Enhanced Recovery from Postischemic Acute Renal Failure

Transcription

1 440 Enhanced Recovery from Postischemic Acute Renal Failure Micropuncture Studies in the Rat WILLIAM F. FINN SUMMARY Recovery from unilateral postischemic acute renal failure produced by 1 hour of complete renal artery occlusion in the rat is incomplete and is associated with the eventual loss of renal mass. The loss in renal mass can be reversed by removal of the contralateral. In the present study, clearance and micropuncture techniques were used to compare whole and individual nephron function of normal and postischemic s. In sham-operated control animals, the left weight (LKW) averaged 0.41 g/100 g body weight (BW), the inulin clearance (Ci n ) averaged 541 pl/min per 100 g BW and single nephron glomerular filtration rate (SNGFR) averaged 15.4 nl/min per 100 g BW. The calculated number of nephrons, derived from the relationship Ci n /SNGFR, was 37,70. Four weeks after the period of ischemia, the LKW of rats with the contralateral averaged 0.30 g/100 g BW. Ci n averaged 15 /il/min per 100 g BW and SNGFR averaged 17.4 nl/min per 100 g BW. The calculated number of nephrons was In rats in which either the contralateral had been or its ureter ligated 2 weeks following the period of ischemia (2 weeks prior to study) LKW averaged 0.66 g/100 g BW, Ci n averaged 415 /il/min per 100 g BW, and SNGFR averaged 19.4 nl/min per 100 g BW. The calculated number of nephrons was 24,152. The results indicate that the increases in size and Ci n of the postischemic which occurred in response to the contralateral nephrectomy or ureteral ligation were due to the functional recruitment of nephrons which otherwise would have become atrophic. These data also demonstrate that the extent of functional recovery from postischemic acute renal failure is not necessarily dependent on the nature of severity of the initial insult. Circ Res 46: , 190 POSTISCHEMIC acute renal failure produced by 1 hour of complete unilateral renal artery occlusion in the rat is associated with a complex and possibly interrelated series of events involving tubular obstruction, passive backflow of filtrate, and preglomerular vasoconstriction (Eisenbach and Steinhausen, 1973; Tanner et al., 1973; Arendshorst et al., 1975; Tanner and Sophasan, 1976; Arendshorst et al., 1976; Donohoe et al., 197; Venkatachalam et al., 197; Finn, 197). Sequential studies of the function of the postischemic have been performed up to weeks following the period of ischemia (Finn and Chevalier, 1979). These studies indicated that recovery occurs in a biphasic pattern with an early phase most closely associated with the return of anatomical and functional integrity of the tubular epithelium and the relief of intratubular obstruction, and a later phase marked by progressive renal vasodilation. However, recovery is incomplete and is associated with the eventual loss of renal mass. The loss of renal mass can be prevented From the Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina. The author's work was supported by Grant HL from the National Institutes of Health. Presented in part at the VII International Congress of Nephrology, Montreal, Canada, June 1-23, 197. Address for reprints: William F. Finn, M.D., Department of Medicine, University of North Carolina, Chapel Hill, North Carolina Received July 24, 1979; accepted for publication November 2, and even reversed by removal of the contralateral (Koletsky, 1954). The extent to which an increase in whole and individual nephron function parallels the increase in size has not been established. In the present study, clearance and micropuncture techniques were used to examine the function of the postischemic 4 weeks following the period of ischemia. In some rats, the contralateral was left, and in others, the contralateral was or its ureter ligated 2 weeks following the period of ischemia. The results confirm the observation that the postischemic is capable of responding to a reduction in absolute or functional renal mass by an increase in size. The results also demonstrate that the increase in size is associated with a proportionate increase in whole function which is related most closely to the functional recruitment of nephrons that otherwise would have become atrophic. Methods Observations are reported on a total of 39 male Sprague-Dawley rats. Four weeks prior to study, unfasted animals were anesthetized with sodium pentobarbital, 60 mg/kg body weight (BW), ip, and placed on a heated table that maintained body temperature between 37 C and 3 C. The left kid-

2 ACUTE RENAL FAILURE/Fi/m 441 ney was exposed through a small subcostal incision and the left renal artery was isolated. In control animals (n = 16), the incision was closed and the rats were returned to their cages. In experimental animals (n = 23), 10 to 15 units of heparin per 100 g body weight (1000 units/ml, the Upjohn Company, Inc.) were injected intravenously, and a smooth-surfaced tension clamp (Schwartz 1-inch clip; Roboz Surgical Instrument, Co., Inc.) was positioned on the artery so that it was completely occluded. The clamp was after 1 hour. Saline (0.5% sodium chloride) was infused through a catheter placed in a jugular vein at 40 jul/min for 1 hour before and after occlusion. The rate of infusion during the ischemic period was reduced to 20 /nl/min. After recovery from anesthesia, all animals were maintained on their standard rat pellet diet (Purina). Two weeks after the initial surgery, the rats again were anesthetized by intraperitoneal injection of sodium pentobarbital and placed on a heated table. The control animals were divided into two groups. In both groups the was exposed through a subcostal incision. In group I (n = ), the was left whereas, in group II (n = ), the pedicle was ligated and the. The experimental animals were divided into three groups. In group III (n = ), an abdominal incision was made leaving the and ureter intact. In group IV (n = ), the was exposed through a small subcostal incision, the pedicle ligated, and the. In group V (n = 7), the ureter was ligated through a suprapubic incision. The animals were allowed to recover from anesthesia and were maintained on their standard diet for an additional 2 weeks. On the evening prior to study, the animals were deprived of food but allowed free access to water. The rats again were anesthetized by intraperitoneal injection of sodium pentobarbital and placed on a heated table. A tracheostomy was performed and a catheter was placed in a femoral vein for infusion of 0.5% sodium chloride at a rate of 40 fil/min. The left was exposed through an abdominal incision for micropuncture experiments (Gottschalk and Mylle, 1956). The renal capsule, the covering peritoneum, and the perirenal fat were left undisturbed. The left ureter was catheterized with PE-10 polyethylene tubing. Femoral arterial blood pressure (ABP) was recorded continuously with a Statham P23Db pressure transducer connected to a Beckman recorder. After the surgical procedure was completed, appropriate amounts of inulin and paraaminohippurate (PAH) was added to the saline infusion. An equilibration period of 1 hour was allowed to elapse, and measurements were performed during two 30- minute periods. Hydrostatic pressure in random surface proximal convolutions was measured using sharpened glass pipettes (3-7 /xm o.d.) filled with 2 M NaCl and connected to a continuously recording, electronic servonulling apparatus (made in our own laboratory). Tubular fluid also was collected from random proximal convolutions with sharpened, siliconized pipettes having external tip diameters of 9-12 /xm. A block of colored mineral oil approximately 3-5 tubular diameters in length was injected and tubular fluid was collected employing controlled suction at a rate such that the oil block was maintained in as constant a position as possible just distal to the pipette tip. Excessive suction and changes in tubular diameter were avoided. Each sample was transferred into calibrated, constantbore capillary tubing between layers of water-equilibrated mineral oil, and the volume was estimated by measuring the sample length with an eyepiece micrometer. Single nephron glomerular filtration rate (SNGFR) was calculated as fluid to plasma (F/ P) inulin concentration ratio X tubular fluid flow rate in nanoliters per minute. Blood samples were obtained at the midpoint of each period from the tip of the tail and from the renal vein. The hematocrit (Hct) was measured in heparinized capillary tubes. Plasma and urine inulin concentrations were determined by the anthrone method (Fuhr et al., 1955), and tubular fluid inulin concentrations were measured in triplicate by the microfluorescence method of Vurek and Pegram (1966). Plasma and urine PAH concentrations were determined by the technique of Bratton and Marshall (1939) as modified by Smith et al.(1945). The clearance of inulin (Ci n ) was used as a measurement of the glomerular filtration rate (GFR). The extraction ratio of PAH (EPAH) by the left was calculated from the following formula: EPAH = (APAH - VPAH)/A P AH, where APAH and V PA H were the concentrations of PAH in systemic arterial and left venous plasma, respectively. Renal plasma flow (RPF) was estimated from the ratio CPAH/EPAH, where CPAH was the clearance of PAH. Several s from each group were fixed in Helly's solution for histological examination. At the end of each experiment, the s were excised, cleared of perirenal fat, decapsulated, and the left weight (LKW) determined immediately. Data were analyzed via analysis of variance and the least significant difference statistic; differences at the 5% level are considered statistically significant. Values are presented as means ± SEM. Results General Data The mean values for ABP, Hct, BW, and LKW are listed in Table 1. Differences in ABP were noted only in the experimental animals with ureteral ligation. In this group of animals the ABP averaged 146 ± mm Hg and was significantly greater than the values for the other groups. No differences were present in the mean values of Hct. The mean values

3 442 CIRCULATION RESEARCH VOL. 46, No. 3, MARCH 190 TABLE 1 Data from Control Rats and Rats studied 4 Weeks after Temporary Left Renal Artery Occlusion Control Postischemic Femoral arterial blood pressure (mm Hg) Group I 106 ±4, Group II, 10 ±7 Group III, 113 ±6 Group IV, 115 ±11 Group V, ureter ligated ± Hematocrit (ml/100 ml) 50 ±1 4 ±1 49 ±1 51 ±1 50 ±2 Body weight (g) 290 ± ±9 320 ±22 271* ±13 29 ±2 Left weight (g/100 g BW) " * " Ar "' ±0.04 No. of rats Results are means ± SE. P values < 0.05: a vs. group I; 6 vs. group II; c vs. group III; d vs. group IV. of BW also were similar, except for the comparison of the values obtained at the time of study in the two groups of animals with the (P < 0.05). At the time of the initial surgery, the BW averaged 232 ± 6 and 20 ± 13 g, respectively (NS). In both the control and experimental rats, differences in the mean values of the LKW were present. In control animals with the, the LKW averaged 0.41 ± 0.02 g/ 100 g BW. After removal of the, the averaged value of the LKW was 40% greater at 0.57 ± 0.02 g/100 g BW (P < 0.05). In the experimental animals with the, the postischemic LKW averaged 0.30 ± 0.05 g/100 g BW. The postischemic LKW of the rats with the averaged 0.70 ± 0.06 g/100 g BW and, in the animals with the ureter ligated, the postischemic LKW averaged 0.60 ± 0.40 g/100 g BW. The combined value of the postischemic LKW from these 15 animals was 120% greater (P < 0.05) than the value noted for the postischemic LKW from animals with the. Clearance Data Table 2 summarizes the results of the clearance experiments. A comparison of the values obtained in the two groups of animals with the revealed that the Ci n, RPF, and urine flow rate (V) of the postischemic had returned to only 29% (P < 0.05), 39% (P < 0.05) and 3% (P < 0.05) of the respective control values. These data are nearly identical to results previously reported for s studied 4 weeks after the period of ischemia (Finn and Chevalier, 1979). TABLE 2 Clearance and Micropuncture Data from Control Rats and Rats Studied 4 Weeks after Temporary Left Renal Artery Occlusion Inulin clearance (/xl/min per 100 g BW) SNGFR (nl/min per 100 g BW) Renal plasma flow (/il/min per 100 g BW) Urine flow (/il/min per 100 g BW) Group I, 541 ± ± ± ±0.6 Controls Group II, 732" ± ± " ± " ±0.9 Group III, 15"'* ± ± "* ±15 1.1"* ±0.2 Postischemic Group IV, 362"*' ± ± *' ± *' ±0. Group V ureter ligated 476* r ± "'' ± * r ±21 4.9' ±0.4 PAH extraction (%) No. of rats 4 ±2 Results are means ± SE. P values < 0.05: a vs. group I; b vs. group II; c vs. group III; d vs. group IV. 75 ±4 65" ± 69" ±5 67" ±4 7

4 ACUTE RENAL FAILURE/Fmn 443 In the control rats, the removal of the resulted in changes in renal function similar to those reported by others (Kaufman et al., 1975a). The Cin increased by 35% (P < 0.05), the RPF increased by 65% (P < 0.05), and V by 5% (P < 0.05). In the experimental animals, the postischemic also responded to the removal of the by an increase in function. The Ci n increased by 129% (P < 0.05), the RPF increased by 117% (P < 0.05), and V increased by 291% (P < 0.05). Although these changes were proportionately greater than those observed in control animals, the absolute values for Ci n and RPF were approximately 50% of those noted in control animals following removal of the. Qualitatively similar changes in the function of the postischemic were produced by ligation of the ureter, although the increases in Ci n and RPF tended to be more pronounced. Cin increased by 101% (P < 0.05) and RPF increased by 161% (P < 0.05). Neither of these values was significantly different from those obtained in the control animals with the. In each group of experimental animals, the EPAH was below 70%. Micropuncture Data Table 2 also summarizes the mean values of SNGFR obtained in each group of rats. In the control animals with the, the SNGFR averaged 15.4 ±1.2 nl/min per 100 g BW and increased by 29% to 19.9 ± 1.2 nl/min per 100 g BW after removal of the. This increase was similar to the rise in Ci n. In the experimental animals with the, the SNGFR of the postischemic averaged 17.4 ± 1.7 nl/min per 100 g BW. This value was not significantly different from those found in either group of control animals. Moreover, removal of the was not associated with an increase in the mean value of SNGFR which averaged 16.0 ± 2. nl/min per 100 g BW. In the experimental rats with the ureter ligated, SNGFR averaged 23.3 ± 2.3 nl/min per 100 g BW and was significantly greater than values obtained in control animals with the (P < 0.05). In the five groups of rats, no significant differences existed in the mean values of PITP, which averaged 11.5 ± 0.4, 12.3 ± 1.9, 12.4 ± 0.7, 13.3 ± 0.7, and 12.0 ± 1.4 mm Hg, respectively. In each group of rats, the values of SNGFR were compared to whole function in two different ways. In one, the measured values for SNGFR were compared to a calculated value in a fashion similar to that reported by Hayslett et al. (196). The calculated value of SNGFR was obtained by factoring the Cin by 37,500. This latter value approximates the number of glomeruli found by Kaufman et al. (1975b) using a modification of the Damadian technique (Damadian et al., 1965) in s of both sham-operated and uninephrectomized adult male Sprague Dawley rats from the Charles River Breeding Laboratories. This value is also similar to that previously reported for female Wistar rats (Bonvalent et al., 1972). In the control animals, the calculated value of SNGFR was 14.4 ± 0.5 nl/min per 100 g BW with the and 19.5 ± 0.6 nl/min per 100 g BW after removal of the. Although individual variation occurred, no significant difference was found between the measured value for SNGFR and the calculated value for SNGFR (Fig. 1, upper panel). In the experimental rats, with the, the Cin was only 29% of control values and, as a result, the calculated value of SNGFR averaged 4.2 ± 1.0 nl/min per 100 g BW (Fig. 1, middle panel) CONTROL Group I Group Q O 30 * CD 20 o> O O I I POST-ISCHEMIC Group m POST-ISCHEMIC Group BE Group Z O SNGFR (nl/min l00g BW) CALCULATED FIGURE 1 Measured vs. calculated values of single nephron glomerular filtration rates: upper panel, control s; middle panel, 4 weeks after 1 hour of complete unilateral renal artery occlusion, contralateral ; bottom panel, 4 weeks after occlusion, contralateral nephrectomy or ureteral ligation 2 weeks prior to study.

5 444 CIRCULATION RESEARCH VOL.46, No. 3, MARCH 190 Despite the significant increases in Ci n that occurred in the postischemic in response to removal of the or ligation of the ureter, the calculated values of SNGFR averaged only 9.0 ± 2.0 and 12.0 ± 1.4 nl/min per 100 g BW, respectively (Fig. 1, bottom panel). Because the calculated values of SNGFR underestimated the measured values, the use of 37,500 for the number of nephrons with normal filtration rates in the recovering from postischemic acute renal failure was inappropriate. Consequently, a calculated number of nephrons was obtained by factoring the Ci n by the measured value of SNGFR (Fig. 2). In the control animals, the calculated number of nephrons averaged 37,70 ± 4,520 in the animals with the and 37,50 ± 2,750 following removal of the. These values were nearly identical to those obtained by others using the technique of direct glomerular counting (Bonvalent et al., 1972; Kaufman et al., 1975b). In the experimental animals with the, the calculated number of functioning nephrons averaged 9,460 ± 2,960, a value signficantly less than that for either group of control animals (P < 0.05). In contrast to the results obtained in control animals, the effect on postischemic of the removal of the or ligation of the ureter was an increase in the calculated number of functioning nephrons. These values averaged 25,00 ± 6,700 (P < 0.05) and 22,270 ± 4,100 (P < 0.05), respectively. Morphological Observations Among the three groups of experimental animals, the differences in the postischemic LKW and Ci n ,2 '. 24 ^ 16 a. fe GROUP I Right Kidney in ploce CONTROL GROUP II Right Kidney GROUPIE Right Kidney POST-ISCHEMIC GROUP 12. Right Kidney L <0.05-J ' NS 1 -NS- -<O05- GROUP Z Right Ureter ligoted FIGURE 2 Calculated number of functioning nephrons derived from the ratio Ct n /SNGFR. Values are from control s and from s 4 weeks after 1 hour of complete unilateral renal artery occlusion. Contralateral nephrectomy or ureteral ligation 2 weeks prior to study (means ± SE). were associated with marked variation in both their gross and microscopic appearance. The postischemic s from the rats with the were contracted with a granular and occasionally pitted appearance to the surface. Inspection of histological sections (Fig. 3A) revealed that, in many areas, distinct cortical structures were not visible with the result that the corticomedullary junction was poorly defined. Microscopic examination of the cortex (Fig. 4A) indicated that a few relatively normal appearing glomeruli and tubules were intermixed with areas marked by tubular atrophy and the presence of a prominent interstitial infiltrate. In striking comparison, the postischemic s from rats with the or the ureter ligated were enlarged with a slightly irregular or smooth appearance to the surfaces. Cortical structures were easily discernable (Fig. 3B) with a well-defined corticomedullary junction. Microscopic examination of the cortex (Fig. 4B) demonstrated a much greater proportion of normalappearing glomeruli and tubules with areas of atrophy which were reduced and occasionally absent. Discussion This study indicates that the extent of anatomical and functional recovery that can be expected following unilateral postischemic acute renal failure is not necessarily predetermined by the nature or severity of the initial insult. This conclusion is based on the observation that the postischemic is capable of responding to a contralateral reduction in absolute or functional renal mass by an increase in size and a more complete restoration of function. Four weeks following the period of ischemia, the weight of the postischemic in the rats with the undisturbed tended to be less than that of control s, while its surface was somewhat irregular and pitted. The Ci n was less than 30% of control. A most striking finding was that the mean value for SNGFR was not different from the value obtained in control s, although individual values were more heterogeneous than normal. Several explanations for this discrepancy between the relative values of the Cin and SNGFR need to be considered. First, the collection of tubular fluid from sites proximal to the point of obstruction could have resulted in spuriously elevated values of SNGFR. Second, the Ci n could have underestimated the actual glomerular filtration rate due to the continued leak of inulin back across the damaged tubular epithelium. Neither of these possibilities was likely. Tubular fluid was collected from nephrons in which flow rates were brisk and in which intratubular hydrostatic pressures were normal. Furthermore, it has been demonstrated that the tubular epithelium regains its integrity to inulin by the second postischemic week (Finn and Chevalier, 1979). Thus, the most reasonable explanation was that more than 70% of the nephrons were

6 ACUTE RENAL FAILURE/Finn 445 FIGURE 3 Photomicrographs of histological sections of rat s 4 weeks after 1 hour of complete unilateral renal artery occlusion; A: contralateral ; B: contralateral ureter ligated 2 weeks prior to study. Hematoxylin and eosin stain; bar = 1 cm. contributing very little to the overall function of the and that these nephrons had become atrophic, accounting for the decrease in size. Such a pattern was observed in examination of the histological sections and is consistent with earlier anatomical studies which described in detail the evolution of the structual changes following various periods of temporary renal ischemia. For example, Koletsky (1954) studied the effects of 2 hours of complete unilateral renal artery occlusion. He noted that, after an initial enlargement, the postischemic gradually contracted so that, 3 weeks after the period of ischemia, it was reduced to about one- third its original size. Examination of histological sections indicated that repair of necrotic tubular epithelial cells was well established 4 days after the period of ischemia and practically complete within the first 2 weeks. Nonetheless, evidence of tubular atrophy was found by the 1st week and became more impressive over the 2nd and 3rd weeks. Koletsky thought that some nephrons were involved in the atrophic process more than were others and that, in general, the atrophic changes followed the period of necrosis and repair. In other studies, Gowing and Dexter (1956) produced renal ischemia by inducing complete arterial and venous occlusion for

7 446 CIRCULATION RESEARCH FIGURE 4 Photomicrographs of histological sections of rat cortex 4 weeks following 1 hour of complete unilateral renal artery occlusion: A: contralateral ; B: contralateral ureter ligated 2 weeks prior to study. Hematoxylin and eosin stain; magnification, WOx. VOL. 46, No. 3, MARCH hour. They found that, as early as the 5th day, there were groups of regenerated cortical tubules which were collapsed and empty, often appearing as a solid mass of epithelial cells. It was only at a later time that the glomeruli in these areas atrophied. They thought that the essential feature in these s was the failure of some regenerated tubules to mature, and in this regard, disagreed with the view of Koletsky (1954). Several factors could be responsible for the development of atrophic changes in individual nephrons. For example, the effect on these nephrons of temporary occlusion of the renal artery may have been more severe than on those nephrons that subsequently recovered. It is also possible that, following the period of ischemia, reflow of blood to some areas was not sufficient to prevent continued ischemic damage or that following reflow a secondary increase in preglomerular vascular resistance resulted in additional tubular necrosis. If any or all of these possibilities were correct, it might be anticipated that the ultimate number of nephrons to survive would be determined within the first 24 hours and that any improvement in the inulin clearance that followed the contralateral nephrectomy or ureteral ligation would occur as a result of proportionate increases in the filtration rates of existing functional nephrons. Against this conclusion are the additional studies of Koletsky (1954) in which he resected the contralateral 3 weeks following the period of ischemia, at a time the postischemic had become atrophic. This led to a marked increase in size of the atrophic so that, at 30 days, the weight exceeded that of a normal. He observed that the great majority of nephrons participated in the enlargement and that 1 month after resection of the opposite, enlargement of both glomeruli and tubules could be demonstrated. The result was a uniformly enlarged with a fairly well preserved cortical pattern and smooth or slightly granular outer surface. These changes were similar to those observed in the present study. Following the contralateral nephrectomy or ureteral ligation, for each case the weights were more than twice as great as the weights of the postischemic with the undisturbed, and more than 50% greater than the weight of normal s. Moreover, the surface had lost its pitted appearance. The increase in weight was associated with an increase in both RBF and Cin. In the uninephrectomized rats, the increase in Cin was proportional to the increase in weight. Nonetheless, the mean value of SNGFR was unchanged, indicating that the increase in Cin was due to an increase in the number of functioning nephrons rather than an increase in the filtration rates of nephrons already functioning. In the rats with the contralateral ureteral ligation, the increase in Cin was greater than the increase in weight.

8 ACUTE RENAL FAILURE/Fmn 447 This also was associated with a substantial increase in the SNGFR. The ratio of the Ci n to SNGFR indicated that an increase in the number of functioning nephrons similar to that seen after contralateral nephrectomy had been achieved by the ureteral ligation. The specific mechanism by which reduction in the absolute or functional renal mass results in the functional recruitment of nephrons which otherwise would be lost is not apparent from this study. Of note in this regard are the studies of recovery of glycerol-induced acute renal failure in rats (Oken et al., 1970). In these studies, the severity of renal failure was not as marked as with 1 hour of renal artery occlusion, as evidenced by the fact that recovery began as early as 72 hours after the insult. Nonetheless, the pattern of recovery was marked by the sequential increase in the function of individual nephrons, i.e., the increase in total filtration rate was due to a progressive rise in the ratio of GFR/SNGFR. It is interesting to compare the sequence of events which follows unilateral renal artery occlusion with that which follows unilateral ureteral ligation. Each is marked by an initial period of elevated proximal intratubular hydrostatic pressures that occurs as a result of the obstruction to tubular fluid flow. This is followed by an increase in the degree of preglomerular vasoconstriction and a reduction of the glomerular capillary hydrostatic pressure (Jaenike, 1970; Arendshorst et al., 1974). Because blockage of individual nephrons produces a fall in glomerular capillary hydrostatic pressure similar to that observed after unilateral renal artery occlusion and ureteral ligation (Arendshorst et al., 1974; Tanner, 1979), there appears to be a causal relationship between the decrease in tubular fluid flow and the development over time of preglomerular vasconstriction. Similarities also exist in the patterns of recovery. Finn and Chevalier (1979) have reported that, following unilateral renal artery occlusion, intratubular obstruction is relieved prior to a significant rise in estimated glomerular capillary hydrostatic pressure, whereas Jaenike (1970) has presented evidence that release of the unilateral ureteral obstruction does not immediately restore the estimated glomerular capillary hydrostatic pressure to normal levels. Harris and Yarger (1974) have found that, after release of obstruction to a single ureter, the single nephron filtration rate is significantly lower than that found in sham-operated controls. In addition, they observed that many superficial nephrons and most juxtamedullary nephrons were nonfunctional and that there was a marked heterogeneity in the distribution of renal vasoconstriction. These latter findings are consistent with the observations presented in the present report. Furthermore, it has long been appreciated that release of obstruction to a single may not prevent progressive atrophy and permanent loss of function of the previously obstructed. In 1922, Hinman reviewed the work in experimental hydronephrosis which indicated that a that has had a complete obstruction of its ureter for 2 weeks or less may not only regain normal function but be capable also of undergoing a complete compensatory hypertrophy after contralateral nephrectomy. On the basis of these and other observations, he proposed his counterbalance theory. This stated that the extent of recovery of an injured is in some way related to the amount of residual functioning renal tissue. In summary, these studies indicate that recovery from unilateral postischemic renal failure is marked by the presence of a small number of normally functioning nephrons, but that factors of an unknown nature prevent complete recovery. These findings are similar to those in which obstruction is produced by unilateral ureteral ligation rather than by necrotic tubular epithelial cells. In particular, the marked similarity between the pattern of recovery from unilateral ureteral obstruction and unilateral postischemic acute renal failure suggests a common mechanism. Futhermore, removal of the contralateral results in the recruitment of additional nephrons, as has been shown to occur spontaneously in glycerol-induced acute renal failure. This response differs from that attributed solely to compensatory hypertrophy and raises the possibility that maneuvers other than that involving the reduction in renal mass also could result in enhanced recovery. Acknowledgments The technical assistance of Dale R. Kiser and the secretarial assistance of Darlene T. Moore are gratefully acknowledged. References Arendshorst WJ, Finn WF, Gottschalk CW (1974) Nephron stop-flow pressure response to obstruction for 24 hours in the rat. J Clin Invest 53: Arendshorst WJ, Finn WF, Gottschalk CW (1975) Pathogenesis of acute renal failure following temporary renal ischemia in the rat. Circ Res 37: Arendshorst WJ, Finn WF, Gottschalk CW (1976) Micropuncture studies of acute renal failure following temporary ischemia in the rat. Kidney Int 10: S-1O0-S105 Bonvalent JP, Champion M, Wanstok F, Berjal G (1972) Compensatory renal hypertrophy in young rats: Increase in the number of nephrons. Kidney Int 1: Bratton AC, Marshall EK (1939) A new coupling component for sulfanilamide determination. J. Biol Chem 12: Damadian RV, Shawyri E, Bricker NS (1965) On the existence of non-urine forming nephrons in the diseased of the dog. J Lab Clin Med 65: Donohoe JF, Venkatachalam MA, Bernard DB, Levinsky NG (197) Tubular leakage and obstruction after renal ischemia: Structural-function correlations. Kidney Int 13: Eisenbach GM, Steinhausen M (1973) Micropuncture studies after temporary ischemia of rat s. Pfluegers Arch 343: Finn WF (197) Anesthetic induced variation in the renal response to ischemia (abstr). Am Soc Nephrol 11: 90 Finn WF, Chevalier RL (1979) Recovery from post-ischemic acute renal failure in the rat. Kidney Int 16:

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