Long-Term Responses to Loss of Renal Mass: Pathophysiological Aspects: The Influence of Age on the Response to Renal Parenchymal Loss

The effect of age on compensatory hypertrophy and functional adaptation to loss of 75 percent of renal mass was studied in canine puppies. In one group of animals the surgery was done between 1-5 days after birth and in another group, at two months of age. All animals were studied six weeks later. Shamoperated littermates served as controls. The newborn puppies in the experimental group were able to grow and maintain homeostasis as well as their controls, whereas the older experimental animals grew poorly and had significantly higher levels of plasma creatinine than their sham-operated counterparts (p < .05). The increase in mass of the remaining kidney was twice as much in the newborn as in the older dogs. Functional adaptation, as expressed by GFR, was nearly complete in the young, but reached only about 45 percent of controls in the older age group (p<.005). The intrarenal blood flow distribution was similar for experimental and control animals in both groups studied. There were, however, marked differences in the pattern of single glomerular perfusion rates: whereas in the older dogs the increase was confined to the deeper nephrons, in the newborn an increase occurred in all zones of the kidney. These studies demonstrate that compensation for massive loss of renal tissue is complete when the injury is sustained in the immediate postnatal period but only partial when it occurs later on in life. A loss in the adaptive capacity of the superficial nephrons appears to account for this age-related difference.     

Long-Term Responses to Loss of Renal Mass: Pathophysiological Aspects: Role of Solute Excretion in Prevention of Norepinephrine-Induced Acute Renal Failure

Infusion of 0.75 μ g/kgbw/min norepinephrine (NE), for 40 minutes, into one renal artery in anesthetized dogs, induced acute renal failure (ARF). Subsequently there was nearly complete reversal of function within 8 weeks. Isotonic saline volume expansion, or renal vasodilation plus diuresis by acetylcholine (into renal artery: 20 μg/min) did not protect against this type of ARF. Volume expansion with either 5 or 20 percent mannitol partly prevented the fall of GFR 3 hours after NE, this protection being correlated with the magnitude of the osmolar clearance at the time of the insult. IV furosemide (10 mg/kg + 10 mg/kg/h; fluid losses replaced) afforded an even better protection. Proximal tubular necrosis in the “protected” kidneys was as severe as in non-protected kidneys. Glomerular cell morphology (scanning electron microscopy) was not altered by the 40-minute NE infusions. Functional “protection” appeared to depend on solute diuresis at the time of insult.     

Long-Term Responses to Loss of Renal Mass: Pathophysiological Aspects: Changes in Renal Function in Early Pregnancy in Women with One Kidney

In healthy women the 24-hour endogenous creatinine clearance is elevated by some 50 percent within 6 weeks of conception and an analogous increase of the 24-hour glucose excretion occurs. 24-hour glucose excretion later reverts to normal, reflecting a delayed onset of increased tubular reabsorption.Following unilateral nephrectomy there are marked increases in RPF and GFR in the contralateral kidney. Single hypertrophied kidneys apparently can adapt still further as in normal pregnancy. We have studied 5 women, in satisfactory general health prior to the pregnancy, each with only one kidney, before conception and during early pregnancy. Three had had unilateral nephrectomy for renal trauma 6-9 years earlier. two had received renal allografts 3 years earlier. In all cases the endogenous creatinine clearance began to rise in the second half of the menstrual cycle and when pregnancy supervened it rose rapidly to a peak value of 30-40 percent above the midcycle level within 7-10 weeks of the last menstrual period. That early peak was not always sustained and GFR subsequently fell to a level of 25-30 percent above the midcycle level. These changes in renal function were slower and smaller than in healthy women with 2 kidneys but were compatible with a successful outcome of pregnancy in these five cases.     

Long-Term Responses to Loss of Renal Mass: Glomerular Changes: Adaptation of Glomerular Forces and Flows to Renal Injury

The mechanism of glomerular ultrafiltration in normal kidneys or after renal injury is reviewed. The role of increased glomerular plasma flow in mediating increases of nephron filtration rate is evidenced under experimental conditions resulting in filtration pressure disequilibrium along glomerular capillaries. The increase of nephron filtration in hypertrophied kidneys appears to be due mainly to a rise of glomerular plasma flow and, to a smaller extent, to an increase of glomerular capillary hydrostatic pressure, the ultrafiltration coefficient remaining unchanged. In contrast, in the early phases of experimentally induced nephrotoxic serum nephritis, a decrease of the ultrafiltration coefficient was observed; nephron filtration rate, however, remained within the normal range, as a consequence of a higher hydrostatic pressure in the glomerular capillaries of the nephritic kidneys.     

Long-Term Responses to Loss of Renal Mass: Glomerular Changes: Evidence of Induction of New Nephrons in Immature Kidneys Undergoing Hypertrophy

Unilateral nephrectomy performed during the first days or weeks of life may or may not induce the development of new nephrons in the remaining kidney. Such an increase has been reported to occur, as discussed in this review, in newborn rats and mice, but not in guinea pigs. These observations are consistent with other data suggesting different patterns of compensatory adaptation in young and in old animals.     

Long-Term Responses to Loss of Renal Mass: Tubular Changes: Potassium Adaptation After Reduction of Nephron Population

Two weeks after 75 percent nephrectomy in rats fed a normal diet glomerular filtration rate was found to be reduced by 2/3 and there was no hyperkalemia. Normal K balance was maintained by a threefold increase of fractional urinary potassium excretion. When infused with 0.5 M KCl solution, both normal and 75 percent nephrectomized rats increased their fractional excretion, while normal rats kept on a very high K-diet did not further increase their fractional potassium excretion. Adaptation of fractional excretion to infused KCl was blunted in 75 percent nephrectomized rats given a low K diet.Addition of 0.1 M KCl to the drinking water resulted in a three- to fourfold increase of potassium intake in normal rats: within 7 days, the Na-K-ATPase in the outer medulla of the kidney rose by 30 percent but no change occurred in the cortex. Further increases in dietary K load induced an increase of Na-K-ATPase activity, both in outer medulla and cortex, but not in other tissues. After 75 percent nephrectomy, specific Na-K-ATPase activity increased by 20-25 percent in the outer medulla and in the cortex.Dietary K loading, in normal rats, also resulted in a large increase of net potassium secretion into the perfused colon and of specific Na-K-ATPase activity of the colonic mucosa. These effects of potassium loading were not abolished by adrenalectomy and were accompanied by an increase of transmural PD. It was concluded that chronic potassium loading may enhance secretion of potassium into lower nephron tubular fluid and into colonic contents by primarily stimulating the synthesis of Na-K-ATPase and the resulting increase of the number of pumping sites. 75 percent nephrectomy may induce similar changes in the remaining nephrons.     

Long-Term Responses to Loss of Renal Mass: Glomerular Changes: Chronic Reduction of Renal Mass: Glomerular Morphometry by Electron Microscopy

Changes of glomerular volume in rats were measured up to 21 weeks following subtotal nephrectomy, using morphometric methods. A linear increase of glomerular volume was observed between 2 and 21 weeks after subtotal nephrectomy. This progressive increase in glomerular volume may reflect compensatory hemodynamic changes leading to an increased single nephron glomerular filtration rate.     

Long-Term Responses to Loss of Renal Mass: Control Mechanisms: The Role of Renal “Work” in Compensatory Kidney Growth

In a series of studies designed to test the role of renal “work” in compensatory kidney growth we examined the relationship between absolute sodium reabsorption—which constitutes the bulk of renal energy expenditure, and growth of the remaining kidney at various intervals after contralateral nephrectomy.The increase in weight of the remaining kidney preceded the rise in sodium reabsorption and these two processes took place at different rates between 24 hours and 21 days after uninephrectomy.Absolute sodium reabsorption did not change during the first hours after contralateral nephrectomy, at a time when biochemical alterations are known to occur.The rate of [¹⁴C] choline incorporation into renal phospholipid, an early biochemical indicator of compensatory kidney growth, increased significantly one hour after contralateral nephrectomy but remained unchanged after sham-nephrectomy, regardless of the magnitude or direction of the concomitant change in absolute sodium reabsorption (“kidney work”).These results indicate that renal work expended in the reabsorption of glomerular filtrate is neither the initiating, nor the primary controlling factor, of the compensatory kidney growth that follows unilateral nephrectomy.     

Long-Term Responses to Loss of Renal Mass: Tubular Changes: Chronic Reduction in Renal Mass: Micropuncture Studies of Response to Volume Expansion and Furosemide

Chronic nephron loss is compensated by functional adaptations which preserve electrolyte homeostasis. The response to volume expansion and diuretics was tested in dogs. Three phase recollection micropuncture studies were performed to assess the response of the remnant kidney in various stages of renal failure to furosemide administration (10 mg/Kg) and graded volume expansion (3 percent and 10 percent body weight). After the diuretic maneuvers, mean fractional excretion of sodium, potassium and water rose progressively in normal dogs (Stage I), with a greater increase in the remnant kidneys in the presence (Stage II) and absence (Stage III) of the contralateral kidney. Proximal and distal TF/P _Inulin ratios were depressed after 3 percent volume expansion. However, proximal TF/P _Inulin was not further lowered after 10 percent volume expansion and furosemide administration, while distal TF/P _Inulin ratios were progressively depressed. The distal TF/P _Inulin ratios in Stage III were significantly lower than in Stage II under analogous conditions. Our results suggest that the adaptive increase in the response of sodium transport by the remnant kidney to the diuretic maneuvers occurs in the loop of Henle, both in the azotemic and the non-azotemic stage. Adaptation of potassium excretion, as revealed by distal micropuncture, took place in the azotemic Stage III. Chronic functional adaptation for electrolyte transport occurs even before azotemia in the distal nephron and includes the proximal tubule with azotemia.     

Long-Term Responses to Loss of Renal Mass: Control Mechanisms: Glomerulotubular Dimensional Readjustments During Compensatory Renal Hypertrophy in the Hypothyroid Rat

Although growth of tubules is arrested and that of glomeruli retarded by hypothyroidism in rats, unilateral nephrectomy has been found to elicit a vigorous compensatory hypertrophy of the hypothyroid kidney. Microdissection and measurement of the dimensions of glomeruli and proximal convoluted tubules taken from the kidney removed first and from the hypertrophic contralateral organ removed two to three weeks later, disclosed a “normalization” of the typical glomerulotubular dimensional imbalance as a result of greater tubular than glomerular growth. A somewhat more striking but qualitatively identical response was observed in 9 euthyroid animals. Glomerular filtration rate and maximal glucose reabsorptive capacity (Tm_G) increased in both euthyroid and hypothyroid animals in accord with the structural shifts.     

Long-Term Responses to Loss of Renal Mass: Glomerular Changes: Compensatory Renal Hypertrophy in Dogs: Single Nephron Glomerular Filtration Rate

Kidney weight, length of superficial and juxtamedullary proximal tubules, glomerular diameter, kidney filtration rate and PAH clearance, sodium excretion and intrarenal distribution of filtration (with ¹⁴C-ferrocyanide) were measured in the remaining hypertrophic kidneys of dogs 10 days after unilateral nephrectomy. Whereas kidney weight increased to 75 percent of the original total renal mass, proximal tubule length and mean glomerular diameter remained unchanged. PAH and creatinine clearance, and absolute, but not fractional, sodium excretion, rose significantly. The ratio superficial/juxtamedullary filtration rate remained unchanged, indicating parallel increases of filtration in both cortical regions of hypertrophied kidneys.     

Long-Term Responses to Loss of Renal Mass: Tubular Changes: A Micropuncture Study of HCO3 Reabsorption by the Hypertrophied Proximal Tubule

In rats with renal failure produced by excision of one kidney and infarction of large portions of the other kidney, given a low calcium, high phosphorus diet for 2-3 weeks, GFR was reduced by 80 percent, the fractional excretion of sodium increased from 7 to 23 percent, that of bicarbonate from 16 to 23 percent and that of water from 4 to 13 percent. Single nephron GFR in the remaining nephrons was nearly doubled and end-proximal TF/P_In was depressed from 2.3 to 1.8, and proximal TF/P_HCO3 from 0.52 to 0.35, the latter figure corresponding to an increase of absolute proximal HCO₃ reabsorption from 1.7 to 3.5 nEq/min or from 2.8 to 3.2 Eq/L of single nephron glomerular filtrate. Acute parathyroidectomy had no influence on the fall of GFR or the rise of SNGFR in the remaining nephrons and failed to cause any significant changes in proximal tubular bicarbonate reabsorption. Parathyroidectomy, on the other hand, practically prevented the rise of the fractional excretion of sodium and of water and inverted the rise of the fractional excretion of bicarbonate to a fall. The data are interpreted to indicate that secondary hyperparathyroidism in renal failure impairs distal nephron bicarbonate and sodium reabsorption and, thus, contributes to the maintenance of sodium balance, but could possibly aggravate acidosis.     

Biochemical and Molecular Responses to Loss of Renal Mass: Membranes and Protein Synthesis: Metabolic Response to Renal Compensatory Growth

Forty-eight hours after unilateral nephrectomy in young male Sprague-Dawley rats the concentrations of free methionine, alanine and tyrosine in renal cortical tissue were increased by 15-65 percent while the corresponding plasma concentrations decreased by 23-35 percent. The renal cortical concentrations of valine and leucine increased by 41 percent and 26 percent while plasma concentrations remained unchanged. The cortical concentrations of ornithine, serine and threonine remained unchanged while the plasma concentration decreased by approximately one-third. The total free amino acid contained in the cortex was not changed, while total free amino acids in plasma decreased by 7 percent. These data are thought to reflect an increased uptake of methionine and tyrosine into renal cells during compensatory hypertrophy, and an increased incorporation into renal protein of serine, threonine and ornithine. All these changes as well as all other biochemical changes accompanying compensatory hypertrophy with the exception of an increase of the RNA/DNA ratio were prevented by starvation for 48 hours after unilateral nephrectomy.In young male Sprague-Dawley rats and adult male Charles River mice, the incorporation of ¹⁴C-choline into acid-insoluble phospholipids (phosphatidylcholine, lysophosphatidylcholine and sphingomyelin) was already accelerated 5 minutes after contralateral nephrectomy and further rose to +68 ± 7 percent within 20 minutes to 3 hours. Incorporation of ¹⁴C-choline into phospholipids remained accelerated for two to three days and reflected increased rates of phospholipid synthesis rather than increased choline uptake. Three hours after unilateral nephrectomy in mice, incorporation of i.p. injected ¹⁴C-choline into phospholipids was accelerated 25 percent. The rate of turnover of free labelled renal phospholipids was not accelerated during compensatory renal growth. The very early increase of choline incorporation into phospholipids after contralateral nephrectomy, therefore, appears to reflect an increased rate of synthesis of membrane material.     

Biochemical and Molecular Responses to Loss of Renal Mass: Membranes and Protein Synthesis: Messenger RNA in Compensatory Renal Hypertrophy

Experiments that deal with the stability of messenger RNA (mRNA) in normal mouse kidney, and, to some extent, the stability of mRNA during renal growth will be described. We have found a population of mRNA in the cytoplasm of mouse kidney that is short-lived. Such a class of rapidly metabolized mRNA could play an adaptive role at the translational or cytoplasmic level in determining gene expression and may be important during the early phases of compensatory hypertrophy.     

Biochemical and Molecular Responses to Loss of Renal Mass: Membranes and Protein Synthesis: Macromolecular Metabolism in Compensatory Renal Hypertrophy

1. The initial biochemical changes of compensatory hypertrophy occur well within 1 hour of unilateral nephrectomy and perhaps within the first few minutes.2. The initial increment in rRNA is from decreased metabolism rather than from increased synthesis.3. Changes in the processing of mRNA precursors are probably also important.4. Compensatory hypertrophy is regulated by a humoral stimulus or stimuli.5. The stimulus needs to be present virtually all of the time during the early phases of compensatory hypertrophy.6. The stimulus is related to loss of renal mass, not to loss of renal function.