Diabetic Nephropathy

Definition
A microvascular complication of diabetes marked by albuminuria and a deteriorating course from normal renal function to ESRD.

Current Terminology
Kidney, not Renal (or Reno) CKD, not CRF DKD (= diabetic nephropathy) AKI, not ARF Still ESRD (End Stage Renal Disease) Still RRT (Renal Replacement Therapy)

Redefinirea DKD
BRC aparuta la un pacient cu DZ Dg: -macroalbuminurie, indiferent eRFG -eRFG<60, indiferent albuminurie -microalbuminurie + retinopatie prolif. ND presupune + PBR cu glomeruloscleroza nodulara

ESRD Incidence Counts and Rates by Primary Diagnosis (USRDS, 2006)

Better CKD Management?

Importance of Diabetic Kidney Disease

Kidney disease as diabetic complication:
30% of Type 1 Diabetes 40% of Type 2 Diabetes

CKD amplifies CVD risk of diabetes

Pathology
Leziuni specifice
Leziuni nespecifice, dar cu frecventa mai mare si evolutie particulara: - macroangiopatia renala (ATS) - nefroangioscleroza - infectii

Pathology DZ 1
Expansion of mesangial matrix with diffuse and nodular glomerulosclerosis (Kimmelstiel-Wilson nodules) (40-50%) Thickening of glomerular and tubular BM Arteriosclerosis and hyalinosis of afferent and efferent arterioles Tubulointerstitial fibrosis Progresia relativ uniforma a leziunilor

Pathology DZ 2
Heterogenitate crescuta a leziunilor Leziuni glomerulare caracteristice 30-50% Aspect pseudonormal in MO 30% Leziuni caract. altor BRC (GNC) 20-30% Leziuni tubulo-interstitiale si vasculare disproportionat de severe Atrofia tubulara, scleroza interstitiala-R ESRD

Glomerulus = filtering unit

Pathogenesis
Exposure to the diabetic milieu Hyperglycemia
Induce mesangial expansion and injury Increased activity of growth factors Activation of cytokines Formation of ROS accumulation of advanced glycosylation endproducts in tissues

Accumulation of ECM components, such as collagen

Pathogenesis
Genetic predisposition to or protection from diabetic nephropathy
Differences in prevalence of microalbuminuria, ESRD in different patient populations Only half of patients with poor glycemic control will develop diabetic nephropathy Family studies

Multiple genes may be involved

Clasificarea Mogensen
Stade 1 : hyperfiltration glomrulaire Augmentation du taux de filtration glomrulaire de plus de 25% Stade 2 : lsions histologiques paississement de la membrane basale glomrulaire, dpt hyalin dans les artrioles glomrulaires et expansion msangiale Stade 3 : nphropathie dbutante Microalbuminurie: 30 mg/j 300 mg/j RAC* : 2 mg/mmol 20 mg/mmol chez lhomme 2,8 mg/mmol 28 mg/mmol chez la femme Stade 4 : nphropathie patente Diminution du taux de filtration glomrulaire Protinurie permanente: Albuminurie 300 mg/j RAC : 20 mg/mmol chez lhomme 28 mg/mmol chez la femme Stade 5 : insuffisance rnale terminale (eRFG <15ml/min)

Natural History

Diabetic Kidney Disease Screening

WHEN
Type 1: after 5 years, then annually Type 2: at diagnosis, then annually

HOW
Albumin-to-Creatinine ratio in random urine
Microalbuminuria = 30-300 mg/g Macroproteinuria

Estimate GFR (eGFR) from serum creatinine using formulas Retinopathy: useful clue

Formulas for Estimating GFR

CKD-EPI Cockcroft-Gault MDRD (Modification of Diet in Renal Disease Study)
GFR calculator (www.kidney.org)

GFR depends on:

Serum creatinine Age Gender Race

Diagnosis/Screening
Spot urine albumin : creatinine ratio 24 hour urine collection Dip stick
2/3 determinari pozitive in 3-6 luni

Dg diferential
Indicatii PBR chiar daca DZ: Absenta retinopatiei Hematuria macroscopica Durata DZ 1 sub 10 ani la debutul proteinuriei Elemente clinice sau bc ale unei afectari multisistemice Degradarea rapida a functiei renale (>2-3ml/min/luna) Instalarea brusca a unui SN Azotemie (eRFG<60) fara proteinurie Reducere >30% a eRFG in prima luna dupa introducerea IEC

Interventions to Slow CKD Progression

Strong evidence
Blood pressure control ACEI / ARB Glucose control in DM

Weaker evidence
Protein restriction Lowering LDL cholesterol

 Hypertension control:
Lower the BP, slower the decline in GFR in patients with diabetic nephropathy JNC VI recommended BP < 130/85 mmHg in patients with renal insufficiency Patients with CKD and > 1g proteinuria, BP goal should be < 125-130/75-80 mmHg

 Hypertension control:
Linia I: IEC, BRA, diuretice tiazidice Linia II: BCC, BB, alfa-blocante

 Glycemic control
DCCT
1441 patients with type I DM randomly assigned to intensive therapy vs. conventional therapy Intensive therapy reduced microalbuminuria by 39% Reduced albuminuria by 54%

Tinta HbA1c < 7% (ADA), < 6.5% (IDF) Repaglinida Insulina

Management of Albuminuria in Normotensive Diabetic

Normotensive DM patients with macroalbuminuria should be treated with ACEI / ARB

Normotensive DM patients with microalbuminuria : ACEI or ARB should be considered doses croissantes toutes les deux huit semaines jusqu lobtention des doses optimales.

 Il est primordial de traiter la protinurie de faon vigoureuse pour rduire la pression intraglomrulaire et ainsi freiner la dtrioration de la fonction rnale.

Lobjectif vis est une diminution de 60 % de la protinurie initiale ou latteinte dun rapport albumine/cratinine urinaire infrieur 30 mg/mmol.

 ACE inhibitors:
Type I diabetes with nephropathy: Lewis et al. NEJM, 1993. captopril vs. placebo 50% RR of combined end points of death, dialysis and transplantation in ACEI group independent of BP

Angiotensin-receptor blockers:
RENAAL study(2001) 1513 pts with type II DM and nephropathy. Losartan vs. placebo. Losartan reduced the rate of doubling of cr by 16% but no effect on the rate of death. IDNT(2001) 1715 type II DM pts with nephropathy. Irbesartan vs. amlodipine vs. placebo. Irbesartan has 20% lower risk of reaching endpoints compared to placebo and 23% lower incidence than that in the amlodipine group

Conclusions:

ACE inhibitors or ARB have a strong antiproteinuric effect apart from their antihypertensive actions Increasing the dose of the ACEI or ARB beyond the optimum antihypertensive doses further reduces proteinuria Antiproteinuric effect is enhanced by a low Na diet or diuretic ACE inhibitors, ARBs, and nondihydropyridine calcium channel blockers have a greater antiproteinuric effect than other antihypertensive classes in hypertensive patients with DKD

Target dietary protein intake : 0.8 g/kg / day

 Lowering LDL cholesterol:

- Target LDL-C in diabetes and CKD stages 1-4 should be < 100 mg/dL; <70 mg/dL is a therapeutic option. - statin - Treatment with a statin should not be initiated in patients with type 2 diabetes on maintenance hemodialysis who do not have a specific cardiovascular indication for treatment.

Treatment - conclusions
Early screening Tight glycemic control HTA management Use ACEI as first line, if not tolerated, use ARB. Use the maximum dose as tolerated If still hypertensive or proteinuric, consider using combination ACEI and ARB, or ACEI and diuretics

AKI Superimposed on CKD

Dehydration BP too low Obstruction Contrast dye Drugs
Nephrotoxic or allergic or hemodynamic NSAID (including Cox-2 inhibitors) ACEI / ARB

 Lvolution de la nphropathie est habituellement associe au dclin progressif du taux de filtration glomrulaire. Deces prin - ESRD 59-66% (DZ 1 + DKD) - BCV 15-25%

 Supravietuirea in la 1 an la 3 ani la 10ani

HD DP 75% 75% 50% <10% rara

Tx >90% 85; 68% 25%

Posttransplant evolution
Diabetic glomerulosclerosis recurs in renal allografts from 2 to 10 years after transplantation. The earliest and most frequent change is arteriolar hyalinosis. Less than 10% of kidneys develop overt nodular sclerosis. In patients with type 1 DM, simultaneous pancreatic transplantation can protect against recurrent diabetic nephropathy. In patients with type 1 DM, pancreas transplantation can reverse the pathologic lesions of diabetic nephropathy, although reversal requires more than 5 years of normoglycemia .