Beverley L. Ketel

Drug Interaction between St. John's Wort and Cyclosporine

OBJECTIVE: To report a probable drug interaction between the herbal dietary supplement St. Johns wort and cyclosporine. CASE REPORT: A 29-year-old white woman who received a cadaveric kidney and pancreas transplant, with stable organ function and stable cyclosporine concentrations began self-medicating with St. Johns wort. After taking St. Johns wort supplements for four to eight weeks, her cyclosporine concentrations became subtherapeutic; this was associated with organ rejection. Four weeks after stopping St. Johns wort, her cyclosporine concentrations again became therapeutic. Subsequent to this rejection episode, she has developed chronic rejection and now has returned to dialysis. DISCUSSION: St. Johns wort is suspected to be a significant inducer of CYP3A4 isoenzyme activity and of P-glycoprotein (P-gp) expression, both of which are important in the metabolism and absorption of cyclosporine. Cyclosporine exhibits a relatively small therapeutic window and is sensitive to medications that can modulate the CYP3A4 isoenzyme and P-gp in both the liver and small intestines. CONCLUSIONS: Patients taking St. Johns wort concomitant with other prescription medications whose absorption and metabolism are mediated by the CYP3A4 isoenzyme and P-gp require close monitoring. Patient medication histories should include inquiries into the use of herbal dietary supplements.

Herbal supplements: a potential for drug interactions in transplant recipients.

Background. Herbal dietary supplements represent a potential and possibly an overlooked cause for drug interactions in transplant recipients. Methods. Two patients are reported which suggest that St. John’s Wort (SJW) may induce cytochrome P-450 3A4 activity and/or P-glycoprotein expression. Both of these mechanisms are significantly involved in the metabolism and absorption of cyclosporine (CSA) and other immunosuppressants. Results. After two renal transplant recipients started self-medicating with SJW, their CSA concentrations were consistently documented to be subtherapeutic. While on SJW, one patient developed acute graft rejection due to low CSA concentrations. In both patients, termination of SJW returned their CSA concentrations to therapeutic values. Conclusions. Patients taking SJW concomitantly with CSA or other medications whose absorption and metabolism are mediated by cytochrome P-450 and/or P-glycoprotein should require close monitoring. Potential herb-prescription drug interactions are not just limited to SJW. Inquiries regarding the usage of herbal supplements should be an integral component of a transplant recipient’s medication history.

Polyoma viral infection in renal transplantation: the role of immunosuppressive therapy

Background: Polyoma virus infection in renal transplant recipients has been observed with increasing frequency in recent years. Renal allograft involvement in this condition may occur as a result of primary infection or secondary to reactivation of the latent virus. Interstitial nephritis, ureteric stenosis, rise in serum creatinine and allograft function loss have been attributed to this viral infection. 
Methods: In this study we reviewed our experience with 8 patients who developed polyoma viral infection confirmed by allograft biopsy. All patients were receiving mycophenolate mofetil as part of the immunosuppression and 7 of the 8 patients were on tacrolimus. All patients have biopsy proven polyoma viral infection. The following therapeutic maneuvers were carried out following the diagnosis of polyoma viral infection: 1) stopping mycophenolate and 2) switching tacrolimus to cyclosporine or reducing the tacrolimus dose to adjust it at a lower therapeutic trough level. The clinical course and outcome of our patients were reviewed in relation to manipulation of immunosuppressive medications. 
Results: The incidence of this infection in our transplant program in the last 3 yr was 5.3%. Seventy‐five percent of the patients had at least one rejection episode and 63% had more than one rejection episode. The main risk factor for the development of polyoma viral infection was related to the intensity of immunosuppression. The use of antirejection therapy after histological diagnosis of polyoma virus infection was not associated with improvement of renal function despite the histological appearance of acute rejection. Thus, the interstitial nephritis associated with polyoma viral infection appears to be an inflammatory response to the virus rather than acute rejection. Six out of the 8 patients stabilized renal function with reduction in immunosuppression. 
Conclusions: Reduction in immunosuppression was associated with the stabilization of renal function when instituted early. However, these patients were left with a degree of allograft dysfunction and their outcome may be significantly compromised. The lack of effective antiviral therapy for polyoma virus may limit the use of newer and more potent immunosuppressive medications.

Successful management of a nonmalignant esophageal perforation with a coated stent

This case report details our experience in the management of an iatrogenic perforation that recurred after two surgical repairs. A self-expanding coated stent was eventually placed to seal the esophageal perforation with significant improvement in the clinical condition of the patient. At 1-year follow-up, the patient is tolerating an oral diet with no evidence of esophageal leak or gastroesophageal reflux. This case report and a literature review suggest that self-expanding coated stents may be a useful salvage option in the management of inveterate nonmalignant esophageal perforations.

Novel Once-Daily Extended-Release Tacrolimus Versus Twice-Daily Tacrolimus in De Novo Kidney Transplant Recipients: Two-Year Results of Phase 3, Double-Blind, Randomized Trial

BACKGROUND 1-year data from this trial showed the noninferiority of a novel once-daily extended-release tacrolimus (LCPT; Envarsus XR) to immediate-release tacrolimus (IR-Tac) twice daily after kidney transplantation. STUDY DESIGN Final 24-month analysis of a 2-armed, parallel-group, randomized, double-blind, double-dummy, multicenter, phase 3 trial. SETTING & PARTICIPANTS 543 de novo kidney recipients randomly assigned to LCPT (n=268) or IR-Tac (n=275); 507 (93.4%) completed the 24-month study. INTERVENTION LCPT tablets once daily at 0.17 mg/kg/d or IR-Tac twice daily at 0.1 mg/kg/d; subsequent doses were adjusted to maintain target trough ranges (first 30 days, 6-11 ng/mL; thereafter, 4-11 ng/mL). The intervention was 24 months; the study was double blinded for the entirety. OUTCOMES & MEASUREMENTS Treatment failure (death, transplant failure, biopsy-proven acute rejection, or loss to follow up) within 24 months. Safety end points included adverse events, serious adverse events, new-onset diabetes, kidney function, opportunistic infections, and malignancies. Pharmacokinetic measures included total daily dose (TDD) of study drugs and tacrolimus trough levels. RESULTS 24-month treatment failure was LCPT, 23.1%; IR-Tac, 27.3% (treatment difference, -4.14% [95% CI, -11.38% to +3.17%], well below the +10% noninferiority criterion defined for the primary 12-month end point). Subgroup analyses showed fewer treatment failures for LCPT versus IR-Tac among black, older, and female recipients. Safety was similar between groups. From month 1, TDD was lower for LCPT; the difference increased over time. At month 24, mean TDD for LCPT was 24% lower than for the IR-Tac group (P<0.001), but troughs were similar (means at 24 months: LCPT, 5.47 ± 0.17 ng/mL; IR-Tac, 5.8 ± 0.30 ng/mL; P=0.4). LIMITATIONS Trial participant eligibility criteria may limit the generalizability of results to the global population of de novo kidney transplant recipients. CONCLUSIONS Results suggest that once-daily LCPT in de novo kidney transplantation has comparable efficacy and safety profile to that of IR-Tac. Lower TDD reflects LCPTs improved bioavailability and absorption.

The tolerability of newer immunosuppressive medications in a patient with acute intermittent porphyria

Acute intermittent porphyria results from a deficiency of the porphobilinogen deaminase enzyme of heme biosynthesis and is commonly exacerbated by a wide variety of medications. When referred a patient with acute intermittent porphyria for a renal transplant, only steroids and azathioprine were discovered as safe in patients with acute intermittent porphyria. The administration of many newer immunosuppressive medications, including calcineurin inhibitors, has not been documented in acute intermittent porphyria. Actually, cyclosporine is presently considered contraindicated in acute intermittent porphyria. To determine if calcineurin inhibitors would be tolerated in acute intermittent porphyria, cyclosporine and tacrolimus were administered pretransplant and were documented not to exacerbate acute intermittent porphyria. A successful renal transplant was then performed using tacrolimus. This is the first reported patient with documented acute intermittent porphyria to tolerate safely several of the newer immunosuppressive medications, including tacrolimus, mycophenolate, and rabbit antithymocytic globulin following renal transplantation. This patients pretransplant evaluation also suggested that cyclosporine may be safe for some patients with acute intermittent porphyria.

Trauma management in solid organ transplant recipients

With trauma being common in this country and over 110,000 recent organ transplants performed, transplant recipients may become trauma victims. At present, only a few older small series of traumatized transplant patients exist. At the University of Arkansas, over the past 40 months, 12 patients with significant trauma were retrospectively identified (seven with kidney and five with combined kidney and pancreas transplants). The most common causes of trauma were car accidents and falls. All patients suffered closed skeletal fractures, and no transplanted organs were directly injured or lost. Complications included death, deep vein thrombosis, renal failure, sepsis, and pneumonia. In spite of immunosuppression and preexisting renal osteodystrophy, fractures in the surviving patients healed, with a mean follow-up of 15 months. A large series of traumatized transplant patients is presented with a review of the management of traumatic injuries for each type of organ transplant. A trauma transplant registry is needed to formulate appropriate management and follow-up.

Technique for laparoscopy-assisted complicated peritoneal dialysis catheter placement.

Peritoneal dialysis is widely accepted for the chronic management of end-stage renal disease. Especially in patients suspected of having intra-abdominal adhesions, the application of laparoscopic surgical techniques has significantly changed our surgical approach to dialysis catheter placement. The blind placement of peritoneal dialysis catheters in this patient group can be both dangerous, because of the higher risk of bowel injuries, and unsuccessful, because of immediate catheter misplacement or entrapment. We describe a relatively simple step-by-step approach to laparoscopy-assisted peritoneal dialysis catheter placement with omentectomy in these more complicated cases.

Diurnal blood pressure variation in kidney-pancreas transplant recipients

Blood pressure normally follows a characteristic pattern throughout the 24 h cycle with daytime pressures higher than nighttime pressures. Patients lacking a nocturnal decrease in pressure have a higher incidence of end organ damage. This investigation was designed to characterize the diurnal pattern of blood pressure and to evaluate blood pressure load in patients who have received a combined kidney-pancreas (KP) transplant. Ten patients (mean 10 months posttransplant) underwent 48 h of noninvasive ambulatory blood pressure monitoring using a commercially available device (SpaceLabs 90202 or 90207). Blood pressure was measured every 15 min from 6 AM to 9 PM and every 30 min from 9 PM to 6 AM. Ambulatory monitoring revealed a markedly increased nocturnal blood pressure (up to 25% greater than daytime pressures). These patients were found to have a higher nocturnal blood pressure load than during the day. No relationship was demonstrated between diurnal blood pressure variation and immunosuppression regimen, elapsed time after transplantation, or antihypertensive treatment. These results indicate that close attention must be given to the nocturnal blood pressure of KP recipients and suggest that standard antihypertensive medication regimens do not adequately treat the nocturnal hypertension in these patients. This may predispose these patients to further cardiovascular or cerebrovascular complications.

Acute rejection presenting as nephrotic syndrome.

BACKGROUND Early diagnosis and treatment of acute rejection is important to prevent continued renal injury. Acute rejection most commonly presents with asymptomatic rise in serum creatinine. Proteinuria associated with acute rejection is well established; however, there is limited documentation of the presentation of acute rejection as nephrotic syndrome in the literature. METHODS AND RESULTS We report a renal transplant patient who presented with early onset nephrotic syndrome without change in serum creatinine, whose allograft biopsy confirmed acute glomerulitis and vascular rejection. Treatment of the acute rejection was accompanied by resolution of the nephrotic syndrome. A second episode of acute rejection was also manifested as nephrotic range proteinuria. CONCLUSION The nephrotic syndrome in early post-transplantation period should prompt a work-up for acute rejection even in the absence of the common findings of this complication.