Morphologic Evidence to Support the Role of Tubular Leakage as a Cause of Anuria Induced by Mercury Poisoning

The qualitative Hanssen technic was used to study the mechanism of anuria produced in rabbits by mercury poisoning. Twenty-four to 30 hours after intravenous injection of a low dose of HgCl₂, the animals were almost completely anuric. Sodium ferrocyanide injected intravenously was visualized as Prussian blue in essentially all glomeruli in anuric kidneys, and the amount of the dye in the glomerular tufts was almost the same as in control kidneys. Thus there was no evidence for a severe reduction in glomerular capillary blood flow. Besides, the distribution of Prussian blue in tubular lumina indicated that the anuria occurred in the presence of a significant glomerular filtration. Tubular walls of the anuric kidneys showed an abnormally increased permeability to sodium ferrocyanide. These findings suggested that the anuria during this stage was caused more by tubular leakage than by intrarenal vasoconstriction and subsequent cessation of glomerular filtration.     

The effect of clonidine on tubular obstruction in postischemic acute renal failure in the rabbit demonstrated by microradiography and microdissection.

Acute renal failure was produced in vasopression-pretreated rabbits by clamping the left renal pedicle for one hour and removing the opposite kidney. Treatment with clonidine, as antihypertensive drug that blunts the kidney's response to vasopressin, resulted in significantly higher creatinine clearance and urine flow rate in the first 6 hours after unclamping. Clonidine (30 microgram/kg given intravenously 30 minutes before unclamping) also significantly lessened the number of hyaline casts in outer medullary tubules and inner medullary loops of Henle 6 hours after unclamping and reduced the number of abnormal tubular contours in microadiograms produced by infusing barium sulfate into the renal artery at sufficient pressure to rupture glomerular capillaries, causing an escape of contrast material into the tubules. The spaces consistently observed between the ends of barium columns and hyaline casts in microdissection studies and the great lengths of the hyaline casts suggest that hyaline casts obstruct the flow of tubular fluid. Clonidine treatment resulted in fewer, shorter, and thinner hyaline casts. These results indicate that tubular obstruction by hyaline casts plays an important role in early postischemic acute renal failure, and that clonidine's beneficial effect is due in part to a reduction in cast formation.     

Cis-diamminedichloroplatinum (II)-induced acute renal failure in the rat. Correlation of structural and functional alterations

Studies were undertaken to examine the relationship between renal morphologic and functional alterations during the development of cis-diamminedichloroplatinum (II) (CDDP)-induced acute renal failure (ARF). Control and CDDP-treated rats (10 mg/kg, intraperitoneally) were housed in metabolic cages for the purpose of renal function determinations. Renal morphology was studied by light and electron microscopy at 6, 24, 48, 72, and 96 hours following treatment. Six hours following CDDP administration, morphologic alterations consisting of nucleolar segregation, ribosome dispersion, and the formation of aggregates of smooth endoplasmic reticulum were observed throughout the P3 portion of the proximal tubule located in the outer stripe of the outer medulla and medullary rays. These changes became more frequently observed throughout P3 during the course of the study. At 24 and 48 hours, focal changes were also observed involving the P1 and P2 segments of the proximal tubule which make up the pars convoluta. ARF, indicated by a reduced creatinine clearance, was first apparent 48 hours following CDDP administration. The development of ARF was associated with focal, primarily sublethal, cell injury throughout the proximal tubule. By 72 and 96 hours necrosis primarily affecting P3 became widespread, and renal function progressively worsened. The establishment of ARF prior to the development of tubular necrosis suggests that the processes of tubular obstruction and/or tubular fluid backleak are not involved in the initiation of ARF in this model. Instead, the alterations involving P1 and P2 appear to be most important during the early stages of CDDP-induced ARF. The severity of the convoluted tubular injury at 48 hours showed a significant correlation with the degree of renal function impairment. The tubular injury affecting P3 did not correlate with the loss of renal function at any of the time points studied. However, tubular injury in P3 did appear responsible for some degree of renal function impairment at 72 and 96 hours, probably as a result of tubular obstruction and/or tubular fluid backleak.     

Possible involvement of myofibroblasts in cellular recovery of uranyl acetate-induced acute renal failure in rats

Cellular recovery in acute renal failure is a form of wound healing. Fibroblast-like cells or myofibroblasts are involved in wound healing. We examined the serial changes in tubular damage and origin and kinetics of regenerating cells in uranyl acetate-induced acute renal failure, with a special emphasis on interstitial myofibroblasts. Acute renal failure was induced in rats by intravenous injection of uranyl acetate (5 mg/kg). All rats received bromodeoxyuridine intraperitoneally 1 hour before sacrifice. Serial changes in the distribution of tubular necrosis and bromodeoxyuridine-incorporated or vimentin-positive regenerating cells, and their spatial and temporal relation to alpha-smooth muscle actin-positive myofibroblasts as well as ED 1-positive monocytes/macrophages were examined. Necrotic tubules initially appeared around the corticomedullary junction after uranyl acetate injection, then spread both downstream and upstream of proximal tubules. Peritubular alpha-smooth muscle actin-positive myofibroblasts appeared and extended along the denuded tubular basement membrane, establishing network formation throughout the cortex and the outer stripe of outer medulla at days 4 to 5. Tubular regeneration originated in nonlethally injured cells in the distal end of S3 segments, which was confirmed by lectin and immunohistochemical staining using markers for tubular segment. Subsequently, upstream proliferation was noted along the tubular basement membrane firmly attached by myofibroblasts. During cellular recovery, no entry of myofibroblasts into the tubular lumen across the tubular basement membrane was noted and only a few myofibroblasts showed bromodeoxyuridine positivity. The fractional area of alpha-smooth muscle actin-positive interstitium reached a peak level at day 7 in the cortex and outer stripe of outer medulla, then gradually disappeared by day 15 and remained only around dilated tubules and in the expanded interstitium at day 21. ED 1-positive monocytes/macrophages were transiently infiltrated mainly into the region of injury. They did not show specific association with initially necrotic tubules, but some of them located in close proximity to regenerating tubules. Nonlethally injured cells at the distal end of proximal tubules are likely to be the main source of tubular regeneration, and the transient appearance of interstitial myofibroblasts attached to the tubular basement membrane immediately after tubular necrosis might play a role in promoting cellular recovery in possible association with monocytes/macrophages in uranyl acetate-induced acute renal failure.     

Enzyme histochemistry of rat folic acid nephropathy.

One hour after a single i.v. dose of 250 mg/kg folic acid, the straight portion of distal tubules in the outer medulla of rat kidneys showed a distinct reduction in succinate dehydrogenase, NADH2-diaphorase, glutamate dehydrogenase, cytochrome oxydase, Na+/K+-ATPase, and acid phosphatase activity. In contrast, the proximal tubules exhibited only a reduction in glutamate dehydrogenase and alkaline phosphatase activity. At this time the straight portion of the distal tubules, whose enzyme activity had changed, showed partly regressive epithelial changes. 24 hours after folic acid administration an even greater reduction in enzyme activity had occurred in the straight portion of distal tubules; these structures also became dilated. The adjacent collecting tubules and the corresponding proximal tubules were also severely dilated, the proximal tubules showing a loss in enzyme acitivities similar to those observed in the distal tubules. 48 hours after folic acid administration the changes largely resembled those observed after 24 hours, but were more pronounced. At this time a tubular regeneration was observed. 72 hours after folic administration extensive normalization of the histological and histochemical changes had occured. It is postulated that a disturbance of the hairpin counter-current mechanism occurs as a result of a direct, concentration-dependent effect of folic acid on the enzymes of the energy supplying metabolism. A dilation in the region of the loop of Henle and the collecting tubules occurs subsequently.     

慢性输尿管梗阻解除后兔肾扫描电镜观察

目的从形态学角度探讨慢性输尿管梗阻解除后肾功能不能完全恢复的机制。方法采用新西兰大白兔36只,随机分为正常对照组3只、梗阻对照组3只及实验组30只。后两者均建立单侧输尿管梗阻的兔模型,梗阻对照组2周后处死,实验组2周后行输尿管皮肤造口术,分别于术后12h、24h、3d、7d、14d处死。对同侧的肾乳头及皮质进行扫描电镜观察。结果梗阻解除早期可见近端肾小管上皮细胞气球样变性及刷状缘大量缺失,远端肾小管及集合管亦表现为上皮细胞严重的气球样变性,见不到正常的肾小管结构。2周后多数肾小管上皮细胞恢复正常,然而一些肾小管仍进一步衰变。可见,输尿管梗阻解除后肾小管的恢复存在明显的不均一性。结论部分肾小管进一步衰变可能是慢性输尿管阻解除后肾功能不能完全恢复的主要病理学基础。     

Plasma renin activity in folic acid induced acute renal failure

Summary Peripheral plasma renin activity in acute renal failure induced in rats by a single i.v. injection of folic acid (250 mg/kg b. w., dissolved in 0.3 M NaHCO₃) remained normal during the first 6 hours and fell to low levels 24 hours and 4 days following the injection. Bleeding, however, induced a considerable increase of plasma renin activity on the 4th day after folate injection. There was no evidence of a participation of renin in the development of the functional and morphological renal disturbances produced by folic acid.Supported by Deutsche Forschungsgemeinschaft.     

Prevention of ischemic acute renal failure with impermeant solutes

Studies were performed to evaluate the effect of solute permeability and extracellular osmolality in protecting against ischemic acute renal failure. The functional protective effect of a 1-min intrarenal perfusion (prior to intrarenal norepinephrine 0.75 micrograms . kg-1 . min-1) of a hypertonic permeant solute (hypertonic saline, 1,400 mosmol/kg H2O) and an isotonic impermeant solute (isotonic mannitol, 280 mosmol/kg H2O or isotonic polyethylene glycol, IPEG, 300 mosmol/kg H2O) was evaluated. Three hours after ischemia, the glomerular filtration rate was significantly lower in hypertonic saline group vs. either the isotonic mannitol- or IPEG-treated animals (2.4 vs. 8.9 and 10.4 ml/min, respectively; both P less than 0.05). Mean renal blood flow was similar in all three groups. The effects of hypertonic saline and IPEG on glomerular filtration pressure and tubular obstruction were also evaluated. Stop-flow pressure, as an index of glomerular filtration pressure, was higher in the IPEG- vs. the hypertonic saline-treated animals (40 vs. 35 mmHg, P less than 0.001). Although proximal tubular pressure was increased in both groups, transglomerular hydrostatic pressure was higher in the IPEG vs. the hypertonic saline group (13 vs. 6 mmHg, P less than 0.01). Tubular microperfusion studies demonstrated increases in proximal tubular pressure in the hypertonic saline but not the IPEG studies. The present results indicate that isotonic, impermeant solutes provide functional protection against ischemic acute renal failure. The beneficial effect of impermeant solute is mediated, at least in part, by better maintenance of transglomerular hydrostatic pressure and prevention of secondary tubular obstruction.     

Up-regulation of galectin-3 in acute renal failure of the rat

Galectin-3, a multifunctional beta-galactoside-binding lectin, is known to participate in development, oncogenesis, cell-to-cell attachment, and inflammation. We studied to determine whether galectin-3 is associated with cell injury and regeneration in two types of acute renal failure (ARF), namely ischemic and toxic ARF. In ischemia/reperfusion renal injury in rats (bilateral renal pedicles clamped for 40 minutes), galectin-3 mRNA began to increase at 2 hours and extended by 6.2-fold at 48 hours (P: < 0.01 versus normal control rats), and then decreased by 28 days after injury. In addition, a significant negative correlation between galectin-3 mRNA expression and serum reciprocal creatinine was shown at 48 hours after injury (n = 13, r = -0.94, P: < 0.0001). In folic acid-induced ARF, galectin-3 mRNA was found to be up-regulated at 2 hours after injury and increased levels continued until at least 7 days post-injury. In immunohistochemistry, at 2 hours following reperfusion, galectin-3 began to develop in proximal convoluted tubules. From 6 hours up to 48 hours, galectin-3 was also found in proximal straight tubules, distal tubules, thick ascending limbs, and collecting ducts. In later stages of regeneration, galectin-3 expressions were found in macrophages. In conclusion, we demonstrated that galectin-3 expressions were markedly up-regulated in both ischemic and toxic types of ARF. Galectin-3 may play an important role in acute tubular injury and the following regeneration stage.     

Reduction of folic acid-induced acute tubular injury by diuresis: An experimental model

Folic acid (200 μgm/gm body wt) either alone or in combination with fursemide (25 μgm/gm body wt) was administered intraperitoneally to 40-day-old male Charles River mice. Sequential assays of renal weight, protein, RNA, and DNA were made to determine if diuresis would prevent the acute tubular injury produced by folic acid and segregate the reparative renal growth response to injury from growth response induced by folic acid alone. The response of control animals (ip saline) and animals receiving fursemide only was similar, with progressive growth over the 14-day observation period and gains of 25, 28 and 27% in renal weight, RNA, and DNA, respectively. Those animals receiving folic acid alone demonstrated an increase in renal weight (83%), RNA (45%), and DNA (23%) 4 days after injection with subsequent losses in all by the fourteenth day. Those animals which received both folic acid and fursemide showed a pattern similar to the two control groups but with smaller increases in renal weight (15%), RNA (17%), and DNA (10%) during the observation period. Folic acid-induced acute tubular injury manifest by a reduction in the early growth response can be modified by diuretic administration. It is felt that the diuresis prevents renal tubular occlusion by the sloughed tubular cells and precipitated folic acid.     

Beagle犬药物诱导急性肾损伤模型的研究

目的 建立顺铂诱导的Beagle犬急性肾损伤模型,为开展肾毒性生物标志物研究奠定基础.方法 通过对Beagle犬单次静脉注射3、4和5 mg/kg顺铂,探讨采用顺铂建立急性肾小管损伤模型的给药方案.密切观察动物给药后临床症状,测定不同时间点的传统血清及尿液新型肾损伤生物标志物的动态变化,在试验结束时解剖动物并进行肾脏组...     

Precipitable tissue proteins can cause experimental acute renal failure

A previous investigation demonstrated that intravenous infusion of a saline-liver extract into rats causes acute renal failure (ARF), manifested by severe azotemia, extensive cast formation, and patchy tubular necrosis. The purpose of the present study was to explore its pathogenesis. Histologic assessments of rat kidneys made 1.5 hours after liver extract infusion demonstrated eosinophilic material within glomerular capillaries, Bowman's space, and proximal tubular lumina, distal nephron cast formation, and tubular dilation without evidence of tubular necrosis. Renal blood flow at this time was normal but the rats were anuric. Assessments made 24 hours after liver extract infusion demonstrated persisting ARF (blood urea nitrogen, 132 +/- 8; creatinine, 2.54 +/- 0.19 mg/dl), profound cast deposition almost exclusively in the inner medulla/papilla, and the appearance of patchy proximal tubular necrosis. Sephacryl S200 fractionation and 10% polyacrylamide gel electrophoresis of liver extract showed high and low molecular weight proteins (less than 30,000). Proteins in both regions demonstrated prominent acid precipitability (pH 4.5) and autoaggregation (at 37 degrees C). Trace amounts of spontaneously precipitated protein recovered from urine during liver extract infusion demonstrated a predominance of low molecular weight proteins by polyacrylamide gel electrophoresis. Infusing rats with filterable low molecular weight proteins (cytochrome c, ribonuclease, myoglobin) without autoaggregation/acid precipitation characteristics or liver extract made devoid of precipitable proteins failed to induce ARF. However, infusing a kidney extract containing acid precipitating/autoaggregating proteins caused inner medullary/papillary cast formation and ARF. Conclusion: normal parenchymal tissues contain proteins which can undergo glomerular filtration and which can spontaneously aggregate under conditions which exist in the distal nephron. If released into the circulation, or if shed from tubular cells into lumina after nephrotoxic or ischemic renal injury, they could help to induce intratubular obstruction and ARF.     

A Rat Model of Progressive Chronic Renal Failure Produced by Microembolism

We report a new model of chronic progressive renal failure in rats, produced by a single injection of microspheres (20 to 30 micrometer in diameter) into the left renal artery after right nephrectomy. Significant proteinuria appeared after 4 weeks, followed by hypoalbuminemia and hypercholesterolemia, in rats that received approximately 5 x 10(5) microspheres (0.8 mg). Renal function partially recovered by 4 weeks after nephrectomy and injection from postoperative dysfunction, but deteriorated again 12 weeks after operation. In the early stage, histologic examination showed tubules with cuff-like thickening of basement membranes scattered among apparently intact tubules. Many epithelial cells in the atrophic tubuli were immunoreactive for proliferating cell nuclear antigen (PCNA). Dilated tubules became apparent several weeks after development of tubular atrophy, most likely representing distal tubules. Dilated tubuli were mostly negative for the proliferation marker. These results showed similarity to findings in human chronic renal failure and strongly suggested that tubular atrophy and dilation in chronic tubulointerstitial lesions differ in pathogenesis. This new model of renal failure induced by microembolism should be useful for studying the interaction between normal and diseased tissue elements in histologically heterogenous lesions as well as the pathogenesis of interstitial fibrosis in disturbance of microcirculation.     

Tubular dilatation in the repair process of ischaemic tubular necrosis

To elucidate the mechanisms of renal tubular dilatation in acute tubular necrosis (ATN), morphological findings after 60 min ischaemia were studied in rats. The characteristics of the tubular basement membrane (BM) were also examined. A morphometric analysis of cell proliferation, epithelial cellularity and the circumference of damaged tubules was performed. The ischaemic injury resulted in widespread necrosis of renal tubules at day 1, and the BM of damaged tubules appeared thin. The intensity of the immunohistochemical staining for BM components decreased. The epithelial cell proliferation was particularly active in the early phase. Dilatation of the damaged tubules began at day 2, and the degree of dilatation increased up to day 6. Regenerative epithelial hyperplasia occurred and abnormalities of tubular BM were seen. Epithelial hyperplasia and dilatation of damaged tubules was most prominent at day 6 and the tubular BM was thickened by newly produced BM components. Tubular obstruction was not seen and tubules returned to normal size by day 28. Epithelial hyperplasia and abnormalities of tubular BM disappeared progressively. Regenerative tubular epithelial hyperplasia and abnormalities of tubular BM may play an important role in pathogenesis of tubular dilatation in ATN, and tubular dilatation is not due to tubular obstruction.     

Partial protection by chlorpromazine in mercuric chloride-induced acute renal failure in rats

Previous studies have demonstrated that the anesthetic amine, chlorpromazine hydrochloride (CPZ), prevents cell necrosis in experimentally induced ischemic liver and heart disease and decreases the extent of galactosamine-induced cell death in the liver. The present model was designed to determine whether CPZ exerts a similar beneficial effect in kidney in a nephrotoxic model of acute renal failure in rats induced by the administration of mercuric chloride (2 mg/kg of body weight). The functional and structural changes in the kidney were evaluated and quantitated in animals pretreated with CPZ (40 mg/kg of body weight) or saline and then subjected to nephrotoxic injury. Compared to controls, the glomerular filtration rate was significantly lower (p less than 0.001) in saline- and CPZ-pretreated rats receiving mercuric chloride. Twenty-four hours after mercuric chloride administration the glomerular filtration rate was 446 +/- 38 microl/minute/gm of kidney weight, the fractional sodium excretion was 0.4 +/- 0.2%, and the urinary osmolality was 1440 +/- 193 mOsmoles/kg of H2O in the CPZ-treated animals compared to 26 +/- 18 microl/minute/gm of kidney weight (p less than 0.001), 10.1 +/- 9.8% (p less than 0.025), and 353 +/- 28 mOsmoles/kg of H2O (p less than 0.005), respectively, in the animals receiving mercuric chloride alone. The percentage of proximal tubule cell necrosis was 26.5 +/- 8.9% in the CPZ-pretreated group compared to 88.1 +/- 3.6% in the untreated group (p less than 0.001). Metabolic cage studies were performed to follow the time course of this model for 48, 72, and 96 hours after mercury injection. The serum creatinine values and fractional sodium excretions were significantly less in animals receiving CPZ compared to the untreated group at all time intervals examined. The serum urea nitrogen concentration and glomerular filtration rate were similar for the two groups after 48 hours, but the serum urea nitrogen level was significantly lower and the glomerular filtration rate higher after 72 and 96 hours in the animals pretreated with CPZ. In agreement with these findings were observations that animals pretreated with CPZ had significantly fewer necrotic cells 48 and 72 hours after mercury administration, and tubular regeneration appeared to be markedly accelerated. These results suggest that pretreatment with CPZ markedly lessens the degree of structural and functional impairment seen in mercuric chloride-induced acute renal failure in rats and increases the rate of recovery.     

Intra- and extrarenal vascular changes in the acute renal failure of the rat caused by high-dose folic acid injection

Summary Male Wistar rats were investigated 9, 24 and 48 h and 4 and 8 days after a single s.c. injection of 500 mg folic acid (FA)/kg b.wt. dissolved in 0.3 M NaHCO₃. Temporary acute renal failure (ARF) developed after the injection. In the early stage of ARF most renal tubules appeared to be obstructed mainly by intratubular FA-precipitates. Necrosis of tubular epithelium developed at the same time. Its maximum extent was reached 48 h post-injection, particularly in the partes rectae of the proximal tubules. By this time the FA-precipitates had already diminished and were predominantly localized in the ascending thick limb of Henle's loop. Signs of intrarenal vasomotor changes and structural lesions of the vascular wall were also found. The most impressive finding was the development of fibrinoid medial lesions, mostly in the arcuate and interlobar arteries. The smooth muscle cells (SMC) of these generally dilated vascular segments appeared to be edematous and had imbibed blood plasma material, some had become necrotic. In many of these damaged cells intracellular fibrin (or fibrinogen) precipitates were seen. Subendothelial fibrin deposits were not detected. The vascular lesions were patchy and irregularly scattered throughout the kidneys but were also found in the pancreas, mesentery, heart, occasionally in the brain, and, in one rat, also in the liver. They occurred as early as 9 h post-injection but reached their greatest renal and extrarenal extent 48 h post-injection when azotemia, electrolyte disturbances and tubular damage were likewise at a maximum. Systemic arterial blood pressure was not elevated. The fibrinoid lesions were decreased 4 days post-injection and had completely disappeared (with one exception) 8 days post-injection. Residual damage and reactive changes, however, seemed to persist for some time. The regression of the vascular lesions was accompanied by regeneration of the tubular epithelium and marked improvement of renal function. FA-precipitation, tubular necrosis, vascular lesions and renal insufficiency were largely prevented or at least diminished by further alkalinization of the injection solution (using 1 M NaHCO₃ as solvent). It is concluded that the intratubular precipitation of FA in the main experiment resulted in functional tubular obstruction which induced considerable vasomotor changes, and thereby vascular lesions and circulatory disturbances — probably independent from the juxtaglomerular apparatus. The circulatory disturbances might be of special importance in the maintenance of FA-induced ARF. A temporary impairment of renal autoregulation might be considered since this autoregulation depends on the functional integrity of the renal vessels.Dr. Dieker is senior nephrologist at the Kreiskrankenhaus Siegen, Haus Hüttental     

Effects of lysine and other amino acids on kidney structure and function in the rat.

Lysine is a major constituent of amino acid parenteral nutrition solutions which have recently been shown to increase the severity of various types of acute renal failure in the rat. In previous studies the authors have shown that high-dose lysine alone is capable of causing acute renal failure. However, it has remained unclear what the morphologic expression of this type of acute renal failure is in the maintenance phase of the syndrome, whether other amino acids produce a similar lesion, and whether lysine in lower doses also produces acute renal failure. In the present study the authors show that lysine, when given in a dose of 600 mg/rat over 4 hours, produced persisting acute renal failure which at 48 hours was characterized morphologically by a picture similar to that in human "acute tubular necrosis"--little overt tubular necrosis, but a focal loss of individual tubular cells with regenerative changes and mitotic figures. Extensive hyaline cast formation was seen, particularly in the thin limbs of the loops of Henle, and these thin limb casts were shown to contain Tamm-Horsfall protein. Equivalent doses of glycine, arginine, and glutamic acid and lower doses of lysine produced no significant renal morphologic or functional changes.     

Effects of mannitol on the postischemic kidney. Biochemical, functional, and morphologic assessments

To determine the effects of mannitol on the postischemic kidney rats were subjected to 25 minutes of renal artery occlusion and immediately after vascular clamp release they received a 2-ml intravenous mannitol bolus (20%). Equimolar urea-injected rats and sham-injected rats served as controls. Postischemic renal blood flow, tubular metabolic work (renal O2 consumption), adenine nucleotide pools, renal oxidant stress (tissue glutathione, malondialdehyde levels), and tubular cell/mitochondrial swelling (histomorphometry) were assessed at variable times during the early vascular reflow period (15 to 60 minutes). The severity of acute renal failure was determined by serial blood urea nitrogen and serum creatinine studies (24, 48 hours), and by renal histology (48 hours). Mannitol increased postischemic renal blood flow (2-fold), renal O2 consumptions (3-fold), and urine flow compared to urea-injected and sham-injected controls. Postischemic glutathione levels were equally depressed (reduced 33%) in all three treatment groups. Malondialdehyde did not rise. Mannitol significantly lowered total adenine nucleotide content without changing ATP at 15 minutes post renal artery occlusion. At 60 minutes post renal artery occlusion, mannitol- and urea-treated groups had comparable ATP levels, 25% higher than the noninjected controls. Mannitol and urea induced comparable decrements in proximal tubular cell swelling, returning cell volumes to normal values. However, mitochondrial swelling was unabated. Mannitol and urea caused significant and nearly identical degrees of functional and morphologic amelioration of renal injury. Conclusions: Mannitol administered after renal ischemia ameliorates both functional and morphologic aspects of acute tubular injury despite dramatically increasing tubular aerobic work. This protection appears not to be due to early postischemic improvements in adenine nucleotide content, to increased renal blood flow, to increased urine flow, or to a lessening of oxidant stress. The data are consistent with the view that protection results from acute hypertonic solute loading which either directly or indirectly decreases tubular cell but not mitochondrial swelling.     

Vimentin metaplasia in renal cortical tubules of preneoplastic, neoplastic, aging, and regenerative lesions of rats and humans.

Vimentin expression was studied immunohistochemically in renal cortical tubules of untreated male rats of various ages, rats exposed to toxins (barbital sodium, folic acid) and carcinogens (streptozotocin, N-bis(2-hydroxypropyl)nitrosamine, barbital sodium, and in humans of various ages with or without renal epithelial tumors. Fetal, neonatal, and young adult rats did not express vimentin in renal cortical tubules. Regenerative renal tubular lesions from rats with aging nephropathy and from rats with toxic nephropathy both expressed vimentin. Mitogenic lesions induced by folic acid at 24 hours, however, were not immunoreactive for vimentin. Carcinogen-induced preneoplastic renal cortical tubular lesions in rats were most often focally immunoreactive whereas strong vimentin expression was found in almost all induced renal tumors. In kidneys of three children (younger than 2 years of age), vimentin was not found in renal cortical tubular cells except in rare individual cells in one case. Vimentin was abundant in basophilic regenerative tubules in kidneys of aged individuals, however. Most (7/10) human renal carcinomas and latent preneoplastic or neoplastic renal tubular lesions found incidentally at autopsy (2/4) showed vimentin expression. The authors suggest that the switching to vimentin expression in phenotypically normal renal cortical tubular cells in rats and humans, which do not usually express the intermediate filament protein vimentin, should be considered vimentin metaplasia. Vimentin expression is dissociated from increased cell proliferation in hyperplastic and neoplastic lesions, however. Instead the degree of dedifferentiation of the tubule cells and changes in phenotype were associated with vimentin expression.     

A further family with congenital renal proximal tubular dysgenesis.

A new syndrome of oligohydramnios, Potter's syndrome, and anuric renal failure leading to stillbirth or neonatal death from respiratory failure has recently been described. Histologically, there is renal tubular dysgenesis, especially of the proximal tubules, and apparent glomerular crowding. To date, five families have been reported, in four of which there have been affected sibs and in two parental consanguinity. The disorder is, therefore, thought to be inherited in an autosomal recessive manner.