Diabetic NephropathyDiabetic Nephropathy

Angus JonesAngus Jones

PlanPlan

Pathogenesis/Pathogenesis/HistopathologyHistopathology

Natural historyNatural history

Screening and preventionScreening and prevention

InvestigationInvestigation

ManagementManagement

Selected drugs and renal failureSelected drugs and renal failure

Astral trialAstral trial

Diabetic NephropathyDiabetic Nephropathy

Progressive increase in urine albumin Progressive increase in urine albumin excretion accompanied by rising BP and excretion accompanied by rising BP and declining GFRdeclining GFR

30-35% cumulative incidence30-35% cumulative incidence

Up to 40% of end stage renal diseaseUp to 40% of end stage renal disease

Strong association with cardiovascular riskStrong association with cardiovascular risk

Pathogenesis 1Pathogenesis 1

HyperglycaemiaHyperglycaemiaEarly histological lesions reversibleEarly histological lesions reversible

with normoglycaemiawith normoglycaemia

HypertensionHypertensionPredicts microalbimunuria,Predicts microalbimunuria,

Development of proteinuria paralleled by Development of proteinuria paralleled by gradual rise in BPgradual rise in BP

Correlation between BP and rate of decline of Correlation between BP and rate of decline of GFRGFR

Pathogenesis 2Pathogenesis 2

ProteinuriaProteinuriaInduces tubulointerstitial damage/contributes to Induces tubulointerstitial damage/contributes to progressionprogression

Highly selective in early diseaseHighly selective in early disease

Inflammatory mediatorsInflammatory mediatorsProtein kinase CProtein kinase C

Genetic influenceGenetic influence

HistopathologyHistopathology

Pathological features occur in both Pathological features occur in both glomerulus and interstitiumglomerulus and interstitium

Macroscopic - increase in kidney sizeMacroscopic - increase in kidney size

Microscopic Microscopic – Thickening of GMBThickening of GMB– Expansion of mesangiumExpansion of mesangium– Fibrosis in efferent and afferent arterioles Fibrosis in efferent and afferent arterioles

(nodular or diffuse glomerular sclerosis)(nodular or diffuse glomerular sclerosis)

Natural historyNatural history

19-24% of patients with 19-24% of patients with microalbuminuria go on to develop overt microalbuminuria go on to develop overt nephropathynephropathyProgressive rise in urine albumin Progressive rise in urine albumin excretion, rising BP, declining GFRexcretion, rising BP, declining GFRMicroalbuminuria can appear within 10 Microalbuminuria can appear within 10 yrs of T1DMyrs of T1DM

Natural History 2Natural History 2

GFR decline once proteinuria present GFR decline once proteinuria present 12ml/min/year untreated12ml/min/year untreatedPatients of die of other causes (CVS Patients of die of other causes (CVS disease) before ESRFdisease) before ESRF– CVS risk rises 2-3X with microalbuminuria, 9-CVS risk rises 2-3X with microalbuminuria, 9-

10X with clinical proteinuria10X with clinical proteinuria

Higher rates of ESRF in T1DMHigher rates of ESRF in T1DM

Factors associated with progression of Factors associated with progression of renal disease:renal disease:– HypertensionHypertension– Poor glycaemic controlPoor glycaemic control– Baseline albumin excretionBaseline albumin excretion– Dyslipidaemia/smoking – less consistantDyslipidaemia/smoking – less consistant

ScreeningScreening

Annual Urine ACR (ideally first pass Annual Urine ACR (ideally first pass specimen)specimen)– Repeat twice within 3-4/12 if positive if raisedRepeat twice within 3-4/12 if positive if raised– ≥≥2/3 raised = confirmed microalbuminuria2/3 raised = confirmed microalbuminuria

Annual Creatinine and EGFRAnnual Creatinine and EGFR

DiagnosisDiagnosisAlbumin:Albumin:

creatinine ratio creatinine ratio (mg/mmol)(mg/mmol)

Overnight Overnight urine urine collection collection (ug/min)(ug/min)

24hr urine 24hr urine collection collection (mg/24hr)(mg/24hr)

NormoalbuminuriaNormoalbuminuria

Female:Female:

Male:Male:

<2.5<2.5

<3.5<3.5

<20<20 <30<30

MicroalbuminuriaMicroalbuminuria

Female:Female:

Male:Male:

2.5-302.5-30

3.5-303.5-30

20-20020-200 30-30030-300

ProteinuriaProteinuria

Female:Female:

Male:Male:

>30>30

>30>30

>200>200 >300>300

Differential diagnosis of Differential diagnosis of microalbuminuriamicroalbuminuria

ExerciseExercise

Acute illness/feversAcute illness/fevers

MenstruationMenstruation

Pregnancy, pubertyPregnancy, puberty

SemenSemen

Orthostatic proteinuriaOrthostatic proteinuria

UTIUTI

Short term hyperglycaemiaShort term hyperglycaemia

Severe hypertensionSevere hypertension

LVFLVF

Other renal diseasesOther renal diseases

40% normal day to day variation in albuminuria40% normal day to day variation in albuminuria

Prevention Prevention

Glucose control:Glucose control:– 1% reduction HBA1C – 20-40% reduction in risk of 1% reduction HBA1C – 20-40% reduction in risk of

microalbuminuriamicroalbuminuria– DCCT – 39% relative risk reduction microalbuminuria DCCT – 39% relative risk reduction microalbuminuria

intensive group (A1C 7 vs 9.1%)intensive group (A1C 7 vs 9.1%)– UKPDS 30% reduced RR at 9-12 yrs A1C 7 vs 7.9%UKPDS 30% reduced RR at 9-12 yrs A1C 7 vs 7.9%– No lower HBA1C threshold foundNo lower HBA1C threshold found

BP controlBP control– UKPDS mean BP 144/82 vs 154/87 – 29% reduction UKPDS mean BP 144/82 vs 154/87 – 29% reduction

in risk of microalbuminuria over 6 yrsin risk of microalbuminuria over 6 yrs

InvestigationsInvestigations

Microalbuminuria/proteinuria – NICE guidenceMicroalbuminuria/proteinuria – NICE guidenceSuspect renal disease, other than diabetic nephropathy Suspect renal disease, other than diabetic nephropathy and consider further investigation or referral when the and consider further investigation or referral when the albumin:creatinine ratio (ACR) is raised and any of the albumin:creatinine ratio (ACR) is raised and any of the following apply:following apply:– there is no significant or progressive retinopathythere is no significant or progressive retinopathy– blood pressure is particularly high or resistant to treatmentblood pressure is particularly high or resistant to treatment– had a documented normal ACR and develops heavy proteinuria had a documented normal ACR and develops heavy proteinuria

(ACR >100 mg/mmol)(ACR >100 mg/mmol)– significant haematuria is presentsignificant haematuria is present– the glomerular filtration rate has worsened rapidlythe glomerular filtration rate has worsened rapidly– the person is systemically ill.the person is systemically ill.

Investigations 2Investigations 2

Renal impairment in diabetic patientRenal impairment in diabetic patient– Evidence of significant proteinuria/no Evidence of significant proteinuria/no

haematuria/other microvascular disease haematuria/other microvascular disease present present →→ treat as diabetic nephropathy treat as diabetic nephropathy

– No evidence of albuminuria – look for other No evidence of albuminuria – look for other disease (renovascular disease common)disease (renovascular disease common)

Management 1Management 1

Preventing progression of renal disease:Preventing progression of renal disease:– Little evidence that improving glucose control alters Little evidence that improving glucose control alters

rate of progressionrate of progressionRegression of histological changes seen 10 yrs post Regression of histological changes seen 10 yrs post pancreatic transplantationpancreatic transplantation

– BP controlBP controlCan reverse decline in albuminuria and slow/stop? decline in Can reverse decline in albuminuria and slow/stop? decline in GFRGFR

Several drugs often requiredSeveral drugs often required

Target BP <130/80 T1 and T2Target BP <130/80 T1 and T2

Management 2Management 2

ACE inhibitorsACE inhibitors– 11STST line treatment line treatment– Additional decrease in proteinuriaAdditional decrease in proteinuria– Effect plateaus – 45% reduction 2 yrsEffect plateaus – 45% reduction 2 yrs– Renal, cardiovascular and mortality benefitsRenal, cardiovascular and mortality benefits

Angiotensin 2 inhibitorsAngiotensin 2 inhibitors– Similar effects to ACE in short term studiesSimilar effects to ACE in short term studies– Long term studies A/WLong term studies A/W– Effect on non renal outcomes not yet Effect on non renal outcomes not yet

demonstrateddemonstrated

Management 3Management 3

Dual ACE/Angiotensin 2 blocker therapy?Dual ACE/Angiotensin 2 blocker therapy?– Greater reduction in proteinuriaGreater reduction in proteinuria– Short term data onlyShort term data only– High rates adverse events?High rates adverse events?

Low protein diet (?)Low protein diet (?)– <8g/kg<8g/kg

Management 4Management 4

Reduce cardiovascular risk:Reduce cardiovascular risk:– Treat as per secondary prevention Treat as per secondary prevention

(aspirin/statin)(aspirin/statin)

Avoid nephrotoxic drugsAvoid nephrotoxic drugs

Glycaemic control in renal failureGlycaemic control in renal failure

Management of established renal disease:Management of established renal disease:– In conjuction with a renal physicianIn conjuction with a renal physician– Referral guidelinesReferral guidelines

Drugs and Renal FailureDrugs and Renal Failure

Metformin – 2008 NICE guidance:Metformin – 2008 NICE guidance:– Review metformin dose if serum creatinine > Review metformin dose if serum creatinine >

130 μmol/litre or estimated glomerular 130 μmol/litre or estimated glomerular filtration rate (eGFR) < 45 ml/minute/1.73-m2.filtration rate (eGFR) < 45 ml/minute/1.73-m2.

– Stop metformin if serum creatinine > 150 Stop metformin if serum creatinine > 150 μmol/litre or the eGFR < 30 ml/minute/1.73-μmol/litre or the eGFR < 30 ml/minute/1.73-m2.m2.

Drugs and renal failure 2Drugs and renal failure 2

Sitagliptin – avoid EGFR <50Sitagliptin – avoid EGFR <50

Exenetide – avoid EGFR <30Exenetide – avoid EGFR <30

Statins – caution ERGF <30Statins – caution ERGF <30

ACE inhibitorsACE inhibitors– <25% non progressive creatinine rise on <25% non progressive creatinine rise on

introduction allowableintroduction allowable

ASTRAL TrialASTRAL Trial

806 patients with atherosclerotic renal 806 patients with atherosclerotic renal vascular disease – intervention vs medical vascular disease – intervention vs medical therapy alonetherapy alone

≥ ≥ 1 year follow up1 year follow up

No differences in the change in kidney No differences in the change in kidney function, blood pressure control or the rates function, blood pressure control or the rates of major cardiovascular illness of major cardiovascular illness

3 per cent of revascularisation - serious 3 per cent of revascularisation - serious procedural complication procedural complication

SummarySummary

Common cause of end stage renal failureCommon cause of end stage renal failure

High mortality – CVS riskHigh mortality – CVS risk

Intensive BP and CVS risk factor controlIntensive BP and CVS risk factor control