Surveillance and monitoring of pancreas allografts

Recipients of pancreas allografts are routinely monitored by clinical and biochemical markers that include ultrasound and imaging of the pancreas, serum levels of amylase, lipase, blood glucose, C-peptide, and immunosuppressive drug levels and measurement of urinary amylase for bladder-drained grafts. The specificity of many of these tests is rather low, with a predictive value for acute rejection generally around 50 to 75%. Biopsies of pancreatic allografts remain the most specific marker for acute rejection of the pancreas and help explain other reasons for pancreatic dysfunction. Protocols of surveillance biopsy of solitary pancreas allografts may be associated with a beneficial increase in the one-year graft survival rate and can minimize graft loss secondary to acute rejection. Fine Needle Aspiration Cytology is a low risk procedure for monitoring the intra-graft events and constitutes a complimentary technique to histology. The purpose of this review is to describe the overall clinical monitoring of pancreas transplant recipients with special emphasis on the role of pancreatic histology and to describe the clinicopathologic correlation of the various morphologic findings

Clinical utility of histological features of polyomavirus allograft nephropathy

BACKGROUND: The purpose of this study was to determine if histological features of polyomavirus allograft nephropathy (PVAN) are associated with the clinical presentation and outcomes of PVAN. METHODS: We examined the histological features of initial and follow-up biopsies of 20 kidney and kidney-pancreas transplant recipients with PVAN during a time prior to routine surveillance. The subjects' demographics, clinical characteristics, and outcomes were compared based upon classification of histological features of PVAN on initial biopsy. RESULTS: Diabetes mellitus (45%) and a history of tacrolimus-induced nephrotoxicity (35%) appeared to be prevalent in subjects with PVAN. Although histological severity of PVAN did not predict or correlate with the clinical course of PVAN, subjects with pattern C on initial PVAN biopsy presented later posttransplant, had higher serum creatinine level at presentation, and had significant allograft deterioration at follow-up than subjects with either pattern A or B on initial biopsy. Resolution of PVAN was noted in 60% of follow-up biopsies and occurred more frequently in subjects with pattern B on initial biopsy. Most subjects developed chronic allograft nephropathy after PVAN and viral clearance did not abrogate the progression to chronic allograft nephropathy. CONCLUSIONS: These data indicate that histologic patterns of PVAN may have clinical correlation to disease presentation and prognosis

Tubulointerstitial nephritis in systemic lupus erythematosus: innocent bystander or ominous presage

SLE-associated tubulointerstitial injury (SLE TIN) is increasingly recognized in two forms, i.e., secondary and primary. The secondary form coexists with lupus glomerulonephritis, whereas the primary form develops against the background of no or mild glomerular or vascular involvement. Secondary SLE TIN is frequent, but its frequency and severity correlate with the class of the associated lupus glomerulonephritis (GN), being almost universal in Class IV lupus GN and less frequent in GN of other classes. Although the presence of underlying GN may mask its clinical manifestation, secondary SLE TIN has a major prognostic implication for the renal outcome. Yet, SLE TIN is not factored in the current therapyfocused International Society of Nephrology/Renal Pathology Society schema of renal lupus classification, and its management remains to be elucidated. The pathogenesis of secondary SLE TIN is either immunologic, i.e., the tubulointerstitial injury being mediated by SLE-related immunologic mechanisms akin to those responsible for lupus GN; or non-immunologic, i.e., a nonspecific tubulointerstitial injury secondary to any type of advanced glomerular lesion, regardless of etiology. Primary SLE TIN is rare with about 15 reported cases. It has a rather uniform and distinctive clinical manifestation including acute kidney injury with no or mild proteinuria. It responds well to steroid and usually carries a good prognosis. Its pathogenesis is almost certain immunologic, with immunoglobulin/complement deposits along the tubular basement membrane in each reported case. In spite of these profound clinical implications, the current review underlies a limited knowledge on the pathobiology of SLE TIN

Comparison of sirolimus-based calcineurin inhibitor-sparing and calcineurin inhibitor-free regimens in cadaveric renal transplantation

INTRODUCTION: This study examines the efficacy and toxicity of sirolimus used as primary immunosuppression in combination with reduced dose tacrolimus (calcineurin inhibitor [CI]-sparing regimen) or mycophenolate mofetil (CI-free regimen) in high-risk cadaveric renal transplantation. METHODS: Seventy subjects were treated in a quadruple sequential protocol in which 41 were treated with a CI-sparing regimen and 29 were treated with a CI-free regimen. The efficacy and toxicity profiles of these regimens were prospectively monitored and compared. RESULTS: The study consisted of African Americans (71%), cadaveric donors (100%), donors aged more than 50 years (30%), and patients with delayed graft function (47%). At 1 year, patient survival, graft survival, and incidence of biopsy-proven acute rejection were 98%, 80%, and 10%, respectively, in the CI-sparing group and 100%, 89%, and 7%, respectively, in the CI-free group. Three-month protocol biopsies were performed in 41% (17/41) and 67% (20/29) of the subjects in the CI-sparing and CI-free groups, respectively. Subclinical rejection was detected in 6% (1/17) and 15% (3/20) of the subjects in the CI-sparing and CI-free groups, respectively. Histologic evidence of chronic allograft nephropathy was more prevalent in the CI-sparing group. At 1 year, the mean estimated creatinine clearance was higher in the CI-free group than in the CI-sparing group (72.4 +/-20.0 mL/min vs. 50.5 +/-20.8 mL/min, P <0.01). The two regimens had similar toxicity profiles (hospital readmission, infection, wound complications, and metabolic complications). CONCLUSIONS: Both sirolimus-based CI-sparing and CI-free regimens are safe and effective in a population with high immunologic risk. The CI-free regimen is associated with better renal function at 1 year post-transplant. Long-term follow-up will aid in determining the risk and benefit ratio of these regimens

Improving results in solitary pancreas transplantation with portal-enteric drainage, thymoglobin induction, and tacrolimus/mycophenolate mofetil-based immunosuppression

Advances in surgical techniques and clinical immunosuppression have led to steadily improving results in pancreas transplantation (PTX). The purpose of this study was to analyze retrospectively the outcomes in patients undergoing solitary PTX with portal-enteric (P-E) drainage and contemporary immunosuppression. From June 1998 through December 2000, we performed 28 solitary PTXs with antibody induction and tacrolimus/mycophenolate mofetil maintenance therapy. The first 13 patients received daclizumab (DAC) induction, while the next 15 received thymoglobulin (rabbit anti-human thymocyte gamma globulin; Thymo) induction. The study group included 13 pancreas alone (PA) and 15 sequential pancreas-after-kidney-transplantations (PAKT). Solitary PTX was performed with P-E drainage in 18 patients and systemic-enteric (S-E) drainage in ten. Patient and pancreas graft survival rates were 96% and 79%, respectively, with a mean follow-up of 22 (range 1-39) months. The 1-year actual death-censored pancreas graft survival rate was 89%. One PAKT patient died with a functioning graft at 1 month; three patients (11%) experienced early graft loss due to thrombosis and were excluded from the immunological analysis, leaving 24 evaluable patients. The incidence of acute rejection was 54%, including 50% in PA and 58% in PAKT recipients ( P=NS). In patients receiving Thymo induction, the rate of acute rejection was slightly lower (43% Thymo vs 70% DAC). Moreover, P-E drainage was associated with a slightly lower rate of acute rejection (44% P-E vs 75% S-E; P=NS). In patients with both Thymo induction and P-E drainage ( n=11), there was a tendency toward less rejection (the incidence of acute rejection was 36%). Two immunological graft losses occurred (one due to non-compliance), both in patients with P-E drainage. Only one patient had a cytomegalovirus (CMV) infection. Event-free survival (no rejection, graft loss, or death) was slightly higher in patients receiving Thymo (47%) than in those on DAC (23%) induction ( P=NS). We can conclude that solitary PTX with P-E drainage and Thymo induction may be associated with improved intermediate-term outcomes and a possible immunological advantage

Observations regarding the use of sirolimus and tacrolimus in high-risk cadaveric renal transplantation

BACKGROUND: Balancing the risk of acute rejection (AR) with drug-induced toxicities complicates the selection of the optimal immunosuppressive regimen, especially in the high-risk renal transplant recipient. This study was designed to determine the optimal dosage combinations of tacrolimus and sirolimus in a high-risk cadaveric renal transplant population. METHODS: Primary cadaveric renal transplant recipients were randomly assigned to receive either standard tacrolimus (trough levels of 10-15 ng/mL) plus reduced sirolimus (trough levels of 5-10 ng,mL) (Group I) or to receive reduced tacrolimus (trough levels of 5-10 ng,mL) plus standard sirolimus (trough levels of 10-15 ng/mL) (Group II). All patients received Thymoglobulin induction and steroids. RESULTS: Thirty-nine (16 in Group I and 23 in Group II) high-risk renal transplant recipients (100% cadaveric donors, 79% African-American recipients, and 59% delayed graft function) are the subjects of this report. At 6 months, the patient survival rate was 94 and 100% and the graft survival rate was 94 and 83% in Groups I and II, respectively. The incidence of biopsy-proven AR was 6 and 5% in Groups I and II, respectively. Eight patients (50%) in Group I required discontinuation of tacrolimus, seven because of biopsy-proven tacrolimus nephrotoxicity and one secondarily to interstitial pneumonitis. Wound complications were the most frequent adverse event reported in both groups. CONCLUSIONS: The combination of tacrolimus and sirolimus was associated with a low risk of AR in this cohort of high-risk renal transplant recipients. However, 50% of patients who received standard tacrolimus and reduced sirolimus combination had to be discontinued from the regimen because of biopsy-proven nephrotoxicity. These preliminary results provide evidence that sirolimus should not be added to tacrolimus without dosage adjustments. We have discontinued recruitment of patients to the standard tacrolimus and reduced sirolimus combination and we have tightened our criteria for selection of marginal donor kidneys with our high-risk renal transplant recipients

Renal allograft loss as the result of polyomavirus interstitial nephritis after simultaneous kidney-pancreas transplantation: results with kidney retransplantation

BACKGROUND: Polyomavirus (PV) infection in kidney transplant patients has been reported to cause interstitial nephritis and subsequent graft loss. The cornerstone of current therapy is a reduction in immunosuppression, which can subsequently lead to kidney allograft rejection. This dilemma becomes even more challenging in the setting of simultaneous kidney-pancreas transplantation, because a reduction in immunosuppression may result in rejection of the pancreas allograft. Antiviral therapy has not been shown to be clinically successful in decreasing the risk of graft loss secondary to PV infection. Furthermore, because of limited experience, the decision to perform retransplantation in patients who lost their primary kidney grafts to PV interstitial nephritis becomes a difficult one. METHODS: Retrospective review and case studies. RESULTS: We report two successful living donor kidney retransplants in simultaneous kidney-pancreas transplant patients who lost their first kidney grafts to PV infection. Both patients are receiving rimantadine therapy and performing well, with functioning kidney and pancreas grafts and no evidence of recurrent PV interstitial nephritis 22 and 37 months after retransplantation. CONCLUSIONS: Although follow-up is limited, our initial experience would indicate that graft loss secondary to PV interstitial nephritis is not an absolute contraindication for kidney retransplantation

Risk factors and consequences of delayed graft function in deceased donor renal transplant patients receiving antithymocyte globulin induction

BACKGROUND: Induction rabbit antithymocyte globulin (rATG) is largely used in renal allograft recipients at risk for delayed graft function (DGF) and immunologic rejection. The purpose of our study was to characterize risk factors and outcomes associated with DGF when it occurs in recipients undergoing routine rATG induction. METHODS: We retrospectively reviewed our experience in a predominantly high-risk population receiving modern immunosuppressive regimens. RESULTS: Of 231 deceased-donor transplants, high-risk characteristics included African American race (68%), retransplants (12%), peak panel reactive antibody of atleast 20% (19%), expanded criteria donor kidney (15%), and cold ischemia time exceeding 24 hr (27%). DGF occurred in 29% of patients. rATG was continued to a dose of 7.3 mg/kg in DGF patients and 5 mg/kg in non-DGF patients (P<0.0001). Risk factors for DGF were recipient body mass index greater than 30 kg/m(2) (odds ratio [OR]=1.5, P=0.02), female donor/male recipient pairings (OR=1.5, P=0.033), sirolimus use (OR=1.7, P=0.003), and donor creatinine more than 1.5 mg/dL (OR=1.6, P=0.016). One-year patient survival (99% non-DGF, 91% DGF; P=0.001) and acute rejection incidence through 36 months (11% non-DGF, 22.4% DGF; P=0.025) differed between groups. DGF patients experienced a higher rejection rate during the second and third years posttransplant. Death-censored graft survival was similar throughout 36 months. CONCLUSION: In kidney transplantation with routine rATG induction, DGF was related to size and gender, donor creatinine, and immunosuppressive protocol. Despite low first-year rejection rates, DGF was associated with inferior patient survival. Importantly, patients with DGF continued to be at risk for rejection beyond the first year. Donor and recipient selection impacts short-term outcomes, and induction alone may not confer a long-term advantage without further modification of baseline therapy