Diabetic Nephropathynew horizon

Dr. Muhamed Al Rohani,MD

Definition

Classical definition: progressive rise in urine albumin excretion coupled with increasing BP and leading to declining GFR and CKD

Abnormal urine albumin excretion• >30 mg/24 hours

and/or

diabetic glomerular lesions

and/or

loss of glomerular filtration rateADA recommendations, Diabetes Care, January 2012

Prevalence Incidence

Epidemiology

Increase prevalence of DMIndia china USA4% 1995 – 5.4% 2025 Worldwide:2.8 % 171 million 2000 – 4.4% 366 million 2030

Now: USA 7% (20.8 million) off population has DM

DN prevalence In India: 5.5% and 8.9%Asian Indians in UK 22.3%

Increased mortality rate With protinuria Without proteinuria

Increased CV events

Harris MI. Clin Invest Med. 1995;18:231-239. Nelson RG, et al. Adv Nephrol Necker Hosp. 1995;24:145-156.

World Health Organization. Diabetes Mellitus Fact Sheet 138. 2002.ADA. National diabetes fact sheet. Available at:

http://www.diabetes.org/diabetes-statistics/national-diabetes-fact-sheet.jsp.

Microvascular Complications Macrovascular Complications

Complications of Type 2 Diabetes Affect Every Part of the Body

PeripheralVascular Disease

HeartDisease

Diabetic RetinopathyLeading cause of blindness in working-age adults

Diabetic Nephropathy Leading cause of end-stage renal disease

Diabetic Neuropathy Leading cause of nontraumatic lower extremity amputations

Stroke 2- to 4-fold increase in cardiovascular mortality and stroke

Specific Infections

• Community acquired pneumonia

• Acute bacterial cystitis

• Acute pyelonephritis• Emphysematous

pyelonephritis• Perinephric abscess• Fungal cystitis

• Necrotizing fasciitis• Invasive otitis

externa• Rhinocerebral

mucormycosis• Emphysematous

cholecystitis

Natural history of DN

Type I

Duration:Microalbuminuria after 20 yrs in 20 – 30

% of DM patients ESRD after 10 yrs,

Type 2

Duration:CKD or ESRD in 1% of pts in the time of

diagnosisESRD in 20 -30 % at 20 yrs.

Poor glycemic controlStrict control reduce and slow the risk of microvascular and even

macrovascular complications. Hypertension:

Cause of and results of diabetic renal diseaseIn DM1 5% in 10 yrs

33% in 20 yrs 70% in 40 yrs

Rise with 3 yrs of microalbuminuria with Incidence of 15 – 25%75 – 85% in all diabetic nephropathy

Effect of Increased Glomerular Permeability to Proteins on Progressive Renal Injury.

Remuzzi G, Bertani T. N Engl J Med 1998;339:1448-1456. Gilbert RE, Marsden PA. N Engl J Med 2008;358:1628-1630.

Flow chart for classifying DN.

Tervaert T W C et al. JASN 2010;21:556-563

©2010 by American Society of Nephrology

Representative examples of the morphologic lesions in DN. (A) Glomerulus showing only mild

ischemic changes, with splitting of Bowman's capsule.

Tervaert T W C et al. JASN 2010;21:556-563

©2010 by American Society of Nephrology

Pathological classification of DNClass Description Inclusion Criteria

IMild or nonspecific LM changes and EM-proven GBM thickening

Biopsy does not meet any of the criteria mentioned below for class II, III, or IV

GBM > 395 nm in female and >430 nm in male individuals 9 years of age and oldera

IIa

Mild mesangial expansion

Biopsy does not meet criteria for class III or IV

Mild mesangial expansion in >25% of the observed mesangium

IIb

Severe mesangial expansion

Biopsy does not meet criteria for class III or IV

Severe mesangial expansion in >25% of the observed mesangium

III Nodular sclerosis (Kimmelstiel–Wilson lesion)

Biopsy does not meet criteria for class IV

At least one convincing Kimmelstiel–Wilson lesion

IV Advanced diabetic glomerulosclerosis

Global glomerular sclerosis in >50% of glomeruli

Lesions from classes I through III

Treatment of Diabetic Nephropathy

Hypertension Control - Goal: • lower blood pressure to <130/80 mmHg

– Antihypertensive agents• Angiotensin-converting enzyme (ACE) inhibitors

– captopril, enalapril, lisinopril, benazepril, fosinopril, ramipril, quinapril, perindopril, trandolapril, moexipril

• Angiotensin receptor blocker (ARB) therapy – candesartan cilexetil, irbesartan, losartan potassium, telmisartan, valsartan,

esprosartan

• Aldestrone blockers; spirolactone and eplerenone

Table 2. Recommendations for the Comprehensive Management of T2DM Patients with CKD

Factor Recommendations Lifestyle factors Advice concerning smoking, diet, exercise, and alcohol intake

Blood glucose Treatment goal: HbA1c <7.0%Preprandial plasma glucose 90-130 mg/dlPostprandial plasma glucose <180 mg/dl

Blood pressure Goal ≤130/80 mm HgUse maximal tolerated dose of ACE inhibitor or ARB before adding a second agent

Cholesterol Goal <4.0 mmol/L for total cholesterol and <2.0 mmol/L for LDL-C Consider use of a statin irrespective of baseline lipid values for the secondary prevention of cardiovascular disease

Platelets Consider use of low dose aspirin for the secondary prevention of cardiovascular disease

Monitoring Annual monitoring of eGFR and ACR

Criteria for the Diagnosis of DiabetesA1C ≥6.5%

ORFasting plasma glucose (FPG)

≥126 mg/dL (7.0 mmol/L)Ono caloric intake for at least 8h2-h plasma glucose ≥200 mg/dL(11.1 mmol/L) during an OGTT

ORA random plasma glucose ≥200 mg/dL (11.1 mmol/L)

ADA. I. Classification and Diagnosis. Diabetes Care 2012;35(suppl 1):S12. Table 2.

A1c Target :Intensive / conventional

Outcome

UKPDS 10 yrs

7% / 7.9% Significant reduction of microvascualr comp. in intensive group

ADVANCE5 yrs

6.5% / 7.3% Reduction of macro and micro vascuar and meanly nephropathy

ACCORD <6% / 7- 7.9% Stopped because of increased incidence of hypoglycemic evets

Prediabetes: IFG, IGT, Increased A1C

Categories of increased risk for diabetes (prediabetes)*

FPG 100–125 mg/dL (5.6–6.9 mmol/L): IFGOR

2-h plasma glucose in the 75-g OGTT140–199 mg/dL (7.8–11.0 mmol/L): IGT

OR

A1C 5.7–6.4%

*For all three tests, risk is continuous, extending below the lower limit of a range and becoming disproportionately greater at higher ends of the range.

ADA. I. Classification and Diagnosis. Diabetes Care 2012;35(suppl 1):S13. Table 3.

Category Spot collection (µg/mg creatinine)

Normal <30

Microalbuminuria 30-299

Macroalbuminuria (clinical) ≥300

Recommendations: Nephropathy

• To reduce risk or slow the progression of nephropathy– Optimize glucose control (A)– Optimize blood pressure control (A)

ADA. VI. Prevention, Management of Complications. Diabetes Care 2012;35(suppl 1):S34.

• Assess urine albumin excretion annually– In type 1 diabetic patients with diabetes duration of ≥5 years– In all type 2 diabetic patients at diagnosis

• Measure serum creatinine at least annually– In all adults with diabetes regardless of degree of urine albumin

excretion– Serum creatinine should be used to estimate GFR and stage level of

chronic kidney disease, if present

The therapeutic strategies for DKD are limited due to several factors: – Lack of screening for DKD, – Lack of implementation of optimal standard therapy for

DKD, – Current therapies primarily slow down, but do not halt the

progression of DKD. These therapies include:

1. blood pressure, RAS blockers2. lipid, glycemic, and weight control; 3. diet and lifestyle modifications; 4. antiplatelet aggregation therapy;

Statins have been shown to have 5. multiple antioxidant properties and improve vascular

remodeling (Briones et al., 2009). 6. shown to reduce proteinuria (Nakamura et al., 2005)7. Shown to reduce the progression of DKD (Agarwal, 2007).

ACE inhibitors TrailHeart Outcome Prevention Trail

Captopril Prevention Trail

Fosinopril versus Amliodepine Cardiovascular Events Trail

Appropriate BP Control Diabetes Trail

UK prospective Diabetes Study

Diabetes Exposed to Telmisartan And EnalapriIL Trail

BENEDICT TRAIL

ACE Inhibitors can prevent progression of renal failure

120

160

200

240

280

320

350

400

800 1 2 3 4 5 6

Years

Ann Intern Med 118 577-581.1993J Am Soc Nephrol 2006

Placebo

Enalapril 85

90

95

100

105

110

800 1 2 3 4 5 6

Years

Placebo

Enalapril

Normotensive Type 2 Diabetics

Proteinuria

(mg/day)

% Initial GFR

Risk reduction is 51%Reduce microalbuminuria All causes of mortality

Ruggenenti P et al. N Engl J Med 2004;351:1941-1951.

ConclusionsIn subjects with type 2 DM and HTN but with normoalbuminuria, the use of trandolapril plus verapamil and trandolapril alone decreased the incidence of microalbuminuria to a similar extent. The effect of verapamil alone was similar to that of placebo.

Olmesartan for the Delay or Prevention of Microalbuminuria in Type 2 Diabetes

• 4447 patients to receive olmesartan 40 mg once daily or placebo for a median of 3.2 years.

• BP <130/80 mm Hg. • The primary outcome was the time to the first• onset of microalbuminuria. • The times to the onset of renal and CV events were analyzed as

secondary end points.Conclusion:• Olmesartan was associated with a delayed onset of

microalbuminuria, even though blood-pressure control• The higher rate of fatal cardiovascular events with olmesartan among

patients withpreexisting coronary heart disease is of concern.

Incidence of Progression to Diabetic Nephropathy during Treatment with 150 mg of Irbesartan Daily, 300 mg of Irbesartan Daily, or Placebo in Hypertensive

Patients with Type 2 Diabetes and Persistent Microalbuminuria.

Parving H et al. N Engl J Med 2001;345:870-878.

Bardoxolyne methyl, has been shown to significantly improve the creatinine GFR and cystatin C GFR in patients with DKD after only 4 weeks

(Schwartz, Denham, Hurwitz, Meyer, & Pergola, 2009).

Recent landmark phase 2 trial of 227 adults with CKD and type 2 DM demonstrated that bardoxolone methyl ( 75 mg is the optimal dose) improved GFR by at least 8.2 +/-1.5 ml/min over placebo after 24 weeks of treatment and that this effect was maintained after a year of therapy.

(Pergola, et al., 2011).

Bardoxolone methyl did not improve urinary albumin excretion.

In 3 phase BEACON study in CKD 4 stage disappointing results

PIRFENIDONE: Antifibrotic (reduction of: ECM deposition, fibrogenic growth factor, fibroblast proliferation)Anti-inflammatory (reducation of: inflam. Cytokinase and inflam.cell accumulationAntioxidant reduction of: markers of oxid. Stress, and its response.

Paricalcitol RuboxistaurtinAllopurinol

Metformin in Patients with T2DM and CKD

first-line treatment weight neutral, inexpensive, Low ris of hypoglycemia inhibits the generation of glucose in the liver. excreted unchanged by the kidney• The recommendation from NICE in England and Wales,[24] and supported by

the ADA/EASD position paper,[8] is that metformin can be used – down to an eGFR of 30 mL/min/1.73 m2, – the dose of metformin should be reduced when eGFR is less than 45 mL/min/1.73 m2. – Kidney function should be checked regularly (every 6 months)– discontinued if eGFR falls below 30 mL/min/1.73 m2. – prescribed with caution in patients with an eGFR less than 45 mL/min/1.73 m2, which

is rapidly deteriorating.[22,24] – All patients should be warned that if they develop a condition that can lead to

dehydration.• Contradictory to guidance from NICE, the Study of Treatment and Prevalence

of Renal Disease in UK Diabetes Mellitus

Keys of diabetic nephropathy

Glomerulus:Increased intraglomerular hypertensionLoss of neg. charged glycosaminoglycans in GBMIncreased GBM pore size Podocyte changes and damages

Pathological abnormalities:Thickening of GBMAccumulation of mesangial matrixIncrease numbers of mesangial cells

Tubular part: Thickening of TBM Tubular atrophyInterstitial fibrosis

Arteriosclerosis

Hypoglycemia as glucose toxicity.Glycation and formation of advanced glycation

products Increased flux through the polyol and hexosamine

pathwaysOxidative stress Fibrotic changes seen in mesangium and

interstitium caused by• Transforming growth factor B-1 • Connective tissue growth factor

Glomerular hyperfiltration and hypertrophy due to: • Growth fator• Insulin-like growth factor -1

Vascular endothelial growth factor synthesised by the podocyte maintains the fenestrae in glom. endothelial cells, its cause constriction of the efferent glomerular arteriole, angiotensin II increases glomerular capillary permeability to proteins stimulate mesangial cell proliferation and accumulation of mesangial matrix

Anti-DM drugs in CKD Believed to be safe Gliplzide

Repaglidine

Glitazones

Linagliptin

Modifying dose Insulin

DDP-4 ISitaVildaSaxa

C/I metformin

GlebincamideGlimepridenataglinide

GLP -1 anginast

Poor food intakeInsufficient exerciseUraemia –induced anorexia Insulin metabolism disorder

Insulin resistance Reduced insulin clearance Inadequate drug therapy

Fluctuation of blood glucose and monitoring of glycemia

Recommended diabetes targets : A1C

The Renal Association 2011 7.5%Joint British societies 2005 6.5%NICE 2011 6.5 – 7.5 % (individualize)

Indication of pancreas transplantation

Pancreas alone Pancreas after kidney Both K and P

- Low C peptide- Rapid progressive diab. Complications

- Low C peptide - successful KT- GFR > 40 ml/min/1.7 m2

-Low C peptide- advance nephropahy- GFR < 20 ml/min/1.7 m2

Avoid too many pain medicationsDrink plenty of water Prevention urinary tract infections

Correlated with Prevention Kidney Disease:Healthy body weightExercise (30 min/day: improve diabetic control, BP

control, and heart function,body weight).9. Normal blood lipid levels

Slowing & preventing Kidney Disease

PathogenesisAbnormalities of

vasodilatation

Risk factors:Common risk factors:

Greater duration of DMMetabolic syndrome

HTNHyperlipidemiaCholesterolLDLTriglycerides

Poor DM controlSmokingObesity

Higher waist circumference Lower adiponectin

Higher CRPAlbuminuria

CVD Mortality

GFR < 60ml/min/1.73m2

Hyperglycemia

Increased glucagon secretion

Decreased insulin

secretion

Increased lipolysis

Decreased glucose uptake

Muscles

Increased glucose

reabsorption Kidney

Increased HGP

Neurotransmitter

Dysfunction

Criteria for Testing for Diabetes in Asymptomatic Adult Individuals (1)

•Physical inactivity• First-degree relative with diabetes• Women who delivered a baby

weighing >9 lb or were diagnosed with GDM

• Hypertension (≥140/90 mmHg or on therapy for hypertension)

• HDL cholesterol level<35 mg/dL (0.90 mmol/L) and/or a triglyceride level >250 mg/dL (2.82 mmol/L)

• Women with polycystic ovarian syndrome (PCOS)

• A1C ≥5.7%, IGT, or IFG on previous testing

• Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans)

• History of CVD

*At-risk BMI may be lower in some ethnic groups.

1. Testing should be considered in all adults who are overweight(BMI ≥25 kg/m2*) and who have one or more additional risk factors:

ADA. Testing in Asymptomatic Patients. Diabetes Care 2012;35(suppl 1):S14. Table 4.

Pathogenesis:Abnormalities of glomerular endothelial barrier:

Stage of Increased filtrationReduction of renal tubular cell albumin degradation

Glomerular hypertensionInflammationOxidative stress

All this cause albuminuria