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Biomedical subjects

L C Racusen

Publications and source records attributed to L C Racusen.

At least 55 records · Page 3Linked to original sources
PubMed1992

Acute tubular necrosis associated with Lowe's syndrome: possible role of rhabdomyolysis.

The oculo-cerebral-renal syndrome of Lowe is an X-linked recessive disorder characterized by severe mental retardation, congenital cataracts, renal tubular dysfunction, growth retardation, hypotonia, glaucoma, and rickets. Recently, it has been found that serum concentrations of the muscle enzymes are elevated, providing evidence that there is primary muscle involvement in this disorder. The renal functional abnormalities that occur have also been further delineated. Renal tubular dysfunction presents within the first year of life, followed by a serum creatinine level that increases with age. Renal failure generally occurs in the fourth decade of life. We report two patients with Lowe's syndrome who presented with new onset of acute renal failure (ARF). Workup of their ARF established the diagnosis of acute tubular necrosis with evidence of rhabdomyolysis in one case. These patients were treated aggressively with dialysis and had subsequent recovery of renal function to their baseline state. We suggest that patients with Lowe's syndrome who present with an acute change in their renal function should be treated early with vigorous hydration therapy. If dialysis is indicated, it should be initiated. Furthermore, these patients should be promptly evaluated for evidence of rhabdomyolysis with alkalinization of the urine if possible.

Biopsy↗
PubMed1991

Culture of renal tubular cells from the urine of patients with nephropathic cystinosis.

Nephropathic cystinosis represents a prototype for lysosomal storage diseases and is the most common cause of renal tubular Fanconi's syndrome. Mechanisms of the tubular transport defects in this disease have not been defined, however, in part because the cells readily cultured from affected patients, leukocytes and fibroblasts, do not express epithelial transport functions. Except for a single autopsy report, renal tubular cells from these patients have not been studied in vitro. In these studies, noninvasive harvesting and culture of renal tubular cells from the urine of patients with cystinosis is described. Cultures of renal tubular cells could be established from over 50% of the isolates which contained viable cells and which remained uncontaminated in vitro. Cells had an epithelial morphology in culture, and the majority of cultured cells expressed proximal tubular brush border marker enzyme. Cultured cells also expressed the storage defect in vitro, containing cystine levels up to 100 times those of normal cells. Cultured cells could be depleted of cystine by using the thiol cysteamine. This in vitro model system should be very useful for studying the mechanisms of renal tubular transport defects in this disease.

Cells, Cultured↗
PubMed1991

Dissociation of tubular cell detachment and tubular cell death in clinical and experimental "acute tubular necrosis".

"Acute tubular necrosis" in humans is often characterized histologically by tubular cell loss and nonreplacement rather than by frank cellular necrosis. It has been assumed that tubular cells detach from the tubular basement membrane after the occurrence of irreversible cell injury and/or cell death. We examined voided urine from patients with native kidney and transplant kidney "acute tubular necrosis" and found significant tubular cell shedding with up to 100% viability of voided tubular cells, as determined by exclusion of trypan blue. Histochemical stains for the brush border enzyme gamma-glutamyl transpeptidase and electron microscopy of cell isolates demonstrated that 30 to 100% of the voided cells were of proximal tubule origin. Moreover, epithelial cell cultures were readily established from noncontaminated voided specimens, and more than 80% of the cells in monolayers expressed gamma-glutamyl transpeptidase activity in vitro. Electron microscopy of cell monolayers confirmed proximal tubular differentiation in the majority of cells in the monolayer, with the remainder having an appearance more consistent with distal origin. In rabbit models of acute ischemic (pedicle clamp) and toxic (HgCl2 and glycerol-induced) injury, tubular cell shedding was also significant, with a mean of 25 to 30% of the voided cells viable. Epithelial cells were successfully cultured and passed from animals with ischemic renal injury. In vitro studies were carried out in cultured human proximal tubular cells to assess suitability of this system for more direct study of the phenomenon of cell detachment in response to injury. We found significant changes in cell shape in response to exposure to anoxia and HgCl2 in these cultures, with extensive cell rounding and retraction at times when cell viability remained high. This in vitro system could prove useful for defining mechanisms of renal tubular cell detachment in response to injury and for examining potential interventions to prevent epithelial disruption and loss of functional integrity. These strategies may ultimately have clinical relevance in patients with "acute tubular necrosis".

Acute Kidney Injury↗
PubMed1991

Structural correlates of renal electrolyte alterations in acute renal failure.

In this review, structural and ultrastructural alterations in the kidney in acute renal failure are described and illustrated in some detail. Morphologic findings in clinical and experimental acute renal failure of the type produced by ischemia and some nephrotoxins, so-called 'acute tubular necrosis' are compared and discrepancies between findings in clinical specimens and experimental models noted and discussed. Since perturbations in intrarenal electrolyte species almost surely play a major pathogenic role in renal injury and dysfunction, correlations between altered intrarenal electrolyte transport and abnormal cellular ion concentrations, and morphologic alterations are emphasized in this review.

Acute Kidney Injury↗
PubMed1991

Ideas in pathology. Exfoliation of renal tubular cells.

"Acute tubular necrosis" is characterized histologically by tubular cell loss and nonreplacement. There is new evidence that tubular cells may be shed from the tubular basement membrane while still viable. This phenomenon is described in both clinical and experimental acute renal failure. Exfoliation of tubular cells may contribute importantly to the pathogenesis of acute renal failure due to tubular cell injury.

Acute Kidney Injury↗
PubMed1990

Cyclosporine lowers seizure threshold in an experimental model of electroshock-induced seizures in Munich-Wistar rats.

We have developed a model of cyclosporin A (CsA) central nervous system toxicity in the Munich-Wistar rat in which CsA, 20 mg/kg/day i.p., produces significant EEG abnormalities and mortality. In the present study we used cohorts of Munich-Wistar rats to assess effects of CsA on the threshold for tonic-clonic electroshock-induced seizures. Rat cohorts were begun on cremephore, CsA-10 mg/kg/day, or CsA-20 mg/kg/day. On day 7 and day 14 of the dosing protocol, cohorts of animals were exposed to maximal electroshock (MES) using a minimal staircase method within each cohort. Multiple logistic regression models were used to determine differences between groups on the relative odds of producing a MES-induced seizure while controlling for other variables. Seizure threshold was significantly affected by shock amperage and body weight, but not by SUN, creatinine, bilirubin, sodium, potassium, weight loss or day the shock was delivered. The odds ratios of seizure induction in the CsA-treated groups versus placebo group were 1.91 for CsA-10 mg/kg/day and 3.63 for CsA 20-mg/kg/d, both statistically significant. These results suggest that cyclosporine lowers seizure threshold and probably increases susceptibility to seizures, the etiology of which may be multifactorial clinically.

Animals↗
PubMed1990

Changes in adrenal oxygen consumption during catecholamine secretion in anesthetized dogs.

Prior attempts to study adrenal medullary O2 metabolism during catecholamine secretion have been unsuccessful because venous blood from medulla mixes with venous blood from the much larger cortex. To circumvent this problem, eight adult mongrel dogs were pretreated for 5-6 wk with the adrenocorticolytic agent 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane (o,p'-DDD). Prednisolone (5 mg/day) and fludrocortisone (0.1 mg.10 kg-1.day-1) were administered orally to prevent adrenocortical insufficiency. Animals were then anesthetized with pentobarbital sodium and subjected to splanchnic nerve stimulation (NS) at 20 and 4 Hz to elicit catecholamine secretion. NS at 20 Hz increased epinephrine secretion from 1.6 +/- 0.7 to 1,780 +/- 762 ng.min-1.g medulla-1 but had no effect on medullary O2 consumption. Medullary blood flow (MQ) increased from 216 +/- 63 to 1,522 +/- 182 ml.min-1.100 g-1, and O2 extraction decreased from 2.7 +/- 0.7 to 0.8 +/- 0.2%. NS at 4 Hz increased epinephrine secretion from 3.1 +/- 1.4 to 76 +/- 17 ng.min-1.g medulla-1 and MQ from 226 +/- 66 to 649 +/- 122 ml.min-1.100 g-1 but had no effect on adrenal O2 consumption or extraction. Cortical blood flow was 342 +/- 98 ml.min-1.100 g-1 at baseline and was unaffected by NS. Gross weight of cortex was reduced by 80% in o,p'-DDD-treated animals, and histological examination of glands from three animals showed only rare islands of glomerulosa cells remaining. These data suggest that increases in MQ during NS do not occur in response to changes in O2 consumption.

Adrenal Glands↗
PubMed1989

Primary acute renal failure ("acute tubular necrosis") in the transplanted kidney: morphology and pathogenesis.

"Acute tubular necrosis" (ATN) in the transplanted kidney, when properly differentiated from other causes of acute renal failure, appears to be a relatively benign condition. It has been widely assumed to be pathologically identical to ATN in the native kidney, but its histopathologic features have not been studied in detail. Because immunosuppressive therapy with cyclosporine adds an additional layer of complexity to the morphologic changes observed, in the present study we have confined our observations to patients immunosuppressed with steroids and azathioprine. Thirteen renal allograft biopsies from patients with ATN and 5 biopsies from patients with normal allograft function were compared with the previously obtained series of 57 native kidney ATN biopsies and 20 control biopsies. Both qualitative and quantitative differences between transplant and native kidney ATN were found. Compared with native kidney ATN, transplant ATN showed significantly less thinning and absence of proximal tubular brush border and less variation in size and shape of cells in individual tubular cross-sections. There were also significantly fewer casts and less dilatation of Bowman's space and a significantly greater number of polarizable crystals presumed to be oxalate in transplant ATN. In native kidney ATN the tubular injury sites were mostly characterized by desquamation of individual epithelial cells leaving areas of bare basement membrane (the "non-replacement" phenomenon). In transplant ATN, sites of tubular injury, although rare and affecting only short tubular segments, were characterized by the actual presence of identifiable necrotic tubular cells, a finding seldom seen in native kidney ATN. There also was a greater interstitial infiltrate of mononuclear inflammatory cells in transplant ATN compared to native kidney ATN. Electron microscopic studies of 9 transplant ATN biopsies showed a mild reduction in proximal tubular brush border compared with controls but this alteration was significantly less than that observed in native kidney ATN. There was no significant alteration in proximal or distal basolateral infoldings and this contrasted sharply with the marked reduction in basolateral infoldings of the plasma membrane observed in native kidney ATN. Disintegrated necrotic cells were found by electron microscopy in transplant ATN whereas these were not observed in native kidney ATN. There were significantly more cells with apoptosis (shrinkage necrosis) in transplant ATN than in native kidney ATN. There were significantly more cells with apoptosis (shrinkage necrosis) in transplant ATN than in native kidney ATN. On the other hand, there were significantly greater numbers of "non-replacement" sites in the distal tubules in native kidney ATN compared to transplant ATN.(ABSTRACT TRUNCATED AT 400 WORDS)

Actins↗
PubMed1988

Ultrastructural investigation of renal biopsies: a discussion of artifacts and special methodology.

The aim of this presentation is to draw attention to the problems inherent in evaluating the ultrastructure of percutaneous renal biopsies and to discuss some of the special techniques which are useful in this area. It is important to realize that the ultrastructure as it appears in this kind of material does not necessarily reflect conditions in vivo. Comparison with suitable reference material may, however, permit reliable conclusions in terms of pathological diagnosis and pathogenesis. It is advocated that purely qualitative methods, which until now have predominated in ultrastructure work with renal biopsies, be replaced by morphometry and semiquantitative methods when it is possible and practical to do so in any research situation.

Biopsy↗
PubMed1987

Early renal pathophysiology in an acute model of cyclosporine nephrotoxicity in rats.

We have recently described a rat model of acute cyclosporine nephrotoxicity characterized by rapid onset of reproducible mild to moderate renal failure. In the present studies, we have examined early pathophysiologic events and morphologic changes in this model. Following acute intraperitoneal administration of 60 mg/kg of parenteral cyclosporine, renal blood flow (RBF) fell 24% from baseline. Intraperitoneal administration of an oral cyclosporine preparation (60 mg/kg) also reduced RBF (25%), as did administration of an equivalent volume of parenteral cremophore (23%). Renal vascular resistance (RVR) increased significantly in all these groups. In contrast, intraperitoneal administration of mineral oil or olive oil oral vehicle produced no significant change in RBF (4% fall from baseline), and RVR actually decreased in these control animals. Following 2 daily doses of these agents, RBF remained significantly lower in rats given parenteral cyclosporine (5.10 mL/min vs 8.54 mL/min in cremophore rats and 7.28 mL/min in oil control rats) and renal vascular resistance remained high. Systemic blood pressure was also significantly lower in cyclosporine-treated rats at 2 days, and GFR was depressed. Morphologic studies revealed a correlation at 2 days between tubular vacuolation and renal blood flow and renal vascular resistance in cyclosporine-treated rats.

Acute Kidney Injury↗
PubMed1986

Renal blood flow, glomerular filtration rate, and renal morphology in cyclosporine-induced acute renal failure in Munich-Wistar rats.

The mechanism of clinical cyclosporine nephrotoxicity has remained unclear. We have established an animal model of cyclosporine-induced acute renal failure in the male Munich-Wistar rat by giving four daily doses of parenteral cyclosporine 60 mg/kg intraperitoneally (IP). In this model, 20 minutes of bilateral renal ischemia preceding the first cyclosporine dose did not significantly increase the renal failure, but did increase mortality (65% v 17%), which was due in part to the CNS effect of cyclosporine. Pair-fed and pair-watered vehicle and saline controls were used. The renal morphologic changes induced by the castor oil vehicle of the commercial parenteral cyclosporine solution were quantitatively similar to those induced by cyclosporine, although the severity of the changes by light microscopy was considerably less in the vehicle-treated groups. However, by electron microscopy, pale lipid vacuoles were seen only in the cyclosporine-treated groups, whereas dense alterations in lysosomes and dilated endoplasmic reticulum were also seen in other groups. Renal blood flow determined by electromagnetic flow probe showed a significant decline during 2 hours after a single IP injection of cyclosporine (6.6 +/- 0.4 to 5.0 +/- 0.6 mL/min). A similar decline was seen following injection of the castor oil vehicle of the commercial cyclosporine parenteral preparation (6.6 +/- 0.5 to 5.1 +/- 0.5 mL/min), but not after an injection of a similar volume of mineral oil (6.7 +/- 0.3 to 6.3 +/- 0.2 mL/min). These studies suggest that brief renal ischemia does not increase cyclosporine nephrotoxicity significantly in this rat model.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1986

Nephrotoxic tubular and interstitial lesions: morphology and classification.

Nephrotoxic renal injury, and especially drug nephrotoxicity is now a common cause of acute renal failure. The most common patterns of renal injury produced by nephrotoxins, tubular damage, and interstitial nephritis, are discussed here. Toxic agents which are primarily tubular toxins include certain antibiotics, cisplatinum, anesthetics, and radiocontrast agents. In tubules injured by toxins, alterations range from subtle ultrastructural abnormalities to extensive tubular necrosis. Mechanisms of tubular injury include direct tubular cell toxicity, and alterations in intrarenal blood flow producing secondary tubular damage. Other commonly used therapeutic agents, including the penicillins, other antibiotics, and non-steroidal anti-inflammatory agents, produce renal dysfunction by inducing interstitial nephritis. Long-term analgesic abuse is associated with a particularly striking interstitial damage with frank papillary necrosis. Criteria for differentiating primary tubular injury with inflammation and primary interstitial nephritis with tubular injury are discussed. Individual commonly-used therapeutic agents are considered in some detail, with discussion of both clinical and morphological aspects of drug nephrotoxicity.

Acute Kidney Injury↗
PubMed1986

Acute renal failure produced by combining cyclosporine and brief renal ischemia in the Munich Wistar rat.

To evaluate the combined effects of a brief ischemic insult and cyclosporine, four groups of male Munich Wistar rats were given: a) parenteral cyclosporine (60 mg/kg i.p.) for 4 days following 20 minutes of bilateral renal ischemia, b) the castor oil cyclosporine vehicle in a comparable volume and the same ischemic insult, c) saline in the same volume and ischemia, or d) saline and sham surgery. The cyclosporine animals ate and drank poorly, and therefore the other groups were pair-fed and watered with them. The cyclosporine-ischemia group developed significant renal failure. The other groups exhibited only a mild rise in blood urea nitrogen. Tubular vacuolization was a prominent feature in the cyclosporine and vehicle groups, but not in the saline groups. Vacuolization was correlated with severity of renal impairment. Lipid stains showed that many of the vacuoles contained lipid. Eosinophilic cytoplasmic inclusions were seen only in the cyclosporine or vehicle- (castor oil) treated animals. These findings emphasize the probable functional importance of tubular lesions in cyclosporine-induced acute renal failure, and suggest that the castor oil vehicle of parenteral cyclosporine may have renal effects of its own.

Acute Kidney Injury↗