pathophysiology of crf and gtb

1. PATHOPHYSIOLOGICAL BASIS OF ADJUSTMENT
OF GLOMERULOTUBULAR BALANCE IN CRF AND
PATHOPHYSIOLOGY OF CRF
CHAIR PERSON
DR. B. KUMAR
SPEAKER
KOUSHIK MUKHERJEE

2. CONTENTS
• GLOMERULO TUBULAR BALANCE(GTB)
• PATHOLOGICAL CONSIDERATION IN CRF
• ADJUSTMENT OF GTB IN CRF
• TREATMENT TARGETS

3. GLOMERULO TUBULAR BALANCE
• Glomerulotubular Balance refers to the phenomenon
whereby a constant fraction of the filtered load of the
nephron is resorbed across a range of Glomerular
Filtration Rates (GFR).
• In other words, if the GFR spontaneously increases, the
rate of water and solute resorption in the tubule
proportionally increases, thus maintaining the same
fraction the filtered load being resorbed.

4. MECHANISM OF GTB
• Operates in PCT where 67% of filtered load reabsorbed
regardless the value of GFR.
• Precise mechanism unknown.
• Appears to act completely independently of
neuroendocrine regulatory mechanisms.
• Changes in GFR result in modification of the Starling
forces in the peritubular capillaries resulting in
proportionally increased or decreased total nephronic
resorption.
• Recently, a luminal mechanism has also been identified
in which shear strain on the proximal tubule brush
border activates apical co-transporters.

5. MECHANISM CONT…
• In the loop of Henle, GTB is expected to result from the
relatively low affinity of the bumetanide-sensitive salt
transporter for chloride.

6. SIGNIFICANCE OF GTB
• A critical mechanism which protects distal segments of
the nephron from being overloaded in contexts of short-
term increases in GFR.
• can be thought of as an additional layer of protection if
mechanisms of tubuloglomerular feedback, that
normalize rates of GFR, momentarily fail or are slow to
be triggered.
• Avoid disruption of distal tubular regulation.
• Maintain the volume & composition of final urine.

7. CHRONIC RENAL FAILURE
• The term chronic renal failure applies to the process of
continuing significant irreversible reduction in nephron
number and typically corresponds to CKD stages 3–5.
• Short term adaptations of hypertrophy and hyperfiltration
of viable nephrons in case of nephron loss in chronic
kidney disease.
• Adaptive mechanisms become maladaptive as the
increased pressure and flow within the nephron
predisposes to disruption of the filtration barrier leading
to sclerosis and dropout of the remaining nephrons.

8. CAUSES OF CHRONIC KIDNEY DISEASE
43.7
28.4
17.6
1.4
2.3
6.6
Diabetes
Hypertension
Others
urologic
cyctic kdny
Gnephritis
Source: United States Renal Data System. USRDS 2007 Annual Data Report.

10. INTACT NEPHRON HYPOTHESIS
• Developed by Bricker.
• ‘As the number of functioning nephrons decreases, each
remaining nephron must perform a greater fraction of
total renal excretion’.
• He also emphasized- ‘the functional capacity of the
residual nephrons of the diseased kidney is largely
independent of the specific form of renal disease. The
decrease in the number of nephrons is clearly
responsible for many of the abnormalities that develop in
the patient; the persistent nephrons permit the patient to
survive’.

12. ALTERATIONS IN GLOMERULAR
PHYSIOLOGY IN NEPHRON LOSS
• The rise in SNGFR associated with renal mass ablation
referred to as glomerular hyperfiltration and the
elevated glomerular capillary hydrostatic pressure is
termed glomerular hypertension.
• Studies imply that single-kidney GFR (and therefore also
the average SNGFR) increases by 30% to 40% after
uninephrectomy in humans.

13. MAINTENANCE OF GTB IN CHRONIC
KIDNEY DISEASE
Ongoing Nephron loss
Decrease total no of functional nephron in a single kidney.
Single nephron hyper filtration
Increased SNGFR
Increased Filtration fraction
Increased post glomerular capillary protein concentration.

14. Nonlinear increase in oncotic pressure.(Pe)
Increased peritubular capillary resorptive
force (Pr)
Increased resorption of fluid & solute in prox
tubule.

15. MEDIATORS OF GLOMERULAR
HEMODYNAMIC RESPONSE TO NEPHRON
LOSS
 Renin-Angiotensin-Aldosterone System
 Endothelins
 Natriuretic Peptides
 Eicosanoids
 Nitric Oxide
 Bradykinin
 Urotensin II

16. RENAL HYPERTROPHIC RESPONSES TO
NEPHRON LOSS
• Among the earliest responses to unilateral nephrectomy
are biochemical changes that precede cell growth.
• These are-
i) Increased activity of choline kinase and ornithine
decarboxylase
ii) Increased ribosomal RNA, protein and poly(A)-deficient
mRNA synthesis
iii) Increased DNA synthesis
• Renal mass continues to rise for 1 to 2 months until a 40%
to 50% increase is achieved. The degree of compensatory
growth is a function of the extent of renal ablation.

17. MECHANISMS OF RENAL HYPERTROPHY IN
RESPONSE TO NEPHRON LOSS
• Solute load
• Renotropic factors
• Endocrine effects
• Growth factors
• Mesangial cell response
• Tubule cell responses

19. LONG TERM CONSEQUENCES OF
ADAPTATION
Non hemodynamic factors:
• TGF-B
• Angiotensin
• Aldosterone
• HGF
• BMP-7
• Oxidative stress
• Acidosis
• Loss of glomerular permselectivity
Hemodynamically induced
injury:
Endothelial cells
Mesangial cells
Podocytes
Cellular infiltration

27. PATHOPHYSIOLOGY OF DIABETIC
NEPHROPATHY

28. PATHOPHYSIOLOGY OF HYPERTENSIVE
NEPHROPATHY

29. PATHOPHYSIOLOGY OF ESRD IN ADPKD

30. MECHANISM OF ESRD IN RENAL
ARTERY STENOSIS

31. MECHANISM OF ESRD IN SLE
NEPHROPATHY
Deposition of immune complexes
Activation of complement system
Complement mediated damage
Activation of procoagulant factors
Leucocyte infiltration
Release of proteolytic
enzymes/cytokines(IL2, IL1, IL6)
Matrix synthesis
Glomerular cellular proliferation
Fibrosis
ESRD

32. TREATMENT TARGETS- TRADITIONAL
AND NOVEL
Traditional
targets
• RAAS BLOCKADE
• GLYCEMIC CONTROL
• VITAMIN D
• URIC ACID LOWERING
• PHOSPHATE
LOWERING
Novel
targets
• ENDOTHELIN
ANTAGONISTS
• ANTI-INFLAMMATORY
AGENTS
• BARDOXOLONE
• PENTOXYFYLLINE
• CTP-499
• MONOCYTE
CHEMOATTRACTANT
PROTEIN-1 INHIBITION
• URAEMIC TOXIN
ABSORBANTS
KREMEZIN (AST-120)
• VITAMIN B THERAPY