Sarcoidosis within a renal allograft: a case report and review of the literature.

Sarcoidosis is an unusual disorder of unknown etiology. Clinically apparent renal involvement is rare in sarcoidosis. The incidence of recurrence in transplant recipients is unknown with few cases having been reported previously. Herein we report a case of sarcoidosis involving a renal allograft that occurred 3 years after transplantation and provide a literature review.

Spermatocele following kidney transplant.

Lymphocele following kidney transplant is a common occurrence, but on occasion, what appears to be a lymphocele is not. We present an unusual case of a kidney transplant recipient whose presumed lymphocele was actually a spermatocele. Our patient is a 60-year-old man who is 11 years status post his second deceased donor kidney transplant. The original cause of his renal failure was poststreptococcal glomerulonephritis. He was followed with this nonobstructing lymphocele for years, but wished to have it addressed at the time of sigmoidectomy for recurrent diverticulitis. Preoperative imaging included CT scan, which showed a 12 cm × 6 cm collection, of greater density than simple fluid, adjacent to the bladder, and causing mass effect on the bladder. Intraoperatively, the collection was somewhat atypical for a lymphocele, and located posterior to the bladder. Cultures were negative, but evaluation of the fluid revealed it to be a spermatocele. Postoperative ultrasound demonstrated full resolution of the collection.

Treatment of acute graft-vs-host disease after simultaneous pancreas-kidney transplantation: a case report.

Whereas neutropenia is common after solid-organ transplantation, graft-vs-host disease is unusual, especially after simultaneous pancreas-kidney transplantation. Most cases reported in the literature give few details of treatment approach, and all were fatal. A 45-year-old man with diabetes underwent simultaneous pancreas-kidney transplantation at our center, with organs from a female donor. Two weeks postoperatively, he was readmitted with fever, malaise, and neutropenia. A bone marrow biopsy specimen demonstrated that two-thirds of the lymphocytes were of female karyotype. Graft-vs-host disease was diagnosed. Aggressive immunosuppression therapy was administered; however, the patient died. To our knowledge, this is the first case report with specific details of a treatment protocol and sequential short tandem repeat data.

Sweet syndrome after kidney transplantation.

The association between Sweet syndrome (acute febrile neutrophilic dermatosis) and malignancies, infection, and drugs has been well established, but the disorder has never been reported in a solid organ transplant recipient. We have presented the first reported case of Sweet syndrome connected with solid organ transplant. Our patient is a 38-year-old man who underwent deceased donor kidney transplant for focal and segmental glomerulosclerosis and after resuming dialysis 6 weeks posttransplant, was readmitted 2 months later with high fevers and multiple head, neck, chest, and back lesions. Cultures were negative, and skin biopsy was consistent with Sweet syndrome. The lesions responded to higher doses of prednisone. Sweet syndrome has been linked to multiple drugs and malignancies, but has also been linked with states of altered immunity. Posttransplant immunosuppression may be related to this occurrence.

A phase I/II randomized open-label multicenter trial of efalizumab, a humanized anti-CD11a, anti-LFA-1 in renal transplantation.

Leukocyte function associated antigen-1 (LFA-1) has a multifaceted role in the immune response, including adhesion and trafficking of leukocytes, stabilizing the immune synapse of the MHC-TCR complex and providing costimulation signals. Monoclonal antibodies to the CD11a chain of LFA-1 have been seen to result in effective immunosuppression in experimental models. Efalizumab, a humanized IgG1 anti-CD11a, is approved for use in psoriasis and may provide effective immunosuppression in organ transplantation. Thirty-eight patients undergoing their first living donor or deceased renal transplant were randomized to receive efalizumab 0.5 or 2 mg/kg weekly subcutaneously for 12 weeks. Patients were maintained on full dose cyclosporine, mycophenolate mofetil and steroids or half dose cyclosporine, sirolimus and prednisone. At 6 months following transplant patient survival was 97% and graft survival was 95%. Clinical biopsy-proven acute rejection in the first 6 months after transplantation was confirmed in 4 of 38 patients (11%). Three patients (8%) developed post transplant lymphoproliferative disease, all treated with the higher dose efalizumab and full dose cyclosporine. The two doses of efalizumab resulted in comparable saturation and modulation of CD11a. This phase II trial suggests that efalizumab may warrant further investigation in transplantation.

Transforming growth factor-beta levels in human allograft chronic fibrosis correlate with rate of decline in renal function.

BACKGROUND: Long-term renal transplant function is limited primarily by a progressive scarring process loosely termed "chronic rejection, chronic allograft nephropathy, or allograft fibrosis." Although the etiology of transplant fibrosis is uncertain, several possible factors including chronic cyclosporin A (CsA) exposure may contribute to its pathogenesis. CsA stimulates renal fibrosis perhaps through the induction of the potent pro-sclerotic growth factor, transforming growth factor beta (TGFbeta). Previously, we demonstrated that, in human transplant biopsies, acute CsA toxicity but not acute tubular necrosis is associated with elevated levels of renal TGFbeta protein. We now examine whether long-term CsA treatment (>1 year) is associated with elevated levels of intra-allograft TGFbeta and whether heightened expression of TGFbeta is clinically significant. METHODS: Using immunohistochemical techniques, we determined the relative level of expression of intrarenal TGFbeta protein in transplant biopsies. We studied biopsies obtained from 40 CsA-treated patients that were diagnosed as having chronic allograft fibrosis. Biopsies were scored as having minimal or high levels of TGFbeta. RESULTS: Seventy-two percent of patients expressed high levels of intra-allograft TGFbeta. This group of patients lost renal function at an average rate of -19.5+/-17.3 ml/min/year. In contrast, patients with minimal or no TGFbeta expression experienced a decline of only -6.2+/-4.1 ml/min/year (P=0.01). CONCLUSIONS: These results suggest that the majority of CsA-treated patients with biopsy proven chronic fibrosis have elevated levels of intra-graft TGFbeta that correlates with an increased rate of decline in renal function.

The role of tacrolimus in adult kidney transplantation: a review.

The use of tacrolimus (FK506) in adult kidney-transplant recipients has been the subject of a number of single- and multi-center studies. This review article focuses on those studies in which tacrolimus was used either as rescue therapy in patients who developed refractory rejection on cyclosporine (CyA)-based regimens or as primary immunosuppression in adult renal-allograft recipients. Twenty-five prospective and retrospective studies conducted in the US, Japan and Europe, including single- and multi-center experiences, were identified in the medical literature. Of these studies, most show a 74-98% initial success rate for tacrolimus rescue therapy. Comparative studies reviewed herein demonstrate comparable patient- and graft-survival rates between tacrolimus- and CyA-treated patients. Many studies have shown that rejection episodes occur with similar or lower frequency among patients treated with tacrolimus than among those given CyA as primary immunosuppression. The major toxicities associated with tacrolimus are nephrotoxicity, neurotoxicity and diabetogenicity. Results from several studies have also demonstrated an association between these tacrolimus side effects and high whole-blood trough levels of tacrolimus. In many cases, a reduction in dosage can reverse these adverse effects. In summary, based on both single- and multi-center data, tacrolimus has been demonstrated to be efficacious when used for either primary immunosuppression or as rescue therapy for refractory acute rejection in adult renal-allograft recipients.

Long-term function and survival of elderly donor kidneys transplanted into young adults.

BACKGROUND: Traditionally, elderly donor kidneys have not been widely accepted for transplantation on the assumption of inferior performance. However, the United Network for Organ Sharing reports an increase in the number of elderly donors from less than 2% in 1982 to 24% in 1995. This trend is commensurate with the increase of older dialysis patients and an overall increase in the elderly population in the United States (1). Optimal utilization of these kidneys is essential to overcome the acute organ shortage. METHODS: In this study, we transplanted 25 kidneys from elderly donors (ages 56-72 years) into young adult recipients (ages 20-50 years) (group 1) over a 4-year period. We compared the results with matched recipients of young adult donor kidneys (group 2) with regard to long-term kidney function and graft survival. A pretransplant biopsy of elderly donor kidneys was carried out and a frozen section report was obtained. Only those kidneys showing glomerulosclerosis of less than 20% were accepted for transplantation. All cadaveric kidneys were preserved in University of Wisconsin solution. RESULTS: Pretransplant biopsies of elderly donor kidneys showed structural deficits, which included glomerulosclerosis in 85%, arteriolar and/or mesangial thickening in 75%, and interstitial lymphocyte infiltration in 30%. The mean serum creatinine was 2.4+/-0.74, 2.2+/-0.56, and 2.9+/-0.76 mg/100 ml in group 1 and 1.5+/-0.55, 2.3+/-2.24, and 1.7+/-0.62 in group 2 at 1, 3, and 5 years, respectively. The patient survival was 92%, 92%, and 88% in group 1, and 100%, 100%, and 100% in group 2 at 1, 3, and 5 years, respectively. The graft survival was 80%, 64%, and 56% in group 1 and 100%, 96%, and 88% in group 2 at similar time intervals. The differences in the serum creatinine and graft survival between the two groups were statistically significant (P < 0.05). CONCLUSIONS: Most of the elderly donor kidneys with structural deficits transplanted into young adults provided suboptimal function and inferior long-term graft survival. To maximize the utilization and optimize the survival of elderly donor kidneys, we propose transplantation of these kidneys into age-matched recipients with similar physiological requirements as those of donors, with regard to kidney function.

An open-label, concentration-ranging trial of FK506 in primary kidney transplantation: a report of the United States Multicenter FK506 Kidney Transplant Group.

This was a multicenter, open-label, concentration-ranging trial of FK506 and cyclosporine in 120 patients undergoing primary cadaveric kidney transplant. Patients were randomized to a cyclosporine-based regimen or to one of three FK506-based regimens designed to achieve low (5-14 ng/ml), medium (15-25 ng/ml), or high (26-40 ng/ml) trough whole blood levels. Corresponding initial doses of FK506 were 0.2, 0.3, and 0.4 mg/kg/day. Patients were evaluated at 42 days after transplant for the occurrence of the first episode of acute rejection or toxicity, necessitating a dosage reduction. There was no significant difference among the three FK506-based regimens and the cyclosporine-based regimen for rejection or toxicity at 42 days. However, the incidence of acute rejection was significantly lower (14% for FK506 and 32% for cyclosporine; P=0.048) for the aggregate of all FK506-treated patients versus cyclosporine. The incidence of neurotoxic and gastrointestinal events was higher among FK506-treated patients during the first month after transplant. A significant trend was observed for increasing toxicity with increasing maximum trough FK506 concentrations (P=0.01) and for decreasing rates of rejection with increasing minimum trough FK506 concentrations (P=0.021). FK506 was effective in preventing early rejection in kidney transplant recipients. The target range of whole blood levels that optimizes efficacy and minimizes toxicity seems to be 5-15 ng/ml. The corresponding recommended initial dose of FK506 for kidney transplant recipients seems to be 0.2 mg/kg/day.

A multicenter trial of FK506 (tacrolimus) therapy in refractory acute renal allograft rejection. A report of the Tacrolimus Kidney Transplantation Rescue Study Group.

A multicenter trial was conducted to evaluate the efficacy and safety of tacrolimus in the treatment of refractory renal allograft rejection. Renal transplant recipients experiencing biopsy-proven recurrent acute allograft rejection were eligible if the current rejection episode was refractory to corticosteroids. A total of 73 patients were enrolled, of whom 59 (81%) had previously received at least one course of antilymphocyte antibody as rejection therapy. One-year follow-up was available in 93% of patients. Median time to tacrolimus rescue therapy was 75 days after transplantation (range, 18-1448 days). Therapeutic responses to tacrolimus included improvement in 78% of patients, stabilization in 11%, and progressive deterioration in 11%. The risk of experiencing progressive deterioration was related to the pretacrolimus serum creatinine level: serum creatinine < or = mg/dl, 3%; 3.1-5 mg/dl, 16% (P < 0.04); > 5 mg/dl, 23% (P < 0.02). Twelve-month (from the time of initiation of tacrolimus therapy) actuarial patient and graft survival rates were 93% and 75%. Graft loss occurred in 19 patients (25%) at a median time of 108 days. Fourteen episodes of recurrent rejection were diagnosed in 10 patients (14%), at a median time of 101 days. Eleven episodes of recurrent rejection were treated (three patients underwent transplant nephrectomy), with resolution achieved in nine patients. Antilymphocyte antibody therapy was not used to treat recurrent rejection. Serum creatinine values improved during tacrolimus therapy: median serum creatinine level before tacrolimus, 3.2 mg/dl; median at 1 year after tacrolimus, 1.8 mg/dl. Twelve infections were documented in 11 patients (15%), including cytomegalovirus infection in three patients (4%). Posttransplant lymphoproliferative disorder was diagnosed in a single patient. Tacrolimus whole blood levels averaged 15.0 +/- 9.9 ng/ml at day 7 of tacrolimus therapy and 9.4 +/- 5.1 ng/ml at 1 year, and were consistent among individual centers. Treatment outcome did not correlate with tacrolimus blood levels. The most commonly observed adverse events were neurological and gastrointestinal. Seventy-four percent of patients received tacrolimus for at least 1 year. Tacrolimus therapy was discontinued in 18% of patients for rejection (11% for progressive, unrelenting rejection, and 7% for recurrent rejection). Tacrolimus therapy was discontinued in 8% of patients due to adverse events. In conclusion, tacrolimus rescue therapy provides (1) prompt, effective reversal of refractory renal allograft rejection, (2) good long-term renal allograft function, (3) a low incidence of recurrent rejection, and (4) an acceptable safety profile in renal allograft recipients experiencing refractory rejection.

One-year follow-up of an open-label trial of FK506 for primary kidney transplantation. A report of the U.S. Multicenter FK506 Kidney Transplant Group.

Patients undergoing primary cadaveric kidney transplantation were followed for 1 year as part of a phase II, multicenter, open-label concentration-ranging trial of FK506 and cyclosporine. One hundred twenty patients were randomly assigned to a cyclosporine-based regimen or one of three FK506-based regimens designed to achieve low (5-14 ng/ml), medium (15-25 ng/ml), or high (26-40 ng/ml) trough whole blood levels. Corresponding initial doses of FK506 were 0.2, 0.3, or 0.4 mg(kg/day, respectively. Patients with toxicity to FK506 had their target concentration reduced by lowering the dose of FK506. Ninety-two patients completed a 1-year follow-up to determine patient and graft survival and long-term safety. At 1-year, the patient survival rate was 98% for FK506 and 92% for cyclosporine, and the graft survival rate was 93% and 89% in the FK506 and cyclosporine groups, respectively. The incidence of acute rejection was significantly lower (14% FK506, 32% cyclosporine, P=0.048) at day 42 after transplantation. However, the incidence of rejection episodes requiring treatment at 1 year was similar in both groups (33% for FK506 and 32% for cyclosporine). Nephrotoxicity occurred with a similar frequency with FK506 and cyclosporine, but the incidence of neurotoxic events and the incidence of new insulin use were higher among FK506-treated patients. The target range of whole blood levels that optimizes efficacy and minimizes toxicity seems to be 5-15 ng/ml. The corresponding recommended initial dose of FK506 for kidney transplant recipients is 0.2 mg/kg/day. These results indicate that the efficacy and safety of FK506 were comparable to that for cyclosporine for primary immunosuppression in patients undergoing cadaveric kidney transplantation.

Correcting prolonged bleeding during renal transplantation with estrogen or plasma.

OBJECTIVE: To determine the efficacy and relative effectiveness of conjugated entrogens (CE) and fresh-frozen plasma (FFP) in normalizing prolonged preoperative bleeding times during renal transplantation. DESIGN: Prospective, randomized trial. SETTING: A university regional referral center for transplantation. PATIENTS: Patients scheduled for renal transplantation with preoperative bleeding times greater than 10 minutes (normal, < 7 minutes) following informed consent were asked to participate in the randomized protocol. Those with bleeding times of 8 to 9.5 minutes were asked, following informed consent, to be a control group receiving neither CE nor FFP. INTERVENTIONS: Following induction of anesthesia and drawing of baseline laboratory tests, patients were administered randomly, using a table of random numbers, either 50 mg of CE or 2 U of FFP. MAIN OUTCOME MEASURES: Bleeding time measurements and other laboratory tests were repeated at the end of surgery as well as at 24 and 48 hours postoperatively. RESULTS: Treatment with CE and FFP decreased the patients' bleeding times from 16.68 +/- 0.8 (SEM) and 17.13 +/- 0.85 minutes to 7.67 +/- 0.79 (P < .001) and 10.50 +/- 1.27 minutes (P < .001), respectively, by the end of surgery. At 24 and 48 hours postoperatively, the CE group had bleeding times of 9.77 +/- 0.99 and 9.81 +/- 1.24 minutes (P < .001 for both), respectively, whereas the FFP group bleeding times were 12.76 +/- 1.57 (P = .003) and 12.14 +/- 1.56 minutes (P = .001), respectively. There were no statistical differences for the control group compared with baseline either at the end of surgery or at 24 hours. CONCLUSIONS: Although both CE and FFP significantly decreased prolonged preoperative bleeding times during renal transplantation, CE might be preferred because of lower risk and cost, as well as a longer duration of action.

Impact of donor/recipient size matching on outcomes in renal transplantation.

Interest in nonimmunologic factors affecting longterm graft survival has focused on adequacy of nephron dosing. Body surface are (BSA) is a reliable surrogate for nephron mass. In a retrospective study of 378 primary recipients of paired kidneys from 189 cadaveric donors, we assessed the impact of matching donor and recipient BSA on outcome over 7 years. BSA of donors was 1.82 +/- 0.26 m2. Initially, paired recipients of kidneys from a single donor were divided into two groups. Group 1 included the recipient with the larger BSA of the pair (1.97 +/- 0.17 m2), while group 2 consisted of smaller BSA recipients (1.69 +/- 0.19 m2). Although early function was better in group 2 patients, graft survival at 1 year (77% vs. 79%) and 5 years (54% vs. 55%) was identical between groups, as were most recent serum creatinine levels (2.0 +/- 0.1 vs. 2.1 +/- 0.1 mg/dl). A second analysis divided patients with a functioning allograft at discharge from initial transplant hospitalization (n = 345) into three groups based solely on donor to recipient BSA ratio: the ratio of group A (n = 30) was < or = 0.8, that of group B (n = 255) was between 0.81 and 1.19, and that of group C (n = 51) was > or = 1.2. Graft survival and kidney function over 5 years did not differ among groups. In multivariate analysis of 17 variables, donor:recipient BSA, independent of other risk factors, did not affect risk allograft loss. These data indicate that including nephron mass as a criterion for cadaveric organ allocation is unlikely to improve long-term results in renal transplantation.

Progress in renal transplantation. A single center study of 3359 patients over 25 years.

OBJECTIVE: The study analyzed 3359 consecutive renal transplant operations for patient and graft survival, including living related, cadaveric, and living unrelated patients. The analysis was separated into three groups according to immunosuppression and date of transplant. SUMMARY BACKGROUND DATA: Improvements in renal transplantation in the past 25 years have been the result of better immunosuppression, organ preservation, and patient selection. METHODS: A single transplant center's experience over a 25-year period was analyzed regarding patient and graft survival. Potential risk factors included patient demographics, tissue typing, donor characteristics, number of transplants, acute and chronic rejection, acute tubular necrosis, primary disease, and malignancy. RESULTS: The primary cause of graft loss was rejection. Improvement in cadaveric graft survival since 1987 with quadruple therapy was not apparent in living donor patients. Race continued to be a negative factor in graft survival. Avoiding previous mismatched antigens and the use of flow cytometry improved allograft survival. The leading cause of death in the past 7 years in cadaveric recipients was cardiac (52%). CONCLUSIONS: Improved graft survival in the past 25 years was related to 1) advances in immunosuppression, 2) better methods of cytotoxic antibody detection, and 3) human lymphocyte antigen match.

Preferential rejection of the kidney in a simultaneous kidney-pancreas transplant.

A case of selective kidney allograft rejection with stable pancreas function in a patient who received simultaneous kidney-pancreas allograft from the same donor is reported. Pancreas function was shown to be normal within the first month posttransplant by both a glucose tolerance test (despite a high corticosteroid dose) and stable urinary amylase values during biopsy-proven acute renal allograft rejection. This patient subsequently rejected his kidney allograft as documented by histopathologic evidence of severe chronic vascular rejection and acute tubulointerstitial rejection, yet his pancreas function remained intact. He subsequently received a six-antigen-matched kidney, continues to have normal fasting glucose and normal glucose tolerance by oral glucose tolerance test, and is without evidence of glucosuria. He has never had a clinical rejection of his pancreas, as evidenced by either a decline in urinary amylase or hyperglycemia, and has not required insulin except in the perioperative period of his second kidney transplant, at which time he was receiving high doses of both corticosteroids and cyclosporin. It is suggested that preferential rejection and subsequent loss of the kidney, although infrequent, do occur in combined renal-pancreas allografts and that maintenance of immunosuppression is justified until retransplant of kidney is available.