Renal toxicity after total body irradiation

PURPOSE: To evaluate the incidence of renal dysfunction after total body irradiation (TBI). METHODS AND MATERIALS: Between 1990 and 1997, 64 patients (median age 50 years) received TBI as part of the conditioning regimen before bone marrow transplantation (BMT). Five patients with abnormal renal function at the beginning of treatment or with incomplete data were excluded. All patients received a total of 12 Gy (6 fractions twice daily for 3 consecutive days) prescribed to the peak lung dose (corrected for lung transmission) at a dose rate of 7.5 cGy/min. Renal shielding was not used. Renal dysfunction was assessed on the basis of the serum creatinine levels measured at the start and end of TBI and at 6, 12, 18, and 24 months after completion of BMT. Cox proportional hazard analysis was used to evaluate the various factors known to affect renal function. RESULTS: Only 4 patients had elevated serum creatinine levels at 12 months and subsequently only 2 of the 33 surviving patients had persistent elevated renal serum creatinine levels 24 months after BMT. A fifth patient developed proteinuria and mildly elevated serum creatinine levels at 2.5 years. In 2 patients, the elevation coincided with disease relapse and normalized once remission was achieved. In the third patient, the elevation in serum creatinine levels coincided with relapse of multiple myeloma and the presence of Bence-Jones proteinuria. The fourth patient was the only patient who developed chronic renal failure secondary to radiation nephritis at 2 years. The etiology of the fifth patient's rise in creatinine was unknown, but may have been secondary to radiation nephritis. On univariate analysis, but not on multivariate analysis, a significant correlation was found between TBI-related renal dysfunction and hypertension before and after BMT. CONCLUSION: A dose of 12 Gy at 2 Gy/fraction resulted in only 1 case of radiation nephritis in the 59 patients studied 24 months after the completion of TBI and BMT.     

Sequential infusions of methotrexate and 5-fluorouracil in advanced cancer: pharmacology, toxicity, and response

Preclinical studies have suggested that synergistic antitumor toxicity occurs when methotrexate (MTX) is administered prior to 5-fluorouracil (FUra). A protocol of sequenced, overlapping infusions of MTX and FUra was designed to achieve 5 microM MTX serum levels lasting 36 h and 1 to 5 microM FUra levels lasting 24 h, with leucovorin started at the end of the MTX infusion. Thirty-nine patients with metastatic neoplasms received a total of 127 treatment courses; two-thirds of the patients had received prior treatment with radiation therapy or chemotherapy; most of the latter treatment regimens included MTX or FUra. In three patients, the duration of FUra infusion was prolonged up to 72 h to determine the toxic limits of therapy. Blood samples were collected during treatment courses to estimate the half-lives and total-body clearances of MTX and FUra. The initial serum half-lives and total-body clearances of both MTX and FUra appeared within the range of reported normal values. The terminal half-life of MTX appeared less than previously reported values, and there appeared to be a substantial delay in achieving a FUra steady-state concentration; these two differences may have resulted from either the prolonged intervals of drug infusion or from metabolic interaction between the two drugs. During the 127 courses of treatment, nearly one-half of the patients experienced mild toxicity occurring after at least one treatment, but this toxicity was predominantly Grade I mucositis and/or diarrhea. Of the three patients who received extended intervals of FUra infusion, none was able to tolerate more than 48 h of FUra without developing mucositis. Thirty-four patients were evaluable for response; no one experienced a complete response, but 11 (32%) patients had either a partial or minimal response. Adenocarcinomas as a group, arising from the lung, gut, breast, and unknown site, appeared to respond best. Sequenced MTX-FUra infusion by this schedule is a generally well-tolerated regimen that deserves further clinical assessment.     

Protective role of metallothionein in renal toxicity of cisplatinum

To elucidate the protective role of metallothionein (MT) in the prevention of cisplatinum (cis-DDP) toxicity, we investigated the lethal and renal toxicities caused by cis-DDP in MT-null transgenic mice in comparison with wild-type control mice, and examined the effect of pretreatment with bismuth nitrate or zinc sulfate on the cis-DDP nephrotoxicity. The MT-null mice were of mixed 129 Ola and C57BL/6 genetic background. Since no differences in cis-DDP nephrotoxicity were observed between these strains, C57BL/6J mice were used as the wild-type control. The basal MT levels in the kidneys were negligible in the MT-null mice and 2.93 ± 0.77 μg/g tissue in the C57BL/6J mice. In terms of both the lethal and renal toxicities of cis-DDP, MT-null mice were far more sensitive than C57BL/6J mice. Preinduction of renal MT synthesis by administration of bismuth nitrate or zinc sulfate protected C57BL/6J mice from cis-DDP nephrotoxicity. In the case of MT-null mice, however, renal MT could not be induced by pretreatment with these metal compounds, and renal toxicity of cis-DDP was not prevented by this pretreatment. These results suggest that MT is an important factor with the potential to suppress the development of cis-DDP toxicity. Received: 17 June 1996 / Accepted: 27 November 1996     

Clinical pharmacology of intermediate-dose oral methotrexate

Summary The clinical pharmacology of intermediatedose oral methotrexate (MTX) was studied in nine patients receiving 18 courses of treatment. Serum and urine MTX concentrations were measured by means of a competitive protein binding assay after oral aqueous solution (3 courses), 50-mg tablets (13 courses) or IV drug (2 courses) had been administered in four doses of 100 mg/m² at 6-h intervals or in four doses of 200 mg/m² at 6-h intervals and followed by citrovorum factor rescue. Levels above 150 ng/ml (3.3x10^-7 M) were maintained throughout all treatment cycles, with rapid disappearance of drug after the last dose. A 100% increase in administered dose resulted in only a 42% increase in the concentration-time level. Methotrexate was absorbed well from both aqueous solutions and 50-mg tablets, but serum levels after 50-mg tablets were only 20% of those achieved after IV administration.We conclude that significant serum MTX concentrations can be achieved for prolonged periods of time after oral administration of intermediate doses, but that the proportion of drug absorbed is much less than is seen with lower doses.Preliminary results previously published in abstract form in the Proceedings, American Association for Cancer Research and Am. Soc Clin Oncology 20:100 (1979) (Abstract 402)     

A phase III randomised trial of cisplatinum, methotrextate, cisplatinum + methotrexate and cisplatinum + 5-FU in end stage squamous carcinoma of the head and neck. Liverpool Head and Neck Oncology Group.

We describe a phase III trial on 200 patients with end stage squamous cell carcinoma of the head and neck. The patients were randomised to one of four treatment arms: cisplatinum alone, methotrexate alone, cisplatinum + 5-FU and cisplatinum + methotrexate. There was no significant difference in the response rates, but the survival of the cisplatinum arm was significantly better than that of the methotrexate arm. The survival of patients receiving cisplatinum as a single agent was longer than that of patients receiving cisplatinum in combination with methotrexate or 5-FU, but not significantly so. Nausea/vomiting and anaemia were significantly more common in the cisplatinum arms than in the methotrexate arm, but the toxicity of combination regimens was not significantly greater than that of cisplatinum used as a single agent.     

Clinical pharmacology and toxicity of 4'-O-tetrahydropyranyladriamycin

The clinical pharmacology and toxicity of a novel anthracycline derivative, 4'-O-tetrahydropyranyladriamycin (THP-adriamycin), was investigated in patients with advanced malignant diseases. The starting dose was 30 mg/m2 which was escalated by increments of 10 mg/m2. Twelve patients with a median age of 42 (range, 19-69) years and a median Eastern Cooperative Oncology Group performance score of 2 (range, 1-2) were entered into the study. The diagnoses included four testicular cancers, two breast cancers, two small cell lung cancers, two acute myeloid leukemias, one colon cancer, and one hemangiosarcoma. THP-adriamycin was given as an i.v. bolus injection every 3 weeks. Evaluable were 18 courses for general toxicity, 16 courses for hematological toxicity, and 16 courses for pharmacokinetics. THP-adriamycin had a short initial half-life of 1.4 +/- 0.3 min (mean +/- SD) due to rapid cellular uptake. Peak concentrations in unseparated blood cells were reached 5 min after drug injection and remained higher than in plasma throughout the observation period of 72 h. The half-lives of THP-adriamycin in plasma were 19 +/- 2.8 min in an intermediate and 13 +/- 1.6 h in the terminal phase. A linear correlation was observed between the dose and the areas under the concentration curves for THP-adriamycin in plasma (r2 = 0.97) and blood cells (r2 = 0.99). The volume of distribution was 2124 +/- 221 liters/m2 and the total clearance rate 115 +/- 11 liters/m2h. THP-adriamycin was metabolized to Adriamycin, THP-adriamycinol, and adriamycinol. The major metabolite was Adriamycin with a terminal half-life in plasma of 33 +/- 10 h. The area under the curve of Adriamycin was also correlated to the administered dose (r2 = 0.96). Since excessive peak concentrations of Adriamycin were avoided, the treatment with THP-adriamycin might be an alternative to continuous infusions or weekly administrations. The maximum tolerated dose was 70 mg/m2, and the dose-limiting toxicities were leukopenia and thrombocytopenia. Anemia, nausea, and vomiting were mild to moderate, and no other toxicity was observed. All side effects were dose dependent and reversible. In a patient with breast cancer, a disease stabilization was achieved lasting for 9 weeks. No objective remission was observed. We suggest 60 mg/m2 in pretreated or poor risk and 70 mg/m2 in untreated or good risk patients every 3 weeks for further clinical trials.     

Renal dysfunction during and after high-dose methotrexate

Purpose  To evaluate renal dysfunction in adult patients encountered during and immediately after repeated administrations of high-dose methotrexate (HDMTX) for treatment of primary central nervous system lymphoma (PCNSL). Methods  In this single-center, retrospective, open label trial, 23 consecutive adult patients aged between 19 and 94 years diagnosed with PCNSL were given ≥4 consecutive cycles of HDMTX (8 gm/m²/dose) every 14 days as per institution protocol. Serum creatinine and serum methotrexate levels were measured at 24, 48 and 72 h after beginning of HDMTX infusion. Results  Forty-eight percent of all patients (30% of all HDMTX cycles) experienced a ≥200% increase in baseline creatinine during treatment. Nine percent of patients met requirements for administration of carboxypeptidase-G₂ (glucarpidase) under compassionate use from National Cancer Institute. Thirty percent of patients at the conclusion of HDMTX therapy demonstrated a NCI Common Toxicity Criteria (CTC) grade 2 or higher increase in post-treatment serum creatinine compared to pre-treatment serum creatinine amongst whom ten patients (43%) had levels outside of the normal range. Conclusion  Renal dysfunction of CTC grade 2, 3 or 4 is common during treatment with HDMTX in the treatment of PCNSL, occurring in 40% of all cycles. Renal dysfunction persists at least 4 months following the conclusion of therapy in nearly 30% of patients. Male patients age greater than 50 years are at greatest risk of renal dysfunction.     

Renal toxicity of mitomycin-C

The clinical spectrum and the pathological findings of renal toxicity in four patients treated with mitomycin-C are described. Our experience and evidence in the literature indicates that the renal impairment appears to be total-dose-related, with most patients developing renal symptoms after receiving at least 60 mg of mitomycin-C. The renal morphologic changes reveal a glomerular and vascular process similar to that seen in a number of clinical situations associated with the hematologic findings of microangiopathic hemolytic anemia. In patients with malignant disease, it may be that the use of mitomycin-C either alone or in combination with other drugs causes endothelial vascular damage with resultant activation of the coagulation system. There is evidence that early detection of the renal impairment and withdrawal of mitomycin-C might halt further progression of renal failure.     

A phase I and pharmacology study of continuous-infusion low-dose methotrexate administration

Continuous intravenous infusion of methotrexate (MTX) was evaluated in a Phase I study designed to establish the optimal dose rate to provide a minimum of 28 days of constant 24-hour drug exposure. Twenty-six courses were administered to 21 patients at dose rates of 0.75 mg/M2/day to 3 mg/M2/day. Dose-limiting toxicity was predominantly stomatitis at the highest dose rates. Thrombocytopenia (platelet count less than 100,000) without leukopenia developed in 8 of 26 courses at the lower dose rates, with or without stomatitis, and was rapidly reversible. Serial blood levels revealed detectable serum MTX concentrations at all dose rates delivered with mean MTX concentrations varying from 12.8 nM at 0.75 mg/M2/day to 140 nM at 2.5 mg/M2/day. Total-body clearance of MTX approximated renal creatinine clearance. The recommended dose rate for continuous infusion of methotrexate is 0.75 mg/M2/day for 28 days, and for shorter durations (less than or equal to 14 days), the optimal dose rate is 1.5 mg/M2/day. The continuous-infusion schedule for MTX, therefore, results in a substantial decrease in the delivered dose compared with that achieved with a bolus schedule.     

Renal impairment following the combined use of high-dose methotrexate and procarbazine

Summary A major side-effect of high-dose methotrexate is renal toxicity, wich may develop unexpectedly despite adequate standard precautions such as hydration and alkalinisation of the urine. The pathogenesis is unclear. Recent reports suggest that the combination of high-dose methotrexate with non-chemotherapeutic agents may cause such renal impairment. Three cases of unexpected renal impairment following the combined use of high-dose methotrexate and another cytotoxic agent, procarbazine, are reported. Possible mechanisms of this interaction are discussed, as are recommendations for future combined administration.     

Renal toxicity with cumulative doses of cis-diamminedichloroplatinum-II in pediatric patients with osteosarcoma. Effect on creatinine clearance and methotrexate excretion

Sequential corrected creatinine clearance (CCC) evaluations were obtained in 30 patients treated with intra-arterial and/or intravenous cis-diamminedichloroplatinum-II (CDP). The dose was 150 mg/M2 administered with mannitol diuresis at 2 to 3 weekly intervals. Four hundred fifty-three courses were administered (range, 6-18) over 18 months. Patients also were treated with 283 courses of high-dose methotrexate (MTX) and citrovorum factor "rescue" which were interposed between treatments. Deleterious effects of cumulative courses of CDP manifested as progressive reductions in CCC and delayed excretion of serum MTX. Severe MTX toxicity was aborted by augmenting the fluid intake and prolonging citrovorum factor rescue when elevated levels of serum MTX were detected. The first indication of renal induced CDP toxicity occurred with a cumulative dose of 450 mg/M2. At the termination of treatment (cumulative CDP dose over 1050 mg/M2) renal impairment still was present.     

Clinical pharmacology of oral intermediate-dose methotrexate with or without probenecid

Summary Serum methotrexate (MTX) levels were measured in 20 patients who received an oral, intermediatedose MTX regimen preceded by an IV loading dose, with or without probenecid. Plateau serum MTX levels were relatively modest (2x10^-6 M) during the 24 h of treatment. Pretreatment with probenecid (PBC) led to a doubling of the serum MTX level and a significant increase in the area under the concentration-time curve. Nevertheless, oral therapy is not a suitable means of producing sustained, high (10^-5 molar) MTX levels, even with the addition of PBC.Supported in part by grants CA13148 and CA03013 from the National Cancer Institute     

Renal toxicity of the anticancer drug fostriecin

Purpose: Fostriecin is an inhibitor of topoisomerase II catalytic activity. In a phase I trial we observed renal toxicity, documented as a rise in serum creatinine, which was reversible and non-dose-limiting. The purpose of this study was a detailed analysis of this toxicity. Methods: A total of 20 patients received fostriecin as a 1-h i.v. infusion daily × 5 at doses ranging from 2 to 20 mg/m² per day. Serum creatinine determination and urinalysis were performed daily during drug administration. Renal hemodynamics were measured by means of clearance studies using ¹²⁵I-iothalamate and ¹³¹I-hippuran in eight patients at doses of ≥4 mg/m² per day at baseline, on day 3 or 4 during the first course, and 3 weeks after the second course. Results: The rise in serum creatinine was maximal after one to two doses despite continued administration. This increase showed no correlation with the dose level at fostriecin doses of ≥4 mg/m² per day. Urinary β₂-microglobulin concentrations increased 150-fold (median), which is compatible with impaired tubular reabsorption. The median change in the glomerular filtration rate (GFR) was −36% (range −28% to −44%), that in effective renal plasma flow (ERPF) was −23% (range −11% to −36%), and the filtration fraction (FF) decreased in all patients during the first course of treatment. The values measured 3 weeks after the second course, however, did not differ from baseline. Conclusions: Fostriecin induces reversible renal hemodynamic changes compatible with renal tubular damage. Received: 1 June 1997 / Accepted: 14 November 1997     

Severe renal toxicity due to intermediate-dose methotrexate

Summary Methotrexate (MTX) is a drug widely used in the treatment of patients with malignant disease. Its wellknown side effects include myelosuppression, mucositis and renal damage. These problems are primarily dose-related, tending to occur more frequently when high doses (>1 g/m²) are given. We present four cases in whom severe renal and mucosal toxicity occurred with intermediate doses (200 mg/m²) of MTX despite folinic acid rescue. Possible reasons for this occurrence are discussed and means of avoiding such toxicity are suggested. Three of four patients developed severe loin pain within a few hours of injection; the significance of this symptom in relation to subsequent renal toxicity has implications for early recognition of the problem.     

Renal toxicity of targeted therapies

The use of molecular targeted therapies for the treatment of cancer has increased over the last decade. The benefits of these compounds in terms of efficacy are often relatively modest and counter balanced by the occurrence of significant toxicities. Many of these newer agents used in clinical practice lack specificity and selectivity and have a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined and numerous class-specific toxicities have been described. The kidney is an organ where most of these targeted pathways are expressed. Preclinical data and human renal biopsies have generated an understanding of the mechanisms involved in how targeted agents can cause renal toxicity. This review article discusses the observed nephrotoxicity with this burgeoning class of therapeutics and reviews both the biological reasons for its occurrence and possible ways to prevent significant renal damage.     

Renal toxicity of the neuron-blocking and mitochondriotropic agent m-iodobenzylguanidine

meta-Iodobenzylguanidine (MIBG) is a multipotent drug used in its radiolabeled form as a tumor-seeking radiopharmaceutical in the diagnosis and treatment of pheochromocytoma and neuroblastoma. Nonradiolabeled MIBG has also proved to be effective in the palliation of carcinoid syndromes and, on a predosing schedule, in enhancing the relative tumor uptake of a subsequent [¹³¹I]-MIBG dose in tumors of neuroadrenergic origin. In addition, MIBG is under investigation as an inhibitor of mitochondrial respiration and, as such, for its use in tumor-specific acidification. In this report we describe the side effects of nonradiolabeled MIBG on kidney function in mice. High doses of MIBG (40 mg/kg) reduced renal blood perfusion as measured by ⁸⁶Rb distribution by 50%, which could be antagonized by the bioamine receptor blockers prazosin and cyproheptadine. MIBG also induced reversible renal damage as evidenced from a decrease in [⁵¹Cr]-ethylenediaminetetraacetic acid (EDTA) clearance and from histological damage, which was most pronounced in the distal tubuli. These effects were unrelated to reduced perfusion, however, and could not be antagonized by bioamine receptor blockers, Ca²⁺-channel blockers, or diuretics. Clearance effects of MIBG were mimicked by N-nitro-l-arginine methyl ester (l-NAME), a known inhibitor of nitric oxide synthase (NOS), and MIBG itself (100 μM) also inhibited NOS in vitro, suggesting that NOS inhibition by MIBG may have contributed to the observed reduction in renal clearance. The MIBG analog benzylguanidine (BG), which is equipotent in terms of mitochondrial inhibition, did not affect renal clearance, thus excluding mitochondrial inhibition as the main mechanism of MIBG-induced damage. MIBG, however, was much more cytotoxic than BG to kidney tubular cells in primary cultures. Although the renal effects of high-dose MIBG were reversible, alterations in the pharmacokinetics of concomitant medications by a temporary reduction in renal function should be taken into account in its clinical application. Received: 29 July 1997 / Accepted: 14 November 1997     

Renal tubular transport of methotrexate in the rhesus monkey and dog.

The mechanism and localization of renal transport of methotrexate (MTX) were studied in the rhesus monkey and the dog. It was found that in both animals MTX was bound with plasma protein in a range of 50 to 68% varying with the MTX plasma concentration. Paper chromatographic analysis showed that a negligible amount of MTX was metabolized. The excretion of MTX in rhesus monkey was mainly by tubular secretion which was blocked by probenecid, but in the dog a bidirectional transport mechanism for MTX was indicated. Tubular secretion was localized in the proximal tubules, and a tubular reabsorptive process was in the distal section. Simultaneous administration of folic acid blocked the tubular reabsorption of MTX, resulting in an increase of renal excretion. Maximum tubular excretory capacity determination showed that a maximum tubular excretory capacity value of approximately 5 mumol/100 ml of glomerular filtrate was observed in the rhesus monkey at a plasma concentration of 0.07 mM and a value of 2 mumol/100 ml of glomerular filtrate for the dog. Studies with renal cortical slice technique also indicated that the monkey kidney can accumulate greater amounts of MTX than can the dog kidney.