dm nephropathy

DIABETIC NEPHROPATHY

BY DR MALLUM C.BNEPHROLOGY UNIT

DEPT OF INTERNAL MEDICINEJUTH

INTRODUCTION

• DN (overt nephropathy): clinical syndrome characterized by persistent albuminuria(>300mg/d or 200µg/min), on at least two occasions separated by 3-6 months (attributable to DM)

• Relentless decline in GFR

• Elevated arterial BP

HISTORY

• Proteinuria was 1st recognized in DM in the late 18th century.

• The syndrome was discovered by British physician Clifford wilson(1906-1997) and American physician Paul Kimmelstiel (1900-1970) and published for the first time in 1936.

EPIDEMIOLOGY

• Leading cause of CRF in US & other western countries.(30-40% of all ESRD in US)

• The syndrome can be seen in patients with chronic diabetes(>15yrs after onset)

• Approx 50% of patients with DM > 20yrs have this syndrome.

• Majority of patients have NIDDM.

• Rarely develops before 10 yr’s duration of Type 1 DM

• Approx 3-5% of Type 2 DM have overt nephropathy

• More common in males.

• High prevalence in Pima indians,blacks,peopleof carribean descent.

• More common in older age group(50-70yrs)

• Nearly half of newly diagnosed T2DM have microalbuminuria in Jos

EPIDEMIOLOGY

• Incidence of microalbuminuria in type 1 DM was 12.6% over 7.3 yrs according to European Diabetes prospective complications Study group . Incidence was 33% in an 18yr follow up in a study in Denmark.

• In the UK prospective diabetes study(UKPDS)

Incidence of microalbuminuria was 2% per year.

Prevalence 10 yrs after diagnosis was 25%

RISK FACTORS IN UKPDS 74

Renal impairment• Increased SBP• UAE• Plasma creatinine• Indian-Asian ethnicity• Female sex, • Decreased waist circumference,• Age, • Increased insulin sensitivity, • Previous sensory neuropathy

RISK FACTORS IN UKPDS 74

Albuminuria• Increased SBP• UAE• Plasma creatinine• Indian-Asian ethnicity• Male sex, • Increased waist circumference,• Plasma triglycerides, LDL cholesterol, • HbA1c,• Increased white cell count,• Ever having smoked,• Previous retinopathy

PATHOGENESIS

• Various mechanisms postulated

-Metabolic pathway

-Mechanical/hormonal pathway

Nigerian Society of Endocrinology & Metabolism, Jos, 2006

METABOLIC PATHWAY

• Hyperglycemia-

Glucotoxicity alters expression of glycoprotein synthesis

De Novo synthesis of Heparan sulfate and total GAG content of GBM is reduced resulting in loss of negative charge of GBM and thus proteinuria

Nigerian Society of Endocrinology & Metabolism, Jos, 2006

Brownlee M. Nature 2001;414:813-820.

Potential Mechanism by Which Hyperglycemia-Induced Superoxide

Overproduction May Activate Pathways of Hyperglycemic Damage

HYPERGLYCEMIA

• Advanced glycosylation Endproducts(AGE)-Non enzymatic glycosylation of amino groups on

protein.Structural and circulating proteins.-AGEs cross-link proteins and alter extracellular

matrix structureAGEs accumulates in arterial wall and GBM.Reduced degradation of glycosylated proteins leads

to their accumulation in and expansion of GBM and mesangial matrix

Accumulation of GBM parallels renal insufficiency.

Nigerian Society of Endocrinology & Metabolism, Jos, 2006

Brownlee M. Nature 2001;414:813-820.

Mechanism by Which Intracellular Production of Advanced Glycation

Endproduct (AGE) Precursors Damage Vascular Cells

• Cytokines(IL 1 & TNF) synthesized by membrane bound receptor which scavenges denatured proteins.

• These cytokines increase vascular permeability, cellular proliferation,proteinsynthesis

HYPERGLYCEMIA

• Aldose reductase(AR)- present in papillae, glomerular epithelial cells,distal tubular cells,mesangial cells.

Converts intracellular glucose to sorbitol leading to cellular dysfunction

Sorbitol depletes myoinositol & NADPH leading to oxidative injury.

Increased GFR,decreased proteinuria induced experimentally by inhibitors of AR & myoinositolsupplementation

Nigerian Society of Endocrinology & Metabolism, Jos, 2006

Increased Aldose Reductase Activity and the

Polyol Pathway Contribute to Cellular Oxidative Stress

Brownlee M. Nature 2001;414:813-820.

HYPERGLYCEMIA

• DAG- activates protein kinase C(Beta & delta isoforms) and affects gene transcription for collagen and extracellular matrix

• Decreased eNOS-• Increased Endothelin-1-• Increased VEGF-• Increased TGF-B• Increased PAI-I• Increased NF-kappa B• Increased NADPH oxidase

• Three major histologic changes occur

1.Mesangial expansion : AGEs

2.GBM thickening- augmented thickening or diminished removal.GBM turnover usu takes a year. Inc alpha-2 macroglobulin inhibits mesangial proteases.

3.Glomerular sclerosis

HAEMODYNAMIC/HORMONAL PATHWAY

• Elevated GFR,Renal plasma flow,glomerularcapillary pressure mediate hyperfiltration.

• Elevated glomerular pressure causes physical stress which damages endothelial and epithelial surface.

• Disruption of glomerular barrier leads to accumulation of plasma and lipo- proteins in mesangium.

• There is mesangial expansion secondary to mesangial matrix production from mesangialproteins & suppression of matrix degradation.

• Vasoactive hormones like AG2 and Endothelins mediate these haemodynamicevents.

• Increased Renal expression of TGF-alpha causes renal hypertrophy in DN.

Hyperfiltration-

• Afferent arteriolar vasodilation- secondary to hyperglycemia

• Intraglomerular pressure increases local shearing forces and mesangial cell hypertrophy and extracellular matrix secretion.

• Glomerular sclerosis (Hyalinization)

• Renal hypertrophy in early stages

Nigerian Society of Endocrinology & Metabolism, Jos, 2006

NATURAL HISTORYTYPE 1 DM

• First few yrs-Hyperfiltration, Renal hypertrophy: Raised GFR• 0-5 yrs-GBM thickening,mesangial volume expansion:GFR returns to normal• 5-10 yrs-40% microalbuminuria ,hypertension• 15-25yrs-Overt proteinuria,steady decline in GFR, 50% reach

ESRD in 7-10 yrs

NATURAL HISTORY (TYPE 2)

• Differs from type 1 in that,

-overt proteinuria may be present at diagnosis

-More commonly assoc with hypertension

-Microalbuminuria less predictive of progression

r/o other causes of proteinuria

Hypertension,CCF

Prostate disease

Infection

CLINICAL FEATURESHistory

• -Known diabeticMay present with other complicationsUsually also have concurrent diabetic retinopathy –

virtually all Type 1, and 50-60% of Type 2(if no retinopathy, doubt DN)Oedema secondary to Nephrotic syndromeOther assoc features like hypertension,vascular

occlusive disease,coronary artery diseaseRisk factors for parenteral disease- HIV,Hep B,Hep CUrinary symptoms- UTI,obstruction,stone

• Family history of kidney disease-PKD

• Hypertension during childhood, past history of coke coloured urine or proteinuria-Glomerulonephritis

PHYSICAL EXAMINATION

• Hypertension

• Fundoscopy or fluorescein angiography-diabetic retinopathy

• Peripheral vascular occlusive disease(decreased pulses,carotid bruits)

• Diabetic neuropathy(decreased sensations,diminished tendon reflexes)

• Non healing ulcers/osteomyelitis

DIFFERENTIAL DIAGNOSIS

• Other glomerulopathies

• Interstitial nephritis

• Nephrotic syndrome

• Amyloidosis

• Multiple myeloma

• Renovascular disease

INVESTIGATIONS

• Urinalysis-Annual urinalysis recommendedScreening at diagnosis in type 2 DM(7%

microalbuminuria)5 yrs after diagnosis in type 1 DM-except puberty or

poor glycemic control(18%)With microalbuminuria disease is potentially

reversible.Proteinuria -150mg/dl to >300mg/dl (overt

nephropathy)

INVESTIGATIONS

• 24 hour & timed urine samples cumbersome

• Spot urine sample-

Results of albumin measured as urine albumin conc(mg/L) or urine albumin/creatinine(mg/g or mg/mmol)

Cut off of 17mg/L or 20mg/L(European policy diabetes group)

2 or 3 abnormal samples over 3-6mth period

• Immunoassays for albumin measurement

(may not detect unreactive fraction of albumin)

• High performance Liquid Chromatography-measures both immunoreactive & non-immunoreactive albumin

• Semiquantitative dipstick(Micral strips)

• Some patients noticed to have decreased GFR in the absence of UAE

-Type 1 DM female patients with longstanding DM,HTN,Retinopathy

Type 2 DM 30% of patients without albuminuriaor retinopathy (NHANES III)

• Therefore GFR estimation makes for proper evaluation of DN using Cockcroft-Gaultformula

Nigerian Society of Endocrinology & Metabolism, Jos, 2006

Nigerian Society of Endocrinology & Metabolism, Jos, 2006

Screening for microalbuminuria

Nigerian Society of Endocrinology & Metabolism, Jos, 2006

Albumin creatinine ratio (ACR)

• ACR (mg/mmol)

• Microalbuminuria:

Women: ACR > 3.5mg/mmol ( 50mg/g)

Men: ACR > 2.5mg/mmol (35mg/g)

• Proteinuria: 25mg/mmol

• Urine m/c/s- r/o UTI

• Serology- ANCA, anti-DNA, C3,C4

Renal USS

• Kidneys enlarged in early stages

• Shrunken in late stages

r/o obstruction

Renal biopsyif diagnosis is in doubtIf other kidney disease suggestedIf atypical features present ego Type 1 DM< 10yrso No retinopathyo Nephrotic range proteinuria without progressing

through microalbuminuriao Macroscopic haematuriao Red cell casts

Light microscopy-

Increase in solid spaces in the tuft with coarse branching of Solid PAS +ve material (Diffuse glomerulopathy)

Large acellular accumulations that are circular on cross section are Kimmelstiel-wilsonnodules.

• ImmunofluorescenceDeposition of IgG along the BM in a linear

pattern(not diagnostic),no immune depositsFeatures of atherosclerosis in renal vasculature-Concomitant hyperlipidemia,hypertensive

arteriosclerosis.Electron microscopyMesangial expansion within the tuft with increased

matrix.thickening of capillary wall BM.

• Urine microscopy-

r/o nephritic picture.

r/o other primary glomerulopathies

• Serum and urine electrophoresis-

Exclude multiple myeloma

Classify proteinuria(mainly glomerular)

MANAGEMENT

• Goals are to slow progression of kidney damage and control related complications

MANAGEMENT

• Glycemic control-

Intensive therapy can partially reverse glomerular hypertrophy & hyperfiltration.

Delays development of microalbuminuria

Stabilize or even decrease protein levels in microalbuminuria

MANAGEMENT

• Glycemic control-Hyperglycemia has been shown to be a major determinant of

the progression of diabetic nephropathyDCCT: 39% reduction in microalbuminuria, 54% reduction in

nephropathy, 5.8 additional years free from ESRD• UKPDS: 35% reduction in microvascular complications• Insulin requirements fall as renal function declines• Sulphonylureas and Metformin (serum Cr>1.5mg/dl)

accumulate and are contraindicated in advanced disease• Repaglinide,Nateglinide have a safety profile in renal

impairment

MANAGEMENT

• Blood pressure control-

Antihypertensives,regardless of type, slow development of diabetic glomerulopathy but

ACE-Is confer superior long term protection.

ACE-Is also show beneficial effect on progression of diabetic retinopathy.

Target of 130/80mmHg for diabetics

And 125/75mmHg in proteinuria/renal impairment.

Blood pressure control

• UKPDS: the beneficial effects of blood pressure control were greater than the beneficial effects of glycemic control. Lowering blood pressure to moderate goals (144/82 mmHg) reduced the risk of DM-related death, stroke, microvascular end points, retinopathy, and heart failure (risk reductions between 32 and 56%)

ACE INHIBITORS

• ACEIs are superior in the longterm to triple therapy with Reserpine, hydralazine, and hydrochlorothiazide/nifedipine

• Benefit is most significant in Type 1 DM

• ARBs are show to be beneficial in Type 2

• Increase dose every 2-3 months till proteinuriadisappears or maximum dose is reached

• ACE-I & ARB combination more beneficial than ACE-I or ARB alone

• Aldosterone escape phenomenon-

RAS inhibition leads to increased aldosteronelevels.

40% of T2DM with early nephropathy during short term ACE therapy

AEP assoc with increased GFR loss

Combination of spironolactone with ACE-I more effective in reducing UAE,BP in micro & macro type 2 DM than ACE-I alone.

OTHER MEASURES

• Dietary Protein Restriction?– Benefit not proven

– ADA suggests modest restriction to 10% of daily caloric intake (0.5-0.8g/kg/d)

– Beneficial effect on GFR,creatineclearance,albuminuria

– Decreased saturated fat,increased polyunsaturated fat

– Replacing red meat with chicken

– In advanced nephropathy, potassium restriction, use of phosphate binders.

OTHER MEASURES

• Treatment of risk factors• -Hyperlipidemia- both a risk factor for progression and

a risk factor. Use of Statins• LDL-C<100mg/dl for diabetic patients• & <70mg/dl for diabetic patients + cardiovascular

disease. Total cholesterol 175mg/dl, TG- 150mg/dl• -Cessation of smoking• -Correction of anaemia:Target Hb 12-13g/dl• -Iodine containing contrast & NSAIDS should be

avoided• Use of Aspirin >100-150mg/d

RENAL REPLACEMENT THERAPY

• Options include hemodialysis, peritoneal dialysis kidney transplantation, or combined kidney-pancreas transplantation

• Hemodialysis complicated by

– Hypotension

– More difficult vascular access

– Accelerated progression of retinopathy

HEMODIALYSIS

• Insulin requirements are often reduced

• Adequate control of glycemia is important to prevent hyperglycemia-induced thirst, which can lead to volume overload and hyperkalemia

• Optimize nutrition

• Correct anemia

• Control hypertension and hyperlipidemia

• Atherosclerosis is leading cause of death in diabetic individuals on dialysis

KIDNEY TRANSPLANTATION

• Best option and should be the goal (discuss early)

• Generally restricted to young IDDM patients

• Good results in NIDDM patients with low cardiovascular risk

• Kidney & pancreas transplant

• Higher risk of rejection (highly immunogenic pancreas)

• However 1-year rates are similar to those with kidney transplant alone

COMPLICATIONS OF RENAL REPLACEMENT

• Hypoglycemia-decreased excretion of insulin

• Hyperkalemia

• severe hypertension

• complications of haemodialysis

• complications of kidney transplant

• Peritonitis

PREVENTION

• Optimal blood glucose control (Hba1c <7%)

• Control of hypertension (BP <120/70)

• Avoidance of potentially nephrotoxicsubstances such as NSAIDs and aminoglycosides

• Early detection and optimal management of diabetes

PROGNOSIS

• Worse in our environment due to late presentation, inadequacy of renal replacement

• ESRD and cardiovascular disease – major cause of death

NEW THERAPEUTIC STRATEGIES

• High doses of thiamine & bentothiamineretards microalbuminuria-activation of Protein kinase C,decreased glycation,

• ALT-711- cross linker of AGEs

• Protein Kinase C inhibitor(Ruboxistaurin)

• Use of a modified Heparin GAG in rat models

• Sulodexide- A GAG reduced albuminuria

• Pimagedine- inhibitor of AGE endproducts