ADAPTATION TO NEPHRON LOSS



The kidney has great functional reserve and is able to compensate for progressive loss of func­tioning nephrons. The homeostatic, excretory and, in part, endocrine functions of the kidney are maintained even when function of the kidney is only 10 per cent of normal. Further degrees of nephron loss usually result in clinical sequelae.

The adaptation to nephron loss can be illus­trated for a single solute such as sodium. In an individual with a glomerular filtration rate of 100 ml/min and ingesting 100 mEq of so­dium per day, the urinary excretion of sodium must be 100 mEq/day in order to maintain con­stant body weight and composition of body fluid compartments. In such an individual, 25,000 mEq of sodium are filtered at the glomerulus per day. Since only 100 of the 25,000 mEq of sodium that are filtered at the glomerulus are excreted, the fractional rate of excretion is 0.4 per cent. If the filtration rate were to be reduced by 50 per cent, the filtered load of sodium would be reduced pro­portionately. In order to maintain overall balance, 100 mEq of sodium would still have to be ex­creted. Under these circumstances, the fractional excretion of the filtered load of sodium by the kid­ney would be increased to 0.8 per cent. In the face of progressive reductions in the rates of filtration, the constancy of the composition and volume of body fluid compartments is maintained by pro­gressive increases in the fractional rates of excre­tion of filtered sodium such that intake and output are matched. As renal function decreases, how­ever, there is a narrowing of the range of intake that can be tolerated. In general, renal adjustments in the rate of excretion are ad­equate to accommodate normal rates of intake down to rates of filtration of 10 to 20 per cent of normal.

The above example highlights several impor­tant points in the adaptation to nephron loss. The nephrons that remain functional in the presence of a decrease in total number of functioning units are not damaged units. Rather, they behave in a normal or supernormal manner and respond ap­propriately to physiological stimuli. The above defines the concept of the “intact nephron hy­pothesis.” Said in another way, in a kidney that has sustained loss of nephrons, the remaining nephrons display a high degree of organization and respond appropriately to the needs of the or­ganism.

The adaptive changes in nephron function are mediated by stimuli generated both outside the kidney and within the kidney itself. The nature of the stimuli is not known for all solutes but has been well studied in the adaptation of calcium and phosphate metabolism to progressive renal disease. In the presence of a constant intake of phosphate and progressive loss of neph­rons, the following sequence of events ensues. With each decrease in the glomerular filtration rate, the dietary intake of phosphate results in a transient increase in serum phosphate and, as a consequence, a decrease in the serum concentra­tion of ionized calcium. The decrease in ionized calcium causes release of parathyroid hormone. Parathyroid hormone, in turn, causes an increase in the urinary excretion of phosphate and a nor­malization of the serum concentrations of calcium and phosphate. The intact nephrons respond appropriately to parathyroid hormone. In this ex­ample, normal plasma concentrations of calcium and phosphate are maintained, but there is a pro­gressive rise in the concentration of parathyroid hormone. Thus, the intact nephron hypothesis has been extended to include the “trade-off hypoth­esis.” In this circumstance, normal calcium and phosphate homeostasis is maintained at the ex­pense of development of secondary hyperpara­thyroidism. The negative aspect of this trade-off is hyperparathyroid-associated disease of bone and dysfunction of other organ systems. The trade-offs for maintenance of balance of other sol­utes aside from phosphate have not been eluci­dated clearly, but it is likely that the general thesis applies to multiple regulatory functions of the kidney.

When renal failure is far advanced, the adaptive response of the kidney to changes in the dietary intake of solute is severely compromised and the urinary excretion rates tend to become fixed. This loss of regulatory capacity of the kidney provides an explanation for the findings that in patients with advanced renal failure, alterations in dietary intake can be associated with states of depletion or excess. For example, ingestion of amounts of sodium in excess of the excretory capacity of the kidney results in expansion of the extracellular fluid volume. Conversely, ingestion of amounts of sodium that are less than the fixed rate of urinary excretion results in depletion of the extracellular fluid volume.