DIABETIC NEPHROPATHY &
CHRONIC RENAL FAILURE /
CHONIC KIDNEY DISEASE
Incipient Nephropathy
Predictors?
Hyperfiltration
Microalbuminuria
Rising BP
Poor glycemic contol
0
2
5
Onset
Of DM
Functional changes
GFR increase (renal hypertrophy)
reversible albuminuria
increase kidney size
IDDM, 30-40% DN
NIDDM, 10-20% DN
HTN
11-23
13-25
15-27
Onset of
Proteinuria
Rising
S.Cr
ESRD
Structural changes
increase GBM thickening
Mesangial expansion
nodular (Kimmelstiel-Wilson) & diffuse forms of
intercapillary glomerulosclerosis
capsular drop lesion
fibrin cap lesion
Morphologic changes
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Glomeruli:
– increase GBM thickening
– Mesangial expansion
– nodular (Kimmelstiel-Wilson) & diffuse forms of intercapillary
glomerulosclerosis
– capsular drop lesion
– fibrin cap lesion
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Tubulointerstitium,& tubular functional defects
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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
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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
• 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
• Microvascular
– Retinopathy
– Nephropathy
• Macrovascular
– Peripheral vascular disease
– Coronary artery disease
– Cerebrovascular disease
• Diabetic neuropathy, incl. gastroparesis
• Hyperkalemic RTA
Syndrome ‘X’
• Obesity
• Decreased glucose tolerance, Insulin
resistance & hyperinsulinemia
• Hypertension
• Hyperlipidemia, esp triglycerides
• Increased risk for atheroscerosis
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
• 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
usg
CKD
• Diabetic Nephropathy
• Hypertension
• Glomerulonephritis
– Acute
– Rapidly Progressive GN
– Chronic GN
– Secondary GN ( Infections, Malignancies,
Autoimmune Ds,…)
• Drugs & Toxins
• Hereditary : Alport’s, PCKD, ….
• Congenital : VU Reflux
• Obstructive Nephropathy
Signs & Symptoms
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Edema
High Blood Pressure
Nocturia
Frequency & Dysuria
Loin pain unrelated to movements
Hematuria
Proteinuria
CRF & ESRD
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Poor appetite. Nausea & vomiting
Insomnia & Restlessness
Labile mood swings
Asthenia
Shortness of breath.
– Pulmonary edema. Metabolic acidosis
Cardiac arrhythmias. Hyperkalemia
Hypertensive urgencies / emergencies
LVH
Anemia
Malnutrition
Hyperphosphatemia
Hyperparathyroidism
KIDNEY DIDEASE
• Prevalent in identifiable groups
– Aging , > 50
– DM
– Hypertension
– Cardiovascular disease, CVD
– Family members
– Herbal medicine (jamu), Analgetics
RISK FACTORS(+)---
CHECK URINE & CR -----MCU
NORMAL
HEMATURIA/PROTEINURIA
START
NONSPEC IFIC
THERAPY
REGULAR
CHECKS
HIGH CR
PREVENTIVE
ACTION
RENAL US--------CRF/Hydronephrosis
ESTIMATE GFR / 24H U CCT
SPOT U Prot/Cr RATIO / 24H U Prot
IMMUNOLOGY SEROLOGY :C3,C4,ANA,ANCA , a-dsDNA,
GBM-Ab
ETIOLOGY???
RENAL BIOPSY
DIAGNOSIS & PROGNOSIS
SPECIFIC THERAPY : STEROID, IMMURAN
CYCLOPHOSPHAMIDE, CYCLOSPORIN, MMF/CELLCEPT
Therapy CKD
• Specific Therapy. depends on etiology &
histopathology
• Decrease proteinuria / albuminuria
• Tightly control Blood Pressure < 125 / 75
– ACE-I, ARB, non-dihydropyridine-CCB,….
• Tightly control Blood Sugar
• Manage hyperlipidemia
• Stop smoking
• Low protein diet 0.6 – 0.8 g /kg BW/day
• Manage Anemia and other co morbidities,
• Manage Cardiovascular ds,
• Complications of decreased kidney
function
• Preparation for kidney failure and RRT
• Initiation of RRT
Progression of CKD
• Mechanisms of ongoing renal injury
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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
• 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
## NEPHRONS
Pcap +flow
Glomerular
injury
Protein
flux
Glomerulosclerosis
## NEPHRONS
Glomerular
hyperfiltration
• 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
Volume
Urine,
Uosm,
U(Na,K,H)
• 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).
• 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
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Using experimental animals; urine from each kidney was collected seperately
Before
K1
K2
GFR
NH3 excr
NH3 excr/100mlGFR
50
49
100
50
51
100
After
K1
K2
End
K2
55
66
120
14
25
121
24
40
167
K2 was partially
removed
K1 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
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Nervous system
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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
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Anemia is invariably present when renal function fall <30%
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Bleeding diathesis: easy bruising, slow clotting
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Decreased RBC survival, response to EPO,
Deficiencies of Fe, B12, folate, aluminium overload
Blood loss
Hyper PTH
Inflammation – malnutrition
Bone marrow fibrosis
Inadequate dialysis
Prolonged BT & abnormal platelet function
PF3 concentration are generally low, impaired aggregability
Reduced von Willebrand’s factor HMW multimers
Uremic toxins & PTH
Immune function
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Impaired Ab response to viral Ag (not to bacterial)
Decreased T-cells
Cutaneous anergy
• 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)
• DIALYSIS / Renal Replacement Therapy
– Hemodialysis
– Peritoneal Dialysis
– Continues Renal Replacement Therapies
• Kidney Transplant
– Cadaver
– Living related / unrelated