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: 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: 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: 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.     

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.     

Biochemical and Molecular Responses to Loss of Renal Mass: Atpase and Cyclic Nucleotides: Changes in Renal Cyclic Nucleotides as a Trigger to the Onset of Compensatory Renal Hypertrophy

In adult male Wistar rats contralateral nephrectomy was followed, within 10 minutes, by a nearly twofold rise of the content of cGMP in renal tissue. 20 and 40 minutes after contralateral nephrectomy cGMP fell to one half its control level to rise again to its normal level within 90 minutes. The initial rise of the concentration of cGMP was accompanied by a simultaneous fall of the concentration of cAMP by about 30 percent: the cAMP concentration remained 10-20 percent below control level for approximately two hours and rose again to its initial level after three hours. Cross-circulation of a nephrectomized rat with an intact animal led to a sharp increase of cGMP in the kidneys of the latter with a peak at 10 minutes after initiating cross-circulation and also to a fall of the cAMP concentration. When the same nephrectomized donor rat was subsequently cross-circulated with one, or even two, intact receiver animals, similar short-lasting changes of cyclic nucleotide concentrations were recorded in the kidneys of all the receivers. When a normal kidney was transplanted to the neck of a rat, subsequent removal of one of its own kidneys did not result in any change in cyclic nucleotide content in either the remaining or the transplanted kidney. The data are interpreted to indicate that renal tissue produces a factor inhibiting renal growth which counteracts a circulating humoral kidney growth stimulating factor of unknown origin. An initial rise of cGMP and a fall of cAMP may trigger the subsequent stimulation of protein synthesis responsible for hypertrophy.     

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.     

Biochemical and Molecular Responses to Loss of Renal Mass: Atpase and Cyclic Nucleotides: Factors Influencing the Increase in Na-K-ATPase in Compensatory Renal Hypertrophy

An increase in Na-K-ATPase in kidney homogenates usually accompanies compensatory renal hypertrophy. While it may be evident in both the cortex and medulla of the kidney, it is most marked in the outer medulla and may be present only in that region. The increase in enzyme activity does not depend on an intact adrenal cortex and can be elicited in the absence of adrenal glucocorticoids. It is not seen in the form of renal hypertrophy produced by potassium depletion, in which the transport of sodium and potassium by the kidney is not increased. When present in compensatory renal growth, the enzyme change is correlated with an increase in the reabsorption of sodium, or the excretion of potassium, or both, per unit of renal tissue. It proceeds in the presence of either, but not in the absence of both.     

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: 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: 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.     

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: Atpase and Cyclic Nucleotides: Evidence for Altered Cyclic Nucleotide Metabolism During Compensatory Renal Hypertrophy and Neonatal Kidney Growth

In adult male Sprague-Dawley rats contralateral nephrectomy was followed by an initial fall of the concentration of cGMP in renal cortical tissue followed by a rise to a peak level of 300 percent of the initial concentration within two hours. cGMP concentration in the remaining renal cortex remained at about 300 percent of the initial value during the subsequent 72 hours and slowly declined to 150-200 percent in the following two weeks. The changes in cGMP concentration were due to exactly parallel changes in the soluble fraction of renal cortical guanylate cyclase activity, while cGMP-phosphodiesterase activity remained unchanged. cAMP concentration after contralateral nephrectomy fell significantly by about 25 percent within two hours and remained below baseline level for up to eight hours. In the kidneys of newborn rats the concentration of cAMP was approximately one-half that found in adult kidneys: it slightly fell between the fourth and the seventh day after birth and subsequently continuously rose to reach adult values approximately two weeks after birth. The concentration of cGMP was significantly greater four days after birth than in adult rats, further rose between the fourth and the seventh day after birth and subsequently gradually declined to adult levels. The increased cGMP concentration appears to be due to an increase of guanylate cyclase activity in total kidney homogenates which, in turn, was mainly due to an increase of the particulate (membrane-bound) fraction of the enzyme. cGMP-phosphodiesterase activity, however, was also increased in respect to adult levels, one or three weeks after birth. Renal growth from the seventh day after birth to adulthood is accompanied by a continuous increase of the ratio cAMP/cGMP. Removal of one kidney four to seven days after birth resulted in a slower increase of this ratio. The data suggest that cGMP may trigger renal growth and that increases of cGMP concentration in the kidneys are the result of a primary increase in the activity of guanylate cyclase.