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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DIABETIC NEPHROPATHY & CHRONIC RENAL FAILURE / CHONIC KIDNEY DISEASE

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Diabetic nephropathy chronic renal failure chonic kidney disease

DIABETIC NEPHROPATHY & CHRONIC RENAL FAILURE /CHONIC KIDNEY DISEASE


Diabetic nephropathy chronic renal failure

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


Chronic kidney disease ckd

CHRONIC KIDNEY DISEASECKD


Diabetic nephropathy chronic renal failure

usg


Diabetic nephropathy chronic renal failure

, a-dsDNA, GBM-Ab


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


Diabetic nephropathy chronic renal failure

## NEPHRONS

Pcap +flow

Glomerular Protein Glomerular

injury flux hyperfiltration

Glomerulosclerosis

## NEPHRONS


Diabetic nephropathy chronic renal failure

  • 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


Diabetic nephropathy chronic renal failure

Volume

Urine,

Uosm,

U(Na,K,H)


Diabetic nephropathy chronic renal failure

  • 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).


Diabetic nephropathy chronic renal failure

  • 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


Diabetic nephropathy chronic renal failure

  • 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


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