High incidence of delayed renal graft function.
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Biopsy↗
Biomedical subjects
David Goldfarb
Publications and source records attributed to David Goldfarb.
Expression of IL-8 during reperfusion of renal allografts is dependent on ischemic time.
BACKGROUND: Ischemia/reperfusion injury is an inherent consequence of solid organ transplantation that increases tissue inflammation and negatively impacts organ transplant function and survival. This study investigated the expression levels of chemokine and chemokine receptor genes in living versus cadaver donor renal allografts before and after reperfusion. METHODS: This study involved 39 renal transplant patients (19 cadaveric and 20 living donor). The ischemia biopsy was taken just before graft declamping and the reperfusion biopsy 30 min after declamping. Whole-cell RNA was isolated and chemokine (IL-8, CCL2/MCP-1, CXCL10/IP-10 and CCL5/RANTES) and chemokine receptor (CCR2 and CCR5) expression was tested by quantitative PCR. RESULTS: Just prior to declamping, ischemic cadaveric donor grafts had higher expression of CXCL10/IP-10 but not IL-8 or CCL2/MCP-1 than living donor grafts. IL-8 expression increased 50% from ischemia to reperfusion in living donor grafts but increased more than 13-fold during reperfusion of cadaver donor grafts. Increased total ischemia time induced greater IL-8 expression during reperfusion. MCP-1 expression also increased during reperfusion of living and cadaver donor grafts but differences were not observed between the two groups of grafts. RANTES, CCR2, and CCR5 expression did not change in ischemic vs. reperfusion biopsies. CONCLUSIONS: The expression of chemokines directing neutrophil and macrophage recruitment increases during reperfusion of living and cadaveric donor renal allografts. Expression levels of IL-8 correlate with the ischemic time imposed on the renal graft. Early tissue injury may be attenuated by strategies antagonizing chemokines directing the recruitment of neutrophils and macrophages into kidney grafts.
Chemokine CCL2↗
Posttransplant diabetes mellitus in kidney transplant recipients receiving calcineurin or mTOR inhibitor drugs.
BACKGROUND: The aim of this study was to evaluate the incidence and risk factors for posttransplant diabetes mellitus (PTDM; defined as new insulin use and/or new hyperglycemia) in 528 kidney recipients using different immunosuppressive agents. METHODS: Maintenance therapy included mycophenolate mofetil or azathioprine plus glucocorticoids in combination with Group I cyclosporine (263); Group II tacrolimus (60); or Group III sirolimus (205). RESULTS: The mean follow-up was 39.2 (range 9.0-103.8) months. Overall, the number of patients needing insulin was 7.4% (39/528). The incidences for Groups I, II, and III of 7.6%, 11.7%, and 5.9%, respectively, were not statistically different. Characteristics of patients with PTDM included older age (P=0.007); greater body weight (kg) at transplant, 6 months, and 12 months, respectively (P<0.001); greater BMI (kg/m2) at transplant, 6 months, and 12 months, respectively (P<0.001); more acute rejection episodes 28.2% vs. 13.5% (P=0.012); and increased incidence in African Americans (P=0.03). Multivariable analysis demonstrated increased risk for PTDM (defined as new insulin use) for tacrolimus, (hazard ratio [HR] 3.794, P=0.007); treated rejections (HR 2.491, P=0.0115); age (HR 1.407, P=0.0116); and BMI (HR 1.153, P<0.0001). New insulin use occurred sooner and with less total glucocorticoid dose for tacrolimus patients. If PTDM is defined as all cases of new hyperglycemia, then no immunosuppressive drug group demonstrated an increased risk. CONCLUSION.: The risk for developing PTDM is greatest among older recipients, and those obese at the time of transplant; those given steroid pulse therapy were at exceptionally high-risk. PTDM risk reduction should focus on weight loss in the obese end-stage renal disease population prior to transplant.
Adult↗
Laparoscopic donor nephrectomy gene expression profiling reveals upregulation of stress and ischemia associated genes compared to control kidneys.
We compared gene expression profiles from six donor kidneys prior to surgical manipulation to six kidneys removed after laparoscopic donor nephrectomy (LDN) and several hours of CO2 pneumoperitoneum. Biopsies were obtained from renal cortex and hybridized to Affymetrix HG-U133A GeneChips. For control kidneys, we identified 1380 genes present on all six samples that had a signal intensity >1,000. Functional classification of these revealed genes for cellular signaling (201; 15%), regulation of transcription (156; 11%), cellular transport (144; 10%) and cellular metabolism (111; 8%). A class comparison between the controls and LDN kidneys yielded 865 differentially expressed genes. Functional classification of the 502 genes differentially upregulated in LDN kidneys identified associations with apoptosis, cell adhesion, cell signaling, regulation of cell growth/proliferation, immune/inflammation, ischemia/stress response and proteolysis/peptidolysis. These data demonstrate an altered renal transcriptome induced by several hours of CO2 pneumoperitoneum and laparoscopic surgery characterized by upregulation of ischemia and injury associated genes.
Adult↗
Simultaneous vs. sequential laparoscopic bilateral native nephrectomy and renal transplantation.
We reviewed our experience with simultaneous single incision bilateral native nephrectomy and renal transplantation in 11 patients (Group 1), compared to seven recipients who underwent staged laparoscopic bilateral nephrectomy followed by kidney transplantation (Group 2). Mean age, donor source, sex, cause of ESRD, and specimen size were similar in both groups (P=0.1). All Group 2 patients and 9 of 11 Group 1 patients had autosomal-dominant polycystic kidney disease. Perioperative Group 1 complications included: bowel injury, transplant urine leak, necrotic pancreatitis, delayed bowel movement, and severe shoulder pain secondary to diaphragmatic irritation. Seven (63.6%) Group 1 patients required an additional surgical procedure: midline incisional hernia, repair ureteral fistula, and repair enterocutaneous fistula. One Group 1 patient lost his graft secondary to bowel injury and intra-abdominal sepsis. No major complications, reoperations, or graft loss occurred in Group 2. For simultaneous bilateral native nephrectomy and kidney transplantation, over 60% of patients required an additional surgical procedure. Laparoscopic bilateral nephrectomy followed by kidney transplantation is a safe and feasible alternative.
Adult↗
The effect of 2-gram versus 1-gram concentration controlled mycophenolate mofetil on renal transplant outcomes using sirolimus-based calcineurin inhibitor drug-free immunosuppression.
BACKGROUND: We performed a sequential study to determine the efficacy and side effects of low-dose (1 g) mycophenolate mofetil (MMF) in a CNI drug avoidance regimen including sirolimus/steroids. METHODS: A total of 260 kidney-only recipients were given basiliximab (232) or thymoglobulin (28) induction, and sirolimus/steroids. In addition, 160 recipients were begun on standard MMF 1 g twice daily (2-g group), while 100 recipients were begun on low-dose MMF 500 mg twice daily (1-g group). The 1-g recipients were concentration controlled to keep mycophenolic acid (MPA) C0 levels at 1.8-4 microg/ml. RESULTS: There were no statistically significant differences in demographics between the groups. At 6 months there were no significant differences between the 2-g and 1-g MMF groups in patient survival (96.8% vs. 96%), graft survival (92.5% vs. 95%), biopsy-confirmed and treated acute rejection (8.8% vs. 13%), or mean creatinine mg/dL (1.41+/-0.52 vs. 1.47+/-0.67), respectively. Mean MPA C0 levels microg/ml were (4.7 vs. 2.3) at 1 month, (4.1 vs. 3.1) at 3 months, and (3.9 vs. 2.4) at 6 months. There were no significant differences at 1, 3, or 6 months in mean WBC, HgB, or platelets, or wound complications. There were significant reductions in the number of patients reporting nausea-vomiting-dyspepsia (20.6% vs. 8%, P=0.007), diarrhea (34.3% vs. 20%, P=0.01), and abdominal pains (10.6% vs. 4%, P=0.05), between the 2-g and 1-g MMF groups, respectively. CONCLUSIONS: The use of concentration-controlled 1-g MMF results in comparable transplant outcomes with less GI toxicity during the first 6 months posttransplant in a CNI drug-free sirolimus based immunosuppressive regimen.
Adolescent↗
Thematic Issue "Apoptosis-like cell death programs in yeasts".
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Apoptosis↗
The influence of various maintenance immunosuppressive drugs on lymphocele formation and treatment after kidney transplantation.
PURPOSE: We compared the incidence of lymphocele formation and treatment in kidney transplant recipients given 3 immunosuppressive drug regimens. MATERIALS AND METHODS: Consecutive series of adult kidney only recipients, including group 1-152 who received sirolimus/mycophenolate mofetil (MMF)/prednisone (P), group 2-168 who received cyclosporine/MMF/P and group 3-193 who received cyclosporine/azathioprine/P, were analyzed for post-transplantation lymphocele formation. All available records and imaging studies were reviewed, such as ultrasound, computerized tomography, magnetic resonance imaging etc, for peritransplant fluid collections greater than 2.5 cm. Demographic characteristics and the risk factors for lymphocele were compared in these 513 recipients using univariate and multivariate analysis. RESULTS: The overall incidence of lymphocele formation was 174 of 513 cases (33.9%) and the incidence of treated lymphoceles was 81 of 513 (15.7%). In groups 1 to 3 the incidence was 45.5%, 33.9% and 24.7%, respectively. These differences were significantly higher in group 1 vs groups 2 or 3 (p = 0.014) but they were not significantly different between groups 2 and 3. Similarly the incidence of treated lymphoceles was 23%, 12.5% and 12.9%, respectively. Findings were again statistically higher in group 1 vs groups 2 and 3 (p = 0.003) but not statistically significant between groups 2 and 3. A greater number of group 1 patients required surgical interventions compared with those in groups 2 and 3 (13.8% vs 4.7% and 4.8%, respectively, p = 0.019). In addition, acute rejection (p = 0.001) and body mass index greater than 32 (p = 0.02) were significant risk factors on multivariate analysis. CONCLUSIONS: The combination of sirolimus/MMF/P, obesity with a body mass index of greater than 30 kg/m and acute rejection are independent risk factors for lymphocele formation and treatment after kidney transplantation. Patients should be counseled and consideration should be given to prophylactic measures in this higher risk renal transplant population.
Adult↗
The impact of sirolimus, mycophenolate mofetil, cyclosporine, azathioprine, and steroids on wound healing in 513 kidney-transplant recipients.
BACKGROUND: The aim of this study was to determine whether there has been an increase in the incidence or severity of wound-healing complications that can be attributed to the introduction of newer immunosuppressive drugs. METHODS: Consecutive series of adult kidney-only transplant recipients were selected from our Unified Transplant Database backward from September 2002. There were 513 patients divided into groups on the basis of their maintenance immunosuppression given for at least the first 30 days posttransplant. Group I (152) was given sirolimus, mycophenolate mofetil, and prednisone (SRL/MMF/P) between March 2000 and September 2002; group II (168) was given cyclosporine A (CsA)/MMF/P between January 1999 and July 2002; and group III (193) was given azathioprine (AzA)/CsA/P between January 1993 and December 1997. A classification system for wound-healing problems was developed, and each of the three groups was analyzed by univariate and multivariate analysis. RESULTS: From groups III to II to I, there was a significant increase in mean age (42.4 vs. 49 years), percent of patients diabetic (17% vs. 29%), mean body mass index (BMI) (24.2 vs. 27.1 kg/m2), and percent BMI greater than 30 (13.5% vs. 27%). The cumulative percentage of all wound-healing problems between group I (19.7%) vs. group II (16.1%) and group III (15.6%) was not significantly different. The most significant risk factor was a recipient BMI greater than 30 (P=0.0012) and delayed graft function (P=0.0041). CONCLUSIONS: During a 10-year period marked by changing recipient demographics, the introduction of MMF and SRL did not result in a significant increase in transplant wound-healing complications. The most significant risk factor associated with transplant wound-healing complications remains body weight, which was the major influence for each of the immunosuppressive drug combinations described.
Adrenal Cortex Hormones↗
Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus versus cyclosporine.
BACKGROUND: Progressive nephrotoxicity caused by calcineurin inhibitor drugs contributes to the long-term decline in renal function in kidney transplant patients. METHODS: We conducted a randomized, prospective trial of calcineurin inhibitor drug avoidance in 61 adult primary kidney transplant recipients. Each patient received induction therapy with 20 mg basiliximab on days 0 and 4, and maintenance therapy with mycophenolate mofetil 1 g two times per day and steroids. Thirty-one patients received sirolimus, 5 mg daily after a 15-mg loading dose. Doses were then concentration-controlled to keep 24-hr trough levels at 10 to 12 ng/mL for 6 months and 5 to 10 ng/mL thereafter. Thirty patients began cyclosporine therapy at 6 to 8 mg/kg per day in divided doses and were then concentration-controlled to keep 12-hr troughs of 200 to 250 ng/mL. RESULTS: Mean follow-up is 18.1 months (range, 12-26 months). The percentages of 1-year patient survival, graft survival, and biopsy-confirmed acute rejection rates were not significantly different between the sirolimus-treated patients (96.7%, 96.7%, and 6.4%, respectively) and the cyclosporine-treated patients (100%, 95.4%, and 16.6%, respectively). At 6 and 12 months, respectively, the sirolimus-treated patients enjoyed significantly better (P=0.008 and P=0.004) mean serum creatinine levels (1.29 and 1.32 mg/dL) and calculated creatinine clearances (77.8 and 81.1 mL/min) than cyclosporine-treated patients (1.74 and 1.78 mg/dL, and 64.1 and 61.1 mL/min, respectively). Sirolimus-treated recipients have significantly (P=0.001) higher 1-year trough levels of mycophenolic acid (4.16 ng/mL) than cyclosporine-treated patients (1.93 ng/mL). Sirolimus also delays the repopulation of basiliximab-depleted CD25 T cells compared with cyclosporine. CONCLUSIONS: Calcineurin inhibitor drug avoidance with basiliximab induction and sirolimus provides comparable 1-year transplant outcomes, with significantly better renal function in primary renal allograft recipients.
Adolescent↗
The effect of two different cyclosporine formulations on the long-term progression to chronic rejection in renal allograft recipients.
INTRODUCTION: The introduction of the microemulsion formulation of cyclosporine (CsA) (Neoral-NEO) has been shown to provide improved absorption and less intrapatient variability than the previous formulation (Sandimmune-SIM) in kidney transplant recipients. It has been suggested that the use of the microemulsion formulation results in less acute rejection, and therefore permits better long-term transplant outcomes. Our aim was to determine whether the microemulsion formulation of cyclosporine has reduced the long-term (5 yr or more) rates of chronic rejection (allograft nephropathy) in a renal transplant population. METHODS: The study population included 792 (508 cadaveric and 284 living donor) transplants performed in 786 patients at the Cleveland Clinic Foundation and its affiliate hospitals between July 1, 1987 and July 1, 1998. Patients who were less than 18-yr-old or had less than 12 months of graft function were excluded from the analysis. Over 90% of the cadaveric and 11% of the live donor recipients were given an induction antibody. A total of 591 patients were given the SIM formulation and 201 the NEO formulation of cyclosporine. Additional maintenance therapy included either azathioprine or mycophenolate mofetil, and steroids. All patients were followed to graft loss, death, or return to dialysis. The NEO group was followed until December 2001. The diagnosis of acute rejection was biopsy confirmed in >92% of cases. Chronic rejection was identified by clinical and biopsy criteria. Demographic and clinical data was collected from medical records, interviews, and phone contact with patients and treating physicians. RESULTS: The mean follow-up was 84 +/- 31 months for the SIM group, and 54 +/- 14 months for the NEO group. At 70 months there was no significant difference (p = 0.17) - actuarial patient survival between the SIM (90.7%) vs. the NEO (93%) treated patients. In addition, at 70 months there was no significant difference (p = 0.55) in death censored actuarial graft survival between the SIM (84.3%) and the NEO treated (85.7%) patients. The acute rejection-free rate was 10% higher for the NEO vs. the SIM patients (79 vs. 69%, p = 0.0004). Chronic rejection was diagnosed in 141 of 591 (24%) of the SIM patients and in 56 of 201 (28%) of the NEO patients (p = ns). At 5 yr the mean serum creatinine (mg/dL) was 2.07 +/- 1.69 for the SIM and 2.15 +/- 1.61 for the NEO patients (p = ns). CONCLUSIONS: The use of the microemulsion formulation of CsA has led to the improved delivery of the parent drug, and a decrease in the number of acute rejection episodes post-transplant. However, patient and graft survival, renal function, and progression to chronic allograft nephropathy at 5 yr were no different. The advantages of greater drug exposure from the microemulsion formulation may be counterbalanced by increased drug induced nephrotoxicity over time.
Adult↗
Solitary massive right ventricular metastasis of renal cell carcinoma without inferior vena cava or right atrium involvement.
Right ventricular metastases from renal cell carcinoma without inferior vena cava or right atrium involvement are rare. A 67-year-old male presented with hematuria and congestive heart failure. Computed tomography revealed a left renal mass. In addition, an intra-cardiac mass was found during the preoperative workup, causing right ventricular outflow tract obstruction. His past medical history included previous coronary bypass grafting. The patient underwent combined radical nephrectomy and removal of right ventricular mass. Pathology confirmed renal cell carcinoma with extensive sarcomatoid features in both the left kidney and right ventricle. His postoperative recovery was unremarkable.
Aged↗