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.

The Rumel technique for lateral thoracotomy closure.

The closure of the commonly used lateral thoracotomy incision usually includes pericostal sutures which encircle the ribs. Risks of these pericostal sutures include the injury and/or the entrapment of the intercostal neurovascular bundle located along the inferior underedge of each rib. The simple adaptation of the Rumel tourniquet technique is described as an aid for the primary closure of a lateral thoracotomy which may avoid some of the potential complications inherent to thoracotomy incisions.

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.

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

Pretransplant evaluation of a patient with acute intermittent porphyria.

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.

St John's wort: a hidden risk for transplant patients.

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.

Drug interaction between St. John's wort and cyclosporine.

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.

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.

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.

Prophylactic wound antibiotics for combined kidney and pancreas transplants.

For combined kidney and pancreas transplant recipients infectious complications remain a major source of morbidity. With as many antibiotic protocols as transplant centers, the exact type and duration for prophylactic wound antibiotics remains undefined. A retrospective review of our series of 40 combined kidney and pancreas transplants was performed using a single 1 g dose of cefazolin preoperatively along with cefazolin bladder and intra-abdominal irrigation. Two patients developed superficial wound infections for a rate of 5% (2/37). The deep wound infection rate was 11% (4/37), and all followed either a bladder anastomotic leak or the initial development of transplant pancreatitis. Our overall rate of 16% is very comparable with other series of combined kidney and pancreas transplant recipients. To help eliminate the potential development of superinfections and resistant organisms, a single dose of antibiotics appears to be as effective for wound prophylaxis in these patients when compared to multiple-antibiotic and multiple-day regiments. A randomized prospective study of prophylactic antibiotics in combined kidney and pancreas transplants is needed.

Combined kidney and pancreas transplants through lower transverse abdominal incisions.

Improvements in the surgical aspects of combined kidney and pancreas transplants have resulted in better overall graft and patient survival. Pancreas transplants were initially performed through lower transplant flank incisions opposite the kidney. However, because of high wound complication rate, most centers now perform pancreas transplants through lower midline incisions. We retrospectively reviewed our experience in 40 combined kidney and pancreas transplant recipients with an initial group of 6 midline incisions and 34 later lower transverse abdominal incisions. The number of midline incisions was too small to make a direct comparison, but our series of patients with transverse incisions was compared with the reported literature using a midline incision. The overall infectious and hernia rates for the transverse incision were 12% and 6% respectively which are both very acceptable. The average operative time was 5.5 h. The transverse incision may be associated with less pain, shorter ileus, and fewer pulmonary complications. A lower transverse incision has the major advantage of excellent exposure directly over the iliac vessels and is our incision of choice.

Candida arteritis: are GI endoscopic procedures a source of vascular infections?

A 53-year-old woman, 11 years after a renal transplant on chronic immunosuppression, presented with a sudden onset of a painless left groin mass. Ultrasound revealed a 3 cm common femoral artery pseudoaneurysm and a 3 cm saccular aneurysm of the infrarenal aorta. Operative repair was excision and patch angioplasty of the aortic aneurysm with internal iliac artery and interposition grafting of the femoral artery aneurysm with saphenous vein. Postoperatively, Candida albicans was identified in the aortic and common femoral arterial cultures. Candida infections often occur in patients with impaired cellular immunity due to seeding from urinary tract infections, vascular catheters, or manipulation of the gastrointestinal tract. Our patient, without any prior history of a fungal infection, had undergone a colonoscopy 3 weeks earlier. Without any other possible source being identified, the proposed mechanism for fungal entry into the vascular system was via the gastrointestinal tract, with seeding from the portal venous system. The exact medical and surgical management of these patients remains undefined, and a transplant vascular registry is really needed. However, immunocompromised solid organ transplant recipients undergoing gastrointestinal endoscopic procedures may be at a greater risk for the development of subsequent septicemia. Further reports are really needed to confirm the possible need in these patients for both periprocedural antibiotic and antifungal prophylactic coverage.

An update of solid organ transplantation at UAMS.

The one year survival for solid organ transplants is 70 to 90%. Encouraged by this success, the University of Arkansas for Medical Sciences is expanding its organ transplant center and will offer renal, pancreas, liver, heart, and lung within a year. The limiting factor in transplants continues to be a shortage of Donor organs and the need for increased referral of potential donors.

The role of transplantation in diabetics with end-stage renal disease.

At our center, KPT is the treatment of choice for diabetics with ESRD who are not irreversibly disabled by their secondary complications of diabetes. Mortality, as a result of cardiovascular complications, has a significant impact on the outcome of patients in both the KPT and KTA groups. Metabolic complications are problematic in the early posttransplant period. Infectious complications are frequent but not life threatening in the combined recipients. Excellent graft outcome (pancreas and kidney) can be achieved in those patients selected to undergo the KPT procedure.

Gastroduodenal complications in kidney transplant recipients.

Oral antacids taken every two hours while awake provided the only prophylaxis against gastroduodenal ulceration for 167 kidney transplant recipients between 1968 and July 1978. Either perforation or major hemorrhage occurred in eight patients within 30 days after transplantation. Between July 1978 and January 1981, bleeding occurred within 30 days in two of 147 recipients who were treated with both antacids and cimetidine. Of the 147 patients, eleven with a history of ulcers had undergone pretransplant vagotomy; neither perforation nor hemorrhage occurred in any of the eleven patients. Despite reports that cimetidine enhances certain types of immune responses, we observed slightly greater graft survival in the group treated with cimetidine.

Effect of splenectomy on first cadaver kidney transplants.

A prospective study was begun in January 1975 to evaluate the effect of splenectomy on graft and patient survival in recipients of first cadaver kidney transplants. Ninety-two cases were evaluated. Splenectomy increased the survival of both grafts and recipients. The benefit from splenectomy compensated readily for the perioperative morbidity of splenectomy and the long-term increased risk of sepsis from certain bacteria for the asplenic patient. Splenectomy exerted its effect by reducing the incidence and intensity of rejection episodes. It was not clear whether the observation resulted from a direct immunosuppressive effect of splenectomy or from the increased tolerance to azathioprine observed in asplenic recipients. Finally, splenectomy negated an effect of race that had been observed earlier for survival of cadaver transplants and recipients.