An updated overview of diabetic nephropathy

Jesús Egido MD, PhD Catedrático de Medicina UAM

Jefe del Servicio de Nefrología e Hipertensión Director del Laboratorio de Patología Renal y Vascular Fundación

Jimenez Díaz. Madrid CIBERDEM

Tony Scully. S 2 | N AT U R E | VO L 4 8 5 | 1 7 M AY 2 0 1 2

Diabetes Prevalence Exploding Globally Approximately 1/3 will Develop Nephropathy

The estimated prevalence of T2DM by 2050 in de US is 1 in 3 adults

Diabetic nephropathy in type 1 diabetes: has the outlook improved since the 1980s?

Marshall et al. Diabetologia (2012) 55:2301–2306

Changing cumulative incidence of persistent proteinuria in type 1 diabetes by duration of diabetes

Steno cohort, diagnosed before 1953 Pittsburgh cohort, diagnosed 1950–1980

Intensively managed DCCT cohort, diagnosed 1978–1988

New terminology in renal diabetes field. Does it really matter?

Former term New term

Normoalbuminuria Microalbuminuria Macroalbuminuria severely increased albuminuria

>300 mg/day or >300 mg/g

moderately increased albuminuria 30 and 300 mg/day or between 30 and 300 mg/g

Normal albuminuria

<30 mg/day or 30 mg/g

Diabetic nephropathy (DN) Diabetic Kidney Disease (DKD)

Berhane et al .Clin J Am Soc Nephrol 6: 2444–2451, 2011

Quantitative albuminuria added to eGFR improves the risk for diabetes ESRD and death

2420 type 2 diabetic Pima Indians followed 1982-2005 (mean 10.2 years). 287 individuals developed ESRD

9.3 times than normo

Ten-year mortality in type 2 diabetes by kidney disease manifestation.

Afkarian M et al, J Am Soc Nephrol 24: 302–308, 2013

15,064 participants in the NHANES III

Diagnosis of diabetic nephropathy

Clinical predictors of non-diabetic renal disease

•  Lack of retinopathy •  Short duration of DM •  Hematuria (microscopic red blood cell [RBC]

or dysmorphic RBC on urinanalysis) •  Less prominent proteinuria •  Lower glycosylated hemoglobin •  Other

He F et al Diabetologia (2013) 56:457–466

Proliferative diabetic retinopathy is a highly specific indicator for diabetic nephropathy.

CLASS I: Glomerular Basement Membrane Thickening ( mild or nonspecific LM changes) - GBM > 395 nm in females and > 430 nm in males

>glomerular hyperfiltration

Pathologic classification of diabetic nephropathy Renal pathology Society . JASN 2010

CLASS IIa: Mild mesangial expansion in >25% of the observed mesangium . IIb: Severe mesangial expansion in >25% of the observed mesangium

CLASS III: Nodular sclerosis (Kimmelstiel-Wilson lesions ), at least one convincing Kimmelstiel-Wilson lesions

CLASS IV : Advanced diabetic glomeruloesclerosis ( Global glomerular sclerosis in > 50% of glomeruli)

Interstitial and vascular lesions

The modern spectrum of renal biopsy findings in patients with diabetes

Sharma SG et al. Clin J Am Soc Nephrol. 2013 Jul 25

Among 2642 native kidney biopsies , 620 (23.5%) were from patients with diabetes (year 2011)

Acute tubular necrosis, hypertensive nephrosclerosis and a myriad of glomerular lesions: focal segmental glomerulosclerosis, IgA nephropathy, and membranous nephropathy , among others

Diabetic nephropathy with superimposed IgA nephropathy

Acute kidney injury episodes and chronic kidney disease risk in diabetes mellitus

Thakar Charuhas V. et al. Clin J Am Soc Nephrol 6: 2567–2572, 2011

Frequency of reaching stage 4 CKD by patient groups.

3679 diabetics followed 1999-2008; 1822 required at least one hospitalization ; 530 of 1822 patients experienced one AKI episode ;157>2 AKI

Hazard ratio for reaching stage 4 CKD: AKI 3.56, proteinuria 3.54, hypertension 1.82

Normoalbuminuric chronic kidney disease (eGFR<60) in type 2 diabetes

•  NHANES III, 36% of adults with type 2 diabetes. JAMA 2003; 289:3273–3277.

•  UKPDS-74 : 51%. Diabetes 2006; 55:1832–1839.

•  Austin Health, Melbourne, Australia .23%. .Diabetes Care 2004; 27:195–200.

•  Bardoxolone trial 30% of participants ( stage CKD 4 were normoalbuminuric)

Histological appearances representative of normoalbuminuric cases.

normal glomerulus and arteries

advanced diabetic GS and arteriosclerosis

minimal mesangial expansion and severe arteriosclerosis

Ekinci EI et al.

Diabetes Care. 2013 Jul 8

N=6

1. Strict control of blood glucose,blood pressure and lipids 2. Decreasing proteinuria beyond the RAS 3. Emergent therapies modulating intracelullar pathways

Treatment approach in patients with diabetes kidney disease

Nutritional management and physical activity are also key elements in patients with diabetes and CKD

Friedman et al. Clin J Am Soc Nephrol 8: 2013

Short-term changes after a weight reduction intervention in advanced diabetic nephropathy

36% reduction in albuminuria Significant reduction in serum creatinine

Six obese individuals with advanced diabetic nephropathy (estimated GFR ,40 ml/min per 1.73 m2, urine albumin excretion >30 mg/d) . 12% reduction in weight (12 weeks)

Summary of recommendations for glycemic , blood pressure, and lipid control for most adults with diabetes. ADA 2012

ADA .Diabetes Care; Jan 2012; 35. S11

Glycated Hemoglobin and the Risk of Kidney Disease in Adults

11,357 participants followed for 14 years (ARIC Study)

Stepwise logistic regression analysis model of DKD progression (n = 270)

Nephrol Dial Transplant (2012) 27: 1847–1854

A study of the natural history of diabetic kidney disease (DKD)

Selvin et al.Diabetes 60:298–305, 2011

Intensive vs conventional glucose therapy on Albuminuria in patients with diabetes and CKD. A KDOQI review

Patients with type 1 or 2 diabetes; from 2003 to 2010; 5 studies (n =27,159)

A Systematic Review for a KDOQI Clinical Practice Guideline Am J Kidney Dis. 2012. 60:747-769

Hyperglycemia control on renal function in patients with diabetes and CKD.

A KDOQI review

A Systematic Review for a KDOQI Clinical Practice Guideline

A strict blood glucose control was associated with a 2.5-fold increase in severe hypoglycemia

The long-term risk of RENAL FAILURE was significantly lower on intensive vs conventional therapy

The DCCT/EDIC Research Group*

N Engl J Med. 2011 December 22; 365: 2366–2376

1,441 patients with type I diabetes

• UKPDS 80 4309 patients T2DM, 17 years follow up reduction in cardiovascular lesions •  Post hoc ADVANCE trial ; 11,140 participants, intensive vs conventional , 5 years follow up

Perkovic V et al. Kidney International (2013) 83, 517–52

Am J Kidney Dis. 2012;60:850-886

microalbuminuria

Vejakama P et al . Diabetologia 2012. 55:566–578

Reno-protective effects of renin–angiotensin system blockade in type 2 diabetic patients: a systematic review and network meta-analysis

ACEI/ARB vs

Vejakama P et al . Diabetologia 2012. 55:566–578

Reno-protective effects of renin–angiotensin system blockade in type 2 diabetic patients: a systematic review and network meta-analysis

Doubling of serum creatinine ACEI/ARB vs

The same was seen on ESRD (End -Stage Renal Disease)

Decreasing residual proteinuria in Diabetes Kidney Disease

•  Pentoxifylline :mean reduction 15% •  Omega -3 :mean reduction 18% •  Glycosaminoglycans (Sulodexide) :SunMACRO trial ,no effect •  Thiazolidinediones : mean reduction 24%; increase CV events

•  Mineralcorticoid receptor antagonists :mean reduction 30-40% •  Endothelin antagonists :mean reduction 40% (Atrasentan Trial; SONAR)

•  VDR activators (Paricalcitol): mean albuminuria reduction 28%

The treatment with either ACEi or AT1R reduces proteinuria by 35%

The addition of Aldosterone antagonists to RAS blockers reduces proteinuria in diabetic and non diabetic CKD patients

Navaneethan SD et al. Clin J Am Soc Nephrol 2009:4; 542-551

A meta-analysis of 7 trials, 372 patients

Increase risk of hyperkalemia. Need of long-term renal outcomes and

mortality

% of patients with proteinuria reduction >50% of baseline values during follow up

Morales E , Nephrol Dial Transplant 2013 ;28:405-12

30 40 50 60 70 80 90

100

1 6 12 24 36 48 Last visit

Months

%

All patients Diabetics eGFR<60 mL/min/1.73 m2

72 patients with CKD and proteinuria receiving spirolactone (25mg/day) in addition to RAS blockade for 48 months

2013

Diabetic retinopathy

Atherosclerotic lesions

Diabetic Nephropathy

JAK/STAT pathway inhibitors in diabetic nephropathy

With or without hyperlipidemic

Diabetic mice

Local administration of jak/stat inhibitors compounds

e-PREDICE Early Prevention of Diabetes Complications in Europe FP7-HEALTH-2011

To assess the long-term effects of different therapeutic regimens, both

pharmacological and lifestyle interventions, for the early prevention of

diabetic complications in 3,000 people with intermediate hyperglycaemia

and screen-detected diabetes.

The biobank is located at IISFJD

“Millions of high-risk people can avoid developing type 2

diabetes by losing 7% of their body weight”

Renal and Vascular Research Lab.

Fundación Jiménez Díaz . Autónoma University. Madrid.