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Diabetic nephropathy
Diabetic nephropathy
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  2. 2. Diabetic nephropathy is characterized by • Persistent albuminuria (>300 mg/24 hr) • Presence of diabetic retinopathy • Absence of clinical or laboratory evidence of other kidney or renal tract disease. • Declining GFR
  3. 3. Pathology of Diabetic Nephropathy in Patients with Type 1 Diabetes and Proteinuria ALWAYS PRESENT 1.Glomerular basement membrane thickening. 2.Tubular basement membrane thickening. 3.Mesangial expansion with predominance of increased mesangial matrix. 4.Interstitial expansion with predominance of increased extracellular matrix material.
  4. 4. OFTEN OR USUALLY PRESENT 1. Kimmelstiel-Wilson nodules (nodular glomerulosclerosis) 2. Global glomerulosclerosis 3. Focal segmental glomerulosclerosis 4. Atubular glomeruli 5. Foci of tubular atrophy 6. Afferent and efferent arteriolar hyalinosis
  5. 5. SOMETIMES PRESENT 1. Hyaline caps or fibrin caps (Highly characteristic of diabetic nephropathy) 2. Capsular drops (Highly characteristic of diabetic nephropathy) 3. Atherosclerosis. 4. Glomerular micro-aneurysms.
  6. 6. Mechanism of hyperglycemia induced damage Four major hypothesis have been generated: • Increased polyol pathway flux • Increased hexosamine pathway flux • Increased intracellular formation of advanced glycation end products • Activation of protein kinase C
  7. 7. Comparison of nephropathy in type1 diabetes and type2 diabetes • About one third of the patients with type2 had changes similar to those typically seen in type1 diabetes • One third had marked increase in percentage of sclerosed glomeruli associated with severe tubulointerstitial lesions, whereas non-sclerosed glomeruli showed only mild diabetic changes • In third group there were typical changes of diabetic nephropathy and superimposed changes of proliferative glomerulonephritis, membranous glomerulopathy and so on
  8. 8. • Renal structure changes in type2 diabetes are more heterogeneous and diabetic nephropathy lesions are less severe than in type1 patient with similar albuminuria level • Non diabetic glomerulopathy is seldom seen in proteinuric type 1 diabetic patients, whereas this condition is common in proteinuric type 2 diabetic patients without retinopathy
  10. 10. NATURAL HISTORY OF DIABETIC NEPHROPATHY FIVE STAGES Stage 1: Hyperfiltration • Increased Glomerular Filtration Rate (GFR >90ml/min) • Concomitant renal hypertrophy (glomerular and tubular) • Various factors contributing are: 1. Intra renal hemodynamic abnormalities 2. TGF-β 3. Increased salt absorption 4. Osmotic load and toxic effect of high sugar levels on kidney cells
  11. 11. Stage 2 : The Silent Stage • The GFR has returned to normal with no evidence of albuminuria  Glomerular damage occurs in the form of basement membrane thickening and mesangial expansion. Ambulatory BP monitoring studies have shown modest rise in BP and absence of nocturnal dip
  12. 12. Stage 3: Incipient nephropathy /Microalbuminuria • Urine AER has increased to 30 to 300 mg/24 hrs • Renal functions could be normal or reduced • 30-50% of patients may show reversal of microalbuminuria • Persistent microalbuminuria , if untreated, will progress to end-stage renal disease (ESRD). • Therefore, all diabetes patients should be screened for microalbuminuria on a routine basis.
  13. 13. Stage 4 : Macroalbuminuria/Overt Nephropathy • The urine AER is more than 300 mg of albumin in a 24-hour period. • Over two thirds of patient in this stage have Hypertension . • If untreated a vicious cycle of progressive renal impairment develops leading to ESRD.
  14. 14. Stage 5: Uremia GFR has fallen to <15 ml/min and renal replacement therapy (i.e., haemodialysis, peritoneal dialysis, kidney transplantation) is needed.
  15. 15. Diabetic nephropathy is a clinical syndrome characterized by 1)Persistent albuminuria 2)Decline in GFR 3)Raised arterial BP 4)Enhanced cardiovascular morbidity and mortality Albuminuria is the first sign and peripheral edema is the first symptom of diabetic nephropathy
  16. 16. Risk factors associated with progression
  17. 17. Proteinuria induced renal damage
  18. 18. Screening and diagnosis of diabetic nephropathy • Diabetes should be screened annually with serum creatinine and eGFR and urine alb:creatinine (ACR) ◦ Starting 5 yrs after diagnosis of type 1 ◦ Starting at the diagnosis of type II • Elevated urine ACR confirmed ≥ 2 times and not in setting of UTI ,acute febrile illness, vigorous exercise, uncontrolled hypertension, and heart failure ◦ Microalbuminuria: ACR 3-30 mg/mmol ◦ Macroalbuminuria: ACR >300 mg/mmol
  19. 19. FACTORS AFFECTING URINARY ALBUMIN EXCRETION INCREASED AER DECREASED AER Strenuous exercise  Poorly controlled DM  Heart failure  UTI  Acute febrile illness  Uncontrolled HPT  Hematuria  Menstruation  Pregnancy NSAIDs  ACE inhibitors
  20. 20. • Screening should be done when the person is free from acute illness and with stable glucose levels • Early morning urine sample is preferred • Serum creatinine level should also be measured annually • Recently serum Cystatin C - A naturally circulating protein, freely filtered by glomerulus has been suggested as an alternative to creatinine measurement.
  21. 21. Treatment Major therapeutic interventions include - • Control of blood glucose to near normal level • Antihypertensive treatment • Lipid lowering therapy • Restriction of dietary proteins • Cessation of smoking
  22. 22. Glycemic control Primary prevention: • Diabetic Control and Complications Trial showed that intensive glycemic control reduces the occurrence of microalbuminuria • ADVANCE study and VETERAN trial recently confirmed similar findings.
  23. 23. Secondary prevention : • UKPDS proves that tight glycemic control reduces progression from microalbuminuria to overt nephropathy • A recent trial also confirms that ESRD development was retarded by multifactorial interventions Nephropathy: • Once overt nephropathy develops , results are disappointing regarding metabolic control in preventing further progression of disease
  24. 24. KDIGO guidelines for management of hyperglycemia and general diabetes care in CKD • Target Hemoglobin A1c(HbA1c) of 7.0% to prevent or delay progression of the microvascular complications of diabetes, including DKD. • No treatment if HbA1c target is <7.0% in patients at risk of hypoglycemia.
  25. 25. • Target HbA1c can be extended to > 7.0% in individuals with co-morbidities or limited life expectancy • Metformin to be continued in people with GFR ≥ 45 ml/min/1.73 m(GFR categories G1-G3a) Its use should be reviewed in those with GFR 30– 44 ml/min/1.73 m(GFR category G3b) Discontinued in people with GFR <30 ml/min/1.73 m(GFR categories G4-G5) and risk of hypoglycemia.
  26. 26. Blood pressure control • ACE-I or ARB’s are not recommended for the primary prevention of diabetic nephropathy in normotensive normoalbuminuric patients with diabetes • ACE inhibitors and ARB’s are effective in slowing the progression of kidney disease characterized by microalbuminuria in hypertensive patients with type 1 or type 2 diabetes. • ACE inhibitors, ARBs, and nondihydropyridine calcium channel blockers have a greater anti-proteinuric effect than other antihypertensive classes in hypertensive patients with diabetic nephropathy.
  27. 27. • Dihydropyridine calcium channel blockers, when used alone in the absence of ACE inhibitors or ARB’s are less effective than other agents in slowing progression of diabetic nephropathy. • ADA states “ In patients with type 2 diabetes, hypertension, macroalbuminuria and renal insufficiency ARBs have shown to delay progression”
  28. 28. KDIGO GUIDELINES FOR MANAGEMENT OF HYPERTENSION IN DIABETIC NEPHROPATHY AND PROTIENURIA • Both diabetic and non-diabetic adults with CKD and urine albumin excretion <30 mg/24 hours whose office BP is consistently >140/90 mm Hg, be treated with BP-lowering drugs to maintain a BP that is consistently ≤ 140/90 mm Hg. • Both diabetic and non-diabetic adults with CKD and with urine albumin excretion of >30 mg/24 hours whose office BP is consistently >130/80 mm Hg, be treated with BP-lowering drugs to maintain a BP that is consistently ≤ 130/80 mm Hg.
  29. 29. • ARB or ACE-I can be used in diabetic adults with CKD and urine albumin excretion of 30– 300 mg/24 hours. • ARB or ACE-I can be used in both diabetic and non-diabetic adults with CKD and with urine albumin excretion of >300 mg/24 hours • There is insufficient evidence to recommend the combination of an ACE-I with an ARB to prevent progression of CKD.
  30. 30. Precautions taken while starting an ACE-I or an ARB • Monitoring of blood pressure, potassium, and serum creatinine level is important. • Potassium level up to 5.5 mEq/L and an increase in serum creatinine up to 30% from baseline within the first three months with close monitoring is tolerable • Medication needs to be reduced or discontinued if potassium levels remain elevated at > 5.5mEq/L or if the serum creatinine continues to rise or does not improve.
  31. 31. • Avoid in people with suspected functional renal artery stenosis • Start at lower dose in people with GFR <45 ml/min/1.73 m • Assess GFR and measure serum potassium within 1 week of starting or following any dose escalation • Temporarily suspend during intercurrent illness, planned IV radiocontrast administration, bowel preparation prior to colonoscopy, or prior to major surgery • Do not routinely discontinue in people with GFR <30 ml/min/1.73 m as they remain nephroprotective
  32. 32. TREATMENT GOAL FOR LIPIDS IN DIABETIC NEPHROPATHY • Low-density lipoprotein <2.6 mmol/L (100 mg/dL) • High-density lipoprotein >1 mmol/L (40 mg/dL) in men, >1.3 mmol/L (50 mg/dL) in women • Triglycerides <1.7 mmol/L (150 mg/dL)
  33. 33. KDIGO guidelines for management of dyslipidemia in diabetes and CKD • Dyslipidemia is common in people with diabetes and CKD. Cardiovascular events are a frequent cause of morbidity and mortality in this population. • Lowering low-density lipoprotein cholesterol (LDL-C) with statin-based therapies reduces risk of major atherosclerotic events in patients with CKD including those with diabetes.
  34. 34. • LDL-C lowering medicines, such as statins or statin+ezetimibe combination reduces risk of major atherosclerotic events in patients with diabetes and CKD, including those who have undergone kidney transplant. • Not recommended to initiate statin therapy in patients with diabetes who are treated by dialysis.
  35. 35. Dietary Protein Restriction • A low protein diet reduces urinary albumin excretion and hyperfiltration independent of changes in glucose control and blood pressure. KDIGO GUIDELINE FOR PROTIEN INTAKE • Lowering protein intake to 0.8 g/kg/day in adults ± diabetes and GFR<30 ml/min/ 1.73 m2(GFR categories G4-G5) with appropriate education. • Avoiding high protein intake (>1.3 g/kg/day) in adults with CKD at risk of progression
  36. 36. MANAGEMENT OF ANEMIA IN DIABETIC NEPHROPATHY • In diabetic patient with renal failure anemia is more frequent and more severe at any given level of GFR. • In patients with DN, anemia is an independent risk factor associated with decline in GFR. • Renal hypoxia resulting from anemia aggravates interstitial fibrosis by stimulation of factors like TGF-β and VEGF. • Hypoxia-inducing factor-1 (HIF-1) and ANG-II also play a major role.
  37. 37. KDIGO GUIDELINES FOR ANEMIA • Anemia in adults and children >15 years with CKD is when the Hb concentration is <13.0 g/dl in males and <12.0 g/dl in females To identify anemia in patients with CKD by measuring Hb level • When clinically indicated in patients with GFR >60 ml/min/1.73 m2(GFR categories G1-G2) • Annually in patients with GFR 30–59 ml/min/1.73 m2 (GFR categories G3a-G3b) • Twice a year in patients with GFR<30 ml/min/1.73 m2 (GFR categories G4-G5) Treatment of anemia with recombinant human EPO and darbepoetin-α
  38. 38. Treatment of End-Stage Renal Disease (ESRD) 1. Transplantation(kidney only, simultaneous pancreas with kidney, pancreas after kidney) 2. Hemodialysis 3. Continuous ambulatory peritoneal dialysis
  39. 39. HEMODIALYSIS • Renal replacement therapy should be started earlier than in non diabetic patient at an • Intradialytic hypotension is common in diabetic patient on dialysis because of autonomic neuropathy and disturbed left ventricular compliance • Following approach is used to avoid intradialytic hypotension - Long dialytic session, omission of antihypertensive drugs before dialytic session, controlled ultrafiltration, correction of anemia by EPO therapy, alternative modalities such as CAPD
  40. 40. • High prevalence of cardiovascular complications in diabetic patients entering dialysis programme • Diabetic patients are also more prone for cardiac arrest during dialysis session • Dialysis partially reverses the insulin resistance and requirement compared prior to dialysis
  41. 41. PERITONEAL DIALYSIS • According to heaf and co worker, during the first 2 years, survival is better for diabetic patient treated with CAPD compared to HD • Survival advantage no longer demonstrated beyond 2 years as by then residual renal function has already decayed • CAPD provides slow and sustained ultra filtration without rapid fluctuation of fluid volume and electrolyte concentration, a feature that is advantageous for BP control and prevention of heart failure
  42. 42. KIDNEY TRANSPLANT • Survival of diabetic patients with kidney graft is worse compared to non diabetic patients. And survival of diabetic nephropathy patients on dialysis is poorer when compared to patients with kidney graft. • Simultaneous kidney with pancreas transplantation(SPK) should be the preferred treatment for type1 DM who meet the selection criteria: Age <55 years and GFR<40. Exclusion criteria for SPK: Active smoking, morbid obesity and uncorrected CVD
  43. 43. • Pancreas after kidney transplantation – An alternative strategy, must be considered in a diabetic patient who has a living kidney donor. Firstly the living kidney is transplanted and subsequently once stable renal function is achieved (GFR>50 ml/min), cadaveric pancreas is transplanted • Results of Islet cell transplantation are inferior to whole pancreas transplantation
  44. 44. Agents with negative result or potential harm • Endothelin antagonists – In diabetic nephropathy, endothelin 1 levels are increased and contribute to proteinuria and glomerulosclerosis. The ASCEND trial studied the effects of endothelin A receptor antagonist in type 2 DM population and found- Increase in cardiac deaths, higher fluid retention and congestive heart failure despite a reduction in the albumin:creatinine ratio
  45. 45. • Bardoxolone methyl – Bardoxolone is an antioxidant with anti- inflammatory activity Early studies seemed promising in improving GFR but the BEACON trial was terminated early due to increased adverse events and mortality noted in the Bardoxolone arm
  46. 46. • AGE inhibitor- Aminoguanidine (Pimagedine), an AGE inhibitor was tested in a randomized control trial for type 2 DM but was terminated due to other significant adverse events, such as glomerulonephritis and lupus like reactions.  Pyridoxine, another AGE inhibitor was studied in a randomized control trial, but there was no significant improvement in renal function or albuminuria
  47. 47. Some potential therapy for diabetic nephropathy • Sodium coupled glucose co-transporter 2 (SGLT2) inhibitors-  90% of glucose is absorbed through SGLT2 found in kidney and intestine.  A phlorizine derivative, able to inhibit the activity of this transporter and result in glycosuria. However this may increase the risk of genitourinary tract infection and volume depletion by osmotic diuresis
  48. 48. • Connective tissue growth factor(CTGF)- Increases the activity of pro-fibrotic cytokines such as TGF-β and promotes fibrosis. FG309 a human monoclonal antibody to CTGF has shown to reduce proteinuria in type 2 DM
  49. 49. • VITAMIN-D: Vitamin-D has shown to have an inhibitory effect on the RAAS and suppresses the plasma renin expression and activity. Vit-D also exerts anti inflammatory effect by decreasing pro-inflammatory cytokines.
  50. 50. • INHALED INSULIN approved by FDA in 2014 – AFREZZA 1. Rapid acting insulin taken before each meal or soon after starting the meal 2. Doesn’t replace the need of injectable long- acting insulin, hence not suitable for diabetic emergencies such as DKA 3. Common side effects - Low blood sugar, cough, scratchy/sore throat 4. Should not be used in smokers and individuals with lung disease.