Adaption of the kidney to renal injury

Adaption of the Kidney to Renal InjuryDr. Juan Carlos Becerra Martínez, MD, FACC

Cardiólogo Intervencionista

Introduction• Humans have between 225,000 and 900,000 nephrons in each kidney

• These nephrons determine how well the kidney will adapt to:• The physiologic demands of blood pressure and body size• Various environmental stresses,• Unwanted inflammation leading to chronic renal failure.

Harrison’s Principles of Internal Medicine. 18e

Introduction• Residual nephrons hyperfunction to compensate for the loss of those

nephrons succumbing to primary disease.

• This compensation depends on adaptive changes produced by:• Renal hypertrophy • Adjustments in tubuloglomerular feedback • Adjustments in glomerulotubular balance

• Some physiologic adaptations to nephron loss also produce unintended clinical consequences and eventually some adaptations accelerate the deterioration of residual nephrons (hyperfiltration hypothesis)


Common Mechanisms of Progressive Renal Disease• When the initial complement of nephrons is reduced by a sentinel event,

such as unilateral nephrectomy, the remaining kidney adapts by enlarging and increasing its glomerular filtration rate.

• The remaining kidney grows by compensatory renal hypertrophy.

• This compensatory renal hypertrophy is only partially understood:• Studies suggest roles for angiotensin II transactivation of heparin-binding epithelial

growth factor, PI3K, and p27kip1, a cell cycle protein that prevents tubular cells exposed to angiotensin II from proliferating, and the mammalian target of rapamycin (mTOR), which mediates new protein synthesis.


Common Mechanisms of Progressive Renal Disease• Hyperfiltration during pregnancy or in humans born with one kidney or who

lose one to trauma or transplantation generally produces no ill consequences.

• By contrast, experimental animals that undergo resection of 80% of their renal mass, or humans who have persistent injury that destroys a comparable amount of renal tissue, progress to end-stage disease.

• There is a critical amount of primary nephron loss that produces maladaptive deterioration in remaining nephrons. This maladaptive response is referred to clinically as renal progression, and the pathologic correlate of renal progression is the relentless advance of tubular atrophy and tissue fibrosis.


Common Mechanisms of Progressive Renal Disease


Progression of chronic renal injury

Common Mechanisms of Progressive Renal Disease• There are six mechanisms that hypothetically unify this final common pathway:

1. Persistent glomerular injury local hypertension in capillary bed increases their single-nephron glomerular filtration rate protein leak into the tubular fluid

2. Significant glomerular proteinuria, accompanied by increases in the local production of angiotensin II induces the accumulation of interstitial mononuclear cells

3. Cytokine bath: Cytokines and chemokines4. The initial appearance of interstitial neutrophils is quickly replaced by macrophages

and T lymphocytes producing interstitial nephritis5. Some tubular epithelia respond to this inflammation by disaggregating from their

basement membrane to undergo Epithelial-mesenchymal transitions forming new interstitial fibroblasts

6. Surviving fibroblasts lay down a collagenous matrix that disrupts adjacent capillaries and tubular nephrons, eventually leaving an acellular scar (Fibrosis).



6 stages that include:1.- Hyperfiltration2.- Proteinuria3.- Cytokine bath4.- Mononuclear cell infiltration5.- Epithelial-mesenchymal transition,6.- Fibrosis.

Response to Reduction in Numbers of Functioning Nephrons• The response to the loss of many functioning nephrons produces:• Vasoconstriction in postglomerular efferent arterioles (and not in afferent

arterioles) increasing the intraglomerular capillary pressure hyperfiltration

• Persistent intraglomerular hypertension is associated with progressive nephron destruction.

• A number of vasoconstrictive and vasodilatory substances have been implicated:• Chief among them being Angiotensin II (incrementally vasoconstricts the efferent arteriole)• Rol of ARB-II


Tubular Function in Chronic Renal Failure• Sodium:• Remains near normal until limitations from advanced renal disease

inadequately excrete dietary Na+ intake.

• Eventually, with advancing nephron loss, the atrial natriuretic peptides lose their effectiveness and Na+ retention results in intravascular volume expansion, edema, and worsening hypertension.


Tubular Function in Chronic Renal Failure• Urinary dilution and concentration:• Patients with progressive renal injury gradually lose the capacity either to

dilute or concentrate their urine

• Urine osmolality becomes relatively fixed about 350 mOsm/L (specific gravity ~1.010).

• Tubulointerstitial damage also creates insensitivity to the antidiuretic effects of vasopressin


Tubular Function in Chronic Renal Failure• Potassium:• Normally, the kidney excretes 90% of dietary K+, while 10% is excreted in the

stool with a trivial amount lost to sweat.

• Although the colon possesses some capacity to increase K+ excretion—up to 30% of ingested K+ may be excreted in the stool of patients with worsening renal failure

• Aldosterone is released in direct response to elevated levels of serum K+


Tubular Function in Chronic Renal Failure• Acid-Base Regulation:• The kidneys excrete 1 meq/kg/day of noncarbonic H+ ion on a normal diet.• To do this, all of the filtered HCO3

2– needs to be reabsorbed proximally so that H+ pumps can secrete H+ ions • Metabolic acidosis• Type IV renal tubular acidosis. • Once GFR falls below 25 mL/min, noncarbonic organic acids accumulate• The level of serum HCO3

2– falls severely


Tubular Function in Chronic Renal Failure• Calcium and Phosphate:• The expression of 1alpha-hydroxylase by the proximal tubule is reduced

lowering levels of calcitriol less Ca++ absorption by the gut.

• Loss of nephron mass reduces the excretion of PO4 decreases levels of Ca secretion pf PTH Ca movilization from bone Ca/PO4 precipitation in vascular tissues abnormal bone remodeling bone demineralized from secondary hyperparathyroidism.


Tubular Function in Chronic Renal Failure

Nature Reviews

Tubular Function in Chronic Renal Failure• Calcium and Phosphate:


Modifiers Influencing the Progression of Renal Disease


Gracias

Health & Medicine

Adaption of the kidney to renal injury