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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