Long-term Follow-up of Kidney Transplant Recipients in the Spare-the-Nephron-Trial.

In the Spare-the-Nephron (STN) Study, kidney transplant recipients randomized about 115 days posttransplant to convert from CNI (calcineurin inhibitor)/MMF to sirolimus (SRL)/MMF had a significantly greater improvement in measured GFR (mGFR) at 12 months compared with those kept on CNI/MMF. The difference at 24 months was not statistically significant. From 14 top enrolling centers, 128 of 175 patients identified with a functioning graft at 2 years consented to enroll in an observational, noninterventional extension study to collect retrospectively and prospectively annual follow-up data for the interval since baseline (completion of the parent STN study at 24 months posttransplant). Overall, 11 patients died, including 5 (7.6%) in the SRL/MMF group and 6 (9.7%) in the CNI/MMF group. Twenty-two grafts have been lost including 10 (15.2%) in the SRL/MMF arm and 12 (19.4%) in the CNI/MMF arm. Death and chronic rejection were the most common causes of graft loss in both arms. There were modestly more cardiovascular events in the MMF/SRL group. Estimated creatinine clearance (Cockcroft-Gault) from baseline out to 6 additional years (8 years posttransplant, ITT analysis, SRL/MMF, n = 34; CNI/MMF, n = 26) was 63.2 ± 28.5 mL/min/1.73 m in the SRL/MMF group and 59.2 ± 27.2 mL/min/1.73 m in the CNI/MMF group and was not statistically significant, but there is a clinically meaningful trend for improved long-term renal function in the SRL/MMF group compared with the CNI/MMF group. The long-term decision for immunosuppression needs to be carefully individualized.

Routine ultrasonography surveillance of native kidneys for renal cell carcinoma in kidney transplant candidates.

Renal cell carcinoma (RCC) has a high incidence in the kidney transplant population and annual surveillance detects these tumors early in their natural history. Minimal guidelines exist regarding RCC surveillance in ESRD patients awaiting transplant. A retrospective review of our kidney transplant database examined the outcomes of annual ultrasonographic surveillance during initial kidney transplant evaluation and upon annual reassessment. Of 2642 patients listed for transplant, 145 patients were found to have masses during initial kidney transplant evaluation or annual imaging consistent with new complex cystic disease or RCC. A total of 71 patients had RCC identified, with 52 found on initial kidney transplant evaluation and 19 identified on annual surveillance. Male gender and African-American race were independently associated with RCC (P<.05). RCC was detected a median of 2.0 years after listing (two annual ultrasonography studies). Patients with complex cysts were more likely to undergo transplantation (48.7%) compared to patients with RCC (21.1%; P<.001). There was no significant difference in survival between RCC patients and those found to have complex cystic disease, suggesting incidental RCC can be diagnosed early in the natural history and at a curable stage through implementation of a biennial surveillance program.

Late presentation of adenovirus-induced hemorrhagic cystitis and ureteral obstruction in a kidney-pancreas transplant recipient.

We report a late presentation of adenovirus-induced renal allograft and bladder infection causing azotemia and hemorrhagic cystitis in a patient 5 years after simultaneous kidney-pancreas transplantation. Adenovirus has been increasingly recognized as a cause of morbidity and mortality in both solid organ and stem cell transplant recipients. We wish to emphasize the importance of early detection, as treatment options involve reduction of immunosuppression, followed by the addition of antiviral agents and supportive care.

West Nile virus infection in kidney and pancreas transplant recipients in the Dallas-Fort Worth Metroplex during the 2012 Texas epidemic.

BACKGROUND: In 2012, the United States experienced one of its worst West Nile virus (WNV) epidemics, reporting 5,387 human cases and final death toll of 243. Texas was at the epicenter of the outbreak, with 1,875 reported cases and 89 deaths that year. The Texas outbreak centered mainly in the Dallas-Fort Worth area where 30 deaths were reported. We report three cases of severe WNV infection complicated by meningoencephalitis in our organ transplant population. METHODS: Clinical data were collected from chart review. Therapy and outcomes on three identified patients were reviewed and compared with previously reported cases of WNV infection in kidney/pancreas transplant recipients and the general population. RESULTS: Two recipients of kidney and one recipient of a combined kidney and pancreas transplant were treated at our center for WNV infection. All three patients presented with a rapid decline in mental status within 24 hours of admission consistent with meningoencephalitis. Diagnosis was made based on detection of WNV IgM in the serum. All patients received intravenous immunoglobulin (IVIG) therapy at 400 mg/kg × 3 to 4 doses. As a result, two patients had a full recovery, and one patient died. CONCLUSION: Transplant recipients have a higher risk of neurologic complications from WNV infection. In areas where WNV is endemic, clinicians must have a high index of suspicion when treating patients presenting with fever, headache, and confusion. Full recovery in two of three patients suggests a potential role of IVIG therapy in controlling active WNV infection, particularly in immunosuppressed patients.

Reducing the incidence of short-term disability: testing the effectiveness of an absence prediction and prevention intervention using an experimental design.

OBJECTIVE: This multi-employer, prospective, randomized, controlled trial validated a quantitative model to identify employees at high risk of short-term disability (STD) and evaluated the impact of a health advocate nurse-led intervention on STD incidence. METHODS: Following prospective randomization, the control group received usual and customary services while the intervention group received usual and customary plus additional services from Cigna.* RESULTS: At the 12-month assessment, 16.8% of the intervention group had documented STD claims compared with 19.8% of the control group (P = 0.06). Duration of STD and return to work rate were not statistically different. CONCLUSION: While not statistically significant, these results suggest that the intervention for employees at high risk of STD achieves practical and clinical significance by achieving absolute and relative reductions in risk of STD of 3% and 15%, respectively.

Whole-organ pancreas transplantation at Baylor Regional Transplant Institute: a chance to cure diabetes.

The success of pancreas transplantation has improved over the past several decades with advancements in surgical technique, immunosuppressive medicines, and immunologic testing. We retrospectively reviewed our experience with pancreas transplantation from 1995 to 2008. At the Baylor Regional Transplant Program, 151 pancreas transplants were performed in 147 patients: 135 were simultaneous pancreas-kidney transplants, 10 were pancreas transplants after kidney transplants, and 6 were pancreas transplants alone. Follow-up information was available for 138 patients. The 1-year acute cellular rejection rate was 31.6%; the 30-day surgical reexploration rate was 10%; and the technical failure rate was 5.3%. Five-year pancreas graft survival rates were 67% for simultaneous pancreas and kidney transplants and 50% for pancreas transplants after kidney transplants. These outcomes exceed expected results as calculated by the Scientific Registry of Transplant Recipients. In addition, the median time to transplant was 3.8 months, compared with a US median of 14.1 months. Pancreas transplantation is currently the closest thing to a cure for diabetes and should be given as an option for diabetic patients with or without end-stage renal disease.

Predicting renal failure after liver transplantation from measured glomerular filtration rate: review of up to 15 years of follow-up.

BACKGROUND: The immunosuppressive medications that have contributed greatly to the success of liver transplantation are also associated with posttransplant renal dysfunction. We reviewed measured glomerular filtration rate (GFR) data from patients who underwent transplantation more than 10 years ago to assess whether results from specific time points can predict renal failure. METHODS: The GFR data were obtained at initial evaluation (IE), at month 3, and at years 1, 2, 5, 10, and 15. Two groupings were compared, one based on GFR at IE and the other at month 3. Patients were further stratified into three GFR (mL/min/1.73 m2) groups: G1, GFR more than 80; G2, GFR 60 to 80; and G3, GFR less than 60. RESULTS: A total of 592 liver transplant recipients met the inclusion criteria; 114 had paired GFR data from IE to year 15. Analysis of paired and censored data based on IE GFR showed that 62.2% of G3 patients developed renal failure by year 5; another 6.7% did so by year 10 (P=0.027). The month 3 GFR data showed that 56.3% of G3 patients developed renal failure by year 5; another 15.6% did so by year 10. Surprisingly, 37.0% of G2 patients experienced renal failure by year 5; another 11.1% did so by year 10 (P=0.0024). CONCLUSIONS: The month 3 data indicate a slow but steady decline in GFR over years. The lower the initial GFR is after transplant, the sooner renal failure develops. Patients with GFR less than 60 mL/min per 1.73 m2 at month 3 have a higher risk of renal failure; however, those who avoid renal failure seem to maintain renal function long term.

Indications for combined liver and kidney transplantation: propositions after a 23-yr experience.

The frequency of combined liver and kidney transplants (CLKT) persists despite the pronounced scarcity of organs. In this review, we sought to ascertain any factors that would reduce the use of these limited commodities. Seventy-five adult CLKT were performed over a 23-yr period at our center, 29 (39%) of which occurred during the Model for End-stage Liver Disease (MELD) era. Overall, patient survival rates were 82%, 73%, and 62% at one, three, and five yr, respectively. There was no difference in patient survival based either on pre-transplant hemodialysis status or by glomerular filtration rate (GFR) at the time of transplant. Patients undergoing a second CLKT or a liver retransplantation at the time of CLKT had a survival rate of 30% at three months. In the MELD era, patient survival was unchanged (p = NS) despite an older recipient population (p = 0.0029) and a greater number of hepatitis C patients (p = 0.0428). In summary, patients requiring liver retransplantation with concomitant renal failure should be denied CLKT. Renal allografts may also be spared by implementing strict criteria for renal organ allocation (GFR < 30 mL/min at the time of evaluation) and considering the elimination of preemptive kidney transplantation in CLKT.

Acute kidney injury following liver transplantation: definition and outcome.

The incidence of acute kidney injury (AKI) has been reported to vary between 17% and 95% post-orthotopic liver transplantation. This variability may be related to the absence of a uniform definition of AKI in this setting. The purpose of this study was to identify the degree of AKI that is associated with long-term adverse outcome. Furthermore, to determine the best definition (for use in future studies) of AKI not requiring dialysis in post-liver transplant patients, we retrospectively reviewed the effect of 3 definitions of AKI post-orthotopic liver transplantation on renal and patient outcome between 1997 and 2005. We compared patients with AKI to a control group without AKI by each definition. AKI was defined in 3 groups as an acute rise in serum creatinine, from the pretransplant baseline, of >0.5 mg/dL, >1.0 mg/dL, or >50% above baseline to a value above 2 mg/dL. In all groups, the glomerular filtration rate was significantly lower at both 1 and 2 years post-transplant. Patient survival was worse in all groups. Graft survival was worse in all groups. The incidence of AKI was highest in the group with a rise in creatinine of >0.5 mg/dL (78%) and lowest in patients with a rise in creatinine of >50% above 2.0 mg/dL (14%). Even mild AKI, defined as a rise in serum creatinine of >0.5 mg/dL, was associated with reduced patient and graft survival. However, in comparison with the other definitions, the definition of AKI with the greatest impact on patient's outcome post-liver transplant was a rise in serum creatinine of >50% above baseline to >2 mg/dL.

The correlation of potassium content and moisture in bovine liver samples analyzed for trace mineral concentrations.

Beef cattle in the United States are often found to be deficient in essential trace minerals such as copper and zinc. Established reference ranges for mineral concentrations exist and usually designate a concentration as adequate, marginal, deficient, or excessive. This research investigates a new method of interpreting detected elemental concentrations in bovine liver that will add confidence to the final diagnosis. This is based on the hypothesis that a correlation exists between potassium concentration and moisture in a bovine liver sample. This relationship between potassium and moisture content enables the diagnostician to more accurately predict mineral concentrations and wet weight regardless of sample moisture loss. Correlations were found between potassium content and percentage of moisture in experimental samples, clinical biopsies, and a validation study, to a statistical significance of P < 0.001. Experimental samples had a correlation coefficient of R2 = 0.95 and the mathematical relationship y = 2513.2x(-1.0662). Clinical biopsies had a correlation of R2 = 0.83 and the mathematical relationship y = 2203.4x(-0.991). The validation study had a correlation of R2 = 0.55 and a mathematical relationship y = 2321.4x(-0.952). An exponent of -1 is predicted by conservation of potassium mass. These findings have practical significance in maintaining and improving cattle growth, health, reproduction, and food safety.

Grassroots advocacy campaign for HIV/AIDS prevention: lessons from the field.

There are many guides written for developing strategies and tactics related to advocacy, and many pages of text are devoted to developing advocacy plans. Less well described is the context within which grassroots advocacy campaigns can be successful. This article describes a successful campaign to establish a needle-exchange program (NEP) in Guilford County, North Carolina. The authors briefly describe NEPs in general, the history of NEPs in North Carolina, the mission of the North Carolina Harm Reduction Coalition (NCHRC), and why this approach was considered particularly important for Guilford County. Then the context of the successful adoption of an NEP in Guilford County and the progress to make it legal will be examined, including describing the specific advocacy activities facilitated by members of NCHRC. The article concludes with a discussion of lessons learned that may be applicable to other grassroots advocacy initiatives.

Pharmacokinetics, safety, and efficacy of mycophenolate mofetil in combination with sirolimus or ciclosporin in renal transplant patients.

AIMS: To compare the pharmacokinetics of mycophenolic acid (MPA) and its metabolite (MPAG) when mycophenolate mofetil (MMF) is administered in combination with sirolimus or ciclosporin (CsA) in renal allograft recipients. Safety and efficacy (biopsy-proven acute rejection (BPAR)) were also assessed. METHODS: Patients (n = 45) were randomized 2 : 1 to receive treatment with sirolimus (n = 30; dosed to maintain trough concentrations of 10-25 ng ml(-1) until week 8, and then 8-15 ng ml(-1) thereafter) or CsA (n = 15; administered as per centre practice) both in combination with daclizumab, oral MMF and corticosteroids. Pharmacokinetic assessments were performed at day 7, week 4, and months 3 and 6 post-transplant. The primary endpoint was the AUC(0,12 h) for MPA and MPAG. The pharmacokinetics of sirolimus were also assessed. RESULTS: MPA exposure was 39-50% lower (month 6 mean AUC(0,12 h) (95%CI): 40.4 (33.8, 47.0) vs. 68.5 (54.9, 82.0) microg ml(-1) h) and MPAG exposure was 25-52% higher (722 (607, 838) vs. 485 (402, 569) microg ml(-1) h at month 6) in the presence of CsA compared with sirolimus across visits. BPAR was 40.0% with sirolimus and 13.3% with CsA. The incidence of hypertension, tremors and hirsutism was higher with CsA than with sirolimus, while the incidence of diarrhoea, hyperlipidaemia and impaired wound closure was higher with sirolimus. No deaths, malignancies or graft losses were reported. CONCLUSIONS: Co-administration of sirolimus with MMF led to greater MPA exposure, but lower MPAG exposure, than co-administration with CsA. As rejection rates were higher in the absence of CsA, further study of calcineurin inhibitor-free regimens is required before general recommendations can be made.

Cadaveric orthotopic auxiliary split liver transplantation and kidney transplantation: an alternative for type 1 primary hyperoxaluria.

Liver transplantation (LTX) corrects the enzymatic defect responsible for type 1 primary hyperoxaluria (PH1). It has been advocated in combination with kidney transplantation (KTX) in patients with renal failure from PH1 because KTX alone can result in early graft loss. A 58-year-old male patient with PH1 on hemodialysis underwent resection of the left lateral segment of the liver followed by orthotopic auxiliary left lateral segment liver transplantation and kidney transplantation from a deceased donor. The serum oxalate dropped from 34.8 micromol/L before transplant to 3.6-8.3 in the first months posttransplant to <1 micromol/L (normal range 0.4-3.0). One year after posttransplant, the patient has an iothalamate glomerular filtration rate of 58 ml/min. Orthotopic auxiliary LTX is an alternative to whole LTX in PH1. By using a split deceased donor liver, it does not deprive the donor pool and protects the recipient from liver failure in case of graft loss.

Rabies encephalomyelitis: clinical, neuroradiological, and pathological findings in 4 transplant recipients.

BACKGROUND: Three patients received solid organ transplants from a common donor and were subsequently discharged from the hospital following an uneventful hospital course. Within 30 days, all 3 organ recipients returned to the hospital with varying symptoms that progressed to rapid neurological deterioration, coma, and death. OBJECTIVE: To describe the clinical, neuroradiological, and pathological findings of rabies virus infection in organ transplant recipients infected from a common donor. DESIGN: Case series involving a common donor and 3 organ recipients ascertained through review of clinical course and autopsy findings. A fourth case was determined by review of pending autopsy cases in which death occurred within the same time interval. Portions of postmortem central nervous system and organ tissues were frozen and formalin-fixed. Fluids and tissues were also collected for cultures, serology, and molecular studies. Postmortem fluids and tissues and antemortem fluids and tissues from all 4 transplant recipients and serum and banked lymphocyte or spleen cells from the donors were sent to the Centers for Disease Control and Prevention for further evaluation. SETTING: Transplant unit of an urban teaching hospital. RESULTS: Antemortem cerebrospinal fluid analysis for 3 of the 4 recipients was consistent with a viral etiology. Neuroimaging and electroencephalogram studies were suggestive of an infectious encephalitis or a toxic encephalopathy. Initial laboratory testing did not demonstrate an infectious etiology. Postmortem histologic analysis, immunohistochemistry, electron microscopy, and direct fluorescence antibody testing revealed rabies virus infection. Serological testing done postmortem confirmed rabies virus infection in the common donor. CONCLUSIONS: These cases demonstrate a risk for transmitting rabies virus infection through solid organ and tissue transplantation, and this diagnosis should be considered in any rapidly progressing neurological disease.

Preoperative and perioperative predictors of the need for renal replacement therapy after orthotopic liver transplantation.

BACKGROUND: Acute renal failure developing after orthotopic liver transplantation (OLTx) requiring renal replacement heralds a poor prognosis. Our center has previously reported a 1-year survival of only 41.8%. We undertook this study to determine whether we could identify preoperative and perioperative factors that would predict which patients are at risk. METHODS: OLTxs performed between January 1, 1996, and December 31, 2001, were included in our retrospective database review. Combined kidney-liver transplants or patients with preoperative renal replacement therapy (RRT) were excluded. A total of 724 OLTxs were studied, which were divided into group I: no RRT, n=637; group II: hemodialysis only post-OLTx, n=17; and group III: continuous RRT post-OLTx, n=70. Univariate and stepwise logistic multivariate analyses were performed. RESULTS: Preoperative serum creatinine greater than 1.9 mg/dL (odds ratio [OR] 3.57), preoperative blood urea nitrogen greater than 27 mg/dL (OR 2.68), intensive care unit stay more than 3 days (OR 10.23), and Model for End-Stage Liver Disease score greater than 21 (OR 2.5) were significant. A clinical prediction model was constructed: probability of requiring dialysis posttransplant=(-2.4586+1.2726 [creatinine >1.9] + 0.9858 [blood urea nitrogen >27] + 0.4574 [Model for End-Stage Liver Disease score >21] + 1.1625 [intensive care unit days >3]). A clinical prediction rule for patients with a score greater than 0.12 was applied to OLTx recipients who underwent transplantation in 2002. A total of 15 of 20 patients who received RRT and 111 of 121 who did not were correctly classified with the model. CONCLUSIONS: This model allowed us to identify patients at high risk for developing the need for RRT postoperatively. Strategies for these patients to prevent or ameliorate acute renal failure and reduce the need for RRT postoperatively are needed.

Equivalent pharmacokinetics of mycophenolate mofetil in African-American and Caucasian male and female stable renal allograft recipients.

African-American (AA) renal transplant recipients require higher doses of mycophenolate mofetil (MMF) than Caucasians. A hypothesized pharmacokinetic (PK) difference was tested in stable renal transplant recipients. Whole blood was collected before, and 20, 40 and 75 min, and 2, 3, 4, 6, 8 and 12 h after the MMF dose. Mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) were analyzed using HPLC. Analysis of variance was performed for the primary end-points of dose-adjusted PK parameters AUC0-12 and Cmax of MPA using log-transformed values. Differences between races and genders were estimated: 90% confidence intervals (CI) were calculated. Back-transformation gave estimates of the race and gender ratio and their CI. Equivalence of the groups was determined if the 90% confidence limits were included in the interval (0.80, 1.25). The calculated PK parameters were comparable among the four subgroups (Caucasian, AA, Male, Female). The 90% CIs for the ratio of dose-adjusted AUC0-12 of MPA between races were between 89.7 and 112.9%. There were no race, gender or race-by-gender effects (p-values = 0.196) nor differences between diabetics and nondiabetics. This study demonstrates that dosing requirement for MMF in AA and Caucasians is unlikely to be related to different exposures to MPA.

Cyanide toxicosis in goats after ingestion of California Holly (Heteromeles arbutifolia).

Cyanogenic glycosides are found in many native and naturalized plants throughout North America. The glycosides themselves are not toxic, but they yield hydrogen cyanide (hydrocyanic or prussic acid) when they are hydrolyzed by beta-glycosidases, either as a result of injury to the plant cells or by microbial action in the rumen. Hydrogen cyanide is readily absorbed from the gastrointestinal tract. Cyanide ion binds with iron in cytochrome oxidase, interfering with cellular respiration. The clinical effects are peracute, often resulting in death less than 1 hour after ingestion. This study describes a case that resulted in significant morbidity and mortality in a herd of goats after exposure to California holly (Heteromeles arbutifolia).

Rhabdomyolysis after concomitant use of cyclosporine, simvastatin, gemfibrozil, and itraconazole.

OBJECTIVE: To report a case of rhabdomyolysis in a patient receiving cyclosporine, simvastatin, gemfibrozil, and itraconazole. CASE REPORT: Rhabdomyolysis occurring in transplant patients receiving both cyclosporine and the hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor lovastatin has been well documented. The exact mechanism by which this interaction leads to rhabdomyolysis is unknown. Experience with newer agents of the statin drug class in transplant patients is limited. Since the interaction between cyclosporine and HMG-CoA reductase inhibitors involves the CYP3A4 enzyme system, the possibility of amplifying this interaction exists when other drugs affecting the same enzyme system are coprescribed. We describe a case in which a heart transplant recipient stable on a drug regimen that included cyclosporine, simvastatin, and gemfibrozil developed rhabdomyolysis after initiation of the antifungal agent itraconazole. DISCUSSION: Drug-drug interactions due to shared metabolism via the CYP3A4 pathway can result in significant adverse outcomes. This article discusses concurrent use of an HMG-CoA reductase inhibitor with other drugs that inhibit the CYP3A4 isoenzyme, leading to a case of possible fatal rhabdomyolysis. CONCLUSIONS: Clinicians must be aware of drugs metabolized via cytochrome P450 isoenzymes and identify those requiring risk-versus-benefit analysis before prescribing. Patients need to be educated as to signs and symptoms requiring immediate physician intervention.