Progression of Chronic Renal Disease

Nephron adaptation to injury:

Intact nephron hypothesis: throughout the course of chronic renal disease the changes in the excretory profile of the residual nephrons are orderly, predictable and appropriate for the maintenance of homeostasis.

Trade-off hypothesis: adaptive Ý in nephron function that may be accomplished at the expense of one or more abnormalities of the uremic state.

Ex: Hyperparathyroidism and progressive Chronic Renal Failure: Phosphate excretion ß and serum [Ca⁺⁺]ß Þ PTH release Ý to restore serum [Ca⁺⁺]. The trade off: osteitis fibrosa cystica may develop from PTH effect on bone

Change in function	Beneficial Effect	Adverse effect
Ý GFR	Ý solute excretion	Accelerates glomerular injury
Ý fractional excretion of Na	Prevents Ý ECF	Slow adaptation to Na restriction
Ý PTH	ß phosphate retention	Bone disease
Ý NH3 secretion	ß systemic acidosis	Ý progression of tubulointerstitial disease

Mechanisms of injury initiation:

Immune mechanism: humoral and cell-mediated immunity both involved in primary and secondary processes

primary process: mechanisms that initiate glomerulonephritis
secondary process: cascade of responses activated by the initial stimulus

Antibody mediated glomerular injury Mechanisms (humoral):

(1) Binding of antibody to either:

structural component of glomerulus – e.g., Goodpasture’s syndrome: auto-antigen to GBM (Type IV collagen))
material not intrinsic to glomerulus by ‘planted" there due to physicochemical characteristics – e.g., SLE: histone-DNA complexes bind to glomerular cell surfaces and glomerular basement membrane

(2) Circulating antigen-antibody complexes form, escape clearance by reticuloendothelial system and deposit in glomerulus

Cell mediated immune mechanisms: unclear

Mechanisms of renal disease progression

Hemodynamic theory: renal damage Þ chronic afferent renal vasodilation, which leads to Ý afferent flow and Ý glomerular pressure Þ hyperfiltration and intraglomerular HTN Þ abnormal intravascular stress and strain Þ glomerular sclerosis (fibrosis)

Intrinsic population of kidney cells (Resident cells) become "activated" after injury and participate in the subsequent destructive and restorative processes.

Extracellular matrix: abundance and composition is modified. Matrix remodeling in response to injury generates signals different from those transmitted by normal glomerular matrix
Apoptosis
Programmed cell death
Active egress of inflammatory cells and generation of anti-inflammatory molecules (lipoxins)

End stage renal Disease

Overall findings: Chronic reduction in Renal Mass

Intrinsic kidney cells develop new structural changes which may lead to fibrosis Þ end organ damage

Contributing factors to the development of ESRD:

Environmental/Demographic: ethnicity, age, access to care, toxin

Genetic: genotype
Clinical: underlying disease, BP, blood sugar, disease process, therapies

Management of renal disease progression:

Goal: slow progression of chronic renal failure:

Treatment strategies:

Angiotensin-Converting Enzyme (ACE) inhibitors: prevents deterioration in renal function of patients with incipient diabetic nephropathy: slows deterioration in renal function

Benefit greatest in nephrotoxic patients

Blood pressure control: reduction of mean arterial blood pressure (MAP) to less than 92mmHG

"renal-protective" anti-hypertensives: ACE inhibitors, Calcium channel blockers

Proteinuria: independent risk factor for renal disease progression:

ACE inhibitors: ß proteinuria. Mechanism unclear

Diabetic proteinuria: requires aggressive blood glucose control.

Nutritional management: adequate protein and calorie intake: avoid malnutrition