Stuart M. Greenstein

Characteristics associated with liver graft failure: The concept of a donor risk index

Transplant physicians and candidates have become increasingly aware that donor characteristics significantly impact liver transplantation outcomes. Although the qualitative effect of individual donor variables are understood, the quantitative risk associated with combinations of characteristics are unclear. Using national data from 1998 to 2002, we developed a quantitative donor risk index. Cox regression models identified seven donor characteristics that independently predicted significantly increased risk of graft failure. Donor age over 40 years (and particularly over 60 years), donation after cardiac death (DCD), and split/partial grafts were strongly associated with graft failure, while African‐American race, less height, cerebrovascular accident and ‘other’ causes of brain death were more modestly but still significantly associated with graft failure. Grafts with an increased donor risk index have been preferentially transplanted into older candidates (>50 years of age) with moderate disease severity (nonstatus 1 with lower model for end‐stage liver disease (MELD) scores) and without hepatitis C. Quantitative assessment of the risk of donor liver graft failure using a donor risk index is useful to inform the process of organ acceptance.

Prevention of Bone Loss in Renal Transplant Recipients: A Prospective, Randomized Trial of Intravenous Pamidronate

Renal transplant recipients are at risk of developing bone abnormalities that result in bone loss and bone fractures. These are related to underlying renal osteodystrophy, hypophosphatemia, and immunosuppressive treatment regimen. Although bisphosphonates are useful in ameliorating bone mineral loss after transplantation, it is not known whether their use in renal transplant patients leads to excessive suppression of bone turnover and increased incidence of adynamic bone disease. A randomized, prospective, controlled, clinical trial was conducted using the bisphosphonate pamidronate intravenously in patients with new renal transplants. Treatment subjects (PAM) received pamidronate with vitamin D and calcium at baseline and at months 1, 2, 3, and 6. Control (CON) subjects received vitamin D and calcium only. During months 6 to 12, the subjects were observed without pamidronate treatment. Biochemical parameters of bone turnover were obtained monthly and, bone mineral density (BMD) was obtained at baseline and months 6 and 12. Bone biopsies for mineralized bone histology were obtained at baseline and at 6 mo in a subgroup of subjects who underwent scheduled living donor transplantation. PAM preserved bone mass at 6 and 12 mo as measured by bone densitometry and histomorphometry. CON had decreased vertebral BMD at 6 and 12 mo (4.8 +/- 0.08 and 6.1 +/- 0.09%, respectively). Biochemical parameters of bone turnover were similar in both groups at 6 and 12 mo. Bone histology revealed low turnover bone disease in 50% of the patients at baseline. At 6 mo, all of PAM had adynamic bone disease, whereas 50% of CON continued to have or developed decreased bone turnover. Pamidronate preserved vertebral BMD during treatment and 6 mo after cessation of treatment. Pamidronate treatment was associated with development of adynamic bone histology. Whether an improved BMD with adynamic bone histology is useful in maintaining long-term bone health in renal transplant recipients requires further study.

Compliance and noncompliance in patients with a functioning renal transplant: A multicenter study

BACKGROUND Noncompliance with medication is a major cause of renal allograft failure among adult renal transplant patients. We summarize previous studies of noncompliance and report results of a large, multicenter survey designed to identify variables that (1) affect the likelihood of compliance with immunosuppressive medication regimens and (2) distinguish among noncompliant patients. METHODS Questionnaires were distributed to 2500 patients at 56 U.S. transplant centers. Compliance was determined by patient responses to questions concerning whether, within the previous 4 weeks, one or more doses of immunosuppressive medications had been missed. Independent variables included patient and transplant characteristics, memories of dialysis, posttransplant symptoms and beliefs, and beliefs concerning the efficacy and importance of immunosuppressants. RESULTS The incidence of noncompliance reported by the 1402 respondents was 22.4%. A logistic regression model that included age, occupation, time since transplant, and three medication-related beliefs was most predictive of the likelihood of compliance. Donor type and histories of diabetes and of infection entered the multivariate model when belief-related variables were excluded. Cluster analyses identified three distinct profiles of noncompliers: accidental noncompliers, invulnerables, and decisive noncompliers. CONCLUSIONS Results of this study, which included nearly three times more patients than the largest previously reported study, can be used by clinicians to identify patients likely to become noncompliant, by researchers to develop randomized, prospective clinical trials of interventions designed to increase compliance, and by educators to tailor patient education programs.

Determinants of discard of expanded criteria donor kidneys: Impact of biopsy and machine perfusion

We examined factors associated with expanded criteria donor (ECD) kidney discard. Scientific Registry of Transplant Recipients (SRTR)/Organ Procurement and Transplantation Network (OPTN) data were examined for donor factors using logistic regression to determine the adjusted odds ratio (AOR) of discard of kidneys recovered between October 1999 and June 2005. Logistic and Cox regression models were used to determine associations with delayed graft function (DGF) and graft failure. Of the 12 536 recovered ECD kidneys, 5139 (41%) were discarded. Both the performance of a biopsy (AOR = 1.21, p = 0.02) and the degree of glomerulosclerosis (GS) on biopsy were significantly associated with increased odds of discard. GS was not consistently associated with DGF or graft failure. The discard rate of pumped ECD kidneys was 29.7% versus 43.6% for unpumped (AOR = 0.52, p < 0.0001). Among pumped kidneys, those with resistances of 0.26–0.38 and >0.38 mmHg/mL/min were discarded more than those with resistances of 0.18–0.25 mmHg/mL/min (AOR = 2.5 and 7.9, respectively). Among ECD kidneys, pumped kidneys were less likely to have DGF (AOR = 0.59, p < 0.0001) but not graft failure (RR = 0.9, p = 0.27). Biopsy findings and machine perfusion are important correlates of ECD kidney discard; corresponding associations with graft failure require further study.

Multicenter, randomized study of the use of everolimus with tacrolimus after renal transplantation demonstrates its effectiveness

Background. Clinical data are lacking concerning concomitant administration of everolimus and tacrolimus in renal transplant recipients. Methods. In a prospective, multicenter, open-label, exploratory, randomized, 6-month study, 92 de novo renal transplant patients received everolimus, steroids, and basiliximab with low or standard tacrolimus exposure. The primary objective was to compare renal function at 6 months after transplant. Results. Mean 6-month serum creatinine (primary safety variable) was 112±31 &mgr;mol/L (1.26±0.35 mg/dL) and 127±50 &mgr;mol/L (1.44±0.57 mg/dL) in the low and standard tacrolimus groups, respectively, (n.s.); mean estimated GFR (Nankivell) was 75.3±16.6 mL/min and 72.5±15.2 mL/min (n.s.). Biopsy-proven acute rejection occurred in 13 patients: seven (14%) in the low tacrolimus group and six (14%) in the standard tacrolimus group, n.s. One graft was lost in the standard tacrolimus group. No patients died. Conclusions. Tacrolimus exposure reduction in the presence of everolimus, steroids and basiliximab induction results in good efficacy in de novo renal transplant recipients with very well-preserved renal function. Additional studies are warranted because between-group comparisons were limited by the relatively small differences in tacrolimus exposure in the 2 arms; trough levels were toward the upper end of the low-exposure ranges and toward the bottom of the standard-exposure ranges.

Impact of the expanded criteria donor allocation system on the use of expanded criteria donor kidneys.

Background. The U.S. Organ Procurement and Transplantation Network recently implemented a policy allocating expanded criteria donor (ECD) kidneys by waiting time alone. ECD kidneys were defined as having a risk of graft failure ≥1.7 times that of ideal donors. ECDs include any donor ≥60 years old and donors 50 to 59 years old with at least two of the following: terminal creatinine >1.5 mg/dL, history of hypertension, or death by cerebrovascular accident. The impact of this policy on use of ECD kidneys is assessed. Methods. The authors compared use of ECD kidneys recovered in the 18 months immediately before and after policy implementation. Differences were tested using t test and &khgr;2 analyses. Results. There was an 18.3% increase in ECD kidney recoveries and a 15.0% increase in ECD kidney transplants in the first 18 months after policy implementation. ECD kidneys made up 22.1% of all recovered kidneys and 16.8% of all transplants, compared with 18.8% (P<0.001) and 14.5% (P<0.001), respectively, in the prior period. The discard rate was unchanged. The median relative risk (RR) for graft failure for transplanted ECD kidneys was 2.07 versus 1.99 in the prepolicy period (P=not significant); the median RR for procured ECD kidneys was unchanged at 2.16. The percentage of transplanted ECD kidneys with cold ischemia times (CIT) <12 hr increased significantly; the corresponding percentage for CIT ≥24 hr decreased significantly. Conclusions. The recent increase in ECD kidney recoveries and transplants appears to be related to implementation of the ECD allocation system.

Successful rescue therapy with plasmapheresis and intravenous immunoglobulin for acute humoral renal transplant rejection

Plasmapheresis (PP) and intravenous immunoglobulin (IVIg) remove donor-specific antibodies, a cause of acute humoral rejection (AHR). We describe the use of PP and IVIg as rescue therapy for AHR. The records of 143 renal transplants performed between October 1, 2000 and April 1, 2002 were reviewed. Patients who underwent PP and IVIg therapy for AHR were identified. The data reviewed included age, sex, source of transplant, number of human leukocyte antigen mismatches, transplant number, number of PP and IVIg treatments, dose of IVIg, time of AHR, serum creatinine (SCr) level at AHR, SCr level after PP and IVIg at 3 months, days to achieve 30% decline in SCr, and graft survival. Immunosuppression included basiliximab induction, tacrolimus, and prednisone (± sirolimus or mycophenolate mofetil [CellCept, Roche Pharmaceutical, Nutley, NJ]). PP was followed by IVIg infusion. Nine patients were treated for AHR with PP and IVIg. All nine patients demonstrated biopsy-proven AHR. One graft was lost. Mean 3-month and 1-year SCr levels were 1.9 and 1.8, respectively, in the remaining eight patients. AHR in renal transplantation can be effectively treated with PP and IVIg.

Percutaneous transluminal angioplasty. The procedure of choice in the hypertensive renal allograft recipient with renal artery stenosis.

A retrospective review of 547 renal transplants performed over a six-year period revealed allograft renovascular hypertension secondary to RTAS in 39 (7.1%) patients. Percutaneous transluminal angioplasty (PTA) resulted in immediate cure or improvement in 76% of the patients, increasing to 83% in patients with functioning kidneys at a mean follow-up period of 30 months (1–72 months). The renal artery stenosis (RTAS) was equally distributed between living-related and cadaver kidney recipients and did not appear to be more prevalent in end-to-end or end-to-side anastomoses. The blood pressures fell from pre-PTA levels of 167 ± 22 mmHg systolic to 141 ± 23.7 post-PTA and 102 ± 11 mmHg diastolic pre-PTA to 88 ± 12 mmHg post-PTA (P < 0.01). Of 25 cured or improved patients, 24 are on significantly less hypertensive medication. Two patients died of causes unrelated to the PTA and only one patient lost a kidney because of the procedure. Compared with operation, PTA is a safer and more effective procedure for the initial treatment of RTAS.

Late failure of reversed vein bypass grafts.

Late failure of reversed vein bypass grafts is preceded by the appearance of stenotic lesions, which progress to total occlusion. These lesions appear either as intrinsic graft lesions or as new arteriosclerotic lesions in contiguous arteries. The present study summarizes the University of Pennsylvania experience with these lesions in 521 vein grafts inserted from 1979 to 1985. The grafts were grouped according to the site of the distal anastomosis; 231 above-knee popliteal (FP AK), 171 below-knee popliteal (FP BK), and 119 tibial (FT). The overall incidence of stenotic lesions was essentially identical with the three grafts (21%), but the relative incidence of intrinsic graft to arterial lesions was higher with the more distal grafts. The most common graft lesions developed adjacent to the proximal anastomosis, which is the narrowest part of a reversed vein graft. The popliteal artery was the most common site of outflow stenosis. There was negligible incidence of tibial lesions. The most common inflow arterial lesion was located in the common femoral and iliac arteries. The superficial femoral artery (SFA) was a rare site of inflow stenosis, even though it was at risk because 96 grafts originated from the SFA or popliteal artery. Sixty-seven per cent of the graft and 52% of the arterial lesions were treated successfully by percutaneous transluminal angioplasty; the rest had minor surgical revisions. This resulted in a 19%, 10%, and 9% improvement in 5-year patency for the FT, FP BK, and FP AK bypasses. These results justify an aggressive policy of graft surveillance to identify and treat stenotic graft lesions before graft occlusion.

Lack of effect in desensitization with intravenous immunoglobulin and rituximab in highly sensitized patients.

Background We conducted a prospective cohort study in highly sensitized kidney transplant candidates with a calculated panel reactive antibody (cPRA) greater than 50% and on the deceased-donor waiting list for more than 5 years to investigate the effects of intravenous immunoglobulin (IVIG) and rituximab treatment. Methods Desensitization protocol included two doses of IVIG (2 g/kg, max 120 g each dose) and a single dose of rituximab (375 mg/m2). Patients were followed up monthly by Luminex single antigen beads. Whole blood gene expression profiles were studied by Affymetrix Human 1.0 ST GeneChips before and after treatment. Results Forty patients were eligible for desensitization treatment. Thirteen of these patients agreed to participate, and 11 completed the treatment. After a mean follow-up of 334 ± 82 days, two desensitized patients (18%) received a kidney transplant compared with 14 patients (52%) in the nondesensitized group. Comparing with 14 patients who received transplants without any desensitization treatment, desensitized patients showed higher class I (99% vs. 80%) and class II (98% vs. 69%) cPRA levels and more unacceptable antigens (32 vs. 8). Desensitization treatment did not lead to any significant reduction in patients’ class I and II cPRA levels and any change in the mean number of unacceptable antigens or their mean fluorescence intensity values. Whole blood gene expression analysis by microarrays demonstrated down-regulation of immunoglobulin and B-cell–associated transcripts after treatment. Conclusion These results suggested that pretransplant desensitization with IVIG and rituximab was not successful in highly sensitized kidney transplant candidates with cPRA levels higher than 90%.