J. Joseph Walshe

Acute Oliguric Renal Failure Induced by Indomethacin: Possible Mechanism

A patient with compensated congestive heart failure suffered acute deterioration of her renal function and cardiac status, requiring peritoneal dialysis, in association with indomethacin therapy. Discontinuation of this inhibitor of prostaglandin synthesis led to a prompt improvement in both her renal function and cardiac status. The patient was rechallenged with indomethacin and again developed acute reduction of her glomerular filtration rate and severe volume retention, which were again totally reversed when the drug was stopped. Urinary prostaglandin E was measured by radioimmunoassay in this patient and five additional patients with congestive heart failure and prerenal azotemia. All patients were found to have elevated levels of urinary prostaglandin E. The possible role for renal prostaglandin E as a compensatory mechanism to the vasoconstrictive stimuli present in congestive heart failure is discussed. The potential danger of inhibitors of prostaglandin synthesis in patients with congestive heart failure and prerenal azotemia is emphasized.

Improved graft survival in highly sensitized patients undergoing renal transplantation after the introduction of a clinically validated flow cytometry crossmatch.

Background. Flow cytometric techniques are increasingly used in pretransplant crossmatching, although there remains debate regarding the clinical significance and predictive value of donor-specific antibodies detected by flow cytometry. At least some of the discrepancies between published studies may arise from differences in cutoffs used and lack of standardization of the test. Methods. We selected cut-off values for pretransplant flow cytometric crossmatching (FCXM) based on the correlation of retrospective results with the occurrence of antibody-mediated rejection. The impact on long-term renal graft survival of prospective FCXM was determined by comparing graft survival between patients crossmatched with complement-dependent cytotoxicity (CDC) only with those prospectively crossmatched with both CDC and FCXM. Results. Chosen cut-off values gave a positive predictive value of FCXM for antibody-mediated rejection of 83%, and a negative predictive value of 90%. After the introduction of prospective B- and T-cell crossmatching by flow cytometry in addition to CDC in our center, there was a significant improvement in renal graft survival in highly sensitized patients (P=0.017). Four-year graft survival in highly sensitized patients after the introduction of FCXM was 89%, which did not differ significantly from that seen in nonsensitized patients (93%; P=0.638). Conclusions. Our data demonstrate that prospective FCXM improves renal transplant outcome in highly sensitized patients, provided that cut-off values are carefully validated and results interpreted in the context of sensitization history and antibody screening results.

Cortisol pharmacodynamic response to long-term methylprednisolone in renal transplant recipients.

Study Objective. To examine the pharmacodynamic patterns of cortisol and pharmacokinetic values of long‐term methylprednisolone in renal transplant recipients.

Abdominal pain associated with IgA nephropathy: Possible mechanism

A 36-year-old man presented with IgA nephropathy (Bergers disease) and acute abdominal pain. Surgical biopsy of the ileum revealed deposits of IgA, C3, and fibrin in segments of the wall of submucosal arteries. The immune deposits appeared associated with areas of fibrinoid necrosis. These findings support the hypothesis that Bergers disease is a systemic disease, and provide a possible explanation for the abdominal pain associated with IgA nephropathy.

Comparative Methylprednisolone Pharmacokinetics in Renal Transplant Patients Receiving Double- or Triple-Drug Immunosuppression

OBJECTIVE: To assess the pharmacokinetics of chronic methylprednisolone therapy in renal transplant patients receiving double-drug (methylprednisolone and azathioprine) and triple-drug (methylprednisolone, azathioprine, and cyclosporine) immunosuppression. DESIGN: Parallel, randomized trial. PATIENTS: Fourteen renal transplant recipients (aged 29–65 y) evaluated in a public, university-affiliated hospital clinic. INTERVENTIONS: All patients received their chronic oral dose of methylprednisolone via a 10–20-minute intravenous infusion. MAIN OUTCOME MEASURES: Serum methylprednisolone concentrations were determined by HPLC and were used to generate pharmacokinetic parameters for this drug. RESULTS: The mean daily methylprednisolone dosage was 19 ± 19 mg in the double-drug group and 9 ± 2 mg in the triple-drug group. Mean serum creatinine concentrations were 124 ± 44 and 124 ± 27 μmol/L, respectively. Mean methylprednisolone clearances were similar in both groups: 405 ± 205 (double-drug) and 373 ± 365 mL/h/kg (triple-drug) (p>0.05). Mean steady-state volume of distribution was 1.5 ± 0.8 L/kg in the double-drug group and 1.3 ± 0.8 L/kg in the triple-drug group (p>0.05). Plasma half-life ranged from 1.7 to 4.3 h (mean 2.7) in the double-drug group versus 1.4 to 3.4 h (mean 2.6) in the triple-drug group (p>0.05). CONCLUSIONS: These data indicate that cyclosporine had no definitive influence on methylprednisolone disposition. The results reveal a wide variation in methylprednisolone metabolism in renal transplant recipients receiving either a double- or triple-drug immunosuppressive regimen. Typically, methylprednisolone is prescribed according to a standardized dosing protocol that assumes minimal interpatient variation. Therefore, the pharmacokinetic variability noted in this study may have important clinical implications regarding the development of chronic toxicity (e.g., osteoporosis, hypothalamic-pituitary-adrenal suppression) and the attainment of successful immunosuppression.

METHYLPREDNISOLONE DISPOSITION IN RENAL TRANSPLANT RECIPIENTS RECEIVING TRIPLE-DRUG IMMUNOSUPPRESSION

Renal transplant patients commonly receive triple-drug immunosuppression with standardized doses of cyclosporine, azathioprine, and methylprednisolone. Although cyclosporine may decrease the clearance of oral prednisone, data are lacking for methylprednisolone, a glucocorticoid commonly prescribed via a standardized protocol for intravenous therapy and during periods of acute rejection. The disposition of methylprednisolone (doses: 10-60 mg/day) was examined in nine renal transplant patients during the post-transplant period (0.8-14 months). Plasma samples were collected over 24 hr and analyzed for methylprednisolone via HPLC. Pharmacokinetic parameters were determined by noncompartmental analysis. The mean total clearance of methylprednisolone was 379 ml/hr/kg (range 105-672) and the volume of distribution was 1.4 +/- 0.5 L/kg. The mean plasma half-life was 2.7 +/- 1.1 hr. When normalized to a 1 mg dose of methylprednisolone, the mean peak concentration at 1 hr was 10.0 +/- 3.5 ng/ml with an 8 hr concentration ranging from 0.3 to 5.5 ng/ml. An appreciable variability in methylprednisolone metabolism thus exists in renal transplant recipients receiving triple-drug immunosuppression. This may partially explain the variable response to steroid therapy during acute rejection episodes and chronic immunosuppression as well as the unpredictable occurrence of chronic steroid toxicity.

Pharmacokinetics and clinical tolerance of intravenous and oral cyclosporine in the immediate postoperative period

The clinical tolerance and pharmacokinetics of cyclosporine during a prolonged intermittent intravenous infusion (3.5 mg/kg/day three times) followed by an 8 mg/kg daily oral dose was evaluated in eight renal transplant recipients in the immediate postoperative period. Cyclosporine was analyzed from whole blood samples by HPLC. Despite peak drug concentrations of 1463 ± 754 ng/ml during the infusion period, no adverse pulmonary effects were noted; renal function, urine output, and mean arterial pressure also appeared to have been unaffected. The mean trough cyclosporine concentration was 141 ± 50 ng/ml; however, two patients had trough values below sensitivity. Kinetic analysis after the third dose of intravenous cyclosporine revealed a mean total body clearance of 0.31 ± 0.1 L/min and a volume of distribution of 2.88 ± 1.1 L/kg, whereas the elimination half‐life was 12.8 ± 3.8 hours and the mean residence time was 9.5 ± 5.1 hours. After conversion to oral therapy the bioavailability ranged from 0.11 to 0.47, with a mean value of 0.27. Subsequently there was an unpredictable pattern of bioavailability within patients, with mean values of 0.27 ± 0.13 and 0.30 ± 0.25 during the second and third oral study periods, respectively. These data suggest that despite adjusting the intravenous cyclosporine dosage to account for acute changes in patient body weight, variable kinetics may result in subtherapeutic trough values, even when cyclosporine is administered by prolonged infusion. The clinical implications of fluctuating cyclosporine bioavailability and a potential alternative approach to dosing are discussed.

Bilateral renal cortical necrosis in meningococcal meningitis.

Bacterial meningitis is a relatively common infection of the cerebrospinal fluid (CSF) and leptomeninges. The clinical picture evolves rapidly and, if treatment is delayed, can result in a variety of long-term sequelae, including death. Acute kidney injury in the setting of bacterial meningitis usually results from hypotension and volume depletion and resolves with appropriate treatment. Meningococcaemia with profound hypotension, and/or disseminated intravascular coagulopathy (DIC) may very rarely lead to bilateral renal cortical necrosis. In this context, renal recovery is extremely unlikely. We present two cases of meningococcaemia complicated by bilateral renal cortical necrosis and, ultimately, end stage kidney disease. We also present a review of the literature on the subject. The cases outline the importance of early aggressive intervention by a multidisciplinary team.

Comparison of Cyclosporine Assay Methodology in the Immediate Postoperative Period of Renal Transplantation

Summary: The method of measurement of cyclosporine concentrations in renal transplant recipients varies between centers and employs either high-performance liquid chromatography (HPLC) or radioimmunoassay (RIA). The merit of using HPLC for identifying the parent compound versus the RIA technique, which also measures certain cross-reactive metabolites that accumulate during renal impairment, is controversial. As a result of the lack of uniformity among centers, an abundance of complex literature that describes the disposition of this potent immunosuppressive agent, as well as a wide range of guidelines for therapeutic monitoring, has evolved. To examine the influence of assay methodology on the repeated determination of cyclosporine in the immediate postoperative period, a time when renal function is often unstable, eight renal transplant recipients were studied after i.v. and oral administration on up to four separate occasions. Whole-blood samples were analyzed by HPLC and RIA. Intravenous kinetic analysis yielded a mean total body clearance of 0.24 \pm 0.2 L/min (RIA) and 0.31 \pm 0.1 L/min (HPLC) (p > 0.05), the mean volume of distribution was 2.17 \pm 0.6 L/kg (RIA) and 2.75 \pm 1.2L/kg (HPLC) (p > 0.05), and a mean half-life was 11.7 \pm 4.4 h (RIA) and 12.8 \pm 3.8 h (HPLC) (p > 0.05). The mean bioavailability was 0.36 \pm 0.23 (RIA) and 0.28 \pm 0.15 (HPLC) (p > 0.05). Regression of the 12-h cyclosporine (RIA versus HPLC) concentration yielded a line described by the following equation: RIA = 72 + 1.6 (HPLC). The mean ratios (RIA/HPLC) of the area under the blood cyclosporine concentration versus the time curve (AUC) were 1.6, 1.5, and 1.7 during the oral study periods and were poorly correlated with the serum cre-atinine level. Overall, the two assay methods provided similar pharmacokinetic parameter estimates. However, correlation between the 12-h cyclosporine level determined by RIA and the AUC by HPLC yielded an overestimation of the 24-h AUC determined by HPLC and indicates that therapeutic monitoring of the parent drug in the immediate postoperative period may best be accomplished by HPLC analysis.

Acute Renal Failure Secondary to Tuberculosis: A Diagnostic Challenge

Tuberculosis is a multiorgan disease with varied clinical presentations and is reemerging due to increasing immigration and globalization. We present the case of an immigrant female patient who developed acute renal failure with clinical and biochemical features suggestive of lupus nephritis but with a timely renal biopsy showing caseating granulomata in the renal parenchyma consistent with renal tuberculosis. Despite treatment with antituberculosis treatment and resolution of TB on repeat renal biopsy, she remained haemodialysis dependent. We discuss the diagnostic challenges faced in this presentation and also explore possible differential diagnoses. This rare presentation highlights the importance of renal biopsy in the diagnosis and treatment of acute renal failure and the atypical presentation of tuberculosis.