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DIABETIC NEPHROPATHY & CHRONIC RENAL FAILURE / CHONIC KIDNEY DISEASE

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DIABETIC NEPHROPATHY & CHRONIC RENAL FAILURE / CHONIC KIDNEY DISEASE. IDDM, 30-40% DN NIDDM, 10-20% DN. Incipient Nephropathy Predictors? Hyperfiltration Microalbuminuria Rising BP Poor glycemic contol. HTN.

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slide2

IDDM, 30-40% DN

NIDDM, 10-20% DN

Incipient Nephropathy

Predictors?

Hyperfiltration

Microalbuminuria

Rising BP

Poor glycemic contol

HTN

0 2 5 11-23 13-25 15-27

Onset of Rising ESRD

Proteinuria S.Cr

Onset

Of DM

Functional changes

GFR increase (renal hypertrophy)

reversible albuminuria

increase kidney size

Structural changes

increase GBM thickening

Mesangial expansion

nodular (Kimmelstiel-Wilson) & diffuse forms of

intercapillary glomerulosclerosis

capsular drop lesion

fibrin cap lesion

morphologic changes
Morphologic changes
  • Glomeruli:
    • increase GBM thickening
    • Mesangial expansion
    • nodular (Kimmelstiel-Wilson) & diffuse forms of intercapillary glomerulosclerosis
    • capsular drop lesion
    • fibrin cap lesion
  • Tubulointerstitium,& tubular functional defects
    • Interstitial scarring
    • Impaired tubular reabsorption of low MW proteins and albumin
    • Increased Na reabsorption leading to volume expansion
    • Hypercalciuria
    • Impaired excretion of H & K ions
  • Vascular, hyaline thickening of the arteriolar wall
  • Glomerular haemodynamic changes
    • Decreasing Pglom: ACE-I, ARB, low protein diet
transient microalbuminuria
Transient microalbuminuria
  • Hyperglycemia
  • Hypertension
  • Congestive heart failure
  • Urinary tract infection
  • Excessive physical exercise
  • Albumin Excretion Rate / AER
    • Normal < 30 mg/day
    • Microalbuminuria 30-300 mg/d
    • Overt proteinuria AER> 300 mg/d
overt diabetic nephropathy
Overt Diabetic Nephropathy
  • In early DN the albuminuria is secondary to a loss of the anionic charge barrier of the GCW
  • In established DN, the proteinuria is due to the presence of an increased number of nonselective and large pores
  • The presence of persistent proteinuria heralds the overt phase of DN
  • >95% of patients with DN have D Retinopathy
  • Rate of decline in GFR has been reported as linear in a given patient, but wide differing between patients
  • ~ 1 ml/min per month, with 50% of patients reaching ESRD ~ 7 years after the onset of proteinuria.
  • Recent reports suggest that is has slowed down ~10 years
complication of dm
Complication of DM
  • Microvascular
    • Retinopathy
    • Nephropathy
  • Macrovascular
    • Peripheral vascular disease
    • Coronary artery disease
    • Cerebrovascular disease
  • Diabetic neuropathy, incl. gastroparesis
  • Hyperkalemic RTA
syndrome x
Syndrome ‘X’
  • Obesity
  • Decreased glucose tolerance, Insulin resistance & hyperinsulinemia
  • Hypertension
  • Hyperlipidemia, esp triglycerides
  • Increased risk for atheroscerosis
niddm
NIDDM
  • Patients on HD in a dialysis unit ~ 30-50% because of NIDDM & diabetic nephropathy
  • Many patients with NIDDM will die of other causes (cardiovascular) before reaching ESRD
  • Natural history less well characterized
  • Heterogeneous group, with many comorbid conditions, hypertension, obesity
  • 10-20% incidence of DN, mostly after 10-20 y
  • Familial predisposition
management
Management
  • Control of Diabetes, HbA1c <7
  • Control of hypertension, BP<130/80, if proteinuria BP<125/75
  • Low salt diet
  • Control of hyperlipidemia
  • Weight control
  • Smoking cessation
  • Management of other comorbid conditions; cardiovascular, anemia, cerebrovascular, physical inactivity...
  • ACE-I, ARB, combination
progression of ckd
Progression of CKD
  • Mechanisms of ongoing renal injury
    • Deposition IC, Ag, Ab, matrix, collagen, fibroblasts
    • Intracapillary coagulation
    • Vascular necrosis
    • Hypertension & increased Pglom
    • Metabolic disturbances, e.g. DM, hyperlipidemia
    • Continuous inflammation
    • Nephrocalcinosis ; dystrophic & metastatic
    • Loss of renal mass / nephrons
    • Ischemia; imbalance between renal energy demands and supply
  • Results in
    • Glomerulosclerosis
    • Tubular atrophy
    • Interstitial fibrosis
compensatory renal changes in ckd
Compensatory renal changes in CKD
  • Hypertrophy of residual nephrons
  • Increased RBF per nephron, but decreased total RBF
  • Increased Single Nephron GFR / SNGFR
    • Increased osmotic / solute load
    • Hyperfiltration
    • Increased intraglomerular pressure / Pglom
slide36

## NEPHRONS

Pcap +flow

Glomerular Protein Glomerular

injury flux hyperfiltration

Glomerulosclerosis

## NEPHRONS

slide37
Pattern of excretory adaptation
    • Increased filtered load; Cr, BUN
    • Decreased tubular reabsorption; Na, H2O
    • Increased tubular secretion; K+, H+, Cr
  • Limitation of nephron adaptation
    • Magnitude
    • Time, ~response to intake / load, production
      • Abrupt changes in intake / production may not be tolerated
    • Trade off, expense to other systems
      • E.g. to preserve P balance PTH increases
slide38

Volume

Urine,

Uosm,

U(Na,K,H)

slide40
Multiple mechanisms of chronic hypoxia in the kidney.
  • Mechanisms of hypoxia in the kidney of chronic kidney disease include loss of peritubular capillaries (A),
  • Decreased oxygen diffusion from peritubular capillaries to tubular and interstitial cells as a result of fibrosis of the kidney (B),
  • Stagnation of peritubular capillary blood flow induced by sclerosis of "parent" glomeruli (C),
  • Decreased peritubular capillary blood flow as a result of imbalance of vasoactive substances (D),
  • Inappropriate energy usage as a result of uncoupling of mitochondrial respiration induced by oxidative stress (E),
  • Increased metabolic demands of tubular cells (F), and
  • Decreased oxygen delivery as a result of anemia (G).
slide41
Treatment modalities that target chronic hypoxia in the kidney
  • Improvement of anemia by EPO
  • Preservation of peritubular capillary blood flow by blockade of the renin-angiotensin system
  • Protection of the vascular endothelium 
    • VEGF   
    • Dextran sulfate
  • Antioxidants to improve the efficiency of cellular respiration
  • HIF-based therapy    (hypoxia inducible factor)
    • Prolyl hydroxylase inhibitors    
    • Gene transfer of constitutively active HIF
intact nephron hypothesis
Intact nephron hypothesis
  • Using experimental animals; urine from each kidney was collected seperately

Before After End

K1 K2 K1 K2 K2

GFR 50 50 55 14 24

NH3 excr 49 51 66 25 40

NH3 excr/100mlGFR 100 100 120 121 167

K2 was partially K1 removed

removed

  • Conclusion
  • Normal renal tissue undergoes hypertrophy to compensate for loss of
  • functioning nephrons
  • -Normal tubules adapt, increase in function as other tubules are lost
  • -Diseased nephrons / tubules adapt in the same way ~
  • increase NH3 excr / 100mlGFR
  • -Even diseased nephrons can increase their GFR
the uremic syndrome
The Uremic Syndrome
  • Nervous system
    • Impaired concentration, perceptual thinking,
    • Peripheral neuropathy; primarily sensory, paresthesias, restless leg syndrome
    • Autonomic neuropathy; impaired baroreceptor function, orthostatic hypotension, impaired sweating
    • Uremic ancephalopathy
  • Hematology system
    • Anemia is invariably present when renal function fall <30%
      • Decreased RBC survival, response to EPO,
      • Deficiencies of Fe, B12, folate, aluminium overload
      • Blood loss
      • Hyper PTH
      • Inflammation – malnutrition
      • Bone marrow fibrosis
      • Inadequate dialysis
    • Bleeding diathesis: easy bruising, slow clotting
      • Prolonged BT & abnormal platelet function
      • PF3 concentration are generally low, impaired aggregability
      • Reduced von Willebrand’s factor HMW multimers
      • Uremic toxins & PTH
    • Immune function
      • Impaired Ab response to viral Ag (not to bacterial)
      • Decreased T-cells
      • Cutaneous anergy
slide46
Cardiovascular system
    • Cardiovascular disease is the leading cause of death in patients with CKD stage 4-5
    • Accelerated Atherosclerosis / CAD
    • Hypertension, ~ 80% of all uremic patients
    • Pericarditis
  • Metabolic abnormalities
    • Lipids; increase in tot. triglycerides, Lp(a), LDL, decrease HDL
    • Carbohydrate metabolism; insulin resistance, decreased need for OAD / insulin in DM
    • High prolactin; galactorrhea
    • Men : testosteron is low, FSH / LH normal or high
    • Women: pg E2 & progesterone are low, FSH /LH normal or slightly elevated
    • Abnormalities of thyroid gland function test, normal TSH
ckd stage 5 esrd ggt
CKD stage 5 (ESRD / GGT)
  • DIALYSIS / Renal Replacement Therapy
    • Hemodialysis
    • Peritoneal Dialysis
    • Continues Renal Replacement Therapies
  • Kidney Transplant
    • Cadaver
    • Living related / unrelated