Protection from the nephrotoxicity of contrast dye.

Previous studies have reported a 4%-50% incidence of acute renal failure (ARF) following the use of radiocontrast media in patients with preexisting chronic renal insufficiency. In these studies, ARF was defined as a rise of the serum creatinine of at least 1 mg/dl above baseline. Using the same criteria, we studied 214 patients undergoing various intravascular radiocontrast media procedures. Patients were infused with a specially prepared cocktail solution (NSMF) containing 1000 ml half-normal saline, 12.5 g of mannitol (M), I ampule NaHCO3, and 200 mg of furosemide (F) at 100 ml/h from one hour prior to two hours after the procedure. Urinary output was replaced with normal saline for at least 6 h after the procedure. Seven percent of the patients developed acute renal insufficiency. Only 3% of the patients had a rise in serum creatinine greater than 2 mg/dl. No patient required dialysis therapy after the procedure. There was one unrelated death caused by acute myocardial infarction postangioplasty. Risk factors for development of ARF despite cocktail administration included the presence of diabetes mellitus and angiotensin converting enzyme (ACE) inhibitor therapy. We concluded that the properly administered NSMF solution protects against radiocontrast dye induced renal failure. In select patients with chronic renal insufficiency, consideration should be given to withholding ACE inhibitor therapy for 24-48 h prior to administration of intravenous radiocontrast dye. A large controlled trial will be required to establish whether the NSMF solution offers benefit beyond that of saline hydration alone.

Foscarnet alters antidiuretic hormone-mediated transport.

Therapy with foscarnet is associated with acute renal failure. Prior studies have emphasized foscarnet's proximal tubular toxicity, but there have been isolated reports of foscarnet-induced nephrogenic diabetes insipidus. As a phosphate analog, foscarnet is a competitive inhibitor of NaPO4 cotransport. However, foscarnet's effect on antidiuretic hormone (ADH)-induced transport has not been previously investigated. We studied foscarnet's modulation of transport in the toad urinary bladder. Foscarnet at 10 microM to 10 mM did not alter basal water or urea flux. Urea transport induced by a maximal dose of ADH (24 mIU/ml) was inhibited by 0.1 to 5.0 mM foscarnet. In tissues challenged with 0.5 to 1.0 mIU of ADH per ml, 1.0 to 10 mM foscarnet increased water flow but did not alter urea flux. Foscarnet also increased water flow induced by 1.0 to 10 microM forskolin. In tissues pretreated with 10 microM naproxen, foscarnet did not alter water flow induced by 0.5 to 1.0 mIU of ADH per ml or forskolin. These results indicate that foscarnet stimulates water flow induced by 0.5 to 1.0 mIU of ADH per ml at a site proximal to that of the generation of cyclic AMP and inhibits urea flux induced by a maximal dose of ADH at a separate site. In humans, foscarnet nephrotoxicity is likely not limited to the proximal nephron, but extends to the collecting duct. Patients receiving foscarnet should be closely monitored for disorders of urinary concentration.

Dialysis-related amyloidosis manifested as masses in the buttocks.

A 40-year-old man had enlarging painful gluteal masses that developed after 17 years of hemodialysis. Pathologic examination revealed extensive deposition of beta 2-microglobulin amyloid. A bladder biopsy done during evaluation for possible transplantation also showed amyloid deposits. This constellation of findings has not been reported in a patient with beta 2-microglobulin amyloidosis. Patients with dialysis-related amyloidosis should be carefully assessed for systemic involvement. Renal transplantation may prevent further amyloid deposition and provide relief of pain.

The use of fluconazole in the management of Candida peritonitis in patients on peritoneal dialysis.

In patients receiving peritoneal dialysis, fungal peritonitis is generally impossible to eradicate with previously available therapy in the absence of catheter removal. Corbella et al. described a patient with fungal peritonitis treated with fluconazole without catheter removal. We studied this drug's effectiveness in the treatment of 5 patients with peritonitis secondary to Candida species. Patients received a loading dose of 200-400 mg fluconazole, followed by 50-200 mg fluconazole daily. Patients improved initially after therapy with fluconazole. Abdominal pain and fever abated, dialysis returns cleared, cell counts decreased, and, in four cases, cultures were sterilized. Dialysate fluconazole levels were adequate. However, despite maintenance of fluconazole therapy, all patients had recurrent peritonitis within 1 month. Complete cure did not occur unless the Tenckhoff catheter was removed. When the catheter was removed, tip cultures grew pure Candida species, and microscopic examination of catheter sections revealed abundant yeast. Although there may be continued isolated reports of successful eradication of fungal peritonitis without catheter removal, we conclude that in the vast majority of cases catheter removal is required.

Comparative effect of metals on antidiuretic hormone induced transport in toad bladder: specificity of mercuric inhibition of water channels.

We previously reported that HgCl2 inhibits water and urea flux in tissues fixed with glutaraldehyde after antidiuretic hormone (ADH) stimulation and suggested that the ADH-induced water channel may share characteristics of the red blood cell and proximal tubule water transport pathway. To determine the specificity of mercury's action, we examined the effect of numerous other metals. In tissues fixed after ADH stimulation, water flow and urea and sucrose permeabilities are maintained from mucosal bath pH 2.5 through pH 12. Several metals including Ba, Co, Fe, Sr and Zn did not alter flux. Al, Cd, La, Li, Pb and U inhibited urea permeability but not water flow. At pH 2.8, Cu inhibited water flow by 30% and urea permeability by 50%. At pH 4.9-7.4, Cu inhibited urea permeability but not water flow. At pH less than or equal to 3.0, Pt inhibited flow in ADH-pretreated tissues. The inhibitory effect was not present at pH greater than 3.0. At pH less than 3.0, Au inhibited flow by 90% in tissues fixed after pretreatment with ADH but increased the permeability of tissues fixed in the absence of ADH. Ag inhibited flow by 70% but also increased sucrose, urea, and basal permeabilities. This suggests that Ag and Au disrupt epithelial integrity. These results indicate that at physiologic pH, the ADH-induced water channel is specifically blocked by Hg but not by other metals. This specificity may reflect the presence of a large number of sulfhydryl groups in the water channel.

Mercurial reagents inhibit flow through ADH-induced water channels in toad bladder.

Mercurial reagents inhibit the water permeability of erythrocytes and proximal renal tubule. We examined the effect of two such agents on vasopressin-induced water transport across toad urinary bladder. Water flows were measured in unfixed tissues and in tissues fixed either with N-ethylmaleimide (NEM) or with glutaraldehyde. When added concurrently with 20 mU/ml vasopressin, 1 mM mucosal p-chloromercuribenzene-sulfonic acid (p-CMBS) inhibited water flow within 1 h. p-CMBS also inhibited flow in tissues that had been fixed with mucosal NEM after stimulation with vasopressin. However, p-CMBS did not affect flow in glutaraldehyde-fixed tissues. In contrast, HgCl2 inhibited water flow and urea permeability even in tissues that had been fixed with glutaraldehyde after stimulation with vasopressin. Inhibition was more pronounced when HgCl2 was added to the mucosal rather than the serosal bathing medium and was not reversed by dithiothreitol. HgCl2 did not diminish the frequency or area of luminal membrane aggregates observed by freeze-fracture electron microscopy. HgCl2 also did not affect amphotericin-induced water permeability in glutaraldehyde-treated tissues, suggesting that it did not diminish the permeability of cellular barriers to flow. Our results parallel closely those reported by other investigators for water flow across erythrocytes and proximal renal tubule and suggest that mercurial reagents can directly block the vasopressin-induced water channel. The water channel at the apical membrane of the toad bladder may prove to share structural similarity with that constantly present in erythrocytes and proximal renal tubule.

Protein synthesis inhibitors attenuate water flow in vasopressin-stimulated toad urinary bladder.

Vasopressin stimulates the introduction of aggregated particles, which may represent pathways for water flow, into the luminal membrane of toad urinary bladder. It is not known whether water transport pathways are degraded on removal from membrane or whether they are recycled. We examined the effect of the protein synthesis inhibitors cycloheximide and puromycin using repeated 30-min cycles of vasopressin followed by washout of vasopressin, all in the presence of an osmotic gradient, a protocol that maximizes aggregate turnover. "High dose" cycloheximide (200 micrograms/ml) inhibited flow immediately. "Low dose" cycloheximide (1 microgram/ml) did not affect initial flow; however, flow was inhibited by the fourth restimulation. On further rechallenge, inhibition persisted but did not increase. In the absence of vasopressin, inhibition did not develop. Despite the inhibition of flow in vasopressin-treated tissues, the cAMP-dependent protein kinase ratio (-cAMP/+cAMP), an index of in vivo cAMP effect, was elevated in cycloheximide-treated tissues, suggesting modulation at a distal site in the stimulatory cascade. Cycloheximide inhibited flow when 10 microM forskolin or 0.2 mM 8-BrcAMP was substituted for vasopressin in the fourth period; however, MIX (4 mM)-stimulated flow was enhanced by 1 microgram/ml cycloheximide but inhibited by 200 micrograms/ml cycloheximide. [14C]urea permeability was not inhibited by cycloheximide. Puromycin (0.5 mM) also inhibited water flow by the fourth challenge with vasopressin. The data suggest that protein synthesis inhibitors attenuate flow at a site that is distal to cAMP-dependent protein kinase.(ABSTRACT TRUNCATED AT 250 WORDS)

Cholera toxin enhances adenylate cyclase-dependent transport in toad urinary bladder.

Cholera toxin (CT) irreversibly ADP-ribosylates and activates the nucleotide-stimulatory (Ns) subunit of adenylate cyclase in many tissues, thereby eliciting cyclase-dependent functions. Although earlier studies performed at room temperature could not demonstrate CT-stimulated water transport in toad urinary bladder, subsequent work in other tissues has emphasized the need for incubation at 35-37 degrees C to effect ribosylation and the subsequent physiological effects. We found that incubating tissues with amphibian culture media, rather than Ringer solution, maintained tissue viability at this higher temperature and permitted prolonged incubation with CT. At 37 degrees C, in the presence of 0.1 mM phosphodiesterase inhibitor (1-methyl-3-isobutylxanthine, MIX), 0.2-200 nM mucosal CT caused a dose-dependent but submaximal enhancement of water flux and urea transport. Elimination of MIX from the bath diminished subsequent CT-induced stimulation, supporting a role for adenosine 3',5'-cyclic monophosphate (cAMP) as mediator of the CT effect. The increased water flow was stable for greater than 1 h after removal of CT from the bath, consistent with irreversible stimulation of the cyclase. Mucosal CT stimulated transport to a greater degree than serosal CT, paralleling the pattern seen in the intestine, which is compatible with passage of the toxin's a subunit across the cell to the serosal membrane cyclase. Exposure of the tissue's mucosal surface to GM1 ganglioside, (the natural receptor for the CT b subunit) yielded maximal stimulation of water flow and near-maximal urea transport, presumably by increasing CT's binding to the cell membrane.(ABSTRACT TRUNCATED AT 250 WORDS)