The size of a kidney and the total number of nephrons formed late in embryologic development depend on the degree to which the ureteric bud undergoes branching morphogenesis. Humans have between 225,000 and 900,000 nephrons in each kidney, a number that mathematically hinges on whether ureteric branching goes to completion or is terminated prematurely by one or two cycles. Although the signaling mechanisms regulating cycle number are incompletely understood, these final rounds of branching likely determine how well the kidney will adapt to the physiologic demands of blood pressure and body size, various environmental stresses, or unwanted inflammation leading to chronic renal failure.
One of the intriguing generalities regarding chronic renal failure is that 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 and adjustments in tubuloglomerular feedback and glomerulotubular balance, as advanced in the intact nephron hypothesis by Neal Bricker in 1969. Some physiologic adaptations to nephron loss also produce unintended clinical consequences explained by Bricker's trade-off hypothesis in 1972, and eventually some adaptations accelerate the deterioration of residual nephrons, as described by Barry Brenner in his hyperfiltration hypothesis in 1982. These three important notions regarding chronic renal failure form a conceptual basis for understanding common pathophysiology leading to uremia.
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. If the kidneys were initially normal, the filtration rate usually returns to 80% of normal for two kidneys. The remaining kidney grows by compensatory renal hypertrophy with very little cellular proliferation. This unique event is accomplished by increasing the size of each cell along the nephron, which is accommodated by the elasticity or growth of interstitial spaces under the renal capsule. The mechanism of 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.
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 (Fig. 278-1). Clearly, 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. The mechanism for this maladaptive response is the focus of intense investigation. A unified theory of renal progression is just starting to emerge, and most importantly, this progression follows a final common pathway regardless of whether renal injury begins in glomeruli or within the tubulointerstitium.
Progression of chronic renal injury. Although various types of renal injury have their own unique rates of progression, one of the best understood is that associated with type I diabetic nephropathy. Notice the early increase in glomerular filtration rate, followed by inexorable decline associated with increasing proteinuria. Also indicated is the National Kidney Foundation K/DOQI classification of the stages of chronic kidney disease.
There are six mechanisms that hypothetically unify this final common pathway. If injury begins in glomeruli, these sequential steps build on each other: (1) persistent glomerular injury produces local hypertension in capillary tufts, increases their single-nephron glomerular filtration rate and engenders protein leak into the tubular fluid; (2) significant glomerular proteinuria, accompanied by increases in the local production of angiotensin II, facilitates a downstream cytokine bath that induces the accumulation of interstitial mononuclear cells; (3) the initial appearance of interstitial neutrophils is quickly replaced by a gathering of macrophages and T lymphocytes, which form a nephritogenic immune response producing interstitial nephritis; (4) some tubular epithelia respond to this inflammation by disaggregating from their basement membrane and adjacent sister cells to undergo epithelial-mesenchymal transitions forming new interstitial fibroblasts; and finally (5) surviving fibroblasts lay down a collagenous matrix that disrupts adjacent capillaries and tubular nephrons, eventually leaving an acellular scar. The details of these complex events are outlined below (Fig. 278-2).
Mechanisms of renal progression. The general mechanisms of renal progression advance sequentially through six stages that include hyperfiltration, proteinuria, cytokine bath, mononuclear cell infiltration, epithelial-mesenchymal transition, and fibrosis. (Modified from Harris and Neilson.)
Significant ablation of renal mass results in hyperfiltration characterized by an increase in the rate of single-nephron glomerular filtration. The remaining nephrons lose their ability to autoregulate, and systemic hypertension is transmitted to the glomerulus. Both the hyperfiltration and intraglomerular hypertension stimulate the eventual appearance of glomerulosclerosis. Angiotensin II acts as an essential mediator of increased intraglomerular capillary pressure by selectively increasing efferent arteriolar vasoconstriction relative to afferent arteriolar tone. Angiotensin II impairs glomerular size selectivity, induces protein ultrafiltration, and increases intracellular Ca2+ in podocytes, which alters podocyte function. Diverse vasoconstrictor mechanisms, including blockade of nitric oxide synthase and activation of angiotensin II and thromboxane receptors, can also induce oxidative stress in surrounding renal tissue. Finally, the effects of aldosterone on increasing renal vascular resistance and glomerular capillary pressure, or stimulating plasminogen activator inhibitor-1, facilitate fibrogenesis and may complement the detrimental activity of angiotensin II.
On occasion, inflammation that begins in the renal interstitium disables tubular reclamation of filtered protein, producing mild nonselective proteinuria. Renal inflammation that initially damages glomerular capillaries often spreads to the ...