Moo Nahm Yum

Long term effect of Cis‐Diamminedichloride platinum (CDDP) on renal function and structure in man

To examine CDDP induced nephrotoxicity in patients with testicular carcinoma, we measured renal function prior to therapy and at six month intervals for twelve months in fifteen patients and twenty‐four months in seven patients. CDDP was given iv at 20 mg/M2 per day for five days at three week intervals. Eight patients received three courses, four received four courses and three received more than four courses. The mean creatinine clearance ± SD prior to treatment was 112 ± 12 ml/min. By six months, it had decreased to 68.5 ± ml/min (p < 0.01) and it remained at that level. Plasma creatinine and blood urea nitrogen increased significantly. Subjects receiving other potential nephrotoxins in addition to CDDP developed a greater decrease in creatinine clearance (p < 0.05). Proteinuria and functional tubular disturbances were not observed. Microscopic features were characterized by hydropic degeneration of the renal tubular epithelium, thickened tubular basement membranes and mild interstitial fibrosis. Electron microscopy revealed phagolysosomes filled with flocculent material. CDDP resulted in a permanent, nonspecific renal injury in our patients. Although the renal injury has remained subclinical, future courses of CDDP may lead to clinically important chronic renal failure.

Enzymuria in Gentamicin-Induced Kidney Damage

To assess their potential value as early indicators of gentamicin-induced kidney damage, lysosomal hydrolases were measured in the 24-h urines of rats receiving 30 or 60 mg of gentamicin per kg per day for 15 days. Proteinuria, urine osmolality, blood urea nitrogen, and creatinine clearance were also measured. Kidney tissue was examined by both light and electron microscopy. Beta-galactosidase, beta-n-acetyl-hexosaminidase, and alpha-fucosidase were sensitive indicators and were significantly elevated above control values by day 3 at both doses (P < 0.01). Proteinuria, urine osmolality, and tests reflecting glomerular filtration rate were later indicators of nephron damage. Changes by light microscopy were detected on day 5. Necrosis was most prominent in the proximal convoluted tubules on day 10. Electron microscopy revealed numerous cytosomes with myeloid bodies within the proximal tubular epithelium on day 5. Lysosomal enzymuria appears to be an early manifestation of gentamicin nephrotoxicity and may possibly be related to the lysosomal abnormalities seen on electron microscopy. Images

IgA nephropathy in children: significance of glomerular basement membrane deposition of IgA

Seventeen children with IgA nephropathy were grouped according to the absence (group I, n = 10) or presence (group II, n = 7) of glomerular basement membrane (GBM) deposition of IgA to determine whether GBM deposition of IgA correlated with laboratory or pathologic data at diagnosis or clinical status at follow-up. Children in group II had significantly (p less than 0.01) more proteinuria at diagnosis than children in group I. The percentage of glomeruli demonstrating crescent formation was significantly (p less than 0.05) higher in group II biopsies. Chronic changes of fibrous crescents, segmental sclerosis, global obsolescence, tubular atrophy, and interstitial fibrosis were also significantly (p less than 0.001) more common in group II biopsies. After a mean follow-up period of 2 years, all children in group II have persistent proteinuria of more than 1 g/24 h, and 3 of 5 have renal insufficiency (2 require dialysis). In contrast, 2 of 9 group I children have proteinuria exceeding 1 g/24 h, and only 1 has renal insufficiency. We conclude that, as compared to children with IgA localized to the mesangium, children with IgA nephropathy and GBM deposition of IgA have a higher urinary protein excretion at the time of diagnosis, more severe histologic alterations including a greater percentage of glomeruli demonstrating crescent formation, more chronic changes of segmental or global sclerosis, tubular atrophy, and interstitial fibrosis. Such children usually have persistent proteinuria and are more likely to develop progressive renal disease.

Comparative Nephrotoxicities of Netilmicin and Gentamicin in Rats

The relative nephrotoxicities of netilmicin (Sch 20569) and gentamicin were compared in rats at doses of 30, 60, 90, and 120 mg/kg per day for 15 days. Both drugs caused proteinuria and a decrease in urine osmolality; however, netilmicin produced significantly less changes at all doses than gentamicin. Whereas gentamicin resulted in a decline in creatinine clearance at all doses, netilmicin failed to cause a decline in creatinine clearance. Renal-cortical concentrations of antibiotic at sacrifice were similar in animals receiving either drug. Light-microscopic changes were less severe with netilmicin than gentamicin. Cytosegresomes with myeloid bodies were identified electron microscopically in the kidneys of animals receiving either netilmicin or gentamicin at all doses. Electron-microscopic manifestations were similar. The data indicate that in the rat, netilmicin is distinctly less nephrotoxic than gentamicin.

Recovery from Aminoglycoside Nephrotoxicity with Continued Drug Administration

To examine the nephrotoxicity of prolonged gentamicin administration compared to the effect obtained when a less toxic aminoglycoside is substituted during the course of treatment, we gave gentamicin (67.5 mg/kg per day) to rats for 21 days, gentamicin for 14 days followed by either netilmicin or tobramycin for 7 days, or gentamicin for 14 days followed by saline diluent. After initial tubular, necrosis, the animals recovered from renal injury whether the drug was continued or discontinued or another drug was substituted. These data are consistent with the observation that regenerating renal epithelium is resistant to continued or additional nephrotoxic insults. These findings suggest that improvement in renal function during aminoglycoside therapy cannot necessarily be attributed to the substitution of another aminoglycoside or other therapeutic interventions.

Gentamicin Gradient Patterns and Morphological Changes in Human Kidneys

The gentamicin gradient pattern was studied in ten autopsied patients who expired during gentamicin therapy. Although two of the patients had acute renal failure, none was thought to have gentamicin-related nephrotoxicity. Gentamicin concentrations in cortex significantly exceeded those in medulla or serum (p less than 0.05 and p less than 0.01, respectively). No correlation was found between the cortical concentrations and the total drug dose, the time interval between the last injection and death, or the plasma creatinine concentrations in this heterogeneous group of patients. In addition, two specimens were suitable for electron microscopy which displayed cytosegrosomes and myeloid bodies previously noted in experimental animals. We conclude that gentamicin forms a gradient pattern in human kidney similar to that described in experimental animals. Furthermore, it evokes similar morphological changes.

Nephrotoxicity of Cephalosporin-Gentamicin Combinations in Rats

To study the possibility that cephalosporins augment the nephrotoxicity of gentamicin, groups of rats were given four hourly subcutaneous doses of: gentamicin (5 mg/kg), gentamicin plus cephalothin (100 mg/kg), gentamicin plus cefazolin (20 mg/kg), gentamicin plus cefazolin (50 mg/kg), gentamicin plus cephaloridine (50 mg/kg), or saline diluent for 15 days. Periodic measurements were made of urine volume, urine osmolality, urine protein excretion and lysosomal enzymuria, as well as blood urea nitrogen, creatinine clearance, and drug concentrations in renal cortex and medulla. Tissue was examined by light and electron microscopy. Enzymuria and proteinuria increased early in the course of all treatment groups, whereas urine osmolality declined. No distinct patterns of these variables were discernable among the groups. Gentamicin alone, gentamicin plus cephalothin, and gentamicin plus cefazolin (20 mg/kg) caused the same significant fall in glomerular filtrate rate from control values by day 15 (P < 0.05). Gentamicin plus cefazolin (50 mg/kg) and gentamicin plus cephaloridine failed to cause a decline in glomerular filtration rate compared with controls (P > 0.05). Gentamicin concentrations in renal cortex were 5 to 10 times higher than those in medulla in all groups. Cephaloridine and cefazolin (50 mg/kg) also displayed a gradient pattern in renal cortex, whereas cephalothin and cefazolin (20 mg/kg) did not. Cytosegrosomes with myeloid figures were characteristic ultra-structural changes seen in all groups; however, they tended to be smaller with less numerous myeloid bodies in the groups receiving gentamicin plus cephalothin, cefazolin (50 mg/kg), or cephaloridine. Cephalosporins did not augment gentamicin toxicity. High doses of cefazolin and cephaloridine protected kidneys from gentamicin nephrotoxicity. The protection may involve intracellular drug interaction within the renal cortex. Images

Protection from Gentamicin Nephrotoxicity by Cephalothin and Carbenicillin

In rats, cephalothin exerts a protective effect upon the nephrotoxicity of gentamicin. To examine the possibility that this effect is also observed with carbenicillin, we gave the following (milligrams per kilogram) to rats daily for 14 days: gentamicin alone, 60; gentamicin plus cephalothin, 100, 500, or 1,000; gentamicin plus carbenicillin, 50, 100, 250, 500, or 1,000. A 500-mg/kg dose of cephalothin afforded significant partial protection from gentamicin nephrotoxicity, as did a 100-mg/kg dose of carbenicillin. Increasing doses of either drug failed to increase protection. The data suggest that in rats not only does carbenicillin afford some protection from gentamicin nephrotoxicity, but also that it does so at a lower dose than cephalothin. These findings may in part explain the divergent observations regarding the nephrotoxicity of cephalothin-gentamicin combination therapy in rats and humans.

Pseudolymphoma of the lung in a patient with systemic lupus erythematosus

A 47 year old woman with systemic lupus erythematosus was found to have asymptomatic pulmonary nodules. Histologically they represented benign reactive lymphoreticular hyperplasia compatible with the diagnosis of pseudolymphoma. Immunofluorescence and electron microscopy demonstrated immunoreactants and electron-dense deposits in the alveolar and vascular walls, suggesting that an immune complex mechanism may be involved in this case.

Asymptomatic IgA nephropathy associated with pulmonary hemosiderosis

A glomerular lesion identical to that of IgA nephropathy was demonstrated unexpectedly in a 17 year old boy who presented with clinical manifestations of pulmonary hemosiderosis and with no evidence of renal disease. This subclinical glomerular lesion would have remained undetected in this patient unless kidney tissue was obtained and examined by immunofluorescence or electron microscopy. It is unknown if the glomerular lesion in this case is causally related to pulmonary hemosiderosis.