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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.

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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.

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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 patient's pretransplant evaluation also suggested that cyclosporine may be safe for some patients with acute intermittent porphyria.

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Herbal medications may cause prescription drug interactions in transplant recipients. After 2 of our kidney transplant recipients started self-medicating with St John's wort, their cyclosporine concentrations were consistently documented to be subtherapeutic. While on St John's wort, one patient developed acute rejection possibly due to low cyclosporine concentrations. Termination of St John's wort returned both patients' cyclosporine concentrations to therapeutic values. Based on the Naranjo Adverse Drug Reaction Probability Scale, our report would achieve a "probable" score, which supports the existence of a St John's wort-cyclosporine adverse drug interaction. St John's wort may induce cytochrome P-450 3A4 activity and/or P-glycoprotein expression, which are both involved in the metabolism and absorption of cyclosporine. Patients using St John's wort concomitantly with cyclosporine or other medications with similar absorption and/or metabolism to cyclosporine need close monitoring. Transplant coordinators are in a critical position to educate transplant recipients about the potential risks of herbal medication usage.

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The pretransplant evaluation of a patient with a rare diagnosis requires knowledge of the pathophysiology and the transplant literature. A 55-year-old man presented with hypertensive kidney failure and the clinical diagnosis of acute intermittent porphyria. Complications of acute intermittent porphyria, which is a defect of heme production, are due to the accumulation of heme intermediates often precipitated by medications. Based on animal data, cyclosporine is considered unsafe in patients with acute intermittent porphyria. As part of the pretransplant evaluation, the patient received separate trials of tacrolimus and cyclosporine, which did not stimulate his acute intermittent porphyria. Four months after a kidney transplant, the patient still had no signs of rejection or symptoms of acute intermittent porphyria. This is the first documented patient with acute intermittent porphyria who successfully received a kidney transplant using tacrolimus. Because of individual variations, pretransplant testing of calcineurin inhibitors should be continued in patients with acute intermittent porphyria.

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BACKGROUND: Acute rejection is a major risk factor for chronic allograft nephropathy, although the link(s) between these events is not understood. The hypothesis of this study is that alterations in tubular basement membranes (TBMs) that occur during acute rejection may be irreversible and thereby play a role in the development of chronic allograft nephropathy. METHODS: Fourteen renal transplant patients were selected, each having had two or more biopsies performed (42 total). All biopsies were scored for acute and chronic rejection using Banff 1997 criteria. The initial biopsy showed only acute interstitial rejection (type I rejection). No biopsies contained significant chronic arterial lesions of chronic vascular rejection. The entire cortex was examined on Jones methenamine silver-stained sections at x400 for interruption in TBM staining. The number of tubules with TBM abnormalities was counted, and the renal cortical area was measured by image analysis. Periodic acid-Schiff/immunoperoxidase stain was performed on 12 acute rejection biopsies stained for laminin, cytokeratin 7, CD3, CD20, and CD68. Controls consisted of 11 biopsies (8 negative for rejection and 3 acute tubular necrosis). RESULTS: Numerous TBM alterations in silver staining were identified as being associated with acute rejection and tubulitis, consisting of abrupt TBM discontinuities and/or extreme attenuation with segmental or complete absence of TBM. A loss of TBM matrix proteins was confirmed by absent laminin staining in areas of acute rejection and tubulitis. There was herniation of tubular cells into the interstitium through TBM defects confirmed by cytokeratin staining. The TBM defects were spatially associated with inflammatory cells, particularly macrophages. When the biopsies were divided into two groups, <10 and> 10 TBM breaks/mm2, there were statistically significant morphologic and clinical correlations. The number of TBM disruptions correlated with the serum creatinine at the time of biopsy, a combined Banff t + i score, the difference in tubular atrophy between the initial and most recent biopsy and the difference between the nadir creatinine and most recent creatinine. CONCLUSION: Damage to TBM develops in acute rejection as a consequence of interstitial inflammation and tubulitis. These lytic events correlate with the later development of clinical and morphologic evidence of chronic injury in the absence of arterial injury of chronic rejection. We suggest that chronic allograft nephropathy may have an inflammatory interstitial origin.

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OBJECTIVE: To report a probable drug interaction between the herbal dietary supplement St. John's 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. John's wort. After taking St. John's wort supplements for four to eight weeks, her cyclosporine concentrations became subtherapeutic; this was associated with organ rejection. Four weeks after stopping St. John's 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. John's 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. John's 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.

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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.

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It is commonly believed that religion has no influence on medication compliance. We present a case in which belief in faith healing led to discontinuation of immunosuppressive medications after renal transplantation. Conflict occurs when patients believe they are healed but experience continued illness. Religious and spiritual beliefs should be assessed pre- and post-transplant, and efforts made to encourage medication compliance.

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In a previous study we have shown a role for reactive oxygen metabolites in glycerol-induced acute renal failure, a well-established model for myoglobinuric acute renal failure. In the present study we examined the role of glutathione in this model of acute renal failure. Administration of 50% (vol/vol) glycerol at a dose of 10 ml/kg of body weight to rats intramuscularly resulted in significant renal failure associated with depletion of total kidney glutathione (GSH) from 2.6 +/- 0.1 mumol/g (mean +/- SEM control level) to 1.7 +/- 0.1 mumol/g after 6 hr (P less than 0.001). If GSH were important in glycerol-induced acute renal failure, one would anticipate that exogenously administered GSH should afford protection, while injury should be potentiated if endogenous GSH is depleted. We examined the effect of i.p. administration of L-buthionine-(S,R)-sulfoximine (BSO) at 2 mmol/kg (which results in depletion of kidney GSH) and the effect of increasing renal GSH by i.v. administration of reduced GSH (2 mmol/kg every 3 hr) on kidney function in glycerol-treated rats. Glycerol-injected rats treated with BSO showed significantly worse renal failure than did rats given glycerol alone, while administration of GSH resulted in significant amelioration of glycerol-induced acute renal failure [glycerol treatment alone, blood urea nitrogen (BUN) = 96 +/- 10 and creatinine = 2.5 +/- 0.4 mg/dl; BSO + glycerol treatment, BUN = 123 +/- 7 and creatinine = 3.5 +/- 0.1 mg/dl (n = 9, P less than 0.05); GSH + glycerol treatment, BUN = 78 +/- 10 and creatinine = 1.25 +/- 0.2 mg/dl (n = 8, P less than 0.05)]. In separate experiments 1,3-bis(chloroethyl)-1-nitrosourea (BCNU) [which interferes with the enzyme GSH reductase and prevents recycling of oxidized GSH (GSSG) into GSH] resulted in worsening of glycerol-induced acute renal failure similar to that produced by BSO. These functional differences between GSH-depleted and GSH-repleted rats were further substantiated by significant histological differences in tubular injury. Taken together, these results provide evidence for an important role of GSH in glycerol-induced acute renal failure.

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