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• W1979196812 abstract "The era of cyclosporine A (CSA)-based immunosuppression heralded substantial improvements in both patient and graft survival in comparison with that for conventional treatment with azathioprine and corticosteroids.1Calne RY White DJG Thiru S Evans DB McMaster P Dunn DC et al.Cyclosporin A in patients receiving renal allografts from cadaver donors.Lancet. 1978; 2: 1323-1327Abstract PubMed Scopus (830) Google Scholar Although subsequent widespread use of CSA initiated an entirely new generation of improved immunosuppression, a growing body of evidence also documented the unique side effects of CSA. Thus, the quest for optimal protection from rejection was hindered by what has proved to be important toxicity. Nephrotoxicity remains the most common and limiting side effect of CSA-based immunosuppression. In fact, before effective monitoring techniques were available, renal dysfunction was used as a marker of effective CSA dosing.2Starzl TE Klintmalm GBG Porter KA Iwatsuki S Schröter GPJ Liver transplantation with use of cyclosporin A and prednisone.N Engl J Med. 1981; 305: 266-269Crossref PubMed Scopus (374) Google Scholar In addition, several other adverse effects of CSA have been noted: hirsutism (60 to 80%), hypertension (40 to 60%), hepatotoxicity (40 to 60%), gingival hypertrophy, and neurotoxicity, especially tremors (20%).3Thiru S Pathological effects of cyclosporin A in clinical practice.in: Thomson AW Cyclosporin: Mode of Action and Clinical Applications. Kluwer Academic Publishers, Dordrecht (Netherlands)1989: 324-364Google Scholar FK-506 is a potent immunosuppressive agent currently being studied in multicenter trials for prophylaxis against and treatment of rejection in recipients of solid organ transplants. The molecular structure of FK-506 is unrelated to that of CSA, and the two drugs have different cytosolic binding sites. Both drugs inhibit T-lymphocyte activation and expression of interleukin 2; however, FK-506 accomplishes equal immunosuppression at one-hundredth the level of CSA.4Ohara K Billington R James RW Dean GA Nishiyama M Noguchi H Toxicologic evaluation of FK 506.Transplant Proc. 1990; 22: 83-86PubMed Google Scholar Although nephrotoxicity is most frequent, other side effects associated with FK-506 immunosuppression include hyperkalemia (50%), hyperglycemia (35.5%), gastrointestinal upset, and neurotoxicity (8.4%).5Fung JJ Alessiani M Abu-Elmagd K Todo S Shapiro R Tzakis A et al.Adverse effects associated with the use of FK 506.Transplant Proc. 1991; 23: 3105-3108PubMed Google Scholar In contrast to CSA, hirsutism and gingival hyperplasia have not been reported with use of FK-506, and hypertension is at least 50% less frequent. In the first study of FK-506 in humans, this agent was used as a “rescue” drug in patients who had complications and failure of CSA therapy.6Starzl TE Todo S Fung J Demetris AJ Venkataramman R Jain A FK 506 for liver, kidney, and pancreas transplantation.Lancet. 1989; 2: 1000-1004Abstract PubMed Scopus (813) Google Scholar The results of that study demonstrated the impressive ability of FK-506 to reverse ongoing rejection, even in patients in whom long-term changes were observed. In those first patients, however, the combined nephrotoxicity of CSA and FK-506 became apparent. Since that report, a sizable worldwide experience with FK-506 has accumulated. Use of both CSA and FK-506 has been associated with acute and chronic kidney damage.7Bennett WM Pulliam JP Cyclosporine nephrotoxicity [editorial].Ann Intern Med. 1983; 99: 851-854Crossref PubMed Scopus (156) Google Scholar, 8Todo S Fung JJ Starzl TE Tzakis A Demetris AJ Kormos R et al.Liver, kidney, and thoracic organ transplantation under FK 506.Ann Surg. 1990; 212: 295-305Crossref PubMed Scopus (210) Google Scholar Decreased renal blood flow initiates the acute disorder usually within the first 7 days; the damage is dose dependent and reversible. The chronic disorder may be evident as early as 30 days after initiation of treatment and results from direct tubular or glomerular injury, which is invariably permanent and unrelated to dosage or drug levels. Nephrotoxicity is characterized by increased serum creatinine (SCr) levels, decreased glomerular filtration rate (GFR), and reduced renal plasma flow. The renal tubular effect that occurs independently of decreased GFR results in impaired secretion of urea and uric acid and reduced fractional excretion of sodium, potassium, lithium, and phosphate as well as hyperkalemia and diminished reabsorption of bicarbonate. The randomized trial reported by Porayko and colleagues in this issue of the Mayo Clinic Proceedings (pages 105 to 111) is notable for its observation of remarkably similar profiles of nephrotoxicity for CSA and FK-506. These findings are in contrast to the early Pittsburgh report6Starzl TE Todo S Fung J Demetris AJ Venkataramman R Jain A FK 506 for liver, kidney, and pancreas transplantation.Lancet. 1989; 2: 1000-1004Abstract PubMed Scopus (813) Google Scholar that suggested a lower toxicity profile for FK-506 than for CSA. Patients admitted to the study by Porayko and colleagues were required to meet rigorous entry criteria and demonstrate acceptable renal function. In fact, eight patients were excluded from analysis because of poor renal function. Despite good initial renal function in these “blue ribbon” candidates, the mean pretransplant GFR and SCr decreased significantly and similarly in both FK-506 and CSA recipients at 30 days. Although almost identical mean SCr levels were noted at 12 months, GFR was significantly lower in the FK-506 group than in the CSA group. In another study, 282 adult patients who received liver transplants at the University of Pittsburgh underwent assessment for changes in renal function.9McCauley J Fung JJ Todo S Jain A Deballi P Starzl TE Changes in renal function after liver transplantation under FK 506.Transplant Proc. 1991; 23: 3143-3145PubMed Google Scholar Perioperatively, the SCr level increased in most patients but was considered mild to moderate (76% of patients had SCr values of less than 2.0 mg/dL at 7 days postoperatively). Of note were the mean SCr values of 1.5 mg/dL by 12 months in the Pittsburgh patients, which were essentially the same as the 12-month values in the study by Porayko and associates. The detection and evaluation of renal dysfunction in the latter report were based on the level of SCr only; however, GFR may decrease by more than 50% without detectable changes in SCr (because of their nonlinear relationship).10Tomlanovich S Golbetz H Perlroth M Stinson E Myers BD Limitations of creatinine in quantifying the severity of cyclosporine-induced chronic nephropathy.Am J Kidney Dis. 1986; 8: 332-337PubMed Scopus (140) Google Scholar This overestimation of actual GFR by measuring serum or urinary creatinine results from increased tubular creatinine secretion, which occurs as GFR declines. As such, these findings emphasize the critical importance of adequate testing of renal function for an accurate comparison of nephrotoxic effects. In the setting of liver transplantation, acute renal dysfunction is multifactorial and related to a host of preoperative factors such as preexisting renal failure or hepatorenal syndrome, ascites, severe encephalopathy, and high serum bilirubin levels or to perioperative variables such as intraoperative hypotension, massive transfusion, or severe early graft dysfunction and the use of concomitant potentially nephrotoxic drugs. In addition, liver transplant recipients have been noted to have mean decreases in estimated renal blood flow of up to 32% preoperatively. When systemic and regional hemodynamics are compared in patients who receive either CSA or FK-506 during the first month after liver transplantation, important differences are seen.11Textor SC Wiesner R Wilson DJ Porayko M Romero JC Burnett Jr, JC et al.Systemic and renal hemodynamic differences between FK 506 and cyclosporine in liver transplant recipients.Transplantation. 1993; 55: 1332-1339Crossref PubMed Scopus (131) Google Scholar Both groups of patients have an initial increase in arterial pressure; however, in patients who receive CSA, systemic vascular resistive indices increase further to levels associated with systemic hypertension. In contrast, vascular resistance in the kidney is severely increased in patients who receive either immunosuppressive agent and is associated with considerable declines in GFR, which are more pronounced in patients who receive FK-506 than in those who receive CSA. The sparing of the systemic vasculature from vasoconstriction is striking in FK-506-treated patients and may explain the lower frequency of hypertension noted in this group. Even in good-risk candidates, Porayko and colleagues clearly show that initiation of early postoperative intravenous FK-506 therapy results in accelerated renal impairment, characterized by oliguria or anuria and rapid increases in serum creatinine and blood urea nitrogen in up to 20% of patients. These findings have also been noted by other investigators and suggest that early recommendations for both the dose and the therapeutic levels of FK-506 were too high.12McDiarmid SV Colonna II, JO Shaked A Ament ME Busuttil RW A comparison of renal function in cyclosporine- and FK-506-treated patients after primary orthotopic liver transplantation.Transplantation. 1993; 56: 847-853Crossref PubMed Scopus (88) Google Scholar In addition, severe early graft dysfunction can profoundly affect elimination of FK-506 and result in rapid increases in serum levels of FK-506 and, ultimately, a deterioration in renal function.13Abu-Elmagd K Fung JJ Alessiani M Jain A Venkataramanan R Warty VS et al.The effect of graft function on FK506 plasma levels, dosages, and renal function, with particular reference to the liver.Transplantation. 1991; 52: 71-77Crossref PubMed Scopus (102) Google Scholar Which method of measuring FK-506 levels can best relate to the therapeutic or toxic effects and whether FK-506 metabolites are physiologically active or toxic are currently unknown. In contrast to CSA, the absorption of FK-506 seems less dependent on the availability of bile. Transplantation centers that have gained experience with FK-506 have consistently decreased their starting intravenous dosages from 0.15 to 0.1 mg/kg daily and now recognize that renal dysfunction or liver failure may dictate even more aggressive dose reductions. In addition, continuous rather than bolus intravenous dosing or delaying the use of FK-506 until urine output is well established or until good allograft function is secured may ameliorate the early nephrotoxic effects of FK-506. Although not addressed in the current report by Porayko and coworkers, the detrimental effect of long-term CSA therapy on tubular function has also been confirmed in FK-506 recipients. Hyperkalemia has been reported in more than 50% of FK-506-treated patients and, like CSA-related hyperkalemia, responds well to fludrocortisone acetate. Similarly, low magnesium levels and a tendency toward a mild metabolic acidosis have been noted in patients who receive either CSA or FK-506. The issue of renal toxicity in patients who have preexisting renal dysfunction or in those who undergo rescue therapy with FK-506 is more complex. Universal increases in SCr were noted in the first 121 liver transplant recipients whose therapy was converted from CSA to FK-506.14McCauley J Fung JJ Brown H Deballi P Jain A Todo S et al.Renal function after conversion from cyclosporine to FK 506 in liver transplant patients.Transplant Proc. 1991; 23: 3148-3149PubMed Google Scholar This “crossover nephrotoxicity” peaked within the first 2 months and seemed greatest in patients who received rescue therapy for acute hepatic rejection, who invariably required high doses of FK-506. The half-life of CSA may increase up to 9 days in this setting. Generally, toxicity diminishes when the dose of FK-506 is decreased. Strategies to minimize toxicity include avoidance of intravenous administration of FK-506 or discontinuation of CSA therapy several days before FK-506 therapy is initiated. Obviously, all patients who undergo primary liver transplantation under FK-506 immunosuppression are at risk for the development of both early and late renal dysfunction. The decrease in GFR is most impressive during the first month after transplantation; however, the persistence of a low GFR throughout the first year suggests that FK-506 is at least as nephrotoxic as CSA and certainly not less so. Careful assessment of renal function beyond simple measurements of serum creatinine should be implemented in all patients who receive FK-506. Future directions should include elucidation of both the histopathologic and the molecular basis for renal toxicity and direct measures to decrease nephrotoxicity, such as administration of calcium channel blockers or prostaglandin analogues." @default.
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• W1979196812 title "Nephrotoxic Effects of Immunosuppression" @default.
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