminuria & normal serum potassium [21] 9) glycemic control [21] - target hemoglobin A1c 6.5-8.0% depending on risk of hypoglycemia - metformin & SGLT2 inhibitors (flozins) may be of benefit - dapagliflozin + saxagliptin may reduce albuminuria [18] - canagliflozin (Invokana) is FDA-approved to reduce risk of ESRD [19] - glucagon-like peptide-1 agonist (glutide) if metformin &/or flozin contraindicated or an add-on hypoglycemic agent needed [21] - consider glucagon-like peptide-1 agonist (glutide) or SGLT2 inhibitor (flozin) independent of Hgb A1c [2] - semaglutide reduces risk of renal complications & cardiovascular events & mortality in patients with type 2 diabetes regardless of baseline severity of chronic kidney disease [29,33] - SGLT2 inhibitor (flozin) if eGFR >= 20 mL/min [21] - renoprotective [25,26]; slow progression of diabetic nephropathy - once started, flozin may be continued if eGFR declines < 20 mL/min until renal replacement therapy [21] 10) elderly with multiple comorbidities - relax glycemic control - if insulin needed, use once daily long-acting insulin [28] 11) diet a) dietary protein restriction (0.8 g/kg/day) [21] b) < 2 grams of sodium/day 12) neither vitamin D or omega-3 fatty acid supplementation or both preserve renal function in patients with diabetes mellitus type 2 [20] - beneficial role of fish oil in preventing diabetic nephropathy - may be mediated by HbA1c, serum CRP & serum HDL-cholesterol [32] 13) kidney or kidney-pancreas transplantation should be considered when creatinine rises above 4 mg/dL 14) reduction of formation of advanced glycosylation endproducts (AGE) pigments may be of some benefit a) aldose reductase inhibitors b) inhibitors of nonenzymatic glycosylation 15) refer to nephrologist when creatinine > 2 mg/dL

Interactions

disease interactions

Related

diabetes mellitus

General

chronic renal failure (CRF) glomerulonephropathy; glomerulopathy microvascular complication of diabetes mellitus

References

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