Selective use of expanded criteria donors for renal transplantation with good results.

Increasing demand for renal transplants has stimulated expanded criteria for the use of deceased donors. Recently an official category of "Expanded Criteria Donors" (ECD) was designated by UNOS. This category included any deceased donor (1) greater than age 60 years or (2) age 50 to 59 years with any two of: (a) creatinine greater than 1.5 mg/dL (b) cerebrovascular accident cause of death, or (c) hypertension history. It has been anticipated that at 3 years, 70% of ECD kidneys with serum creatinine greater than 1.5 would be lost. We reviewed our experience with the use of this type of kidney prior to the era of officially designated ECD. Survival rates and serum creatinines were compared to standard criteria donor recipients for the same time period whose donor was greater than 50 years of age and correlated with biopsies. From 1996 to 2003, 341 deceased donor kidneys were transplanted at our center. Of these, 37 were ECD kidneys and 46 were standard criteria donors kidneys. Four pretransplant biopsies had greater than 20% sclerosed glomeruli. Four donors had 0% to 25% arteriosclerosis pretransplant; on postperfusion biopsy, eight had 0% to 25% arteriosclerosis, while three had 25% to 50%. The mean donor age was 61 years; mean recipient age was 54 years; recipient sex was 57% male, and 54% of the recipients were African-American. At 1, 2, and 3 years posttransplant, there was no significant difference between the two groups in serum creatinine, graft survival, or patient survival. Despite using ECD donors, good long-term function can be obtained, particularly if selectivity is exercised.

No-load sirolimus with tacrolimus and steroids is safe and effective in renal transplantation.

AIM: Basiliximab (BX) induction, tacrolimus (TAC), and steroids have sharply reduced acute cellular rejection at our institution. However, late graft loss has continued, for which sirolimus (SL) was introduced into the protocol. METHODS: From July 1, 2001 to December 31, 2003, 152 live donor (LD) renal transplant recipients received TAC (level 15 to 20 ng/mL) and steroids, with BX induction. One hundred twenty-two patients (Group 1) received SL (3 mg/d African-americans; 2 mg/d for others) starting on days 2 and 3. The SL level was adjusted to 8 to 10 ng/d, usually by weeks 3 to 4 posttransplant. The TAC doses were then progressively reduced. Records were reviewed for demographics, immunosuppressive drug levels, serum cholesterol and blood pressure, and complications. Graft and patient survival rates were calculated. Comparison was made to 53 LD recipients transplanted from July 1, 1998, to June 30, 2001 (Group 2) receiving BX, steroids and TAC, without SL. Recipients of deceased donor kidneys were excluded because of variability in kidney quality, ischemic time, and patient management. RESULTS: Demographics were similar between groups: African Americans, 25% to 35%; mean age 36 years; mean HLA mismatch 3.7. Wound problems and infection were minimal in both groups. Mean serum creatinine and cholesterol and systolic and diastolic blood pressure measured periodically up to 1 year were similar, as was the incidence of rejection. In 25% of patients, SL was discontinued. CONCLUSIONS: Gradual introduction of SL appears to be associated with minimal wound problems. With more aggressive reduction in TAC, better renal function, and better long-term graft survival may be attainable. We currently lower TAC levels to 5 ng/mL by 3 months.

Primary intestinal posttransplant T-cell lymphoma.

There have been only five reported cases of primary posttransplant T-cell lymphoma. We report the first case associated with the use of sirolimus (Rapamycin, Wyeth-Ayerst, Philadelphia, PA). The patient, receiving prednisone, cyclosporine, and sirolimus treatment, developed ascites, diarrhea, and weight loss 7 months after his second renal transplant. Tissue obtained at laparotomy established the diagnosis of primary T-cell lymphoma. Latent membrane protein-1 for Epstein-Barr virus was negative, but in-site hybridization test for Epstein-Barr-encoded RNA was positive. Despite aggressive chemotherapy, the patient died 8 months posttransplant. This is the sixth reported case of primary intestinal posttransplant T-cell lymphoma, but it is the first case associated with the use of sirolimus. The incidence of posttransplant lymphoproliferative disease in patients receiving sirolimus should be studied.

Basiliximab induction improves the outcome of renal transplants in children and adolescents.

Thirty-two children and adolescents received their renal transplant at the Montefiore Medical Center, in New York, between October 1996 and May 2000. Twenty-four patients received basiliximab, in addition to tacrolimus and steroids (basiliximab group). The remaining eight patients received only tacrolimus and steroids (non-basiliximab group). The 1-year patient survival rate was 100% in both groups. The 1-year graft survival rate was 87.5% for the basiliximab group and 75% for the non-basiliximab group (P=0.45). The rates of acute rejection in the basiliximab and non-basiliximab groups were 26% and 43%, respectively (P=0.36). However, in recipients with

Plasmapheresis treatment for recurrent focal sclerosis in pediatric renal allografts.

Recurrence of focal segmental glomerulosclerosis (FSGS) in pediatric renal allografts is associated with a poor graft survival. This study reports on plasmapheresis for the treatment of recurrent FSGS in pediatric renal transplant recipients. The records of 100 consecutive pediatric (age <21 years) renal transplants were reviewed. Twenty patients had FSGS as the cause of renal failure. Eight of these (40%) had a recurrence (proteinuria >1 g/m2 per day) within 1 month of transplantation. Five of six patients treated with plasmapheresis went into remission (<0.2 g/m2 per day), receiving a total of 42+/-26 (12-73) sessions, with the mean number of sessions required to achieve a remission being 24+/-17 (8-51). One patient had a second recurrence 1 year following cessation of plasmapheresis and responded to another course of plasmapheresis. The 1 patient who did not respond to plasmapheresis had a delay in initiation of therapy of 42 days. Plasmapheresis initiated within 48 h of recurrence resulted in earlier remissions and improved graft survival among our patients. Plasmapheresis appears to be effective in treating recurrent FSGS following kidney transplantation and should be started as soon as possible. The number of plasmapheresis sessions used to achieve remission should be adjusted according to response rather than adhering to a fixed protocol.

Mycophenolate mofetil treatment reduces atherosclerosis in the cholesterol-fed rabbit.

Immune/inflammatory responses of arterial vessel wall constituents to lipid metabolic disturbances have been postulated to contribute to the pathogenesis of atherosclerosis. Mycophenolate mofetil (MMF), an antiproliferative agent used in clinical transplantation, has been shown to inhibit smooth muscle cell (SMC) proliferation and decrease the recruitment of monocytes into sites of chronic inflammation. This study was conducted to determine the effect of MMF on atherosclerotic plaque development after cholesterol-induced injury. New Zealand white rabbits were fed a high-cholesterol diet containing 0.5% cholesterol and 8% peanut oil. The experimental group (n = 10) was given MMF (80 mg/kg/day subcutaneously); the control group (n = 10) received placebo injections. The aortas were harvested at 12 weeks for immunohistochemical analyses. SMCs were identified by reactivity with a monoclonal antibody (mAb) to alpha smooth muscle actin. Monocytes/macrophages were detected with mAb RAM 11. Cross-sectional areas of the media and neointima were measured using computer-assisted image analysis. The density of SMCs and macrophage/foam cells within the neointima was calculated by dividing the number of cells by the area of the plaque. Total cholesterol, triglyceride, high density lipoprotein, and low density lipoprotein were significantly increased compared with levels before the initiation of a high-cholesterol diet, but there were no significant differences between the MMF-treated and untreated groups. Neointimal area in aortic tissue sections of the MMF-treated group (0.586 +/- 0.602 mm(2)) was significantly lower when compared with that in control animals (1.082 +/- 0.621 mm(2)) (P < 0.05). The densities of neointimal SMCs and monocytes/macrophages in the control group were 778 +/- 293 and 341 +/- 90 cells/mm(2), respectively. MMF treatment significantly reduced the number of neointimal SMCs (506 +/- 185 cells/mm(2)) (P < 0.05). The number of monocytes/macrophages was also reduced after MMF treatment (260 +/- 124 cells/mm(2)) but not significantly. Our results demonstrate that the administration of MMF significantly reduced neointimal SMC accumulation and plaque development in a hypercholesterolemic model of atherosclerosis.

Reversible sensorineural hearing loss following administration of muromonab-CD3 (OKT3) for cadaveric renal transplant immunosuppression.

This prospective study is a follow-up to a case report noting reversible sensorineural hearing loss after administration of OKT3 for immunosuppression in a steroid-resistant renal cadaveric transplant patient who was rejecting his transplant. The objective is to determine the interval estimate for incidence of sensorineural hearing loss following treatment with OKT3. Seven patients were admitted to the Renal Transplant Service at Montefiore Medical Center from July 1996 to July 1997 with steroid-resistant rejection of renal cadaveric transplants and received OKT3 as an immunosuppressant. All 7 patients received 3 audiograms: the first, prior to the administration of the first dose of OKT3, the second, 48 to 72 hours after administration of OKT3, and the third, approximately 2 weeks after administration of OKT3. Five of the 7 patients (71%) demonstrated a sensorineural hearing loss of 15 dB or greater at frequencies of 8 to 12 kHz. Four of the 5 patients with audiographic changes had near-complete to complete recovery of their high-frequency thresholds after discontinuation of the drug regimen. In conclusion, OKT3 can cause sensorineural hearing loss. This side effect is mainly reversible after 2 weeks following discontinuation of the drug. Patients receiving OKT3 should be forewarned of this possible side effect prior to the administration of OKT3.

Renal transplantation in patients above 60 years of age in the modern era: a single center experience with a review of the literature.

A retrospective study was conducted of 797 patients receiving renal transplants from January 1985 to March 1997. Patient and graft survival was compared for patients above and below the age of 60. Sixty-nine patients < or =60 years old received 73 kidneys. Race: 73% Caucasian, 26% Black, 1% Other. Sex: 68% M. Hypertension (19) and PCKD (15) were the most common diagnoses. Mean peak panel reactive antibody (PRA) was 37.7%. Donor age was 2 to 66 years. Mean Cold ischemic time was 28.1 hours. Follow-up was until death or until 8/30/97. Patients <60 years included: 62% Caucasian, 34% Black, 4% Other; 60% male, Mean PRA 39.3. Of the 69 study patients, 27 died: 19 with a functioning graft, 8 within one year of transplantation. Cardiovascular causes (19 patients, 72%) and infection (7 patients, 24%) were most common. Common causes of graft loss were death with a functioning graft (19) and chronic rejection (15); other causes were acute rejection and primary non-function. Univariate analysis of 18 risk factors showed CHF and past history of vascular surgery significantly (p < 0.05) affected time of return to dialysis. Multi variate analysis did not show these independent variables to be significant. Abnormal ejection fraction and presence of q waves on EKG significantly affected time to death (p < 0.05) on uni- and multi-variate analysis. After censoring patients that died with functioning grafts, difference in graft survival between > or =60 and <59 years was not significant (p > 0.2). In this study, 68% of older patients had allografts functioning at 1 year. The fact that older patients succumb over time from natural causes should not keep patients from transplantation. Immunosuppressive agents need to be limited to reduce the incidence of infection. Criteria need to be refined to define those who are at prohibitive risk, who may not be candidates for transplantation.

Fifteen-year experience with pediatric renal transplantation at the Montefiore Medical Center.

At Montefiore Medical Center, 140 pediatric recipients have received 155 renal allografts over a 16-year period with an overall 6% mortality. Graft survival was not significantly different based upon race or sex of recipient. Graft survival was significantly better for first time transplants and the youngest recipients. Graft survival was significantly improved using Tacrolimus immunosuppression.

Effects of erythropoietin, angiotensin II, and angiotensin-converting enzyme inhibitor on erythroid precursors in patients with posttransplantation erythrocytosis.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEI) have become the treatment of choice for posttransplantation erythrocytosis (PTE). Yet the pathogenesis of PTE and the mechanisms of action of ACEI remain unclear. Therefore, we studied the dose response to erythropoietin (Ep), angiotensin II (AII), and the ACEI enalaprilat on the in vitro proliferation of erythroid progenitors in patients with PTE and in controls. We also evaluated ACE polymorphism in the two groups. METHODS: Twelve patients with PTE and 12 renal transplant patients without PTE were studied. Erythroid burst-forming units (BFU-E) were isolated from peripheral blood using standard methods. Ep sensitivity was determined for four patients with PTE and three control patients, using 0-3 U/ml Ep. AII dose response was studied in four patients with PTE and five control patients, using AII concentrations of 0-1000 nM. The effect of enalaprilat was studied in eight patients with PTE and eight control patients, using drug concentrations of 0-10 ng/ml. ACE gene insertion/deletion polymorphism was determined by polymerase chain reaction. RESULTS: PTE patients showed a significant shift of the Ep response curve to the left compared with controls, with 50% maximal growth occurring at a lower Ep concentration (0.3 U/ml vs. 0.95 U/ml, P<0.025.) However, there was no difference in the number of BFU-E colonies between PTE patients and controls. AII added to the growth medium produced only minor stimulation in both groups. PTE patients showed significant inhibition of BFU-E growth with 10 ng/ml enalaprilat, but controls showed no inhibition of BFU-E growth with ACEI. There was no difference in ACE polymorphism between PTE and controls. CONCLUSIONS: Our data suggest that PTE is associated with increased erythroid progenitor sensitivity to Ep. The effect of ACEI to decrease hematocrit in patients with PTE may be due to inhibition of red cell precursor growth.

Magnesium repletion therapy improved lipid metabolism in hypomagnesemic renal transplant recipients: a pilot study.

BACKGROUND: Hypomagnesemia has been associated with hypertension, abnormal glucose and lipid metabolism, and accelerated atherosclerosis in nontransplant patients. METHODS: In this prospective short-term pilot study, 14 hypomagnesemic renal transplant recipients with stable renal function were evaluated monthly over a 6-month interval. The first 3 months was the baseline observation period. During the second 3 months, MgO2 was administered to normalize the serum Mg level. Glucose tolerance, lipid levels, blood pressure, weight, and routine chemistries were assessed before and after Mg replacement. All others medications were held constant during the 6-month study. RESULTS: Serum Mg levels increased to normal range after MgO2 therapy, which was well tolerated. There were significant decreases in total cholesterol, low density lipoprotein, and total cholesterol/high density lipoprotein ratio after 3 months of MgO2 therapy. Only three patients had abnormal baseline glucose tolerance tests. All three patients showed improved glucose tolerance after MgO2, but this was not statistically significant. CONCLUSIONS: Mg repletion may be an important ancillary therapy in hypomagnesemic renal transplant patients with hyperlipidemia.

Use of spiral computerized tomography in lieu of angiography for preoperative assessment of living renal donors.

PURPOSE: We evaluate whether spiral computerized tomography (CT) can be used in lieu of renal angiography for preoperative assessment of living renal donors, with special attention to multiplicity of renal vasculature. MATERIALS AND METHODS: A total of 47 living renal donor candidates were evaluated with spiral CT and all but 2 underwent donor nephrectomy. Patients were divided into early and late groups because there was a learning curve with spiral CT. In the early group 18 donors underwent renal angiography as well as spiral CT and 10 underwent nephrectomy after spiral CT only. In the late group 5 had dual radiographic evaluation for ambiguities in spiral CT interpretation and 12 underwent nephrectomy after spiral CT only. Spiral CT was performed and interpreted blind to angiographic results, and vice versa. RESULTS: Spiral CT identified 50 of 52 renal arteries (96%) found at surgery overall and 23 of 25 (92%) found at surgery after spiral CT only. Two accessory arteries were missed in the 10 early group donors evaluated with spiral CT only, yielding an early negative predictive value of 80%. Renal angiography identified another accessory artery missed by spiral CT in the early group. All 3 missed vessels were identified retrospectively. No arteries found at surgery were missed in the late group (negative predictive value 100%), although there were 2 false-positive results detected by spiral CT relative to renal angiography in 1 candidate renal unit. Overall accuracy to predict early renal artery division relative to surgical findings was 93% for spiral CT and 91% for renal angiography. However, early renal artery division was clinically significant for only 1 of 11 vessels found at surgery. Spiral CT demonstrated 4 anomalous venous returns and renal angiography identified none. However, spiral CT missed 2 accessory veins and identified only 1 of 2 fibromuscular dysplasia cases. Total cost for spiral CT and renal angiography was $886 and $2,905, respectively. CONCLUSIONS: Spiral CT is a reasonably good alternative to renal angiography for living renal donor assessment but there is a profound learning curve for performance and interpretation. Renal angiography is still the gold standard with respect to the identification of arterial multiplicity and fibromuscular dysplasia, and it should be used adjunctively in cases with spiral CT ambiguity. Neither spiral CT nor renal angiography is ideal for the assessment of early renal artery division which is seldom an issue. The benefits of spiral CT over renal angiography are potentially lower morbidity, improved donor convenience and reduced cost.

Comparison of clinical features and liver histology in hepatitis C-positive dialysis patients and renal transplant recipients.

OBJECTIVE: Liver biopsies in hepatitis C virus (HCV)-positive end stage renal disease (ESRD) patients before or after renal transplantation were compared to study the effect of transplant-related immunosuppression. METHODS: In this prospective study all patients on the active transplant list and all patients with functioning renal transplants at our hospital were tested for HCV antibody (ELISA-2) over a 30-month period. HCV infection was confirmed by polymerase chain reaction in most patients. All HCV-positive patients were asked to undergo liver biopsy without regard to serum transaminase levels. Patients were interviewed, examined, and had detailed chart review. By protocol, liver histology was evaluated according to stage and inflammatory activity in a blinded fashion. RESULTS: There were 129 HCV-antibody-positive patients, of 795 tested. Sixty-seven agreed to liver biopsy. Of these, 22 patients had never been transplanted and 45 had received transplants. Mean transplant duration before biopsy was 41.2 months (range, 1-204 months). Transplant patients had significantly longer duration of ESRD and estimated duration of HCV infection than patients not transplanted. Dialysis patients had significantly more portal inflammatory activity and lymphoid follicles on biopsy whereas transplant patients had more piecemeal necrosis and steatosis. However, the total histological activity score and stage were similar between groups. Multivariate analysis confirmed the association between transplant and steatosis. But independent variables including transplant duration, HCV infection duration, and ESRD duration were not correlated with histological findings. CONCLUSION: Renal transplantation may not be associated with an increased risk of progressive liver disease in HCV-positive patients, compared with ESRD patients receiving chronic dialysis. Long-term studies with serial liver biopsies are needed to resolve this issue.

Chronic renal allograft rejection: no response to mycophenolate mofetil.

BACKGROUND: Mycophenolate mofetil (MMF) has been previously shown to prevent functional deterioration in an experimental model of chronic renal allograft rejection. METHODS: In this retrospective case-control study, patients with chronic rejection who were receiving cyclosporine or tacrolimus and who had MMF added to their immunosuppressive regimen were compared with patients with chronic rejection who were not receiving MMF. Patients were matched for serum creatinine levels and transplant duration at the time MMF was begun. RESULTS: In the MMF group, the average dose of MMF was 1482 mg/day with an average duration of 19.3 months. Over 36 months, including 12 months before MMF and up to 24 months on MMF, there was no difference in serum creatinine levels between the two groups. Cyclosporine levels and dose were no different. CONCLUSIONS: In this small, retrospective, preliminary study, adding MMF to maintenance immunosuppression provided no clear benefit to renal allograft recipients with established chronic rejection. Larger prospective randomized studies are needed.