Medullary Atrophy Research Articles

Angiotensin type 1 receptor (AT1) double null mice (DKO) exhibit augmented renal renin and neuronal nitric oxide synthase (nNOS) protein expression

DKO mice display reduced blood pressure, renal vascular thickening, medullary atrophy, and tubulointerstitial injury. Juxtamedullary efferent arterioles of AT1A−/− mice, and afferent arterioles of DKO mice exhibit significantly larger baseline vessel diameters compared to wild type (WT). We propose that an imbalance of AngII and nitric oxide signaling produces renal microvascular dilation. Kidneys were harvested from WT, AT1B−/−, AT1A−/−, and DKO mice, fixed, sectioned, and immunostained for renin and nNOS protein localization. The percent of glomeruli positive for JGA renin and the density of JGA renin immunostaining were significantly higher in AT1A−/− and DKO than WT (60±1%, n=3; 56±9%, n=6; 22±3%, n=6 and 15±9; 15±7; 1±0 fold, respectively). Renin expression of AT1B−/− was not different from WT. AT1A−/− and DKO mice displayed significant recruitment of renin protein expression along the afferent arteriole and interlobular artery (15±7%, 7±3 vessels/kidney n=3; 9±3%, 3±1 vessels/kidney n=6, respectively) compared to WT. WT and AT1B−/− kidneys displayed only JGA renin. Percent of glomeruli with positive MD nNOS immunostaining was not different for WT, AT1A−/−, AT1B−/− and DKO kidneys (46±2, 33±4, 34±, 38±5%), however, AT1A−/− kidneys demonstrated a significant increase in the percent of glomeruli with nNOS positive JGA (19±5 WT, 52±3 AT1A−/−, 8±3 AT1B−/−, 33±10 DKO), afferent arterioles, and interlobular arteries. Density of MD nNOS immunostaining was 7.0±2.6 fold in DKO compared to WT. Density of vascular nNOS immunostaining was 20±7 fold in AT1A−/− relative to WT. Loss of AT1 receptor signaling is coupled to enhanced nNOS protein expression in renal tubular and microvascular structures and may lead to increases in nitric oxide generation. NIDDK-62003 & P20RR018766

Dynamic Contrast-Enhanced MR Urography in the Evaluation of Pediatric Hydronephrosis: Part 2, Anatomic and Functional Assessment of Uteropelvic Junction Obstruction

The purpose of our study was to retrospectively review our experience using MR urography in the diagnosis of ureteropelvic junction (UPJ) obstruction in children. Sixty-one studies were performed in 50 children with hydronephrosis but without hydroureter. Anatomic criteria assessed included degree of hydronephrosis, morphology of the renal pelvis, atrophy of medulla, swirling contrast material, fluid levels, and the presence of fetal folds and crossing vessels. Functional criteria included renal transit time, differential renal function, and time-intensity curves when available. Thirty-one kidneys were classified as obstructed, 15 as equivocal, and 15 as nonobstructed. Obstructed systems had more marked hydronephrosis, more extensive medullary atrophy, more fluid levels, and more swirling contrast material. Fetal folds were seen in only the equivocal and nonobstructed groups. Crossing vessels were seen in all groups. Obstructed systems also showed greater functional derangement, decreased split renal function, and abnormal time-intensity curves. MR urography provides both excellent anatomic and functional information in children with UPJ obstruction in a single test that does not use ionizing radiation. MR urography may lead to greater understanding of the pathophysiology of UPJ obstruction.

Thymus atrophy in the nonhuman primate by FK506: An immunohistochemical study

F K 506 is a potent anti-lymphocytic and immunosuppressive agent with a totally distinct structure from the cyclic peptide cyclosporin A (CyA), but with the same selective, inhibitory action on CD4+ lymphocyte activation and cytokine gene expression.‘” FIG06 suppresses both humoral and cell-mediated immunity and is highly effective in prolonging organ allograft survival in a variety of species, including rodents, non-human primates, and man at considerably lower doses than CyA.6-“’ Concerning the adverse effects of immunosuppressive drugs on the thymus, the capacity of CyA to alter the thymic microenvironment in normal or allografted animals is well characterized.” There is evidence that the drug interferes with thymocyte differentiation and maturation both in viva” and in vitro.‘“,‘4 The effects of FKS06 on the thymus have been studied in rats and mice. Thymic medullary atrophy has been demonstrated after short term exposure (6 to 14 days) to the drug.“-*’ There are substantial interspecies differences with regard to the effects of FK.506.831” The discrepant findings concerning the immunosuppressive potency and toxicity of the drug in non-human primates indicated the need for further non-human primate studies. 20-22 Therefore, we investigated the immunotoxic effects of FK506 on the thymic environment and T lymphocyte development in young adult Cynomolgus monkeys.

MRI in chronic progressive radiation myelopathy.

Our goal was to assess medullary lesions in patients suffering from chronic progressive radiation myelopathy (CPRM) using MRI. In a group of 10 patients suffering from CPRM, MRI findings (11 examinations), radiation protocols, and patient prognoses were reviewed. A cord enlargement was demonstrated in five cases, whereas four cases presented with medullary atrophy. As demonstrated by MRI, radiation-induced medullary lesions progressed toward cord atrophy in one patient. When MRI and/or comparison myelogram were performed within 8 months following the onset of the myelopathy, a cord enlargement was usually encountered. When the patient was evaluated > 8 months after the first neurological symptoms, a cord atrophy was always demonstrated. Medullary lesions extended beyond the boundaries of the radiation field in 67% of the cases. However, with the exception of one case, the main focus of the cord damage was included within an irradiated cord segment. An enlarged cord was often associated with a neurologic deterioration and a fatal outcome. In patients with cord atrophy, the neurologic deficit was often static and survival rates were better. These results suggest a revision of classic criteria used for the diagnosis of CPRM. By demonstrating cord lesions, MRI helps to establish disease prognosis.

TOXICITY OF RAPAMYCIN—A COMPARATIVE AND COMBINATION STUDY WITH CYCLOSPORINE AT IMMUNOTHERAPEUTIC DOSAGE IN THE RAT

Sprague-Dawley rats were treated for 14 days with rapamycin (RAP; 1.5 mg/kg/day i.p.), cyclosporine (15 mg/kg/day by gavage), both drugs in combination, or appropriate drug vehicles. Hematological parameters and biochemical indices of renal and hepatic function were determined throughout the experimental period, at the end of which the rats were killed and tissues examined histologically. There was a significant reduction in weight gain in RAP- but not CsA-treated animals, while rats given both drugs showed a reduction in body weight over the 14-day experimental period. There were no significant alterations in absolute or differential white blood cell counts or in T or B cell numbers, except in the drug combination group, in which an absolute lymphopenia was detected on day 14. Small but significant increases in urinary flow rate (UFR) were found with either drug alone, and there was a marked (4-fold) increase in UFR in response to drug combination. Both RAP and CsA caused a small elevation in serum creatinine concentrations, but only with CsA was there a significant elevation in urinary enzyme activity and reduction in 51Cr. EDTA clearance. The drug combination exacerbated renal impairment, the extent of which was greater than the additive effect of either drug alone. Hyperbilirubinemia of similar magnitude was observed in rats receiving either CsA alone or in combination with RAP. In contrast to its effect on renal function, however, the CsA+RAP combination was without additional effect on liver function compared with the minor changes seen with either drug alone. Plasma and urinary glucose levels were elevated in all drug treatment groups and especially in animals given both drugs. RAP administration did not significantly affect whole-blood CsA concentrations, although the possibility of a pharmacokinetic interaction cannot be totally excluded. Histological studies revealed striking thymic medullary atrophy in all drug-treated animals. In addition, all rats given RAP showed focal myocardial necrosis of overall mild-moderate severity. Kidneys of RAP-treated rats appeared normal, whereas mild, focal, acute tubular necrosis was evident in all CsA-treated animals. Pancreases of all drug-treated animals were normal.

IMMUNOSUPPRESSIVE ACTIVITY, LYMPHOCYTE SUBSET ANALYSIS, AND ACUTE TOXICITY OF FK-506 IN THE RAT. A COMPARATIVE AND COMBINATION STUDY WITH CYCLOSPORINE

The immunosuppressive and toxic properties of the recently discovered macrolide antibiotic FK506 were examined in comparison and in conjunction with cyclosporine administration in the rat. Male Sprague-Dawley rats were immunized systemically with sheep erythrocytes and received, from the same time, either FK506 (1 mg/kg/day) intramuscularly or CsA (25 mg/kg/day) by gavage, or both drugs in combination. Seven days after immunization, the splenic plaque-forming cell response and circulating antibody titers were reduced greater than 90% in animals receiving either FK506 or CsA and in the drug combination group. These immunosuppressive effects of FK506 and CsA were accompanied by significant increases in the incidences of splenic OX-8+ cells and by corresponding reductions in the W3/25+:OX-8+ ratio. No further changes in T cell populations were observed in animals given both drugs. A progressive monocytosis was found in response to CsA, but not in FK506-treated rats. Increases in plasma urea were observed in FK-506 and drug-combination or CsA-treated rats on day 7, whereas creatinine levels were raised only in the FK-506 groups. Elevated bilirubin levels and alterations in liver enzyme activities were observed in CsA-treated rats by day 4, whereas FK-506 alone produced no similar effects. CsA-treated rats also exhibited elevated blood and urinary glucose levels from day 4. No biochemical evidence of additive drug toxicity was detected. The only histological abnormalities observed were thymic medullary atrophy in all drug-treated animals, together with very minor reductions in bone marrow cellularity in a proportion of those rats given FK-506. These findings show that, at the dosage selected, the powerful immunosuppressive activities of FK-506 were associated with little evidence of acute toxicity and with no indications of additive toxicity with CsA.

Enhancement of chemically induced bladder carcinoma by cyclosporin A.

The effects of cyclosporin A (CsA) on the induction of bladder carcinoma were investigated in Wistar rats using N-butyl-N (4 hydroxybutyl) nitrosamine (BBN) as a known initiator of carcinogenesis. Rats treated with 0.05% BBN + 5 mg/kg per day CsA or 0.05% BBN + 12.5 mg/kg per day CsA developed a dose-dependent (two to fourfold) enhancement of bladder tumor expansion and infiltration as compared to those treated with 0.05% BBN alone. In control rats receiving CsA at doses of 5 mg/kg per day or 12.5 mg/kg per day, no bladder carcinoma occurred. All CsA-treated groups, with or without 0.05% BBN, displayed slight or moderate medullary atrophy of the thymus. The results indicate that immunosuppression with CsA enhances the induction of bladder tumors by BBN. Furthermore, the immunosurveillance theory that effective expression of the immune response may be important in the control of tumor development was confirmed in the carcinogenesis of epithelial cell tumors.

Sequential analyses of the development of lymphoproliferative disorders in rats receiving cyclosporine.

Cyclosporine (Cys)-associated, atypical lymphoproliferation in gut-associated lymphoid tissue (GALT) was reproducibly observed in male Sprague Dawley rats by feeding a diet containing 0.015% Cys. Sequential morphological changes occurring in the lymphoid organs of the rats on a Cys diet for 8-10 weeks were examined, and these changes were correlated with those observed in electrophoretic patterns of serum proteins. Proliferative lymphoid alterations were detected in the GALT after 2 weeks of feeding, and these progressed through 8 weeks. Atypical lymphoid proliferation was also seen in lymph nodes after 8 weeks of feeding; thymuses showed marked medullary atrophy, and spleens had a diminution of their periarterial lymphoid sheaths. Elevated levels of gamma-globulin were detected after 4 weeks of Cys administration, and became more pronounced by 8 weeks. The lymphoid lesions induced in rats bear striking similarities to the post transplant lymphoproliferative lesions in patients receiving Cys and in patients with the acquired immune deficiency syndrome.