The size of a kidney and the number of nephrons formed late in embryological development depend on the frequency with 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 prematurely terminated by one or two cycles. Although the signaling mechanism regulating cycle number is unknown, 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 made in the course of studying chronic renal failure is that residual nephrons hyperfunction to compensate for the loss of those nephrons falling 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 foundation for understanding common pathophysiology leading to uremia.
Common Mechanisms of Progressive Renal Disease
When the initial complement of nephrons is reduced by a sentinel event, like unilateral nephrectomy, the remaining kidney adapts by enlarging and increasing its glomerular filtration rate (GFR). If the kidneys were initially normal, the GFR 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 and the renal capsule. The mechanism of this compensatory renal hypertrophy is only partially understood, but the signals for the remaining kidney to hypertrophy may rest with the local expression of angiotensin II; transforming growth factor (TGF-); p27kip1, a cell cycle protein that prevents tubular cells exposed to angiotensin II from proliferating; and epidermal growth factor (EGF), which induces the mammalian target of rapamycin (mTOR) to engage a transcriptome supporting new protein synthesis.
Hyperfiltration during pregnancy, or in humans born with one kidney or who lose one to trauma or transplantation, generally leads to no ill consequences. By contrast, experimental animals who 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. 272-1). Clearly there is a critical amount of primary nephron loss that produces a maladaptive deterioration in the remaining nephrons. This maladaptive response is referred to clinically as renal progression, and the pathologic correlate of renal progression is relentless tubular atrophy and tissue fibrosis . The mechanism for this maladaptive response has been 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.
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 GFR, and engenders protein leak into the tubular fluid. (2) Significant glomerular proteinuria, accompanied by increases in the local production of angiotensin II, facilitates (3) a downstream cytokine bath that induces an accumulation of interstitial mononuclear cells. (4) The initial appearance of interstitial neutrophils is quickly replaced by gathering macrophages and T lymphocytes that form a nephritogenic immune response producing interstitial nephritis. (5) 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. (6) Finally, 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. 272-2).
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 intraglomerularhypertension stimulate the eventual appearance of glomerulosclerosis. Angiotensin II acts as an essential mediator of increased intraglomerularcapillary 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 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 tubulointerstitium in association with heavier proteinuria. Many clinical observations support the association of worsening glomerular proteinuria with renal progression. The simplest explanation for this expansion is that increasingly severe proteinuria triggers a downstream inflammatory cascade around epithelia that line the nephron, producing interstitial nephritis, fibrosis, and tubular atrophy. As albumin is an abundant polyanion in plasma and can bind a variety of cytokines, chemokines, and lipid mediators, it might be that these small molecules carried by albumin initiate the tubular inflammation brought on by proteinuria. Furthermore, glomerular injury either adds activated mediators to the proteinuric filtrate or alters the balance of cytokine inhibitors and activators such that attainment of a critical level of activated cytokines eventually damages downstream tubular epithelia.
Tubular epithelia bathed in these complex mixtures of proteinuric cytokines respond by increasing their secretion of chemokines and relocating nuclear factor B to the nucleus to induce proinflammatory release of TGF-, platelet-derived growth factor B (PDGF-BB), and fibroblast growth factor 2 (FGF-2). Inflammatory cells are drawn into the renal interstitium by this cytokine milieu. This interstitial spreading reduces the likelihood that the kidney will survive. The immunologic mechanisms for spreading include loss of tolerance to parenchymal self, immune deposits that share cross-reactive epitopes in either compartment, or glomerular injury that reveals a new interstitial epitope. Drugs, infection, and metabolic defects may also induce autoimmunity through Toll-like receptors that bind to moieties with an immunologically distinct molecular pattern. Bacterial and viral ligands do so, but, interestingly, so do Tamm-Horsfall protein, bacterial CpG repeats, and RNA that is released nonspecifically from injured tubular cells. Dendritic cells and macrophages are subsequently activated, and circulating T cells engage in the formal cellular immunologic response.
Nephritogenic interstitial T cells are a mix of CD4+ helper and CD8+ cytotoxic lymphocytes. Presumptive evidence of antigen-driven T cells found by examining the DNA sequence of T cell receptors suggests a polyclonal expansion that responds to multiple epitopes. Some experimental interstitial lesions are histologically analogous to a cutaneous delayed-type hypersensitivity reaction, and more intense reactions sometimes induce granuloma formation. The cytotoxic activity of antigen-reactive T cells probably accounts for tubular cell destruction and atrophy. Cytotoxic T cells synthesize proteins with serine esterase activity as well as pore-forming proteins, which can affect membrane damage much like the activated membrane attack complex of the complement cascade. Such enzymatic activity provides a structural explanation for target cell lysis.
One long-term consequence of tubular epithelia exposed to cytokines is the profibrotic activation of epithelial-mesenchymal transition. Persistent cytokine activity during renal inflammation and disruption of underlying basement membrane by local proteases initiates the process of transition. Rather than collapsing into the tubular lumens and dying, some epithelia become fibroblasts while translocating back into the interstitial space behind deteriorating tubules through holes in the ruptured basement membrane. Wnt proteins, integrin-linked kinases, insulin-like growth factors, EGF, FGF-2, and TGF- are among the classic modulators of epithelial-mesenchymal transition. Fibroblasts that deposit collagen during fibrogenesis also replicate locally at sites of persistent inflammation. Estimates indicate that half of the total fibroblasts found in fibrotic renal tissues are products of the proliferation of newly transitioned or preexisting fibroblasts. Fibroblasts are stimulated to multiply by activation of cognate cell-surface receptors for PDGF and TGF-.
Tubulointerstitial scars are composed principally of fibronectin, collagen types I and III, and tenascin, but other glycoproteins such as thrombospondin, SPARC, osteopontin, and proteoglycan may be also important. Although tubular epithelia can synthesize collagens I and III and are modulated by a variety of growth factors, these epithelia disappear through transition and tubular atrophy, leaving fibroblasts as the major contributor to matrix production. After fibroblasts acquire a synthetic phenotype, expand their population, and locally migrate around areas of inflammation, they begin to deposit fibronectin, which provides a scaffold for interstitial collagens. When fibroblasts outdistance their survival factors, they die from apoptosis, leaving an acellular scar.
Response to Reduction in Numbers of Functioning Nephrons
The response to the loss of many functioning nephrons produces an increase in renal blood flow with glomerular hyperfiltration. Hyperfiltration is the result of increased vasoconstriction in postglomerular efferent arterioles relative to preglomerular afferent arterioles, increasing the intraglomerular capillary pressure and filtration fraction. The discovery of this intraglomerular hypertension and the demonstration in experimental animals that maneuvers to decrease its effect will abrogate the further expression of glomerular and tubulointerstitial injury led to the formulation of the hyperfiltration hypothesis. The hypothesis explains why residual nephrons in the setting of persistent disease will first stabilize or increase the rate of glomerular filtration, only to succumb later to inexorable deterioration and progression to renal failure. Persistent intraglomerular hypertension is critical to this transition.
Although the hormonal and metabolic factors mediating hyperfiltration are not fully understood, a number of vasoconstrictive and vasodilatory substances have been implicated, chief among them being angiotensin II. Angiotensin II incrementally vasoconstricts the efferent arteriole, and studies in animals and humans demonstrate that interruption of the renin-angiotensin system with either angiotensin-converting inhibitors or angiotensin II receptor blockers will decrease intraglomerular capillary pressure, decrease proteinuria, and slow the rate of nephron destruction. The vasoconstrictive agent, endothelin, has also been implicated in hyperfiltration, and increases in afferent vasodilatation have been attributed, at least in part, to local prostaglandins and release of endothelium-derived nitric oxide. Finally, hyperfiltration may be mediated in part by a resetting of the kidney's intrinsic autoregulatory mechanism of glomerular filtration by a tubuloglomerular feedback system. This feedback originates from the macula densa and modulates renal blood flow and glomerular filtration (Chap. 271).
Even with the loss of functioning nephrons, there is some continued maintenance of glomerulotubular balance, by which the residual tubules adapt to increases in single-nephron glomerular filtration with appropriate alterations in reabsorption or excretion of filtered water and solutes in order to maintain homeostasis. Glomerulotubular balance results both from tubular hypertrophy and from regulatory adjustments in tubular oncotic pressure or solute transport along the proximal tubule. Some studies have indicated that these alterations in tubule size and function may themselves be maladaptive and, as a trade-off, predispose to further tubule injury.
Tubular Function in Chronic Renal Failure
Na+ ions are reclaimed along most of the nephron by various transport mechanisms (Chap. 271). This transport function and its contribution to extracellular blood volume is usually maintained near normal until limitations from advanced renal disease can no longer keep up with dietary Na+ intake. Prior to this point in the spectrum of renal progression, increasing the fractional excretion of Na+ in final urine at reduced rates of glomerular filtration provides a mechanism of early adaptation. Na+ excretion increases predominantly by decreasing Na+ reabsorption in the loop of Henle and distal nephron. Increases in the osmotic obligation of residual nephrons lower the concentration of Na+ in tubular fluid, and increased excretion of inorganic and organic anions obligates more Na+ excretion. In addition, hormonal influences, notably increased expression of atrial natriuretic peptides that increase distal Na+ excretion, as well as levels of GFR, play an important role in maintaining adequate Na+ excretion. Although many details of these adjustments are only understood conceptually, it is an example of a trade-off by which initial adjustments following the loss of functioning nephrons lead to compensatory responses that maintain homeostasis. Eventually, with advancing nephron loss, the atrial natriuretic peptides lose their effectiveness, and Na+ retention results in intravascular volume expansion, edema, and worsening hypertension.
Urinary Dilution and Concentration
Patients with progressive renal injury gradually lose the capacity either to dilute or concentrate their urine, and urine osmolality becomes relatively fixed around 350 mosmol/L (specific gravity approximating 1.010). Although the ability of a single nephron to excrete water free of solute may not be impaired, the reduced number of functioning nephrons obligates increased fractional solute excretion by residual nephrons, and this greater obligation impairs the ability to dilute tubular fluid maximally. Similarly, urinary concentrating ability falls due to the need for more water to hydrate the increased solute load. Tubulointerstitial damage also creates insensitivity to the antidiuretic effects of vasopressin along the collecting duct or loss of the medullary gradient, which eventually disturbs control of variation in urine osmolality. Patients with moderate degrees of chronic renal failure often complain of nocturia as a manifestation of this fixed urine osmolality and are prone to extracellular volume depletion if they do not keep up with the persistent loss of Na+, or hypotonicity if they drink too much water.
Renal excretion is a major pathway for reducing excess total-body K+. 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—the majority of the K+ load continues to be excreted by the kidneys due to elevation in levels of serum K+ that increase this filtered load. Aldosterone also regulates collecting duct Na+ reabsorption and K+ secretion. Aldosterone is released from the adrenal cortex not only in response to the renin-angiotensin system but also in direct response to elevated levels of serum K+, and for a while a compensatory increase in the capacity of the collecting duct to secrete K+ keeps up with renal progression. As serum K+ levels rise with renal failure, circulating levels of aldosterone also increase over what is required to maintain normal levels of blood volume.
The kidneys excrete one meq/kg per day of noncarbonic H+ ion on a normal diet. To do this, all of the filtered HCO32– needs to be reabsorbed proximally so that H+ pumps in the intercalated cells of the collecting duct can secrete H+ ions that are subsequently trapped by urinary buffers, particularly phosphates and ammonia (Chap. 271). While remaining nephrons increase their solute load with loss of renal mass, the ability to maintain total-body H+ excretion is often impaired by the gradual loss of H+ pumps or with reductions in ammoniagenesis leading to development of a non-delta acidosis. Although hypertrophy of the proximal tubules initially increases their ability to reabsorb filtered HCO32– and increase ammoniagenesis, with progressive loss of nephrons this compensation is eventually overwhelmed. In addition, with advancing renal failure, ammoniagenesis is further inhibited by elevation in levels of serum K+, producing type IV renal tubular acidosis. Once the GFR falls below 25 mL/min, organic acids accumulate, producing a delta metabolic acidosis. Hyperkalemia can also inhibit tubular HCO32– reabsorption, as can extracellular volume expansion and elevated levels of parathyroid hormone (PTH). Eventually, as the kidneys fail, the level of serum HCO32– falls severely, reflecting the exhaustion of all body buffer systems, including bone.
Calcium and Phosphate
The kidney and gut play an important role in the regulation of serum levels of Ca2+ and PO42–. With decreasing renal function and the appearance of tubulointerstitial nephritis, the expression of 1-hydroxylase by the proximal tubule is reduced, lowering levels of calcitriol and Ca2+ absorption by the gut. Loss of nephron mass with progressive renal failure also gradually reduces the excretion of PO42– and Ca2+, and elevations in serum PO42– further lower serum levels of Ca2+, causing sustained secretion of PTH. Unregulated increases in levels of PTH cause Ca2+ mobilization from bone, Ca2+/PO42– precipitation in tissues, abnormal bone remodeling, decreases in tubular bicarbonate reabsorption, and increases in renal PO42– excretion. While elevated serum levels of PTH initially maintain serum PO42– near normal, with progressive nephron destruction the capacity for renal PO42– excretion is overwhelmed, the serum PO42– elevates, and bone is progressively demineralized from secondary hyperparathyroidism. These adaptations evoke another classic functional trade-off (Fig. 272-3).
Modifiers Influencing the Progression of Renal Disease
Well-described risk factors for the progressive loss of renal function include systemic hypertension, diabetes, and activation of the renin-angiotensin-aldosterone system (Table 272-1). Poor glucose control will aggravate renal progression in both diabetic and nondiabetic renal disease. Angiotensin II produces intraglomerular hypertension and stimulates fibrogenesis. Aldosterone also serves as an independent fibrogenic mediator of progressive nephron loss apart from its role in modulating Na+ and K+ homeostasis.
Lifestyle choices also have an impact on the progression of renal disease. Cigarette smoking has been shown to either predispose or accelerate the progression of nephron loss. Whether the effect of cigarettes is related to systemic hemodynamic alterations or specific damage to the renal microvasculature and/or tubules is unclear. Lipid oxidation associated with obesity or central adiposity can also accelerate cardiovascular disease and progressive renal damage. Recent epidemiologic studies confirm an association between high-protein diets and progression of renal disease. Progressive nephron loss in experimental animals, and possibly in humans, can be slowed by adherence to a low-protein diet. Although a large multicenter trial, the Modification of Diet in Renal Disease, did not provide conclusive evidence that dietary protein restriction could retard progression to renal failure, secondary analyses and a number of meta-analyses suggest a renoprotective effect from supervised low-protein diets in the range of 0.6–0.75 g/kg per day. Abnormal Ca2+ and PO42– metabolism in chronic kidney disease also plays a role in renal progression, and administration of calcitriol or its analogues can attenuate progression in a variety of models of chronic kidney disease.
An intrinsic paucity in the number of functioning nephrons predisposes to the development of renal disease. A reduced number of nephrons can lead to permanent hypertension, either through direct renal damage or hyperfiltration producing glomerulosclerosis, or by primary induction of systemic hypertension that further exacerbates glomerular barotrauma. Younger individuals with hypertension who died suddenly as a result of trauma have 47% fewer glomeruli per kidney than age-matched controls.
A consequence of low birth weight is a relative deficit in the number of total nephrons; low birth weight is associated in adulthood with more hypertension and renal failure, among other abnormalities. In this regard, in addition to or instead of a genetic predisposition to development of a specific disease or condition such as low birth weight, different epigenetic phenomena may produce varying clinical phenotypes from a single genotype, depending on maternal exposure to different environmental stimuli during gestation, a phenomenon known as developmental plasticity. A specific clinical phenotype can also be selected in response to an adverse environmental exposure during critical periods of intrauterine development, also known as fetal programming. In the United States there is at least a twofold increased incidence of low birth weight among African Americans compared with Caucasians, much but not all of which can be attributed to maternal age, health, or socioeconomic status.
As in other conditions producing nephron loss, the glomeruli of low-birth-weight individuals are enlarged and associated with early hyperfiltration to maintain normal levels of renal function. With time, the resulting intraglomerular hypertension may initiate a progressive decline in residual hyperfunctioning nephrons, ultimately accelerating renal failure. In African Americans, as well as other populations at increased risk for kidney failure, such as Pima Indians and Australian aborigines, large glomeruli are seen at early stages of kidney disease. An association between low birth weight and the development of albuminuria and nephropathy has been reported for both diabetic and nondiabetic renal disease.