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In the early stages of CKD, there are many adaptations structurally and functionally that limit the consequences of the loss of nephrons on total-body homeostasis. In later stages of disease, however, these adaptations are insufficient to counteract the consequences of nephron loss and in fact often become maladaptive.
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Renal counterbalance was defined by Hinman in 1923 as “an attempt on the part of the less injured or uninjured portion (of the kidney) to take over the work of the more injured portion.” Hinman defined “renal reserve” to be of two types: “native reserve, which is the normal physiological response to stimulation . . and acquired reserve, which involves growth or compensation due to overstimulation.” It was known that removal of one kidney results in an increase in size of the contralateral kidney. If, instead of nephrectomy, one kidney is rendered ischemic and the other left intact, there is a resultant atrophy of the postischemic kidney. If the contralateral kidney is removed, however, before the atrophy becomes too severe, then the postischemic kidney increases markedly in size. With the contralateral kidney in place, there is vasoconstriction and reduced renal blood flow to the postischemic kidney. This is rapidly reversed, however, when the contralateral normal kidney is removed. The factors responsible for the persistent initial (prenephrectomy) vasoconstriction and those responsible for the rapid vasodilation and enhanced growth after contralateral nephrectomy are unknown.
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Because nephrons of mammals, in contrast to those of fish, cannot regenerate, the loss of functional units of the kidney, either due to disease or surgery, results in anatomic and functional changes in the remaining nephrons. As described above, there is increased blood flow to remaining glomeruli with potentially adverse effects over time of the resultant increased size of the remaining glomeruli and hyperfiltration (Fig. 333e-1). In addition, there is hypertrophy of the tubules. Some of the mediators of this hypertrophy of the remaining functional tubules are listed in Table 333e-2. In the adult, within a few weeks after unilateral nephrectomy for donation of a kidney, the GFR is approximately 70% of the prenephrectomy value. It then remains relatively stable for most patients over 15–20 years. The hyperfiltration is related to an increase in renal blood flow likely secondary to dilatation of the afferent arterioles potentially due to increases in nitric oxide (NO) production. The rate of increase in GFR is slower in the adult than it is in the young after nephrectomy. There are a number of factors that have been implicated at the cellular and nephron level to account for the compensatory hypertrophy that ensues after removal of functional nephrons (Table 333e-2).
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With increased blood flow to the kidney, there is glomerular hypertension (i.e., an increase in glomerular capillary pressure). There is increased wall tension and force on the capillary wall that is counteracted by contractile properties of the endothelium and elastic properties of the glomerular basement membrane. The force is conveyed to podocytes, which adapt by reinforcing cell cycle arrest and increasing cell adhesion in an adaptive attempt to maintain the delicate architecture of the interdigitating foot processes. Over time, however, these increased forces due to glomerular hypertension lead to podocyte damage and glomerulosclerosis.
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Other Systemic and Renal Adaptations to Reduced Nephron Function
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With reduced functional nephrons, as is seen in CKD, there are many other systemic adaptations that occur to preserve the milieu intérieur because the kidney is involved in so many regulatory networks that are then stressed when there is dysfunction. In the 1960s, Neil Bricker introduced the “intact nephron hypothesis.” According to his concept, with decreases in the number of functioning nephrons, each remaining nephron has to adapt to carry a larger burden of transport, synthetic function, and regulatory function.
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Under normal and abnormal conditions, most of the filtered potassium is reabsorbed in the proximal tubule so that excretion is determined by secretion by the distal nephron. Potassium handling is altered in CKD protecting the organism somewhat from lethal hyperkalemia. Hyperkalemia is a common feature of individuals with CKD. Hyperkalemia (if not severe and dangerous) is adaptive in that it promotes potassium secretion by the principal cells of the collecting duct. When patients with CKD are given a potassium load, they can excrete it at the same rate as patients with normal renal function except that they do so at a higher serum potassium, consistent with the view that the hyperkalemia facilitates potassium excretion. The direct effect of hyperkalemia on potassium secretion by the distal nephron is independent of changes in aldosterone levels, but “normal” levels of aldosterone are necessary to see the effect of hyperkalemia on potassium excretion. Elevated potassium stimulates the production of aldosterone, and this effect is also seen in patients with CKD. Aldosterone increases the density and activity of the basolateral Na+-K+ ATPase and the number of Na+ channels in the apical membrane of the collecting duct. In CKD, the excretion of the dietary load of potassium occurs at the expense of an elevation in serum potassium concentrations.
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As renal function is reduced with CKD, there is a reduced ability to excrete sodium. Thus, patients with advanced kidney disease are often fluid overloaded. In early disease, however, there are functional adaptations that the kidney assumes to help to maintain the milieu intérieur. With loss of functional nephrons, the remaining nephrons are hyperperfused and are hyperfiltering in a manner that can be influenced by dietary protein intake. Although protein restriction can decrease this compensatory hyperperfusion, there is generally more sodium and water filtered and delivered to the remaining nephrons. There is some preservation of glomerulotubular balance with increased proximal tubule sodium and water reabsorption associated with increased levels of the Na/H exchanger in apical membranes of the tubule. The tubuloglomerular feedback (TGF) of the remaining nephrons is sensitive to sodium intake. With high sodium intake in normal renal function, a negative feedback process occurs by which increased distal delivery results in reduced GFR and hence filtration of sodium. In CKD, the TGF becomes a positive feedback process by which increased distal delivery results in increased filtration so that the need to excrete an increased amount of sodium per nephron is achieved. This conversion from a negative feedback process to a positive feedback process may be due to conversion of an adenosine-dominated vasoconstrictive feedback on the afferent arteriole of the glomerulus to a NO-dominated vasodilatory feedback. Like so many of these adaptive responses, this one may turn maladaptive, resulting in higher intraglomerular hydrostatic pressures with increased mechanical strain on the glomerular capillary wall and podocytes and increased glomerulosclerosis as a consequence.
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Acid-base homeostasis
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The kidneys excrete approximately 1 mEq/kg per day of dietary acid load under normal dietary conditions. With decreased kidney functional mass, there is an adaptive response to increase H+ excretion by the remaining functional nephrons. This takes the form of enhanced nephron ammoniagenesis and increased distal nephron H+ ion secretion, which is mediated by the renin-angiotensin system and endothelin-1. NH3 is produced by deamidization of glutamine in the proximal tubule. NH3 is converted to NH4+ in the collecting duct, where it buffers the secreted H+. It has been argued, however, that these mechanistic attempts to enhance H+ secretion can be maladaptive in that they can contribute to kidney inflammation and fibrosis and hence facilitate the progression of CKD.
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In CKD, there is a decrease in the ability of the kidney to excrete phosphate and produce 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. There is a resultant increase in serum phosphate and reduction in serum calcium (Fig. 333e-2). In response, the body adapts by increasing production of parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23) in an attempt to increase phosphaturia. The elevated levels of PTH act on bone to increase bone resorption and on osteocytes to increase FGF-23 expression. Elevated levels of PTH increase FGF-23 expression by activating protein kinase A and wnt signaling in osteoblast-like cells. There are a number of other factors that increase bone FGF-23 production in CKD including systemic acidosis, altered hydroxyapatite metabolism, changes in bone matrix, and release of low-molecular-weight FGFs. Although the production of PTH and FGF-23 initially are adaptive attempts to maintain body phosphate levels by enhancing excretion by the kidney, they become maladaptive due to systemic effects on the cardiovascular system and bone, as renal function continues to deteriorate. PTH and FGF-23 decrease the kidney’s ability to reabsorb phosphate by decreasing the levels of the sodium-phosphate cotransporters NaPi2a and NaPi2c on the apical and basolateral membranes of the renal tubule. FGF-23 also reduces the ability of the kidney to generate 1,25(OH)2D3. In the parathyroid gland, the FGF-23 receptor, the klotho-fibroblast growth factor 1 complex, is downregulated with a consequent loss of the normal action of FGF-23 to downregulate PTH production. PTH and FGF-23 have been implicated in the cardiovascular disease that is so characteristic of patients with CKD. With CKD, there is less klotho expression in the kidney and the parathyroid glands. Klotho deficiency contributes to soft tissue calcifications in CKD. FGF-23 has been associated with increased mortality in CKD and has been reported to be involved causally in the development of left ventricular hypertrophy. PTH also has been reported to directly affect rat myocardial cells, increasing calcium entry into the cells and contributing to death of the cells.
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