Biomedical subjects

Charles Modlin

Publications and source records attributed to Charles Modlin.

10 recordsLinked to original sources

PubMed2006

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↗

PubMed2006

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↗

PubMed2005

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↗

PubMed2005

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↗

PubMed2005

Laparoscopic live donor nephrectomy has equivalent early and late renal function outcomes compared with open donor nephrectomy.

OBJECTIVES: To assess the patterns of early functional recovery and long-term function in laparoscopic and open procured live donor nephrectomy (LDN) kidneys, highlighting the radionuclide scan as an additional tool for assessment, because of concerns regarding renal functional recovery after laparoscopic LDN. METHODS: We reviewed the donor and recipient records of 101 laparoscopic and 35 open LDNs performed between August 1997 and September 2001. Data were collected on demographic, immunologic, and intraoperative variables and ureteral/vascular complications. Delayed renal function recovery in recipients was evaluated by serum creatinine greater than 2.5 mg/dL on postoperative day 5, dialysis in first postoperative week, and two renographic criteria--the time to peak activity and the time to one-half peak activity on postoperative day 5. Long-term outcomes were evaluated by serum creatinine at 1, 3, 6, and 12 months and 2 and 3 years, creatinine clearance at 1 year, and patient and allograft survival. RESULTS: Donor and recipient age, sex, body mass index, and number of HLA mismatches did not differ between the two groups. The mean operating room time and blood loss were comparable. No differences were found in the early functional parameters (renography, creatinine at postoperative day 1 and 5, or dialysis in week 1) or long-term outcome (patient and graft survival, creatinine, and rejection at 1 year and patient and graft survival at 1, 2, and 3 years). CONCLUSIONS: Early recovery of graft function, longer term renal function, and 3-year patient and allograft survival are similar for live donor kidneys obtained by either a laparoscopic or an open surgical technique.

Adult↗

PubMed2004

Salvage of compromised renal vessels in kidney transplantation using third-party cadaveric extenders: impact on posttransplant anti-HLA antibody formation.

Kidney transplant surgery can be complicated by short, attenuated, or injured renal vessels which are now more frequently encountered with laparoscopic right donor nephrectomy. We describe a technique to overcome this problem in seven recipients (2 cadaveric and 5 living donors) by constructing third-party "vascular extenders" using cadaveric iliac vessels retrieved previously and preserved at 4 degrees C in University of Wisconsin solution. Mean vessel cold storage time was 25.7 days (range, 2-56 days). Immunosuppression consisted of sirolimus, mycophenolate mofetil, and steroids. Prompt reperfusion of all allografts was observed, and there were no surgical complications. Integrity of the extenders was confirmed using serial MAG3 renal scans and magnetic resonance angiography. Mean serum creatinine was 1.44 mg/dl at 19.2 months (range, 0.7-2 mg/dl at 3-31 months). Each recipient had a negative posttransplant kidney donor specific flow cytometry crossmatch. Two recipients developed HLA antibodies, one to DR7 and another DR13 (mismatched to the vessel donor) at 4 and 11 months posttransplant, respectively.

Adenosine↗

PubMed2004

Factors related to delayed graft function after laparoscopic live donor nephrectomy.

PURPOSE: Delayed graft function after live donor transplantation affects 5% to 10% of recipients regardless of procurement technique. This delay in function is associated with an increased risk of rejection and decreased graft survival. In the present study we critically assess allograft recovery to identify the risk factors related to delayed graft function. MATERIALS AND METHODS: We retrospectively reviewed donor and recipient medical records from 100 consecutive laparoscopic live donor nephrectomies from August 1997 to October 2001. Four criteria were used to classify delayed graft function: I) requirement of dialysis in postoperative week 1, II) creatinine 2.5 mg/dl or greater at postoperative day 5, III) time to half peak activity (mercaptoacetyltriglycine renal scan) at postoperative day 5 greater than 12.2 minutes (normal range 1 to 12.2) and IV) time to peak activity (mercaptoacetyltriglycine renal scan) at day 5 greater than 6.5 minutes (normal range 2.1 to 6.5). Patients could qualify for multiple outcome categories. Patients who did not match any of these criteria were classified as having normal renal function (outcome 0). RESULTS: The number of patients in the delayed graft function categories were 5 with outcome I, 14 with outcome II, 39 with outcome III and 24 with outcome IV. There were 23 patients represented in more than 1 category and 59 patients were classified as having normal function. Recipient age, donor/recipient gender relationship, unrelated highly mismatched donors and cold/total preservation time were identified as risk factors related to impaired early renal function recovery. None of the variables related to the laparoscopic technique itself represented risk factors for delayed graft function. CONCLUSIONS: Female donor kidneys into male recipients and highly HLA mismatched donors represent factors that may be controlled by donor selection when feasible. All attempts should be made to decrease cold ischemia time and, therefore, total preservation time. Prolonged carbon dioxide pneumoperitoneum, warm ischemia time, renal artery length or use of right kidney did not adversely affect the functional outcome of the allografts procured laparoscopically.

Adult↗

PubMed2004

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↗

PubMed2002

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↗

PubMed2002

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↗