Raja Kandaswamy

Lessons learned from more than 1,000 pancreas transplants at a single institution

ObjectiveTo determine outcome in diabetic pancreas transplant recipients according to risk factors and the surgical techniques and immunosuppressive protocols that evolved during a 33-year period at a single institution. Summary Background DataInsulin-dependent diabetes mellitus is associated with a high incidence of management problems and secondary complications. Clinical pancreas transplantation began at the University of Minnesota in 1966, initially with a high failure rate, but outcome improved in parallel with other organ transplants. The authors retrospectively analyzed the factors associated with the increased success rate of pancreas transplants. MethodsFrom December 16, 1966, to March 31, 2000, the authors performed 1,194 pancreas transplants (111 from living donors; 191 retransplants): 498 simultaneous pancreas–kidney (SPK) and 1 simultaneous pancreas–liver transplant; 404 pancreas after kidney (PAK) transplants; and 291 pancreas transplants alone (PTA). The analyses were divided into five eras: era 0, 1966 to 1973 (n = 14), historical; era 1, 1978 to 1986 (n = 148), transition to cyclosporine for immunosuppression, multiple duct management techniques, and only solitary (PAK and PTA) transplants; era 2, 1986 to 1994 (n = 461), all categories (SPK, PAK, and PTA), predominately bladder drainage for graft duct management, and primarily triple therapy (cyclosporine, azathioprine, and prednisone) for maintenance immunosuppression; era 3, 1994 to 1998 (n = 286), tacrolimus and mycophenolate mofetil used; and era 4, 1998 to 2000 (n = 275), use of daclizumab for induction immunosuppression, primarily enteric drainage for SPK transplants, pretransplant immunosuppression in candidates awaiting PTA. ResultsPatient and primary cadaver pancreas graft functional (insulin-independence) survival rates at 1 year by category and era were as follows: SPK, era 2 (n = 214) versus eras 3 and 4 combined (n = 212), 85% and 64% versus 92% and 79%, respectively; PAK, era 1 (n = 36) versus 2 (n = 61) versus 3 (n = 84) versus 4 (n = 92), 86% and 17%, 98% and 59%, 98% and 76%, and 98% and 81%, respectively; in PTA, era 1 (n = 36) versus 2 (n = 72) versus 3 (n = 30) versus 4 (n = 40), 77% and 31%, 99% and 50%, 90% and 67%, and 100% and 88%, respectively. In eras 3 and 4 combined for primary cadaver SPK transplants, pancreas graft survival rates were significantly higher with bladder drainage (n = 136) than enteric drainage (n = 70), 82% versus 74% at 1 year (P = .03). Increasing recipient age had an adverse effect on outcome only in SPK recipients. Vascular disease was common (in eras 3 and 4, 27% of SPK recipients had a pretransplant myocardial infarction and 40% had a coronary artery bypass); those with no vascular disease had significantly higher patient and graft survival rates in the SPK and PAK categories. Living donor segmental pancreas transplants were associated with higher technically successful graft survival rates in each era, predominately solitary (PAK and PTA) in eras 1 and 2 and SPK in eras 3 and 4. Diabetic secondary complications were ameliorated in some recipients, and quality of life studies showed significant gains after the transplant in all recipient categories. ConclusionsPatient and graft survival rates have significantly improved over time as surgical techniques and immunosuppressive protocols have evolved. Eventually, islet transplants will replace pancreas transplants for suitable candidates, but currently pancreas transplants can be applied and should be an option at all stages of diabetes. Early transplants are preferable for labile diabetes, but even patients with advanced complications can benefit.

Transplantation of Cultured Islets from Two-Layer Preserved Pancreases in Type 1 Diabetes with Anti-CD3 Antibody

We sought to determine whether or not optimizing pancreas preservation, islet processing, and induction immunosuppression would facilitate sustained diabetes reversal after single‐donor islet transplants. Islets were isolated from two‐layer preserved pancreata, purified, cultured for 2 days; and transplanted into six C‐peptide‐negative, nonuremic, type 1 diabetic patients with hypoglycemia unawareness. Induction immunosuppression, which began 2 days pretransplant, included the Fc receptor nonbinding humanized anti‐CD3 monoclonal antibody hOKT3γ1 (Ala‐Ala) and sirolimus. Immunosuppression was maintained with sirolimus and reduced‐dose tacrolimus. Of our six recipients, four achieved and maintained insulin independence with normal HbA1c levels and freedom from hypoglycemia; one had partial islet graft function; and one lost islet graft function 2 weeks post‐transplant. The four insulin‐independent patients showed prolonged CD4+ T‐cell lymphocytopenia; inverted CD4:CD8 ratios; and increases in the percentage of CD4+CD25+ T cells. These cells suppressed the in‐vitro proliferative response to donor cells and, to a lesser extent, to third‐party cells. Severe adverse events were limited to a transient rash in one recipient and to temporary neutropenia in three. Our preliminary results thus suggest that a combination of maximized viable islet yield, pretransplant islet culture, and preemptive immunosuppression can result in successful single‐donor islet transplants.

Decreased surgical risks of pancreas transplantation in the modern era.

OBJECTIVE To document the decreased incidence of surgical complications after pancreas transplantation in recent times. SUMMARY BACKGROUND DATA Compared with other abdominal transplants, pancreas transplants have historically had the highest incidence of surgical complications. However, over the past few years, the authors have noted a significant decrease in the incidence of surgical complications. METHODS The authors studied the incidence of early (<3 months after transplant) surgical complications (e.g., relaparotomy, thrombosis, infections, leaks) after 580 pancreas transplants performed during a 12-year period. Patients were analyzed and compared in two time groups: era 1 (June 1, 1985, to April 30, 1994, n = 367) and era 2 (May 1, 1994, to June 30, 1997, n = 213). RESULTS Overall, surgical complications were significantly reduced in era 2 compared with era 1. The relaparotomy rate decreased from 32.4% in era 1 to 18.8% in era 2. Significant risk factors for early relaparotomy were donor age older than 40 years and recipient obesity. Recipients with relaparotomy had significantly lower graft survival rates than those without relaparotomy, but patient survival rates were not significantly different. A major factor contributing to the lower relaparotomy rate in era 2 was a significant decrease in the incidence of graft thrombosis; the authors believe this lower incidence is due to the routine use of postoperative low-dose intravenous heparin and acetylsalicylic acid. The incidence of bleeding requiring relaparotomy did not differ between the two eras. Older donor age was the most significant risk factor for graft thrombosis. The incidence of intraabdominal infections significantly decreased between the two eras; this decrease may be due to improved prophylaxis regimens in the first postoperative week. CONCLUSIONS Although a retrospective study has its limits, the results of this study, the largest single-center experience to date, show a significant decrease in the surgical risk associated with pancreas transplants. Reasons for this decrease are identification of donor and recipient risk factors, better prophylaxis regimens, refinements in surgical technique, and improved immunosuppressive regimens. These improved results suggest that more widespread application of pancreas transplantation is warranted.

Technical failures after pancreas transplants: Why grafts fail and the risk factors: A multivariate analysis

Background. Technical failure (TF) rates remain high after pancreas transplants; while rates have decreased over the last decade, more than 10% of all pancreas grafts continue to be lost due to technical reasons. We performed a multivariate analysis to determine causes and risk factors for TF of pancreas grafts. Results. Between 1994 and 2003, 937 pancreas transplants were performed at our center in the following transplant categories: simultaneous pancreas-kidney (SPK) (n=327), pancreas after kidney (PAK) (n=399), and pancreas transplant alone (PTA) (n=211). Of these, 123 (13.1%) grafts were lost due to technical reasons (thrombosis, leaks, infections). TF rates were higher for SPK (15.3%) versus PAK (12.2%) or PTA (11.4%), though this was not statistically significant. Thrombosis accounted for 52.0% of all TFs. Other causes were infections (18.7%), pancreatitis (20.3%), leaks (6.5%), and bleeding (2.4%). Thrombosis was the most common cause for TF in all three transplant categories. By multivariate analysis, the following were significant risk factors for TF of the graft: recipient body mass index (BMI) >30 kg/m2 (relative risk [RR]=2.42, P=0.0003), preservation time >24 hr (1.87, P=0.04), cause of donor death other than trauma (RR=1.58, P=0.04), enteric versus bladder drainage (1.68, P=0.06), and donor BMI >30 kg/m2 (1.66, P=0.06). Not significant were donor or recipient age, a retransplant, and the category of transplant. Conclusions. TFs remain significant after pancreas transplants. In SPK recipients, TF represents the most common cause of pancreas graft loss. For isolated pancreas transplants, TF is second only to rejection as a cause of graft loss. Increased preservation times and donor or recipient obesity seem to be risk factors. Minimizing these risks factors would be important to try to decrease TF.

2,500 living donor kidney transplants: A single-center experience

ObjectiveTo review a single center’s experience and outcome with living donor transplants. Summary Background DataOutcome after living donor transplants is better than after cadaver donor transplants. Since the inception of the authors’ program, they have performed 2,540 living donor transplants. For the most recent cohort of recipients, improvements in patient care and immunosuppressive protocols have improved outcome. In this review, the authors analyzed outcome in relation to protocol. MethodsThe authors studied patient and graft survival by decade. For those transplanted in the 1990s, the impact of immunosuppressive protocol, donor source, diabetes, and preemptive transplantation was analyzed. The incidence of rejection, posttransplant steroid-related complications, and return to work was determined. Finally, multivariate analysis was used to study risk factors for worse 1-year graft survival and, for those with graft function at 1 year, to study risk factors for worse long-term survival. ResultsFor each decade since 1960, outcome has improved after living donor transplants. Compared with patients transplanted in the 1960s, those transplanted in the 1990s have better 8-year actuarial patient and graft survival rates. Death with function and chronic rejection have continued to be a major cause of graft loss, whereas acute rejection has become a rare cause of graft loss. Cardiovascular deaths have become a more predominant cause of patient death; infection has decreased. Donor source (e.g., ideally HLA-identical sibling) continues to be important. For living donor transplants, rejection and graft survival rates are related to donor source. The authors show that patients who had preemptive transplants or less than 1 year of dialysis have better 5-year graft survival and more frequently return to full-time employment. Readmission and complications remain problems; of patients transplanted in the 1990s, only 36% never required readmission. Similarly, steroid-related complications remain common. The authors’ multivariate analysis shows that the major risk factor for worse 1-year graft survival was delayed graft function. For recipients with 1-year graft survival, risk factors for worse long-term outcome were pretransplant smoking, pretransplant peripheral vascular disease, pretransplant dialysis for more than 1 year, one or more acute rejection episodes, and donor age older than 55. ConclusionsThese data show that the outcome of living donor transplants has continued to improve. However, for living donors, donor source affects outcome. The authors also identify other major risk factors affecting both short- and long-term outcome.

Prolonged insulin independence after islet allotransplants in recipients with type 1 diabetes

We sought to determine the long‐term outcomes in type 1 diabetic recipients of intraportal alloislet transplants on a modified immunosuppressive protocol. Six recipients with hypoglycemia unawareness received one to two islet infusions. Induction therapy was with antithymocyte globulin (ATG) plus etanercept for tumor necrosis factor‐α blockade. Recipients received cyclosporine and everolimus for maintenance immunosuppression for the first year posttransplant, with mycophenolic acid or mycophenolate mofetil subsequently substituted for everolimus. Recipients have been followed for 1173 ± 270 days since their last infusion for islet graft function (insulin independence, hemoglobin A1c levels and C‐peptide production) and for adverse events associated with the study protocol. Of the six recipients, five were insulin‐independent at 1 year, and four continue to be insulin‐independent at a mean of 3.4 ± 0.4 years posttransplant. None of the six recipients experienced recurrence of severe hypoglycemia. Measured glomerular filtration rate decreased from 110.5 ± 21.2 mL/min/1.73 m2 pretransplant to 82.6 ±19.1 mL/min/1.73 m2 at 1 year posttransplant. In conclusion, islet transplants restored insulin independence for a mean of >3 years in four of six recipients treated with ATG and etanercept induction therapy and with cyclosporine and, initially, everolimus for maintenance. Our results suggest this immunosuppressive protocol may allow long‐term graft survival.

Prednisone-Free Maintenance Immunosuppression—A 5-Year Experience

Concern persists that prednisone‐free maintenance immunosuppression in kidney transplant recipients will be associated with an increase in late allograft dysfunction and graft loss. We herein report 5‐year follow‐up of a trial of prednisone‐free maintenance immunosuppression. From October 1, 1999, through January 31, 2005, at our center, 589 kidney transplant recipients were treated with a protocol incorporating discontinuation of their prednisone on postoperative day 6. At 5 years, actuarial patient survival was 91%; graft survival, 84%; death‐censored graft survival, 92%; acute rejection‐free graft survival, 84% and chronic rejection‐free graft survival, 87%. The mean serum creatinine level (±SD) at 1 year was 1.6 ± 0.6; at 5 years, 1.7 ± 0.8. In all, 86% of kidney recipients with functioning grafts remain prednisone‐free as of April 30, 2005.

Risk factors for slow graft function after kidney transplants: a multivariate analysis

Humar A, Ramcharan T, Kandaswamy R, Gillingham K, Payne WD, Matas AJ. Risk factors for slow graft function after kidney transplants: a multivariate analysis. Clin Transplant 2002: 16: 425–429.

A Prospective Randomized Trial of Steroid‐Free Maintenance Regimens in Kidney Transplant Recipients—An Interim Analysis

We compared three maintenance immunosuppressive regimens in a rapid discontinuation of prednisone protocol. From March 1, 2001, through December 31, 2003, 239 first and second kidney transplant recipients (166 LD; 73 DD) were randomized. All recipients were treated with Thymoglobulin; all received steroids intraoperatively and for 5 days postoperatively. Randomization was to cyclosporine–mycophenolate mofetil (n = 85); high‐level tacrolimus (TAC) (8–12 ng/mL)–low‐level sirolimus (SRL) (3–7 ng/mL) (n = 72); or low‐level TAC (3–7 ng/mL)–high‐level SRL (8–12 ng/mL) (n = 82). We found no difference at 24 months between groups in patient, graft, death‐censored graft, or acute rejection‐free graft survival, or in kidney function.

Rapid Discontinuation of Steroids in Living Donor Kidney Transplantation: A Pilot Study

Steroids are associated with significant postoperative complications (hypertension, cosmetic changes, bone loss, hyperlipidemia, diabetes, and cataracts). Most develop early; in addition, late post‐transplant steroid withdrawal in kidney transplant recipients has been associated with increased acute rejection (AR). To obviate these problems, we studied outcome of a protocol of rapid discontinuation of prednisone (RDS) (steroids stopped on POD6). Between November 1, 1999 and October 31, 2000, 51 adult living donor (LD) first transplant recipients (2 HLA‐id, 28 non‐id relative, 21 LURD) were immunosuppressed with thymoglobulin (1.25 mg/kg intraoperatively and then qdx4); prednisone (P) (500 mg methylprednisolone intraoperatively, 1 mg/kg × 1 day, 0.5 mg/kg × 2 days, 0.25 mg/kg × 2 days, then d/c); MMF, 1 g b.i.d.; and CSA, 4 mg/kg b.i.d. adjusted to achieve levels of 150–200 ng/mL (by HPLC). Exclusion criteria were delayed graft function or 1° disease requiring P. Minimum follow‐up was 5.5 months (range 5.5 to 17.5 months). Outcome was compared vs. previous cohorts of LD recipients immunosuppressed with P/AZA/CSA (n = 171) or P/MMF/CSA (n = 43) (both without antibody induction). Results: For the RDS group, average CSA level (± S.E.) at 3 and 6 months was 190 ± 12 and 180 ± 9; avg. MMF dose, 1.7 ± 0.1 g and 1.7 ± 0.1 g. There was no significant difference in 6‐ and 12‐month actuarial patient survival, graft survival and rejection‐free graft survival between recipients on the RDS protocol vs. historical controls. For RDS recipients, actuarial 6‐ and 12‐month rejection‐free graft survival was 87%. Of the 51 RDS recipients, five (10%) have had AR (at 20 days, 1 month, 3 months, 3 months, and 3.5 months post‐transplant). After treatment, all five were maintained on 5 mg P; there have been no second AR episodes. Two additional recipients were started on 5 mg P due to low white blood count (WBC) and low/no MMF. Of the 51 grafts, one has failed (death with function). Average serum Cr level (± S.E.) at 3 and 6 months for RDS recipients was 1.7 ± 0.5 (NS vs. historical controls). Conclusion: For low‐risk LD recipients, a kidney transplant with an RDS protocol does not increase risk of AR or graft loss. Future studies will need to be done to assess AR rates with an RDS protocol in cadaver transplant recipients and in recipients with delayed graft function.