MOF maintains transcriptional programs regulating cellular stress response.

MOF (MYST1, KAT8) is the major H4K16 lysine acetyltransferase (KAT) in Drosophila and mammals and is essential for embryonic development. However, little is known regarding the role of MOF in specific cell lineages. Here we analyze the differential role of MOF in proliferating and terminally differentiated tissues at steady state and under stress conditions. In proliferating cells, MOF directly binds and maintains the expression of genes required for cell cycle progression. In contrast, MOF is dispensable for terminally differentiated, postmitotic glomerular podocytes under physiological conditions. However, in response to injury, MOF is absolutely critical for podocyte maintenance in vivo. Consistently, we detect defective nuclear, endoplasmic reticulum and Golgi structures, as well as presence of multivesicular bodies in vivo in podocytes lacking Mof following injury. Undertaking genome-wide expression analysis of podocytes, we uncover several MOF-regulated pathways required for stress response. We find that MOF, along with the members of the non-specific lethal but not the male-specific lethal complex, directly binds to genes encoding the lysosome, endocytosis and vacuole pathways, which are known regulators of podocyte maintenance. Thus, our work identifies MOF as a key regulator of cellular stress response in glomerular podocytes.

Combined liver-kidney transplantation in patients with cirrhosis and renal failure: effect of a positive cross-match and benefits of combined transplantation.

Patients with renal failure after liver transplantation have a particularly poor prognosis. Therefore, in the setting of end-stage renal disease requiring dialysis or severe renal insufficiency that will not improve after liver replacement, combined liver-kidney transplantation (LKT) is the preferred approach. We have adopted a policy of LKT in patients with end-stage liver disease and renal insufficiency undergoing dialysis or with a creatinine clearance less than 35 mL/min and evidence of chronic renal dysfunction. Since 1991, we have performed 208 orthotopic liver transplantations. Fourteen patients (8%) have undergone combined LKT, including 6 patients undergoing hemodialysis. Cytotoxic cross-matches (modified Amos technique and antihuman globulin method) were performed on 13 of 14 patients and were positive in 3 patients. Two patients died less than 4 months after LKT and 12 patients are alive and well. Graft survival censored for patient death was 100% for liver allografts and 93% for renal allografts, with a mean follow-up of 39 +/- 24 months. The most recent serum creatinine level in the patients with the 11 functioning grafts was 1.1 +/- 0.6 mg/dL. Biopsy-proven acute rejection occurred in 50% of simultaneous liver allografts. By contrast, only a single episode (6%) of renal allograft dysfunction was attributable to acute rejection. All rejection episodes occurred in the first 90 days after transplantation and were steroid sensitive. Three of 14 combined procedures were performed in the setting of a positive cytotoxic cross-match. In 2 recent patients, the results were confirmed by positive cross-matches to the donor's T and B cells by flow cytometry. Flow cytometric cross-matches reverted to negative 1 hour after liver transplantation and several hours before the administration of antithymocyte globulin. The cross-matches remained negative on postoperative days 1 and 7. Presently, all 3 patients with a positive cross-match enjoy normal hepatic and renal function at 631, 706, and 2275 days follow-up. Renal scans were performed in 4 LKT recipients not previously undergoing hemodialysis and indicated varying and unpredictable degrees of function in the native and transplanted kidneys. In conclusion, combined LKT can be performed safely and is associated with a low rate of acute rejection, even in the setting of a positive cross-match. Predicting which patients with renal insufficiency will benefit from LKT remains challenging; however, these results suggest that LKT should be encouraged in patients with evidence of irreversible renal insufficiency who require liver transplantation.

Two hundred one consecutive living-donor nephrectomies.

OBJECTIVE: To assess donor morbidity, recipient outcome, and changing trends during the past decade in donor nephrectomy for living-donor kidney transplantation. DESIGN AND SETTING: Retrospective review at an academic tertiary care referral center. PATIENTS: We reviewed 201 consecutive living-donor kidney transplantations performed between January 1988 and June 1997. INTERVENTION: Donor nephrectomy and living-donor kidney transplantation. MAIN OUTCOME MEASURES: Donor surgical complications, correlation of preoperative imaging of donor vascular anatomy and operative findings, and donor lengths of stay in the hospital were analyzed. Recipient delayed graft function and actuarial 1- and 5-year patient and graft survival rates were also analyzed. RESULTS: Major donor postoperative complications were bleeding (0.5%), pneumothorax requiring a chest tube (1%), wound infection (1%), and pneumonia (1%). Minor postoperative complications were asymptomatic pneumothorax resolving spontaneously (10%), urinary retention (6%), and urinary tract infection (0.5%). Preoperative imaging failed to detect small accessory renal arteries in 12% of donors. The mean donor length of stay in the hospital was 5.0 days but decreased from 6.2 to 4.0 days during the study. Twenty donors (10%) were unrelated (ie, spouse or friend). Three (1.5%) cases of delayed graft function occurred. Overall recipient patient survival at 1 and 5 years was 97% and 90%, and graft survival was 95% and 83%, with no difference between related and unrelated living donors. CONCLUSIONS: Living-donor nephrectomy is associated with low surgical morbidity. Recent trends include shortened lengths of stay in the hospital, the use of computed tomographic angiography instead of digital subtraction angiography for preoperative imaging of donor vascular anatomy, and an expanded use of unrelated living donors.

Correlation of clinical outcomes after tacrolimus conversion for resistant kidney rejection or cyclosporine toxicity with pathologic staging by the Banff criteria.

BACKGROUND: Refractory rejection and cyclosporine (CsA)-induced nephropathy remain important causes of renal allograft loss. Previous studies demonstrated that 70-85% of the episodes of refractory acute rejection (AR) occurring in renal allograft recipients on a CsA-based immunosuppressive regimen could be salvaged by conversion to tacrolimus. No data are available regarding the correlation between allograft histology at the time of conversion and the response to tacrolimus. We examined the response to tacrolimus conversion in relation to preconversion biopsies stratified by the Banff criteria. METHODS: Since May 1992, we have converted 22 patients from CsA to tacrolimus as part of a rescue protocol. We report on 18 patients in whom 6-month follow-up was available after conversion for biopsy-proven AR (n=13) or CsA toxicity (n=5). Sixteen patients were recipients of renal allografts, including three second transplants, and two were recipients of kidney-pancreas transplants. All patients with AR were treated with one or more courses of methylprednisolone and OKT3 before conversion. Renal allograft biopsies were interpreted by a transplant pathologist blinded to the clinical history, and graded according to the Banff criteria. Responses to tacrolimus were scored as improved (creatinine returned to within 150% of baseline), stabilized (creatinine rise arrested), or failed (returned to dialysis). RESULTS; Mean follow-up was 17.3+/-8 months. Fourteen of 18 patients (78%) showed improvement or stabilization in renal function as assessed by creatinine at 6 months or 1 year (when available). Of the 13 patients with histological AR, nine (69%) improved, including five of six with borderline AR, two of three with grade I AR, and two of four with grade II AR. Of the four other patients with AR, two stabilized and two failed. Three of five patients with severe clinical rejection requiring dialysis (range 2-16 weeks) recovered renal function after conversion. Of five patients with CsA toxicity, two (40%) improved. Seven of eight patients who were converted to tacrolimus less than 90 days after transplantation improved, compared with only 4 of 10 who were converted more than 90 days after transplantation. No grafts were lost in patients with a creatinine <3.0 mg/dl at the time of conversion versus two of seven grafts lost when the creatinine was 3.1-5.0 mg/dl and two of eight grafts lost when the creatinine was >5.0 mg/dl. CONCLUSION: The majority of steroid and antilymphocyte antibody (OKT3 or ATGAM) unresponsive rejections in patients on CsA-based immunosuppression will improve or stabilize after conversion to tacrolimus. There was no correlation with allograft histology stratified by the Banff criteria and the response to tacrolimus. Although there was a trend toward a poorer response with more severe histological rejection, higher serum creatinine at the time of conversion, and longer time from transplantation to conversion, favorable responses were noted in all groups. This indicates that a trial of conversion is warranted, irrespective of the histological severity of injury.

Kidney transplantation in diabetic patients using cyclosporine. Five-year follow-up.

OBJECTIVE: To review our center's experience with kidney transplantation in diabetic recipients; specifically, to compare long-term (5-year) patient and graft survival rates between diabetic and nondiabetic recipients overall and according to donor source using cyclosporine-based immunosuppression. DESIGN: A retrospective review of all kidney transplants performed over the 7-year period from 1987 to 1993. SETTING: A large urban tertiary care referral center with a long history of kidney transplantation and care of the diabetic patient. PATIENTS: All patients receiving a kidney transplant, either alone or simultaneously with a pancreas transplant, were reviewed. MAIN OUTCOME MEASURES: Actuarial patient and graft survival, serum creatinine levels, and causes of late graft loss. RESULTS: There was no significant difference in actuarial 5-year patient or kidney graft survival between diabetic and nondiabetic recipients overall or when analyzed by donor source. There was no significant difference in mean serum creatinine levels at 5 years between diabetic and nondiabetic recipients overall or between diabetic and nondiabetic cadaveric recipients. While chronic rejection was the major cause of late graft loss in nondiabetic recipients, death with a functioning graft, principally due to cardiovascular disease, was the major cause of graft loss in diabetic recipients. CONCLUSIONS: With cyclosporine-based immunosuppression, diabetic kidney transplant recipients have 5-year patient and graft survival rates and allograft function comparable to nondiabetic recipients. Given the high mortality of diabetic patients receiving dialysis, kidney transplantation is the treatment of choice for end-stage diabetic renal disease.

Combined kidney and pancreas transplantation. A 3-year experience.

Between May 1988 and September 1991, we performed 26 simultaneous kidney and pancreas transplants and one pancreas transplant after a kidney transplant. All transplants consisted of bladder drainage via a duodenal segment. Actuarial patient, kidney, and pancreas graft survival rates at 12 months were 96%, 88%, and 85%, respectively, and at 24 months were 96%, 88%, and 81%, respectively, and were not significantly different from those of diabetic recipients of cadaver kidney transplants alone. Excellent long-term glycemic control was obtained as monitored by fasting blood glucose and glycosylated hemoglobin levels and by oral glucose tolerance tests. The mean period of hospitalization and number of hospital admissions in the first year posttransplant were significantly greater for patients who received combined kidney and pancreas transplants than for those who received cadaver kidney transplants alone. Combined kidney and pancreas transplants can be performed with patient and graft survival comparable to those of kidney transplants alone, with excellent long-term glycemic control, but result in increased morbidity in the first postoperative year.

Bioavailability and patient acceptance of cyclosporine soft gelatin capsules in renal allograft recipients.

OBJECTIVE: To evaluate the relative bioavailability and patient acceptance of cyclosporine (CSA) soft gelatin capsule versus oral solution in renal allograft recipients. DESIGN, SETTING, AND PATIENTS: The bioavailability of CSA capsules was compared with that of CSA solution with crossover study design in the outpatient clinic setting. Nine renal allograft recipients with stable renal function participated in this study. METHODS: CSA dose was switched from solution to capsule in each patient for seven days. At steady-state, nine blood samples were obtained over a 12-hour period from each patient on day 7 for CSA solution and on day 14 for CSA capsules. CSA blood samples were analyzed by HPLC and fluorescence polarization immunoassay (FPIA) methods. Time to peak concentration (Tmax), peak concentration (Cmax), and area under the curve (AUC) were calculated on days 7 and 14, and compared using the matched Student's t-test. Patient acceptance was evaluated by patient preference on the questionnaire. RESULTS: For CSA blood concentrations measured by HPLC assay, the Tmax, Cmax, and AUC were 3.4 +/- 1.3 h, 569 +/- 240 nmol/L, and 4659 +/- 2144 h.nmol/L (mean +/- SD), respectively, with solution and 4.2 +/- 2.1 h, 560 +/- 257 nmol/L, and 4765 +/- 1799 h.nmol/L (mean +/- SD), respectively, with capsules. These differences were not significant (p greater than 0.1). The bioavailability was not significantly different between capsules and solutions when it was measured by PFIA assay (p greater than 0.1). The mean (+/- SD) relative bioavailability of capsules compared with solution was 109 +/- 29 percent AUC (0-12 h) measured by HPLC and 111 +/- 27 percent AUC (0-12 h) measured by FPIA. All patients expressed preference for capsules over the solution. CONCLUSIONS: CSA oral soft gelatin capsule is bioequivalent to CSA oral solution and most patients preferred the capsule to the oral solution.

Aortoiliac reconstruction following renal transplantation.

With better survival and extended indications for renal transplantation, it is anticipated that the problem of aortoiliac disease in the posttransplant patient will be seen with increasing frequency. Two patients requiring aortoiliac reconstruction were successfully managed with improvement in graft function after surgery. One patient manifested atheroembolism resulting from aortoiliac occlusive disease; the other had a 2 cm rupture in an aortic aneurysm, which resulted in a large retroperitoneal hematoma, but without frank shock. Perfusion of the transplanted kidney was maintained by the use of a temporary axillofemoral graft, which was removed following aortoiliac repair. The use of this technique involves minimal physiologic disturbance to the patient and the renal graft and allows conventional aortoiliac reconstruction.

De novo development of membranous nephropathy in cadaver renal allografts.

Glomerulonephritis in transplant recipients often reflects recurrence of the immunopathogenetic mechanism causing the original renal disease. Membranous nephropathy (MN), a progressive immune complex mediated glomerular disease and the commonest cause of idiopathic nephrotic syndrome in adults, has been virtually unreported in transplant recipients. Two cases are reported here of typical MN (by clinical, light, immunofluorescent and electron microscopic criteria) developing de novo in the transplants of patients whose original diseases were anti-GBM nephritis and focal glomerular sclerosis. NM developed following episodes of viral hepatitis and renal infarction respectively. Possible mechanisms by which this lesion might develop in these patients are investigated and discussed. Chronic immune complex nephropathy (MN) can develop de novo in immunosuppressed transplant recipients apparently initiated by events in the post-transplant period.

Possible active enhancement of a human cadaver renal allograft with antilymphocyte serum (ALS) and donor bone marrow: case report of an initial attempt.

Nonspecific immunosuppression of transplant patients frequently leads to complications which might be circumvented by inducing donor-specific immune unresponsiveness. Such specific immunosuppression has been produced experimentally, with use of donor antigen and antilymphocyte serum (ALS) for active enhancement. A case is presented in which the recipient of a cadaveric renal allograft (zero antigen match, cross-match negative) was given ALS (first 14 days after operation) and 11 X 10(9) donor bone marrow cells (twenty-fifth postoperative day) along with conventional doses of prednisone and Imuran in an attempt to produce donor-specific immune unresponsiveness. There were no rejection episodes, and serum creatinine remained less than 1.0 mg. per 100 ml. By the second month after transplantation there was no evidence for the persistence of donor erythrocytes or white cells. The conventional immunosuppressive agents were tapered and renal function was normal 8 months after transplantation, when the patient developed fatal peritonitis secondary to perforated sigmoid diverticulitis. At autopsy the renal allograft showed only minimal evidence of rejection. The present case illustrates an attempt to use ALS and donor bone marrow cells for active enhancement of a human cadaveric renal allograft. The infusion of stored donor marrow cells after transplantation is a particularly applicable technique for human cadaveric organ transplantation. The rejection-free course of this patient suggests that attempts to produce active enhancement clinically deserve further trial.

Successful renal transplantation in Wegener's granulomatosis.

Two patients with Wegener's granulomatosis, who were in complete remission secondary to cyclophosphamide therapy but who had end-stage renal failure, were treated with renal transplantation. Neither patient has clinical evidence of recurrent glomerulonephritis 10 and 28 months after receiving the renal transplants. Cytotoxic therapy has been proved to be highly effective in inducing and maintaining remission in patients with Wegener's granulomatosis; thus increasingly larger numbers of patients will be seen who, despite being maintained in complete remission, will have markedly impaired renal function due to previous acute damage. Renal transplantation can now be considered an acceptable alternative form of therapy in such patients.