Matthew J. Koch

Prophylactic versus preemptive oral valganciclovir for the management of cytomegalovirus infection in adult renal transplant recipients

Prophylaxis reduces cytomegalovirus (CMV) disease, but is associated with increased costs and risks for side effects, viral resistance and late onset CMV disease. Preemptive therapy avoids drug costs but requires frequent monitoring and may not prevent complications of asymptomatic CMV replication. Kidney transplant recipients at risk for CMV (D+/R−, D+/R+, D−/R+) were randomized to prophylaxis (valganciclovir 900 mg q.d. for 100 days, n = 49) or preemptive therapy (900 mg b.i.d. for 21 days, n = 49) for CMV DNAemia (CMV DNA level >2000 copies/mL in ≥ 1 whole blood specimens by quantitative PCR) assessed weekly for 16 weeks and at 5, 6, 9 and 12 months. More patients in the preemptive group, 29 (59%) than in the prophylaxis group, 14 (29%) developed CMV DNAemia, p = 0.004. Late onset of CMV DNAemia (>100 days after transplant) occurred in 11 (24%) randomized to prophylaxis, and none randomized to preemptive therapy. Symptomatic infection occurred in five patients, four (3 D+/R− and 1 D+/R+) in the prophylactic group and one (D+/R−) in the preemptive group. Peak CMV levels were highest in the D+/R− patients. Both strategies were effective in preventing symptomatic CMV. Overall costs were similar and insensitive to wide fluctuations in costs of either monitoring or drug.

BK-virus and the impact of pre-emptive immunosuppression reduction: 5-year results.

A 1‐year, single‐center, randomized trial demonstrated that the calcineurin inhibitor or adjuvant immunosuppression, independently, does not affect BK‐viruria or viremia and that monitoring and pre‐emptive withdrawal of immunosuppression was associated with resolution of BK‐viremia and absence of clinical BK‐nephropathy without acute rejection or graft loss. A retrospective 5‐year review of this trial was conducted. In cases of BK viremia, the antimetabolite was withdrawn and for sustained viremia, the calcineurin inhibitor was minimized. Five‐year follow‐up was available on 97% of patients. Overall 5‐year patient survival was 91% and graft survival was 84%. There were no differences in patient‐survival by immunosuppressive regimen or presence of BK‐viremia. Immunosuppression and viremia did not influence graft survival. Acute rejection occurred in 12% by 5‐years after transplant, was less common with tacrolimus versus cyclosporine (9% vs. 18%; p = 0.082), and was lowest with the tacrolimus‐azathioprine regimen (5%, p = 0.127). Tacrolimus was associated with better renal function at 5‐years (eGFR 63 FK vs. 52 CsA mL/min, p = 0.001). Minimization of immunosuppression upon detection of BK‐viremia was associated with excellent graft survival at 5‐years, low rejection rates and excellent renal function. It is a safe, short and long‐term strategy that resulted in freedom from clinically evident BK‐virus nephropathy.

Current and future immunosuppressive strategies in renal transplantation

The past decade has witnessed the introduction of several new immunosuppressive agents. The availability of these new pharmacologic offerings has not diminished the challenge of achieving a balance of adequate graft protection while minimizing the consequences of excessive immunosuppression. For renal transplant recipients, maintenance immunosuppression generally consists of a calcineurin inhibitor in combination with an antiproliferative agent and a corticosteroid; more recently, mammalian target of rapamycin inhibitors have been used. Excellent results have been achieved at many transplant centers with combinations of these agents in a variety of protocols. Regimens designed to limit or eliminate calcineurin inhibitor and/or corticosteroid therapy are actively being pursued in the transplant community. Allograft tolerance and xenotransplantation are being studied, and the knowledge gained from the effort may help in the development of innovative strategies and new immunosuppressive agents.

Focal C4d+ in renal allografts is associated with the presence of donor-specific antibodies and decreased allograft survival.

Diffuse peritubular capillary C4d deposition in renal allograft biopsies is associated with donor‐specific antibodies (DSA) and graft failure. The significance of focal C4d+ is unclear. We reviewed 368 biopsies from 301 patients performed for renal dysfunction or proteinuria over 5 years. Diffuse C4d+, focal C4d+ and C4d‐ detected by immunofluorescence occurred in 9.5%, 20.9% and 69.4% of biopsies, respectively. Patients were similar in gender, age, cause of renal disease, donor source, HLA mismatch, serum creatinine at baseline and interval from transplantation to biopsy. Diffuse and focal C4d+ were associated with acute cellular rejection (p < 0.001). Transplant glomerulopathy was associated with diffuse C4d+. DSA at the time of biopsy, were positive in 79.3% of diffusely C4d+ patients, 68.8% of those with focal C4d+ (p = 0.27) and 9.9% of patients with C4d‐ (p < 0.001, compared to either the focal or diffuse groups, respectively). Allograft survival at 40 months was lower in diffuse C4d+ compared to the C4d‐ group (p = 0.014), but not when compared to the focal C4d+ group. There was a clear trend toward worse graft survival in patients with focal C4d+ in this time interval, but focal C4d+ compared to both diffuse C4d+ and C4d‐groups was not statistically significant (p = 0.08).

Probing bacterial transmembrane histidine kinase receptor–ligand interactions with natural and synthetic molecules

Bacterial histidine kinases transduce extracellular signals into the cytoplasm. Most stimuli are chemically undefined; therefore, despite intensive study, signal recognition mechanisms remain mysterious. We exploit the fact that quorum-sensing signals are known molecules to identify mutants in the Vibrio cholerae quorum-sensing receptor CqsS that display altered responses to natural and synthetic ligands. Using this chemical-genetics approach, we assign particular amino acids of the CqsS sensor to particular roles in recognition of the native ligand, CAI-1 (S-3 hydroxytridecan-4-one) as well as ligand analogues. Amino acids W104 and S107 dictate receptor preference for the carbon-3 moiety. Residues F162 and C170 specify ligand head size and tail length, respectively. By combining mutations, we can build CqsS receptors responsive to ligand analogues altered at both the head and tail. We suggest that rationally designed ligands can be employed to study, and ultimately to control, histidine kinase activity.

Thymoglobulin induction is safe and effective in live-donor renal transplantation : A single center experience

Background. The relative benefit versus safety of induction therapy in live-donor renal transplant recipients is controversial. This paper presents observational data of live-donor recipients who received Thymoglobulin induction and standard maintenance immunosuppressive therapy. Methods. Review and analysis of clinic records and electronic databases of live-donor renal transplants that received Thymoglobulin induction from May 1996 through 2003. Results. Data analysis included 214 live-donor recipients (146 related, 68 unrelated) with a mean follow-up of 3.0±1.9 years. The average age of recipients was 44±13 years, with a majority being Caucasian (86%) and male (64%). Nineteen (9%) received previous transplants. No patients experienced delayed graft function and 10 (5%) developed acute rejection. Overall, predicted five-year patient survival was 96% and graft survival was 82%. The rates of CMV infection (5%), malignancy (3%), and lymphoproliferative disorder (0.5%) were low. When compared to live-donor kidney transplant recipients nationwide, the center cohort demonstrated improved five year patient (96% center versus 90% national, P=0.0326) and graft survival (82% center versus 79% national, P=0.0901), and a lower one-year acute rejection rate (2% center versus 21 % national, P<0.001). Conclusions. In this analysis, the use of Thymoglobulin in live-donor renal transplantation was associated with an absence of delayed graft function, low acute rejection rates, and high patient and graft survival without increasing the risk of infection or lymphoproliferative disorder.

Skull Base Chordoma and Chondrosarcoma: Influence of Clinical and Demographic Factors on Prognosis: A SEER Analysis

OBJECTIVE Chordomas and chondrosarcomas are rare skull base tumors, with similar radiographic and clinical presentations. We investigated factors influencing long-term survival in these 2 tumors using the Surveillance Epidemiology and End Results (SEER) database. METHODS Patients with chordoma (n = 416) and chondrosarcoma (n = 269) within the skull base from 1983 to 2009 were identified within the SEER database. Kaplan-Meier curves and Cox proportional hazards models were used to test associations with survival. t tests and χ(2) tests were used to compare groups. RESULTS Chordoma and chondrosarcoma patients were similar demographically. Survival at 5 years was 65% for chordomas and 81.8% (P < 0.0001) for chondrosarcomas and at 10 years was 32.3% and 49.5% (P = 0.004). Multivariate analysis demonstrated chordomas had a worse prognosis even when we controlled for age and tumor size (hazard ratio 3.0, 95% confidence interval 1.9-4.7, P < 0.0001). For chordomas, multivariate analysis demonstrated increasing age and tumor size were significantly associated with reduced survival. For chondrosarcomas, multivariate analysis demonstrated older age, earlier decade of diagnosis, and mesenchymal subtype were significantly associated with reduced survival. Postoperative radiation was given to 42% and 41% of patients with chordomas and chondrosarcomas, respectively. The addition of radiation did not improve survival. CONCLUSION Consistent with previous case series, skull base chordomas have significantly worse prognosis than chondrosarcomas. Patients in the SEER database had worse survival overall compared with existing case series for both chordomas and chondrosarcomas, suggesting selection bias in the existing literature.

Pharmacokinetics of Tacrolimus in Kidney Transplant Recipients: Twice Daily Versus Once Daily Dosing

Tacrolimus a macrolide immunosuppressant that is routinely given in two equally divided doses every 12 h. However, the time‐dependent pharmacokinetics of tacrolimus suggest that once daily morning administration of tacrolimus may produce appropriate drug exposure. The purpose of this pilot study was to compare the pharmacokinetics and safety of twice vs. once daily administration of tacrolimus in stable kidney transplant recipients. Steady‐state tacrolimus pharmacokinetic parameters were estimated on two occasions in an open‐label, three‐arm, two‐period sequential study: twice daily dosing (Phase I) and once daily dosing (Phase II). In phase II, 18 patients were assigned to one of three arms: those taking 67%, 85% and 100% of their total twice daily dose once in the morning. In phase I, the mean area under the blood concentration–time curve (AUC) was higher after the morning dose, AUC0–12 117 ± 40 vs. AUC12–24 97 ± 30 ng/h/mL, p = 0.012. In the 85% Group, the mean AUC ratio between twice and once daily was 1.0 (95% CI, 0.9–1.1) which predicted the best conversion ratio. Tacrolimus given once daily in the morning, at 85% of the twice daily dose, provides safe and equivalent drug exposure to twice daily dosing. This convenient dosing schedule may help to increase compliance and lower costs.

Serum Sickness After Treatment With Rabbit Antithymocyte Globulin in Kidney Transplant Recipients With Previous Rabbit Exposure

Serum sickness after rabbit antithymocyte globulin administration has a reported incidence of 7% to 27% in kidney transplant recipients. We describe 4 patients with previous exposure to rabbits who developed serum sickness after primary rabbit antithymocyte globulin induction. All patients presented with jaw pain. Three of 4 patients treated with plasmapheresis and steroids had prompt recovery, and 1 patient treated with steroids had slower recovery. We performed a telephone interview of 214 patients who contemporaneously underwent transplantation between November 2006 and July 2008 regarding rabbit exposure. More than half the patients had some type of previous rabbit exposure. There was a suggestion that patients with serum sickness were exposed more frequently to rabbits than those without. Jaw pain appears to be a hallmark symptom, and treatment with plasmapheresis and steroids relieves symptoms more rapidly than steroids alone.

Portal vein thrombosis complicating islet transplantation in a recipient with the Factor V Leiden mutation.

A 31-year-old Native American/ white female with Type 1 diabetes mellitus of 26 years duration enrolled in the international multicenter trial of the Immune Tolerance Network (NS01) to replicate the Edmonton Protocol for islet transplantation. She used oral contraceptives. She had undergone two prior islet transplant procedures complicated by sirolimus induced mucositis, diarrhea, and anemia, treated with replacement of sirolimus with mycophenolate mofetil. She received a third transplant of 314,039 islets (4,906 islet equivalents per kg) with a purity of 30% in 9 ml of packed-cell volume in two aliquots through a 5-Fr cholangiogram catheter in the right branch of the portal vein. Each aliquot contained heparin, 35 u/kg of patient body weight. After one hour, she developed abdominal pain, hypotension, and anemia. Enoxaparin was withheld. An abdominal ultrasound on postprocedure day 1 revealed a perihepatic fluid collection consistent with blood and patent hepatic vessels without evidence of thrombosis. She received 4 units of packed red blood cells over 48 hours, and her hemoglobin stabilized. An abdominal ultrasound on postprocedure day 7 demonstrated a nonocclusive thrombus in the right portal vein, 30 mm in length (Fig. 1). She was anticoagulated with heparin and then warfarin. Serial ultrasounds revealed resolution of the thrombosis by 12 weeks after the event. A thrombophilia evaluation for antithrombin III, protein C and S, anticardiolipin antibodies, homocysteine, prothrombin gene mutation, and Factor V Leiden (FVL) revealed heterozygosity for the FVL mutation, and negative or normal otherwise. Subsequent genetic analysis of her mother revealed heterozygosity for FVL. Portal vein thrombosis after islet allotransplantation has been reported previ