diabetic nephropathy; diabetic glomerulosclerosis; Kimmelstiel-Wilson disease (DMN)
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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
- most common cause of overall cause of nephrotic syndrome in adults
- 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
Clinical manifestations
- diabetes mellitus of long duration
- evidence of microvascular disease (retinopathy)
- evidence of macrovascular disease (cardiovascular disease)
Laboratory
- urine albumin, urine creatinine (microalbuminuria)
- primary predictor of renal disease
- proteinuria precedes decline in glomerular filtration
- urine albumin/creatinine ratio at least annually
- starting with time of diagnosis type 2 diabetes
- start witin 5 years of onset for type 1 diabetes[2]
- serum creatinine
- bacteriuria is not uncommon
- low plasma renin
Management
- tight glycemic control
- delays onset of nephropathy
- prevents progression of microalbuminuria
- does not reverse diabetic nephropathy
- not effective when overt nephropathy is present
- HgbA1c < 6% or > 9% associated with excess mortality[16]
- progression to ESRD not associated with glycemic control[16]
- target hemoglobin A1c of 6.5-8.0% when eGFR > 29 mL/min[21]
- aggressive control of blood pressure (BP)
- 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]
- non-dihydropyridine Ca+2 channel blockers
- no drug better than placebo in terms of survival[15]
- 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), < 140/70 mm Hg
- systolic hypertension: goal is < 160 mm Hg
- ACE inhibitors vs ARBs
- ACE inhibitors
- diminish transglomerular capillary hydrostatic pressure
- slow progression from microalbuminuria to overt proteinuria & decrease degree of microalbuminuria or proteinuria when present
- ACE inhibitors do slow progression of diabetic nephropathy in patients with macroalbuminuria[9][10]
- 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][10]
- 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]
- GLP-1 agonists & SGLT-2 inhibitors diminish risk of hyperkalemia in patients taking ACE-inhibitors or ARBs[31]
- 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]
- 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]
- 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]
- elderly with multiple comorbidities
- relax glycemic control
- if insulin needed, use once daily long-acting insulin[28]
- diet
- dietary protein restriction (0.8 g/kg/day)[21]
- < 2 grams of sodium/day
- 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]
- beneficial role of fish oil in preventing diabetic nephropathy
- 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
- glomerulonephropathy; glomerulopathy
- chronic renal failure (CRF)
- microvascular complication of diabetes mellitus
Additional terms
References
- ↑ Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 608-609
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Medical Knowledge Self Assessment Program (MKSAP) 11, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2009, 2012, 2015, 2018, 2021.
Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022 - ↑ Prescriber's Letter 10(5):26 2003
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/15516697
- ↑ 5.0 5.1 5.2 Parving H-H et al, Aliskiren combined with losartan type 2 diabetes and nephropathy. N Engl J Med 2008, 358:2433 PMID: https://www.ncbi.nlm.nih.gov/pubmed/18525041
Ingelfinger JR Aliskiren and dual therapy in type 2 diabetes N Engl J Med 2008, 358:2503 PMID: https://www.ncbi.nlm.nih.gov/pubmed/18525047 - ↑ 6.0 6.1 Mann JFE et al Effect of telmisartan on renal outcomes: A randomized trial. Ann Intern Med 2009 Jul 7; 151:1 PMID: https://www.ncbi.nlm.nih.gov/pubmed/19451556
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: https://www.ncbi.nlm.nih.gov/pubmed/19451554
Parfrey PS Angiotensin-receptor blockers in the prevention or treatment of microalbuminuria. Ann Intern Med 2009 Jul 7; 151:63. PMID: https://www.ncbi.nlm.nih.gov/pubmed/19581647 - ↑ 7.0 7.1 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: https://www.ncbi.nlm.nih.gov/pubmed/21055801
- ↑ 8.0 8.1 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: https://www.ncbi.nlm.nih.gov/pubmed/21388309 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1007994
- ↑ 9.0 9.1 9.2 9.3 Prescriber's Letter 19(4): 2012 COMMENTARY: Treating Microalbuminuria CHART: Antihypertensive Combinations Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=280425&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 10.0 10.1 10.2 10.3 Prescriber's Letter 19(11): 2012 Which Diabetes Patients Need an ACE Inhibitor or ARB, Aspirin, and Statin? Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=281124&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis. 2007 Feb;49(2 Suppl 2):S12-154. PMID: https://www.ncbi.nlm.nih.gov/pubmed/17276798
- ↑ Johnson SL, Tierney EF, Onyemere KU Who is tested for diabetic kidney disease and who initiates treatment? The Translating Research Into Action For Diabetes (TRIAD) Study. Diabetes Care. 2006 Aug;29(8):1733-8. PMID: https://www.ncbi.nlm.nih.gov/pubmed/16873772
- ↑ de Boer IH, Rue TC, Hall YN et al Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA. 2011 Jun 22;305(24):2532-9. PMID: https://www.ncbi.nlm.nih.gov/pubmed/21693741
- ↑ Batuman V eMedicine: Diabetic Nephropathy http://emedicine.medscape.com/article/238946-overview
- ↑ 15.0 15.1 15.2 Palmer SC, Mavridis D, Navarese E et al Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis. Lancet. 385(9982):20472056, 23 May 2015 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/26009228 <Internet> http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2962459-4/abstract
- ↑ 16.0 16.1 16.2 Navaneethan SD, Schold JD, Jolly SE et al. Diabetes control and the risks of ESRD and mortality in patients with CKD. Am J Kidney Dis 2017 Aug; 70:191 PMID: https://www.ncbi.nlm.nih.gov/pubmed/28196649
- ↑ Perkovic V, Jardine MJ, Neal B et al Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. April 14, 2019 PMID: https://www.ncbi.nlm.nih.gov/pubmed/30990260 https://www.nejm.org/doi/10.1056/NEJMoa1811744
- ↑ 18.0 18.1 Pollock C, Stefansson B, Reyner D et al. Albuminuria-lowering effect of dapagliflozin alone and in combination with saxagliptin and effect of dapagliflozin and saxagliptin on glycaemic control in patients with type 2 diabetes and chronic kidney disease (DELIGHT): A randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2019 Jun; 7:429. PMID: https://www.ncbi.nlm.nih.gov/pubmed/30992195 https://www.thelancet.com/journals/landia/article/PIIS2213-8587(19)30086-5/fulltext
- ↑ 19.0 19.1 Janssen, Johnston & Johnson News Release. Sep 30, 2019 U.S. FDA Approves INVOKANA (canagliflozin) to Treat Diabetic Kidney Disease (DKD) and Reduce the Risk of Hospitalization for Heart Failure in Patients with Type 2 Diabetes (T2D) and DKD. https://www.janssen.com/us-fda-approves-invokana-canagliflozin-treat-diabetic-kidney-disease-dkd-and-reduce-risk
- ↑ 20.0 20.1 de Boer IH, Zelnick LR, Ruzinski J et al Effect of Vitamin D and Omega-3 Fatty Acid Supplementation on Kidney Function in Patients With Type 2 Diabetes. A Randomized Clinical Trial. JAMA. Published online November 8, 2019. PMID: https://www.ncbi.nlm.nih.gov/pubmed/31703120 https://jamanetwork.com/journals/jama/article-abstract/2755300
Lucas A, Wolf M Vitamin D and Health Outcomes. Then Came the Randomized Clinical Trials. JAMA. Published online November 8, 2019. PMID: https://www.ncbi.nlm.nih.gov/pubmed/31703117 https://jamanetwork.com/journals/jama/fullarticle/2755297 - ↑ 21.0 21.1 21.2 21.3 21.4 21.5 21.6 21.7 Navaneethan SD, Zoungas A et al Diabetes Management in Chronic Kidney Disease: Synopsis of the 2020 KDIGO Clinical Practice Guideline. Ann Intern Med 2020. Nov 10 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33166222 Free article https://www.acpjournals.org/doi/10.7326/M20-5938
Navaneethan SD et al. Diabetes management in chronic kidney disease: Synopsis of the KDIGO 2022 clinical practice guideline update. Ann Intern Med 2023 Jan 10; [e-pub] PMID: https://www.ncbi.nlm.nih.gov/pubmed/36623286 Free article https://www.acpjournals.org/doi/10.7326/M22-2904
Saunders M, Laiteerapong N. 2022 clinical practice guideline update for diabetes management of chronic kidney disease: An important first step, more work to do. Ann Intern Med 2023 Jan 10; [e-pub]. PMID: https://www.ncbi.nlm.nih.gov/pubmed/36623285 https://www.acpjournals.org/doi/10.7326/M22-3635 - ↑ National Kidney Foundation KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 Update. Am J Kidney Dis. 2012 Nov;60(5):850-86 PMID: https://www.ncbi.nlm.nih.gov/pubmed/43788 (corresponding NGC guideline withdrawn Jan 2018)
- ↑ Molitch ME et al. Diabetic kidney disease: a clinical update from Kidney Disease: Improving Global Outcomes. Kidney Int 2015 Jan; 87:20. PMID: https://www.ncbi.nlm.nih.gov/pubmed/24786708 PMCID: PMC4214898 Free PMC article
- ↑ 24.0 24.1 Bakris GL, Agarwal B, Anker SD et al Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl J Med. 2020. Oct 3. PMID: https://www.ncbi.nlm.nih.gov/pubmed/33264825 https://www.nejm.org/doi/full/10.1056/NEJMoa2025845
Ingelfinger JR, Rosen CJ Finerenone - Halting Relative Hyperaldosteronism in Chronic Kidney Disease. N Engl J Med. 2020. Oct 3. PMID: https://www.ncbi.nlm.nih.gov/pubmed/33095527 https://www.nejm.org/doi/full/10.1056/NEJMe2031382 - ↑ 25.0 25.1 Zelniker TA, Wiviott SD, Raz I et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: A systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2018 Nov 10; [e-pub]. (https://doi.org/10.1016/S0140-6736(18)32590-X) PMID: https://www.ncbi.nlm.nih.gov/pubmed/30424892
Verma S, Juni P, Mazer CD. Pump, pipes, and filter: Do SGLT2 inhibitors cover it all? Lancet 2018 Nov 10; PMID: https://www.ncbi.nlm.nih.gov/pubmed/30424891 - ↑ 26.0 26.1 Pasternak B et al Use of sodium-glucose co-transporter 2 inhibitors and risk of serious renal events: Scandinavian cohort study. BMJ 2020;369:m1186 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32349963 https://www.bmj.com/content/369/bmj.m1186
Smith SM SGLT2 inhibitors and kidney outcomes in the real world. BMJ 2020;369:m1584 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32349997 https://www.bmj.com/content/369/bmj.m1584 - ↑ Draznin B, Aroda VR, Bakris G, et al; American Diabetes Association Professional Practice Committee. 11. Chronic kidney disease and risk management: standards of medical care in diabetes-2022. Diabetes Care. 2022;45:S175-S184. PMID: https://www.ncbi.nlm.nih.gov/pubmed/34964873
- ↑ 28.0 28.1 Rossing P, Caramori ML, Chan JCN et al Executive summary of the KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease: an update based on rapidly emerging new evidence. Kidney Int. 2022 Nov;102(5):990-999. PMID: https://www.ncbi.nlm.nih.gov/pubmed/36272755 Free article.
- ↑ 29.0 29.1 Perkovic V et al Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. N Engl J Med. 2024. May 23 PMID: https://www.ncbi.nlm.nih.gov/pubmed/38785209 https://www.nejm.org/doi/full/10.1056/NEJMoa2403347
- ↑ American Diabetes Association Older Adults: Standards of Medical Care in Diabetes-2021 Diabetes Care 2021;44(Supplement_1):S168-S179 PubMed: 33298423
- ↑ 31.0 31.1 Fu EL et al. SGLT-2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors and risk of hyperkalemia among people with type 2 diabetes in clinical practice: Population based cohort study. BMJ 2024 Jun 26; 385:e078483. PMID: https://www.ncbi.nlm.nih.gov/pubmed/38925801 PMCID: PMC11200155 Free PMC article https://www.bmj.com/content/385/bmj-2023-078483
- ↑ 32.0 32.1 Ao Y, Ye H, Liu X et a; Fish oil supplementation in relation to the risk of chronic kidney disease among patients with diabetes. Diabetes Obes Metab. 2024 Aug 27. PMID: https://www.ncbi.nlm.nih.gov/pubmed/39192528 https://dom-pubs.onlinelibrary.wiley.com/doi/abs/10.1111/dom.15880
- ↑ 33.0 33.1 Mahaffey KW, Tuttle KR, Arici M et al Cardiovascular outcomes with semaglutide by severity of chronic kidney disease in type 2 diabetes: the FLOW trial. Eur Heart J. 2024 Aug 30:ehae613. PMID: https://www.ncbi.nlm.nih.gov/pubmed/39211948 https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehae613/7745056
- ↑ Kidney Disease of Diabetes http://kidney.niddk.nih.gov/kudiseases/pubs/kdd/index.htm