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Papers by Rino Munda

American journal of surgery, 1977

Thirteen renal artery stenoses occurred in 127 renal allograft transplantations performed at the ... more Thirteen renal artery stenoses occurred in 127 renal allograft transplantations performed at the University of Cincinnati Medical Center over a four year period. The most common symptoms were hypertension and decreasing renal function occurring from three days to three years post transplantation. Eight lesions occurred in patients with a single artery and five when double arteries had been joined together prior to anastomosis rather than implanted separately. The most common causes of renal artery stenosis was intimal hyperplasia of the donor vessel distal to the anastomosis (8 patients), atheromatous plaques (2), technical failure (2), and external compression (1). Surgical correction was facilitated by a midline incision. Resection of the stenotic segment and reanastomosis was the preferred procedure. Surgical failure and recurrence of hypertension were associated with involvement of small arteries or distal arteriolar level. When kidneys with multiple arteries are available, Carr...

Transplantation Proceedings, 2002

Transplantation Proceedings, 2005

Experience with early corticosteroid withdrawal (CSWD) in renal transplant recipients with focal ... more Experience with early corticosteroid withdrawal (CSWD) in renal transplant recipients with focal segmental glomerulosclerosis (FSGS) has not been previously reported. Since corticosteroids are used to treat primary FSGS, concern exists as to whether early CSWD regimens will be associated with an increased risk of FSGS recurrence posttransplant. The purpose of the present study was to evaluate the results of early CSWD in FSGS recipients and compare these results to a historic control group of FSGS patients who underwent renal transplantation under corticosteroid-based immunosuppression. Forty-three patients with FSGS underwent renal transplantation with early CSWD. Results in these patients were compared to FSGS patients that underwent renal transplantation with chronic corticosteroid therapy. All rejection episodes were biopsy proven with grading by Banff criteria. Statistical analyses included Student's t test and chi square tests. Results in 43 patients with a median follow-up of 569 days were analyzed and compared to control patients. There was no significant difference in recurrent FSGS, time to recurrence, or graft loss. CSWD does not increase risk for recurrence of FSGS. These observations indicate that ECSW can be achieved in FSGS patients, thereby affording them the benefits of steroid elimination.

Transplantation, 1990

OKT3 is an IgG2a murine monoclonal antibody directed against the CD3 antigen receptor of human T ... more OKT3 is an IgG2a murine monoclonal antibody directed against the CD3 antigen receptor of human T lymphocytes. A major concern with OKT3 treatment in solid organ transplant recipients is the development of antimouse antibody, which may preclude retreatment with this agent. We have administered OKT3 on 215 occasions (150 renal, 34 hepatic, 26 cardiac, 5 pancreatic) in 179 patients between April 1982 and December 1988. The mean duration of treatment was 10.5 days (range, 2-22 days). Antimouse antibody data were analyzed on the most recent 133 treatment courses where the antibody status was available pretreatment. Determination of antimouse antibody production was elicited by ELISA technology at days 0, 7, 14, and 28 of OKT3 treatment. Patients were categorized according to the antibody response as follows: (a) absence of antibody; (b) low titer (1:100); or (c) high titer (greater than or equal to 1:1000). Our earlier experience has demonstrated that retreatment with OKT3 is successful in groups a and b. The development of antimurine antibodies was analyzed with regard to the following parameters: (1) The duration of OKT3 treatment; (2) treatment type (prophylactic, primary, or secondary); (3) primary treatment or retreatment; (4) concomitant immunosuppressive regimen (double or triple therapy); (5) dosage of concomitant immunosuppressive drugs; and (6) transplant organ type. The following results were obtained. (1) Duration of treatment had no effect on antibody production (11.0 days in antibody negative and 10.0 days in antibody positive). (2) There was no difference in antibody formation rates for the first treatment of OKT3 when it was used as prophylaxis (26%), primary (19%), or secondary (27%) therapy. (3) Antibody formation rate with first treatment was 29%; with retreatment, patients who were antibody negative following first treatment became positive in 28% of cases, and retreated patients who were low titer positive following first treatment converted to high titer in 57% of cases. (4) Antibody formation was higher in patients receiving double immunosuppressive therapy (36%) than in those receiving triple immunosuppressive therapy (21%) during OKT3 treatment. (5) Concomitant immunosuppression was lower in the antibody-positive group during OKT3 therapy: steroids, 61 mg/day vs. 52 mg/day; azathioprine, 89 mg/day vs. 66 mg/day; CsA, 317 mg/day vs. 186 mg/day. (6) Antibody formation rates were lower in non-renal transplants following first treatment with OKT3 (liver 17%, heart 17%, kidney 28%); this reflects the higher doses of concomitant immunosuppressive therapy used in nonrenal transplants.(ABSTRACT TRUNCATED AT 400 WORDS)

Transplantation, 1987

Exocrine secretions of 16 of 22 pancreas allografts were drained into the urinary tract. Seven of... more Exocrine secretions of 16 of 22 pancreas allografts were drained into the urinary tract. Seven of these 16 patients have functioning allografts, six with pancreaticocystostomies and one with duct-to-ureter anastomosis. A notable problem has been a chronic metabolic acidosis, along with weight loss and hypotension, secondary to chronic bicarbonate loss and volume depletion through the urinary pancreatic fistula. This occurred as early as one week posttransplant, and intermittently thereafter up to four years. The syndrome was aggravated by episodes of renal dysfunction (acute tubular necrosis or rejection), and febrile syndromes. An inverse relationship between serum and urine bicarbonate concentrations existed, with a correlation coefficient, r = -0.746, (P less than 0.05). A negative correlation was also noted between serum bicarbonate and serum creatinine, r = 0.726, (P less than 0.05). Hyperchloremic metabolic acidosis with normal anion gap occurred despite periods of marginal pancreas allograft function resulting from ongoing rejection. Treatment consisted of intravenous and/or oral bicarbonate supplementation, and bicarbonate dialysis for uremic patients. In addition, one patient was first seen with severe balanitis and urethritis due to documented activation of trypsinogen and chymotrypsinogen, presumably caused by recurrent episodes of urinary tract infection. Urinary assay revealed a 10(2-3) increase in activated trypsin and chymotrypsin in comparison with other asymptomatic allograft recipients. Conversion to ductal enteric drainage led to resolution of both the balanitis and bicarbonate wasting. Measurement of urinary amylase levels were gross indicators of graft viability since no correlation could be found between these levels, onset of hyperglycemia, and eventual graft rejection confirmed by pathological examination.

Transplantation, 1992

... By Preoperative Donor-Specific Transfusions and Cyclosporine in Human Cadaveric Transplants. ... more ... By Preoperative Donor-Specific Transfusions and Cyclosporine in Human Cadaveric Transplants. ALEXANDER, J. WESLEY; BABCOCK, GEORGE F.; FIRST, M. ROY; DAVIES ... SUNDARAM; CARDI, MICHAEL; MANZLER, ALAN; COHEN, LOREN; MENDOZA, NINA; CLYNE ...

Transplantation, 2005

Background. Weight gain is a known complication of corticosteroid maintenance therapy. The purpos... more Background. Weight gain is a known complication of corticosteroid maintenance therapy. The purpose of the present study was to compare patterns of weight gain under chronic corticosteroid therapy (CCST) with that observed under early (i.e., within 7 days posttransplant) corticosteroid withdrawal (CSWD) in renal-transplant recipients. Methods. Renal-transplant recipients who underwent early CSWD under four prospective, institutional review boardapproved clinical trials were compared with a historic control group of patients receiving maintenance CCST. Results. One hundred sixty-nine patients with early CSWD were compared with 132 patients who received CCST. Mean population weight gain was significantly higher in CCST patients at 3, 6, and 12 months posttransplant. Race influenced weight gain because white CSWD patients demonstrated greater reductions in weight gain compared with African-American patients. Sex also influenced weight gain: women demonstrated a greater benefit from CSWD than did men. Corticosteroid rejection therapy in CSWD patients completely restored weight gain because these patients showed weight gains similar to the CCST group. Finally, pretransplant body mass index (BMI) also influenced weight gain because patients who were overweight or obese (BMIϾ30) demonstrated a greater reduction in weight gain with CSWD than did patients of normal weight (BMIϽ25). Conclusions. Early CSWD minimizes weight gain in renal-transplant recipients. Women, whites, and patients with high pretransplant BMI had greater reductions in weight gain with early CSWD.

Transplantation, 2005

Animal studies have shown that dietary supplementation with arginine and lipids containing the -3... more Animal studies have shown that dietary supplementation with arginine and lipids containing the -3 and -9 fatty acids prolong allograft survival in animals receiving a short course of low-dose cyclosporine. They also reduce cardiovascular complications and infections in humans. Methods. Adult renal transplant patients receiving standard immunosuppression were stratified according to gender, diabetic state, donor source (LD or CD), and first versus repeat transplant, and randomized to receive or not receive supplemental arginine and canola oil (containing both -3 and -9 fatty acids) twice daily. Patients were followed for a minimum of 3 years. Results. Seventy-six patients were randomized to the supplement group (S) and 71 patients to the control group (C). Intent-to-treat analysis revealed that S patients had fewer post-30 day first rejection episodes (5.4%) when compared with the C group (23.7%) (Pϭ0.01) and fewer post-30 day episodes of calcineurin inhibitor (CNI) drug toxicity (9.2% vs. 35.3%, Pϭ0.003). S patients developed new onset diabetes mellitus (NODM) less frequently by 3 years (2.3% vs. 14.5%, Pϭ0.04), had fewer cardiac events (5.0% vs. 17.1%, Pϭ0.05), and fewer episodes of sepsis (6.5% vs. 18.7%, Pϭ0.05).

Transplantation, 1996

This study details 11 pancreas transplant recipients (10 combined kidney and pancreas and 1 pancr... more This study details 11 pancreas transplant recipients (10 combined kidney and pancreas and 1 pancreas after kidney) who were converted to tacrolimus (FK506) due to acute severe cyclosporine nephrotoxicity in 8 cases and persistent rejection with cyclosporine toxicity in three cases. Arteriolopathy was documented by renal histology in all cases. Cyclosporine was discontinued for 24 hr immediately prior to initiation of tacrolimus. Tacrolimus was started orally at 0.1 mg/kg twice daily with dose adjustments to maintain whole blood trough levels of 8-15 ng/mL by IMx. Tacrolimus was initiated a mean of 14.5 months (range 1-81) after pancreas transplantation. The mean serum creatinine level had increased to 2.9 mg/dl from 1.0 mg/dl at the diagnosis of cyclosporine arteriolopathy (P=0.003). The mean serum creatinine and blood glucose levels at the time of initiation of tacrolimus were 2.1 mg/dl and 104 mg/dl, respectively. Serum creatinine was 1.7 mg/dl, 1.9 mg/dl, 1.8 mg/dl, and 1.7 mg/dl after 1, 2, 3, and 6 months of tacrolimus therapy, respectively; ANOVA (P = 0.02). The corresponding blood glucose levels were 117 mg/dl, 112 mg/dl, 109 mg/dl, and 116 mg/dl, respectively (P=NS). Normal C-peptide levels were present before (5.9 ng/ml) and after (6.2 ng/ml), the initiation of tacrolimus therapy (P=NS), and mean HbA1C was 6.1% before and 6.3% after tacrolimus therapy, (P=NS). There were 4 episodes of acute rejection, 3 responded to intravenous methylprednisolone, and 1 required OKT3 during tacrolimus therapy. Reversible tacrolimus nephrotoxicity was noted in three patients without any evidence of progressive vasculopathy. All 11 patients are alive, and 10/11 kidney and pancreas grafts are functioning with a mean follow-up of 7.7 months (range 5-10). In this study, conversion from cyclosporine to tacrolimus in kidney and pancreas recipients resulted in improvement and stabilization of renal function while maintaining stable blood glucose, C peptide, and HbA1C levels.

Transplant International, 2006

The American Journal of Surgery, 1976

Seminars in Nephrology, 2012

Seminars in Dialysis, 2014

Venous stenosis, secondary to venous neointimal hyperplasia (VNH), at the arteriovenous anastomos... more Venous stenosis, secondary to venous neointimal hyperplasia (VNH), at the arteriovenous anastomosis (AV) is a major etiology of vascular access failure in AV fistulas (AVF) and AV grafts (AVG). Recently, our group has reported that severe VNH also occurs prior to vascular access placement. The objective of this study was to perform a comparison of the cellular phenotypes within the neointima from veins collected from subjects at the time of new vascular access creation and stenotic veins from subjects with failed AVGs and AVFs. Vein samples, collected at the time of new access surgery, and stenotic vein segments, collected at access revision, were evaluated for expression of α-smooth muscle actin (SMA), vimentin, and desmin within the neointima, and quantified using semiquantitative scoring. Within the neointima, the majority of cells from vein samples collected at the time of new access surgery were contractile smooth muscle cells, and veins from stenotic AVF and AVG were predominately myofibroblasts. Our results suggest the possibility of different mechanistic pathways in response to vascular injury that occurs prior to vascular access creation vs. after access creation, and that divergent therapeutic approaches may be needed for treating vascular injury in these two settings.

Seminars in Dialysis, 2012

Although the arteriovenous fistula (AVF) is the preferred mode of dialysis vascular access, AVF m... more Although the arteriovenous fistula (AVF) is the preferred mode of dialysis vascular access, AVF maturation failure remains a huge clinical problem, often resulting in a prolonged duration of use of tunneled dialysis catheters. In contrast, polytetrafluoroethylene (PTFE) grafts do not suffer from early failure, but have significant problems with later stenosis and thrombosis. This review will initially summarize the pathology and pathogenesis of PTFE graft dysfunction and will then use this as a basis for describing some novel therapies, which may have the potential to reduce PTFE graft dysfunction. Finally, we will emphasize that the introduction of such therapies could be an important first step toward individualizing overall vascular access care.

Nephrology Dialysis Transplantation, 2009

Background. Haemodialysis vascular access dysfunction (due to venous stenosis and thrombosis) is ... more Background. Haemodialysis vascular access dysfunction (due to venous stenosis and thrombosis) is a leading cause of hospitalization and morbidity. The aim of the current study was to identify the specific cell types present within stenotic tissue samples from patients with AV fistula and graft failure. Methods. Discarded tissue segments were collected from the stenotic portions (usually near the graft-vein anastomosis or the AV anastomosis) of 23 dialysis grafts and 20 AV fistulae, and examined for expression of smooth muscle alpha actin, desmin, vimentin and a macrophage marker. Results. The majority of cells within the venous neointima (both grafts and fistulae) were myofibroblasts, with a smaller number of desmin positive smooth muscle cells. The graft neointima had a similar cellular phenotype, albeit without any desmin positive contractile smooth muscle cells. The majority of cells within the PTFE graft material were macrophages. Analysis of sequential sections revealed the presence of fibroblasts within the venous neointima and intragraft region. Conclusions. Our results demonstrate that contractile smooth muscle cells, myofibroblasts, fibroblasts and macrophages all play a role in the pathogenesis of dialysis access dysfunction (grafts and fistulae). Targeting these specific cell types might result in the development of novel therapeutic paradigms for haemodialysis vascular access dysfunction.

Journal of Clinical Laboratory Analysis, 1990

Orthoclone OKT3 is a murine monoclonal antibody that blocks the generation and function of T lymp... more Orthoclone OKT3 is a murine monoclonal antibody that blocks the generation and function of T lymphocytes. It has been shown to be effective in reversing acute cellular rejection in solid organ transplants. However, potential development of antimurine antibodies restricts the duration that the drug can be used and the ability to reuse the drug. The case reported in this article illustrates the failure of retreatrnent with OKT3 when high titer (1 :3200) antimurine antibodies are present.

Clinical Transplantation, 2005

Blood Purification, 2005

Hemodialysis vascular access dysfunction is a major cause of morbidity in the hemodialysis popula... more Hemodialysis vascular access dysfunction is a major cause of morbidity in the hemodialysis population and contributes significantly to the overall cost of end-stage renal disease programs. At a histological level, most hemodialysis vascular access dysfunction (in both native arteriovenous fistulae and PTFE dialysis access grafts) is due to venous stenosis and thrombosis, secondary to venous neointimal hyperplasia. However, despite a wealth of experimental and clinical data on the use of novel therapeutic interventions that target neointimal hyperplasia in the setting of coronary artery disease, there are unfortunately no effective therapeutic interventions for hemodialysis vascular access dysfunction at the present time. This is particularly unfortunate, since neointimal hyperplasia in the setting of hemodialysis vascular access fistulae and grafts could be the ideal clinical model to test novel therapeutic interventions for neointimal hyperplasia.

American Journal of Transplantation, 2005

The purpose of this study was to define risk factors for acute rejection with early corticosteroi... more The purpose of this study was to define risk factors for acute rejection with early corticosteroid withdrawal (CSWD; within 7 days posttransplant) in renal transplantation. Data from prospective, IRBapproved early CSWD trials were analyzed. Overall acute rejection rate in 308 patients was 17.1%. Acute rejection rates and observed risks (OR) in patients with individual risk factors were: repeat transplants 38.6%; current PRA >25%; 29.4%; African Americans 23.5%; delayed graft function (DGF) 26.1%; HLA DR mismatches >0 17.9%; female gender 19.7%; Thymoglobulin induction 15.3%; type 1 diabetes 30.8%; type 2 diabetes 11.1%; deceased donor recipients 21%; and living donor recipients 14%. Logistic regression analysis provided the following risks (OR) for acute rejection: repeat transplant 2.51; current PRA > 25% 1.53; African Americans 1.47; DGF 1.58; HLA DR mismatches > 0 1.61; female gender 1.43; Thymoglobulin induction 0.61; type 1 diabetes 2.23, type 2 diabetes 0.5, deceased donor recipients 1.11, and living donor recipients 0.9. Risk factors for acute rejection under early corticosteroid withdrawal are similar to those previously defined under chronic corticosteroid therapy. These observations provide implications for future CSWD trials including: use of T cell depleting antibody induction therapy (thymoglobulin) to reduce acute rejection risk, 2) enrollment stratification for high risk groups, and 3) modified immunosuppression for high risk groups.

American journal of surgery, 1977

Thirteen renal artery stenoses occurred in 127 renal allograft transplantations performed at the ... more Thirteen renal artery stenoses occurred in 127 renal allograft transplantations performed at the University of Cincinnati Medical Center over a four year period. The most common symptoms were hypertension and decreasing renal function occurring from three days to three years post transplantation. Eight lesions occurred in patients with a single artery and five when double arteries had been joined together prior to anastomosis rather than implanted separately. The most common causes of renal artery stenosis was intimal hyperplasia of the donor vessel distal to the anastomosis (8 patients), atheromatous plaques (2), technical failure (2), and external compression (1). Surgical correction was facilitated by a midline incision. Resection of the stenotic segment and reanastomosis was the preferred procedure. Surgical failure and recurrence of hypertension were associated with involvement of small arteries or distal arteriolar level. When kidneys with multiple arteries are available, Carr...

Transplantation Proceedings, 2002

Transplantation Proceedings, 2005

Experience with early corticosteroid withdrawal (CSWD) in renal transplant recipients with focal ... more Experience with early corticosteroid withdrawal (CSWD) in renal transplant recipients with focal segmental glomerulosclerosis (FSGS) has not been previously reported. Since corticosteroids are used to treat primary FSGS, concern exists as to whether early CSWD regimens will be associated with an increased risk of FSGS recurrence posttransplant. The purpose of the present study was to evaluate the results of early CSWD in FSGS recipients and compare these results to a historic control group of FSGS patients who underwent renal transplantation under corticosteroid-based immunosuppression. Forty-three patients with FSGS underwent renal transplantation with early CSWD. Results in these patients were compared to FSGS patients that underwent renal transplantation with chronic corticosteroid therapy. All rejection episodes were biopsy proven with grading by Banff criteria. Statistical analyses included Student's t test and chi square tests. Results in 43 patients with a median follow-up of 569 days were analyzed and compared to control patients. There was no significant difference in recurrent FSGS, time to recurrence, or graft loss. CSWD does not increase risk for recurrence of FSGS. These observations indicate that ECSW can be achieved in FSGS patients, thereby affording them the benefits of steroid elimination.

Transplantation, 1990

OKT3 is an IgG2a murine monoclonal antibody directed against the CD3 antigen receptor of human T ... more OKT3 is an IgG2a murine monoclonal antibody directed against the CD3 antigen receptor of human T lymphocytes. A major concern with OKT3 treatment in solid organ transplant recipients is the development of antimouse antibody, which may preclude retreatment with this agent. We have administered OKT3 on 215 occasions (150 renal, 34 hepatic, 26 cardiac, 5 pancreatic) in 179 patients between April 1982 and December 1988. The mean duration of treatment was 10.5 days (range, 2-22 days). Antimouse antibody data were analyzed on the most recent 133 treatment courses where the antibody status was available pretreatment. Determination of antimouse antibody production was elicited by ELISA technology at days 0, 7, 14, and 28 of OKT3 treatment. Patients were categorized according to the antibody response as follows: (a) absence of antibody; (b) low titer (1:100); or (c) high titer (greater than or equal to 1:1000). Our earlier experience has demonstrated that retreatment with OKT3 is successful in groups a and b. The development of antimurine antibodies was analyzed with regard to the following parameters: (1) The duration of OKT3 treatment; (2) treatment type (prophylactic, primary, or secondary); (3) primary treatment or retreatment; (4) concomitant immunosuppressive regimen (double or triple therapy); (5) dosage of concomitant immunosuppressive drugs; and (6) transplant organ type. The following results were obtained. (1) Duration of treatment had no effect on antibody production (11.0 days in antibody negative and 10.0 days in antibody positive). (2) There was no difference in antibody formation rates for the first treatment of OKT3 when it was used as prophylaxis (26%), primary (19%), or secondary (27%) therapy. (3) Antibody formation rate with first treatment was 29%; with retreatment, patients who were antibody negative following first treatment became positive in 28% of cases, and retreated patients who were low titer positive following first treatment converted to high titer in 57% of cases. (4) Antibody formation was higher in patients receiving double immunosuppressive therapy (36%) than in those receiving triple immunosuppressive therapy (21%) during OKT3 treatment. (5) Concomitant immunosuppression was lower in the antibody-positive group during OKT3 therapy: steroids, 61 mg/day vs. 52 mg/day; azathioprine, 89 mg/day vs. 66 mg/day; CsA, 317 mg/day vs. 186 mg/day. (6) Antibody formation rates were lower in non-renal transplants following first treatment with OKT3 (liver 17%, heart 17%, kidney 28%); this reflects the higher doses of concomitant immunosuppressive therapy used in nonrenal transplants.(ABSTRACT TRUNCATED AT 400 WORDS)

Transplantation, 1987

Exocrine secretions of 16 of 22 pancreas allografts were drained into the urinary tract. Seven of... more Exocrine secretions of 16 of 22 pancreas allografts were drained into the urinary tract. Seven of these 16 patients have functioning allografts, six with pancreaticocystostomies and one with duct-to-ureter anastomosis. A notable problem has been a chronic metabolic acidosis, along with weight loss and hypotension, secondary to chronic bicarbonate loss and volume depletion through the urinary pancreatic fistula. This occurred as early as one week posttransplant, and intermittently thereafter up to four years. The syndrome was aggravated by episodes of renal dysfunction (acute tubular necrosis or rejection), and febrile syndromes. An inverse relationship between serum and urine bicarbonate concentrations existed, with a correlation coefficient, r = -0.746, (P less than 0.05). A negative correlation was also noted between serum bicarbonate and serum creatinine, r = 0.726, (P less than 0.05). Hyperchloremic metabolic acidosis with normal anion gap occurred despite periods of marginal pancreas allograft function resulting from ongoing rejection. Treatment consisted of intravenous and/or oral bicarbonate supplementation, and bicarbonate dialysis for uremic patients. In addition, one patient was first seen with severe balanitis and urethritis due to documented activation of trypsinogen and chymotrypsinogen, presumably caused by recurrent episodes of urinary tract infection. Urinary assay revealed a 10(2-3) increase in activated trypsin and chymotrypsin in comparison with other asymptomatic allograft recipients. Conversion to ductal enteric drainage led to resolution of both the balanitis and bicarbonate wasting. Measurement of urinary amylase levels were gross indicators of graft viability since no correlation could be found between these levels, onset of hyperglycemia, and eventual graft rejection confirmed by pathological examination.

Transplantation, 1992

... By Preoperative Donor-Specific Transfusions and Cyclosporine in Human Cadaveric Transplants. ... more ... By Preoperative Donor-Specific Transfusions and Cyclosporine in Human Cadaveric Transplants. ALEXANDER, J. WESLEY; BABCOCK, GEORGE F.; FIRST, M. ROY; DAVIES ... SUNDARAM; CARDI, MICHAEL; MANZLER, ALAN; COHEN, LOREN; MENDOZA, NINA; CLYNE ...

Transplantation, 2005

Background. Weight gain is a known complication of corticosteroid maintenance therapy. The purpos... more Background. Weight gain is a known complication of corticosteroid maintenance therapy. The purpose of the present study was to compare patterns of weight gain under chronic corticosteroid therapy (CCST) with that observed under early (i.e., within 7 days posttransplant) corticosteroid withdrawal (CSWD) in renal-transplant recipients. Methods. Renal-transplant recipients who underwent early CSWD under four prospective, institutional review boardapproved clinical trials were compared with a historic control group of patients receiving maintenance CCST. Results. One hundred sixty-nine patients with early CSWD were compared with 132 patients who received CCST. Mean population weight gain was significantly higher in CCST patients at 3, 6, and 12 months posttransplant. Race influenced weight gain because white CSWD patients demonstrated greater reductions in weight gain compared with African-American patients. Sex also influenced weight gain: women demonstrated a greater benefit from CSWD than did men. Corticosteroid rejection therapy in CSWD patients completely restored weight gain because these patients showed weight gains similar to the CCST group. Finally, pretransplant body mass index (BMI) also influenced weight gain because patients who were overweight or obese (BMIϾ30) demonstrated a greater reduction in weight gain with CSWD than did patients of normal weight (BMIϽ25). Conclusions. Early CSWD minimizes weight gain in renal-transplant recipients. Women, whites, and patients with high pretransplant BMI had greater reductions in weight gain with early CSWD.

Transplantation, 2005

Animal studies have shown that dietary supplementation with arginine and lipids containing the -3... more Animal studies have shown that dietary supplementation with arginine and lipids containing the -3 and -9 fatty acids prolong allograft survival in animals receiving a short course of low-dose cyclosporine. They also reduce cardiovascular complications and infections in humans. Methods. Adult renal transplant patients receiving standard immunosuppression were stratified according to gender, diabetic state, donor source (LD or CD), and first versus repeat transplant, and randomized to receive or not receive supplemental arginine and canola oil (containing both -3 and -9 fatty acids) twice daily. Patients were followed for a minimum of 3 years. Results. Seventy-six patients were randomized to the supplement group (S) and 71 patients to the control group (C). Intent-to-treat analysis revealed that S patients had fewer post-30 day first rejection episodes (5.4%) when compared with the C group (23.7%) (Pϭ0.01) and fewer post-30 day episodes of calcineurin inhibitor (CNI) drug toxicity (9.2% vs. 35.3%, Pϭ0.003). S patients developed new onset diabetes mellitus (NODM) less frequently by 3 years (2.3% vs. 14.5%, Pϭ0.04), had fewer cardiac events (5.0% vs. 17.1%, Pϭ0.05), and fewer episodes of sepsis (6.5% vs. 18.7%, Pϭ0.05).

Transplantation, 1996

This study details 11 pancreas transplant recipients (10 combined kidney and pancreas and 1 pancr... more This study details 11 pancreas transplant recipients (10 combined kidney and pancreas and 1 pancreas after kidney) who were converted to tacrolimus (FK506) due to acute severe cyclosporine nephrotoxicity in 8 cases and persistent rejection with cyclosporine toxicity in three cases. Arteriolopathy was documented by renal histology in all cases. Cyclosporine was discontinued for 24 hr immediately prior to initiation of tacrolimus. Tacrolimus was started orally at 0.1 mg/kg twice daily with dose adjustments to maintain whole blood trough levels of 8-15 ng/mL by IMx. Tacrolimus was initiated a mean of 14.5 months (range 1-81) after pancreas transplantation. The mean serum creatinine level had increased to 2.9 mg/dl from 1.0 mg/dl at the diagnosis of cyclosporine arteriolopathy (P=0.003). The mean serum creatinine and blood glucose levels at the time of initiation of tacrolimus were 2.1 mg/dl and 104 mg/dl, respectively. Serum creatinine was 1.7 mg/dl, 1.9 mg/dl, 1.8 mg/dl, and 1.7 mg/dl after 1, 2, 3, and 6 months of tacrolimus therapy, respectively; ANOVA (P = 0.02). The corresponding blood glucose levels were 117 mg/dl, 112 mg/dl, 109 mg/dl, and 116 mg/dl, respectively (P=NS). Normal C-peptide levels were present before (5.9 ng/ml) and after (6.2 ng/ml), the initiation of tacrolimus therapy (P=NS), and mean HbA1C was 6.1% before and 6.3% after tacrolimus therapy, (P=NS). There were 4 episodes of acute rejection, 3 responded to intravenous methylprednisolone, and 1 required OKT3 during tacrolimus therapy. Reversible tacrolimus nephrotoxicity was noted in three patients without any evidence of progressive vasculopathy. All 11 patients are alive, and 10/11 kidney and pancreas grafts are functioning with a mean follow-up of 7.7 months (range 5-10). In this study, conversion from cyclosporine to tacrolimus in kidney and pancreas recipients resulted in improvement and stabilization of renal function while maintaining stable blood glucose, C peptide, and HbA1C levels.

Transplant International, 2006

The American Journal of Surgery, 1976

Seminars in Nephrology, 2012

Seminars in Dialysis, 2014

Venous stenosis, secondary to venous neointimal hyperplasia (VNH), at the arteriovenous anastomos... more Venous stenosis, secondary to venous neointimal hyperplasia (VNH), at the arteriovenous anastomosis (AV) is a major etiology of vascular access failure in AV fistulas (AVF) and AV grafts (AVG). Recently, our group has reported that severe VNH also occurs prior to vascular access placement. The objective of this study was to perform a comparison of the cellular phenotypes within the neointima from veins collected from subjects at the time of new vascular access creation and stenotic veins from subjects with failed AVGs and AVFs. Vein samples, collected at the time of new access surgery, and stenotic vein segments, collected at access revision, were evaluated for expression of α-smooth muscle actin (SMA), vimentin, and desmin within the neointima, and quantified using semiquantitative scoring. Within the neointima, the majority of cells from vein samples collected at the time of new access surgery were contractile smooth muscle cells, and veins from stenotic AVF and AVG were predominately myofibroblasts. Our results suggest the possibility of different mechanistic pathways in response to vascular injury that occurs prior to vascular access creation vs. after access creation, and that divergent therapeutic approaches may be needed for treating vascular injury in these two settings.

Seminars in Dialysis, 2012

Although the arteriovenous fistula (AVF) is the preferred mode of dialysis vascular access, AVF m... more Although the arteriovenous fistula (AVF) is the preferred mode of dialysis vascular access, AVF maturation failure remains a huge clinical problem, often resulting in a prolonged duration of use of tunneled dialysis catheters. In contrast, polytetrafluoroethylene (PTFE) grafts do not suffer from early failure, but have significant problems with later stenosis and thrombosis. This review will initially summarize the pathology and pathogenesis of PTFE graft dysfunction and will then use this as a basis for describing some novel therapies, which may have the potential to reduce PTFE graft dysfunction. Finally, we will emphasize that the introduction of such therapies could be an important first step toward individualizing overall vascular access care.

Nephrology Dialysis Transplantation, 2009

Background. Haemodialysis vascular access dysfunction (due to venous stenosis and thrombosis) is ... more Background. Haemodialysis vascular access dysfunction (due to venous stenosis and thrombosis) is a leading cause of hospitalization and morbidity. The aim of the current study was to identify the specific cell types present within stenotic tissue samples from patients with AV fistula and graft failure. Methods. Discarded tissue segments were collected from the stenotic portions (usually near the graft-vein anastomosis or the AV anastomosis) of 23 dialysis grafts and 20 AV fistulae, and examined for expression of smooth muscle alpha actin, desmin, vimentin and a macrophage marker. Results. The majority of cells within the venous neointima (both grafts and fistulae) were myofibroblasts, with a smaller number of desmin positive smooth muscle cells. The graft neointima had a similar cellular phenotype, albeit without any desmin positive contractile smooth muscle cells. The majority of cells within the PTFE graft material were macrophages. Analysis of sequential sections revealed the presence of fibroblasts within the venous neointima and intragraft region. Conclusions. Our results demonstrate that contractile smooth muscle cells, myofibroblasts, fibroblasts and macrophages all play a role in the pathogenesis of dialysis access dysfunction (grafts and fistulae). Targeting these specific cell types might result in the development of novel therapeutic paradigms for haemodialysis vascular access dysfunction.

Journal of Clinical Laboratory Analysis, 1990

Orthoclone OKT3 is a murine monoclonal antibody that blocks the generation and function of T lymp... more Orthoclone OKT3 is a murine monoclonal antibody that blocks the generation and function of T lymphocytes. It has been shown to be effective in reversing acute cellular rejection in solid organ transplants. However, potential development of antimurine antibodies restricts the duration that the drug can be used and the ability to reuse the drug. The case reported in this article illustrates the failure of retreatrnent with OKT3 when high titer (1 :3200) antimurine antibodies are present.

Clinical Transplantation, 2005

Blood Purification, 2005

Hemodialysis vascular access dysfunction is a major cause of morbidity in the hemodialysis popula... more Hemodialysis vascular access dysfunction is a major cause of morbidity in the hemodialysis population and contributes significantly to the overall cost of end-stage renal disease programs. At a histological level, most hemodialysis vascular access dysfunction (in both native arteriovenous fistulae and PTFE dialysis access grafts) is due to venous stenosis and thrombosis, secondary to venous neointimal hyperplasia. However, despite a wealth of experimental and clinical data on the use of novel therapeutic interventions that target neointimal hyperplasia in the setting of coronary artery disease, there are unfortunately no effective therapeutic interventions for hemodialysis vascular access dysfunction at the present time. This is particularly unfortunate, since neointimal hyperplasia in the setting of hemodialysis vascular access fistulae and grafts could be the ideal clinical model to test novel therapeutic interventions for neointimal hyperplasia.

American Journal of Transplantation, 2005

The purpose of this study was to define risk factors for acute rejection with early corticosteroi... more The purpose of this study was to define risk factors for acute rejection with early corticosteroid withdrawal (CSWD; within 7 days posttransplant) in renal transplantation. Data from prospective, IRBapproved early CSWD trials were analyzed. Overall acute rejection rate in 308 patients was 17.1%. Acute rejection rates and observed risks (OR) in patients with individual risk factors were: repeat transplants 38.6%; current PRA >25%; 29.4%; African Americans 23.5%; delayed graft function (DGF) 26.1%; HLA DR mismatches >0 17.9%; female gender 19.7%; Thymoglobulin induction 15.3%; type 1 diabetes 30.8%; type 2 diabetes 11.1%; deceased donor recipients 21%; and living donor recipients 14%. Logistic regression analysis provided the following risks (OR) for acute rejection: repeat transplant 2.51; current PRA > 25% 1.53; African Americans 1.47; DGF 1.58; HLA DR mismatches > 0 1.61; female gender 1.43; Thymoglobulin induction 0.61; type 1 diabetes 2.23, type 2 diabetes 0.5, deceased donor recipients 1.11, and living donor recipients 0.9. Risk factors for acute rejection under early corticosteroid withdrawal are similar to those previously defined under chronic corticosteroid therapy. These observations provide implications for future CSWD trials including: use of T cell depleting antibody induction therapy (thymoglobulin) to reduce acute rejection risk, 2) enrollment stratification for high risk groups, and 3) modified immunosuppression for high risk groups.