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The resistance of the immature kidney to ischemic injury is well documented, but the mechanisms involved in this tolerance have been elusive. Previous studies have demonstrated that tubules obtained from immature rats exhibit a bigger stress response than mature tubules. Consequently, we evaluated the developmental expression of HSP-72 in the postnatal kidney and determined whether or not that pattern of expression was correlated with the previously known tolerance of the immature kidney to injury. A distinct pattern of HSP-72 expression with a peak abundance at postnatal day 10 (P10), with a subsequent decline toward values seen in mature rats, was found. Moreover, this stress protein is located predominantly in tubular segments, the site of ischemic injury. To determine if this constitutive, non-induced expression of HSP-72 in the immature rat could be protective of cellular integrity and renal function, both immature (P10) and mature (8 weeks) rats were subjected to 45 min of bilateral renal artery ischemia. The postischemic induction of HSP-72 in the P10 animals was robust and the peak expression 2 h after ischemia was even greater than that detected in mature animals. Thus, the constitutive enhanced expression of HSP-72 did not prohibit or mute the inducible response of this stress protein in the immature animals. Immature animals, when compared with mature rats, also experienced cytoprotection, demonstrated by decreased detachment of Na-/K-ATPase from the cytoskeleton and substantial protection of renal function determined by serum creatinine level. These findings suggest that the developmental expression of heat shock proteins may play a critical and fundamental role in the well-observed tolerance of immature tubules to ischemic or anoxic injury.

The stress response was studied in suspensions of tubules from immature (IT) and mature (MT) rats after noninjury, heat, oxygen, and anoxia. Under all conditions, IT exhibited more exuberant activation of heat shock transcription factor (HSF) than MT. Characterization of activated HSF in immature cortex revealed HSF1. Also, 2 h after each condition, heat shock protein-72 (HSP-72) mRNA was twofold in IT. As the metabolic response to 45 min of anoxia, 20-min reoxygenation was assessed by measuring O2 consumption (O2C). Basal O2C was manipulated with ouabain, nystatin, and carbonylcyanide p-chloromethyoxyphenylhydrazone (CCCP). Basal O2C in IT were one-half the value of MT. After anoxia, basal O2C was reduced by a greater degree in MT. Ouabain reduced O2C to half the basal value in both noninjured and anoxic groups. Basal O2C was significantly stimulated by nystatin but not to the same level following anoxia in MT and IT. Basal O2C was also stimulated by CCCP, but after anoxia, CCCP O2C was significantly less in MT with no decrease in IT, suggesting mitochondria are better preserved in IT. Also, O2C devoted to nontransport activity was better maintained in IT.

The tolerance of immature tissues to injury has been noted over the past several decades. Traditional teaching relates this tolerance to energy derived from anaerobic glycolysis. This mini-review describes investigations of the hypothesis that the immature kidney is less susceptible to oxygen deprivation than the mature kidney. Utilizing proximal tubule suspensions from immature and mature rats, studies assessing ATP levels as an index of cellular energy and lactate dehydrogenase (LDH) release as a determinant of plasma membrane damage demonstrate the developing kidney is resistant to prolonged anoxia. ATP is maintained at twofold higher levels during anoxia in the immature tubule compared with the mature tubule. The contribution of anaerobic glycolysis to the tolerance of the immature renal tubules is investigated by two inhibitors of the glycolytic pathway, L-glucose and iodoacetate. Following 70%-90% inhibition of glycolysis, ATP is decreased to similar levels in immature and mature tubules. However, immature tubules remain resistant to anoxic damage with no significant change in LDH release. Therefore, enhanced glycolytic activity does not play a dominant role in the tolerance of the developing kidney to anoxia, and this tolerance is not primarily dependent on preservation of cellular ATP.

We have previously shown that the immature tubule is tolerant of prolonged anoxia. In addition, cellular ATP is maintained at 2-fold higher levels during anoxia in the immature tubules compared with the mature tubules. The purpose of this study was: 1) to determine whether anaerobic glycolysis contributes to the tolerance to anoxia and preservation of cellular ATP in immature tubules and 2) to evaluate whether the tolerance demonstrated by immature tubules is dependent on preservation of cellular ATP. Suspensions of proximal tubules from immature (8-10 d) and mature (8-10 wk) rats were subjected to 15 and 45 min of anoxia in a standard buffer and in buffers designed to inhibit glycolysis. Lactate dehydrogenase release was used to assess plasma membrane damage, ATP levels were determined as an index of cellular energy and total lactate production was measured to evaluate glycolytic activity. After 45 min of anoxia, total lactate production was less in immature tubules (101 +/- 48 micrograms of lactate/mg of DNA) compared with mature tubules (148 +/- 36 micrograms of lactate/mg of DNA). After inhibition of glycolytic metabolism, ATP decreased to similar levels in both immature and mature tubules. However, immature tubules remained resistant to anoxic damage (lactate dehydrogenase: mature tubules 38 +/- 4%, immature tubules 29 +/- 1.0%). Therefore, enhanced glycolytic activity does not play a dominant role in the tolerance of the developing kidney to anoxia, and this tolerance is not primarily dependent on preservation of cellular ATP.

Very few data are available regarding the decreased susceptibility of the developing kidney to anoxia. Therefore, the purpose of this study was to develop an experimental system that would allow comparison of an anoxic insult in immature and mature proximal tubule segments and to investigate the hypothesis that the developing kidney is resistant to anoxia as compared with the mature kidney. Suspensions of proximal tubules from immature (age 8-10 d) and mature (8-10 wk) rats were obtained. The purity of the tubule suspension from the immature rats was documented by villin staining. A common buffer solution was developed to compare results from the immature and mature tubules. To study the response of the tubules to anoxia, we subjected the tubule suspension from both the immature and mature rats to 15, 30, 45, and 60 min of anoxia. Lactate dehydrogenase release was measured to assess plasma membrane damage, and ATP levels were determined as an index of cellular energy. After a short anoxic insult (15 or 30 min), the percentage of lactate dehydrogenase release was not significantly different from mature tubules. After prolonged anoxia (45 and 60 min) lactate dehydrogenase release continued to increase, whereas membrane integrity stabilized in the immature tubules. ATP levels decreased in both immature and mature tubules after anoxia, but the decline of ATP was greater in the mature tubules, with a plateau at 20% of basal ATP levels as compared with 40% in the immature tubules. Therefore, the developing kidney is resistant to prolonged anoxia.

Twenty-three patients were evaluated from 1-15 (mean 6) years after recovering from an episode of diarrhea-associated associated childhood hemolytic uremic syndrome (DA-HUS). All patients had received only conservative treatment; none had been given experimental, anti-coagulant, or immunological therapies. Follow-up studies included morphologic and duplex Doppler sonograms. Doppler sonography was used to determine the resistive index, a measure of renovascular resistance. Histories and physical examinations revealed no abnormalities. Results of laboratory studies, which included calculated glomerular filtration rates, were all within normal limits, except for one patient with minor urinary abnormalities. Renal sonograms showed no significant abnormalities of kidney length or parenchymal appearance. However, Doppler sonographic examinations revealed that the DA-HUS patients demonstrated less of a decrease in renovascular resistance with age than did the control group (p < 0.0002). After recovery, patients treated exclusively with conservative management during an acute episode of DA-HUS appeared to have an excellent long-term prognosis. Comparison of our results with those from other studies in which investigational therapies have been used during the acute phase of DA-HUS suggests that latent toxicities which cause long term sequelae may not have been appreciated previously. The clinical significance of the altered renal vascular resistance remains to be delineated.

Previous studies from our laboratory have demonstrated that postischemic infusion of thyroxin (T4) will augment the restoration of cellular ATP and enhance the recovery of renal function. It has not been clear, however, whether T4 has a direct effect on mitochondrial ATP synthesis or an indirect effect by stabilization of the plasma membrane. To differentiate these putative effects, rats were subjected to 45 min of renal ischemia and given either normal saline (0.5 mL) or T4 (20 micrograms/100 g body weight) during the first 15 min of reflow. Cellular ATP levels were assessed by 31P-nuclear magnetic resonance spectroscopy, and release of lactate dehydrogenase (LDH) was used as an index of plasma membrane integrity at 30 and 120 min of reflow. In rats given normal saline, renal ATP had returned to only 57.9 +/- 1.4% of preischemic values at 30 min of reflow and 66.1 +/- 1.4% by 120 min. LDH release was 13 +/- 0.89% at 30 min and 14.6 +/- 1.6% at 120 min. In contrast, T4-treated animals had ATP levels of 70.2 +/- 2.0% at 30 min and 84.0 +/- 1.9% at 120 min, whereas LDH release was elevated to values similar to those in normal saline-treated rats, 14.9 +/- 1.5% and 14.4 +/- 0.5% at 30 min and 120 min, respectively (nonischemic LDH 8.8 +/- 0.8%). These data suggest that T4 stimulates the recovery of renal ATP by a direct effect on synthesis rather than an indirect effect related to global improvement in cellular integrity.

Objective: To describe a series of patients in hypertensive crisis who presented primarily with abdominal symptoms., Design: Patient reports., Setting: Referral center after initial presentation in the general community., Participants: Three children, aged 10 months to 4 years, in hypertensive crisis who presented with abdominal symptoms that promptly resolved and did not recur with blood pressure control., Conclusions: Blood pressure should be measured in all children undergoing physical examination; particular attention should be paid to the blood pressure of patients with unexplained abdominal symptoms before extensive diagnostic testing is pursued.

The role of nucleoside uptake in the enhanced metabolic recovery seen with postischemic ATP.MgCl2 was assessed by determining the effect of S-(p-nitrobenzyl)-6-thioinosine (NBTI) on postischemic ATP recovery in rats given normal saline (NS), ATP.MgCl2, or adenosine after 45 min of bilateral renal ischemia. In NS-infused animals, postischemic administration of NBTI (250 nmol) had no significant effect on the pattern of ATP recovery. In animals given 50 mumol ATP.MgCl2, coinfusion of NBTI significantly reduced the renal ATP content 2 h after reperfusion but blocked only one-half of the enhancement in renal ATP content compared with animals given ATP.MgCl2 alone. In animals postischemically infused with [2,5,8-3H]ATP.MgCl2 (50 mumol) there was significant labeling of nucleotides, nucleosides, and bases after 2 h of reperfusion. The specific activity of the adenosine pool was consistent with significant label uptake in the form of adenosine. Coinfusion of NBTI led to a significant reduction in label incorporation into renal ATP and total adenine nucleotide pools. These data are consistent with an important role for an NBTI-sensitive nucleoside uptake mechanism in the enhanced metabolic and functional recovery observed in ischemically injured kidney treated by postischemic infusion of ATP.MgCl2.

In order to elucidate the pattern of redistribution of cellular energy and the restoration of basic cellular metabolism following an ischemic renal insult, suspensions enriched in proximal tubule segments were studied after 45 min of bilateral artery occlusion and 15 min and 2 h of reflow from rats given either normal saline (control), ATP-MgCl2 (which enhances postischemic recovery of ATP), or alpha, beta-methyl adenosine diphosphate (AMPCP), which inhibits nucleotide degradation during ischemia. In non-ischemic control animals, approximately half of the energy is distributed to functional pump activity and half directed for non-transport purposes. When cellular ATP is reduced to 56% of control values, functional pump activity is significantly reduced to 61% of control, while energy delegated for non-transport purposes is decreased by a significantly smaller increment to only 78% of control at 15 min of reflow. In animals given ATP-MgCl2, the cellular and metabolic profile at 15 min of reflow was no different from ischemic control animals with cellular ATP levels similar at 58%. However, by 2 h, cellular ATP levels had increased significantly to 74%, and this was associated with a redistribution of cellular energy to functional pump activity (119% of control) with little change in non-transport function (76%). In animals treated with AMPCP, the cellular ATP levels were 74% of controls, similar to ATP-MgCl2-treated rats after 2 h of reflow. Despite the differences in reflow interval, the distribution of cellular energy was similar (functional pump activity 120% and non-transport activity 79%). By 2 h, cellular ATP was at 95% and both functional pump activity and non-transport activity were 100%.(ABSTRACT TRUNCATED AT 250 WORDS)

The long-term clinical course of 60 children with steroid-responsive nephrotic syndrome, observed for a minimum of 10 years from onset, was studied (mean 14.5 +/- 0.5 years). Four children had only a single episode, seven children experienced only one to three relapses early in their course, and the remaining 49 patients (82%) experienced frequently relapsing steroid-dependent disease. Nearly half of these (47%) continued to relapse into their late teens and early twenties. All 20 children treated with cyclophosphamide because of steroid-induced side effects developed complete remissions of the nephrotic syndrome. These were sustained in 70% for 9.1 +/- 0.6 years, with a reduction of disease severity in the remaining 30%. In contrast, only 48% of patients treated with prednisone alone were in remission at last follow-up (P = .06). Ten of the children treated with cyclophosphamide had the minimal change lesion prior to therapy; 90% of these had permanent remissions. Only 50% of the six children with focal glomerulosclerosis and four children with mesangial proliferation have had permanent remissions. None of the patients developed renal insufficiency. Children treated with prednisone alone were -0.93 +/- 0.3 SD below the mean for height at last follow-up. Cyclophosphamide treatment was associated with an increase in height SD scores from -0.84 +/- 0.4 to -0.28 +/- 0.3. Children with severe growth impairment demonstrated dramatic catch-up growth when treated with cyclophosphamide with SD scores increasing from -2.29 +/- 0.8 to -0.43 +/- 0.6 (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Postischemic administration of ATP-MgCl2 is known to enhance recovery of renal function and accelerate the restitution of cellular ATP levels. To differentiate between a direct and indirect effect of the exogenous nucleotide, rats were subjected to 45 min of bilateral renal ischemia and were infused with either ATP-MgCl2, AMP-MgCl2, or normal saline. The immediate recovery of the cellular ATP was similar in all three groups of animals, whereas the subsequent recovery was accelerated by the infusion of either nucleotide. Since ATP-MgCl2 and AMP-MgCl2 produced similar results, this study provides evidence that exogenous ATP may act by providing precursors for the resynthesis of the cellular adenine nucleotide pool rather than being a direct source of energy.

Serum hemolytic factor D activity, an important component of the ACP, was measured in patients with SR-INS. The mean serum factor D hemolytic activity of patients with SR-INS in relapse was significantly reduced compared to the mean of the control group. Twenty-one of 27 SR-INS patients in relapse (78%) had reduced serum factor D activity. In contrast, the mean serum factor D hemolytic activity of SR-INS patients in remission was not significantly different from that in the control group. Factor D hemolytic activity was also reduced in other types of renal disease with the nephrotic syndrome. Serum factor D values were highly correlated with the serum albumin concentration. Although hemolytic factor D activity could not be detected in the urine, the low molecular weight and the significant correlation with serum albumin concentration suggest that urinary loss is responsible for the low serum levels of factor D. Deficient serum values of factor D may contribute to the increased susceptibility of SR-INS patients in relapse to bacterial infections with organisms which activate the ACP.

This article reviews the current understanding of the pathophysiologic sequence of events that culminate in an acute renal insult. The use of urinary indices to differentiate the physiologic causes of oliguria, namely, diminished intravascular volume or renal perfusion, from an established acute renal failure, is discussed for children and adolescents, as well as for neonates. Treatment modalities for the support of children with acute renal failure are described in detail.

To determine the mode of action of the beneficial effect of adenosine triphosphate (ATP)-MgCl2, recovery of microinjected inulin, proximal tubular pressure (PTP), and cellular damage as quantitated by histomorphometric analysis of necrosis and swelling were evaluated at 2, 6, and 24 hours after 45 minutes of renal ischemia in rats treated with either normal saline or ATP-MgCl2. At 2 hours both groups of rats demonstrated increased permeability to inulin, elevated PTP, and severe ischemic damage and necrosis. By 6 hours ATP-MgCl2 rats had less tubular back leak of inulin, PTP was modestly reduced, and ultrastructural studies demonstrated improved cellular morphologic features with evidence of early regenerative changes. The saline rats had progressive ischemic cellular damage. At 24 hours ATP-MgCl2 rats had reestablished tubular integrity, PtP had fallen, and ischemic alterations were improved, with only focal evidence of necrosis. Saline-treated rats still had a back leak of inulin, elevated PTP, and progressive ischemic injury. This study demonstrates that 1) cellular damage continues to occur for 6 hours after renal ischemia; 2) ATP-MgCl2 enhances recovery of tubular integrity and cellular morphologic features. The salutary effect of ATP-MgCl2 appears related to the preservation of sublethally injured cells and acceleration of the process of restoration and repair of damaged cells.

Children with steroid-dependent frequently relapsing nephrotic syndrome are generally assumed to have a minimal change in histology and therefore to respond favorably to treatment with cyclophosphamide. The clinical course of 38 children with steroid-sensitive frequently relapsing nephrotic syndrome was analyzed. Biopsy samples were obtained from these children several years (mean 6 years) after the onset of their disease but before they were treated with cyclophosphamide. Three histologic types of lesions were found: minimal change lesion, 18 patients (47%); focal and segmental glomerulosclerosis, 11 patients (29%); and mesangial proliferation, 9 patients (24%). Each patient then received cyclophosphamide (2mg/kg of body wt per day) for 12 weeks, and each responded with a complete remission, which lasted 1.5 +/- 0.2 years. During 6 years of followup after cyclophosphamide, 17 patients experienced one or more relapses, but 21 patients remained in sustained remission. The incidence of relapse after cyclophosphamide was significantly greater (P less than 0.01) in the patients with focal and segmental glomerulosclerosis (8/11, 73%) and mesangial proliferation (5/9, 56%), as compared with children with minimal change lesion (4/18, 22%). These data indicate that children with frequently relapsing steroid-dependent nephrotic syndrome (1) will not all develop minimal-change lesions within several years; in fact, approximately half will have either focal and segmental glomerulosclerosis or mesangial proliferation; and (2) after cyclophosphamide treatment, the incidence of relapse will be related to the histopathologic type of lesion present at the time of treatment with cyclophosphamide.

To define the interrelationship between changes in total renal blood flow (TRBF) and proximal tubular hydrostatic pressure (PTP), rats were studied 2, 3, 4, 6, 12, 18, and 24 h after bilateral ureteral occlusion (BUO). In control animals, a peak rise in both TRBF (3.52 +/- 0.26 ml . min-1 . 100 g body wt-1 . kidney-1) and PTP (28.6 +/- 1.3 mmHg) occurred 3 h after BUO. At each subsequent time interval, both TRBF and PTP fell, so that by 24 h after BUO, TRBF was 1.53 +/- 0.34 and PTP was 16.5 +/- 0.6, while in sham-operated rats the values were 2.52 +/- 0.22 ml . min-1 . g body wt-1 . kidney-1 and 12.8 +/- 0.2 mmHg, respectively. In animals treated with indomethacin (10 mg/kg) at the time of BUO, the alterations in both TRBF and PTP were completely ameliorated. At 3 h, TRBF was 1.8 +/- 0.32 ml . min-1 . 100 g body wt-1 . kidney-1 and PTP was 15.3 +/- 1.0 mmHg. TRBF and PTP remained essentially unchanged at each subsequent time period. These data indicate that 1) alterations in TRBF and PTP follow a similar and parallel pattern during BUO; 2) the pattern of changes in TRBF and PTP can be eliminated by treatment with indomethacin; and 3) renal hemodynamics appear to be the dominant factor in producing these changes during the first 12 h after BUO, whereas a sustained increase in tubular hydrostatic pressure may play a primary role in decreasing TRBF 12-24 h after ureteral occlusion.

To evaluate the effect of thyroxin (T4) on recovery from ischemic acute renal failure, rats were treated with T4 (10 or 20 micrograms/100 g body wt.) or normal saline (NS) either immediately prior to, immediately after or 24 h after 45 min of renal ischemia. Animals given T4 prior to ischemia had no significant increase in Inulin clearance (Cin) (377 +/- 40 microliters/min per 100 g body wt.) as compared with saline-treated ischemic controls (306 +/- 54). In contrast, animals treated immediately after ischemia with either dose of T4 demonstrated significantly better kidney function (Cin 515 +/- 59 microliters/min per 100 g body wt., Uosm 842 +/- 88 mosmol/kg, FENa 0.52% +/- 0.12% and Cin 543 +/- 71, Uosm 939 +/- 103, FENa 0.48 +/- 0.12, for 10 and 20 micrograms/100 g body wt., respectively). Moreover, the improvement in renal function was sustained and Cin was significantly better at day 3 (748 +/- 70) and day 7 (990 +/- 75) compared with saline controls (560 +/- 30 and 732 +/- 45, respectively). Animals which received T4 24 h after ischemia showed significantly higher Cin when compared with ischemic controls. To assess the impact of T4 on recovery of renal ATP, 31P-NMR was used. T4-treated rats demonstrated 90% +/- 5% recovery of renal ATP by 120 min of reflow, whereas NS animals had only 64% +/- 1%. In addition, cellular morphology was better preserved in T4 animals. These data indicate that animals treated postischemically with T4 showed accelerated and sustained recovery from acute renal failure. This beneficial effect appears to be related to cellular mechanisms which are essential for the restoration of sublethally injured cells.

At present, the clinician is left in a relatively dependent position when encountering a patient with established acute renal failure (ARF). Clearly, interventional therapies that can significantly influence the process of recovery from ARF are limited. Although a variety of manipulations and drugs will protect against the loss of renal function when administered prior to the initiation of a renal insult, the clinician usually encounters a patient after ARF has been established. Thus, perturbations that will protect against the development of ARF or modify the severity of the renal insult are not applicable. Moreover, it is clear that the mortality and morbidity for patients with ARF is unacceptably high. Although a variety of supportive measures such as peritoneal/hemodialysis or continuous arteriovenous hemofiltration are now applicable to patients of almost any size or weight, patients continue to die with but perhaps not of ARF. This article will review several new agents that act to enhance the restoration of renal function and result in accelerated recovery of both glomerular and tubular function, following an established acute renal insult: adenine nucleotides, thyroxin, and calcium channel blockers.

Children with the idiopathic nephrotic syndrome (NS) are known to be susceptible to bacterial infections. A recent report suggested that splenic hypofunction may be responsible for this immunological defect. We assessed splenic function by counting the circulating pocked red blood cells (PkRBCs) using interference phase contrast microscopy. PkRBCs are removed by the spleen, so that normal eusplenic individuals have less than 2% PkRBCs while asplenics have 15%-30%. Intermediate values are seen in hyposplenism. Thirty-three measurements of PkRBCs were made in 19 children with NS (mean age 7.5 +/- 0.8 years). PkRBCs were normal in all children tested (range 0-0.8%), including two patients with bacterial peritonitis associated with relapse. Thus we were unable to find evidence of hyposplenism in children with NS.

Renal energy metabolism was investigated before, during, and after ischemic insults of varying durations with in vivo 31P NMR spectroscopy. The postischemic recovery of renal ATP was found to be a biphasic process regardless of the length of the ischemia. This two-stage recovery consisted of a quick initial component immediately upon reflow followed by a slower, more gradual return toward preischemic levels. To characterize the source of each phase of the recovery, kidneys were extracted with perchloric acid at the end of the different periods of ischemia (before reflow). Concentrations of adenine nucleotides and breakdown products adenosine, inosine, and hypoxanthine were determined by 1H NMR spectroscopy. Excellent correlation was found between the residual nucleotide pool and the magnitude of the initial phase of ATP recovery. Additionally, the renal ATP content after 120 min of reflow was shown to have a strong correlation with subsequent functional recovery. These experiments show that in vivo 31P NMR can provide new and dynamic information concerning the biochemical recovery from ischemia. Furthermore, this data has the potential to predict the eventual functional recovery of the organ.

Renal vasoconstriction is an important pathophysiological component of an ischemic acute renal injury. The postischemic infusion of ATP-MgCl2 enhances recovery of glomerular and tubular function, accelerates regeneration of sublethally injured tubular cells, and augments resynthesis of cellular nucleotides. Since both ATP and MgCl2 are vasoactive compounds, postischemic enhancement of renal blood flow (RBF) by a pharmacological agent, dopamine, was examined to study the possible contribution of vasodilation. At 2 h, the infusion of dopamine resulted in RBF (1.70 +/- 0.09 ml X min-1 X 100 g body wt-1 X kidney-1) and inulin clearance (CIn, 400 +/- 44 microliter X min-1 X 100 g body wt-1) similar to rats treated with ATP-MgCl2 (1.73 +/- 0.27 RBF, 404 +/- 38 CIn) and significantly (P less than 0.01) greater than saline-treated rats (0.80 +/- 0.04 RBF, 78 +/- 19 CIn; P less than 0.01). However, by 24 h CIn in dopamine animals had not continued to improve (460 +/- 25 microliter X min-1 X 100 g body wt-1) and was similar to normal saline rats (388 +/- 40). In contrast, CIn in ATP-MgCl2 animals showed sustained recovery (676 +/- 28 microliter X min-1 X 100 g body wt-1, P less than 0.01). These differences resulted from improved integrity of tubular epithelium as reflected by decreased cell swelling and necrosis. Moreover, the recovery of renal ATP levels, as assessed by 31P nuclear magnetic resonance, in animals given saline (63 +/- 3%) or dopamine (66 +/- 5%) was slow and incomplete by 120 min after ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

This study was designed to investigate the effects of ATP-MgCl2 when infused immediately 8 or 24 hr after 45 min of bilateral renal artery ischemia and to determine if an initial improvement in clearance of inulin (CIn) would be sustained throughout the course of recovery. In addition, the influence of ATP-MgCl2 on the pattern of recovery of whole kidney and single nephron function was assessed by determining the impact of this agent on proximal tubular pressure and transepithelial backleak. The postischemic administration of ATP-MgCl2 resulted in significantly enhanced recovery of CIn irrespective of the time of the infusion after the initial insult. This beneficial effect was sustained in that the ATP-MgCl2-treated rats had significantly better CIn 1, 3 and 7 days after the injury when compared to normal saline-treated animals. Moreover, single nephron inulin clearance (SNCIn) was better preserved than whole kidney CIn in both groups of animals and in the ATP-MgCl2-treated animals SNCIn was similar to control values even 1 day after the injury. The enhanced recovery of single nephron function in the ATP-MgCl2-treated animals resulted from reduced proximal tubular pressure and diminished backleak of tubular fluid. Animals given ATP-MgCl2 had better preservation of cellular morphology. Horseradish peroxidase was excluded from most epithelial cells and the interstitium in a manner similar to that seen in control animals while saline-treated rats demonstrated backleak of this tracer compound. Based on these studies, it appears that the beneficial effect of ATP-MgCl2 occurs because of the preservation of sublethally injured cells by augmentation of the process of recovery.

Focal glomerulosclerosis, with the nephrotic syndrome and progressive renal insufficiency, developed in a 15-year-old boy who presented initially 1 year earlier with orthostatic proteinuria. Although generally considered to be a benign disorder, this case suggests that on rare occasions, serious glomerular diseases may develop in patients with orthostatic proteinuria or that significant glomerular disease may occasionally present with postural proteinuria.

To determine the effect of thyroxin (T4) on the recovery from toxic acute renal failure, rats were injected, subcutaneously, with K-dichromate (15 mg/kg) and at the peak of the renal injury, each animal was given either T4 (4 micrograms/100 g body weight, i.p.) or normal saline (NS). The T4-treated rats had significantly better CIn (669 +/- 35 microliter/min/100 g body weight), improved FENa (0.49 +/- 0.05%) and increased UOsm (835 +/- 50 mOsm/kg) as compared to animals given only NS (CIn 422 +/- 27; FENa 1.02 +/- 0.12; and UOsm 613 +/- 23). A similar dose of T4 given to non-injured control rats had no effect on renal function. The beneficial effect of T4 on dichromate injected rats was sustained and lead to more prompt recovery of glomerular function. To eliminate any hemodynamic effects of T4, an isolated perfused kidney preparation was utilized, and kidneys from dichromate injected rats treated with T4 had significantly better CIn, urine flow and FENa compared to rats given NS. Cellular morphology was better preserved in T4-treated animals. These data indicate that treatment with T4 results in enhanced recovery from an acute toxic renal insult and that this beneficial effect is unlikely to be related to nonspecific systemic effects of the hormone.

We have evaluated the impact of inhibiting adenine nucleotide dephosphorylation on the metabolic and functional consequences of renal ischemia. Intramuscular injection of the ADP-analogue adenosine alpha, beta-methylene diphosphate (AMP-CP) achieved a 70% reduction in 5'-nucleotidase activity, as measured in crude extracts of rat kidney. AMPCP-treated animals had an increased residual nucleotide pool at the end of 45 min of ischemia compared with untreated rats. Assessment of renal ATP by 31P-nuclear magnetic resonance (31P-NMR) in vivo during reflow demonstrates the following: 1) higher rapid initial recovery of ATP (69.3 +/- 1.2 vs. 50.0 +/- 0.5% control value, P less than 0.005), 2) accelerated rate of ATP restoration (0.20 +/- 0.02 vs. 0.11 +/- 0.01% control/min, P less than 0.005), and 3) significantly enhanced renal ATP content after 120 min (93.6 +/- 2.0 vs. 63.1 +/- 0.7% control, P less than 0.005). Kidney function, as measured by the rate of inulin clearance 24 h after the insult, was also significantly improved in AMPCP-treated rats (725 +/- 50 vs. 313 +/- 28 microliters.min-1.100 g body wt-1). Thus inhibition of 5'-nucleotidase results in enhanced metabolic and functional recovery from a renal ischemic insult.

The concentrations of renal ATP have been measured by 31P-nuclear magnetic resonance (NMR) before, during, and after bilateral renal artery occlusion. Using in vivo NMR, the initial postischemic recovery of ATP increased with the magnitude of the residual nucleotide pool at the end of ischemia. ATP levels after 120 min of reflow correlated with functional recovery at 24 h. In the present study the effect of blocking the degradation of ATP during ischemia upon the postischemic restoration of ATP was investigated. Inhibition of adenosine deaminase by 80% with the tight-binding inhibitor 2'-deoxycoformycin led to a 20% increase in the residual adenine nucleotide pool. This increased the ATP initial recovery after 45 min of ischemia from 52% (in controls) to 62% (in the treated animals), as compared to the basal levels. The inhibition also caused an accelerated postischemic restoration of cellular ATP so that at 120 min it was 83% in treated rats vs. 63% in untreated animals. There was a corresponding improvement in the functional recovery from the insult (increase of 33% in inulin clearance 24 h after the injury). Inhibition of adenosine deaminase during ischemia results in a injury similar to that seen after a shorter period of insult.

Although a number of manipulations prior to or during the initiation phase of an acute renal injury will modify the degree of functional impairment, agents administered after the acute insult usually have been ineffective. In the present study, adenine nucleotides (AMP, ADP, or ATP) combined with magnesium chloride were infused after an ischemic renal injury. Twenty-four hours later: (1) rats that received no infusion or one of the components of the mixture alone had reduced CIn (355 +/- 40 microliter/min/100 g of body wt vs. 977 +/- 40 control value), decreased RBF (3550 +/- 205 microliter/min/100 g of body wt vs. 5095 +/- 171 control value), elevated FENa (0.65 +/- 0.10% vs. 0.17 +/- 0.04 control value), and diminished UOsm (862 +/- 110 mOsm/kg vs. 1425 +/- 132 control value); (2) rats given dopamine or phenoxybenzamine maintained low CIn (365 +/- 50) despite improved RBF (4678 +/- 222); (3) rats infused with either AMP, ADP, or ATP combined with magnesium chloride had markedly improved CIn (594 +/- 44, P < 0.01), increased RBF (4269 +/- 223, P < 0.01); normalized FENa (0.18 +/- 0.07%, P < 0.01), and improved UOsm (1201 +/- 106 mOsm/kg, P < 0.05). In animals given no infusion or only magnesium chloride, ultrastructural studies demonstrated focal cellular necrosis and marked generalized tubular cell and mitochondrial swelling, whereas rats infused with ATP and magnesium chloride had fewer ultrastructural changes with better preservation of cellular morphology. Rats treated with ATP and magnesium chloride had improved CIn despite ischemic periods of 30, 45, and 60- min; and the degree of improvement was directly related to the quantity of ATP and magnesium chloride administered. The cellular content of exogenously administered ATP was 2.5 times greater in previously ischemic kidneys than in nonischemic kidneys. The data indicate that adenine nucleotides combined with magnesium chloride when infused after the initiation of acute renal failure significantly improve both CIn and tubular function and suggest that these agents effectively enhance recovery following an ischemc renal insult.

A viable suspension of proximal tubules that had sustained an in vivo ischemic injury was harvested, and cellular integrity and viability were determined. The histopathological appearance of this preparation has characteristic features of an ischemic injury and ATP levels were comparable to those observed with nuclear magnetic resonance spectroscopy in vivo. Sprague-Dawley rats were subjected to 45 min of bilateral renal artery ischemia and the kidneys were allowed to reperfuse for either 15 min, 2 h, or 24 h before the harvest of the proximal tubule suspension. There was a decrease in base-line oxygen consumption from 34 +/- 0.8 nmol O2.min-1.mg protein-1 to 22 +/- 0.6 at 15 min of reflow. This decline in oxygen consumption persisted during the first 2 h of reflow and returned to control levels by 24 h. Residual respiration in the presence of ouabain was similar at all reflow intervals suggesting that the decrease in basal O2 consumption was related to decreased Na+-K+-ATPase in situ. In contrast, there was no significant difference in Na+-K+-ATPase activity when determined chemically under Vmax conditions in all experimental groups.(ABSTRACT TRUNCATED AT 250 WORDS)

This article will provide a pathophysiologic basis for the assessment of critically ill children who have developed disorders of urine volume. The anatomical and pathophysiologic causes of oliguria and polyuria are considered. The physiologic basis for the use of urinary sodium and osmolarity as a guide to the assessment of patients with disorders of urine volume are discussed in detail. In addition, guidelines for the management of children with acute renal failure, with particular emphasis on the consideration for nutritional support of these patients, is discussed as a part of the comprehensive approach to this problem. This article emphasizes an understanding of the pathophysiology of salt and water excretion by the kidney as a foundation to the diagnosis and management of patients with oliguria and polyuria.