David Wojciechowski

Ciprofloxacin prophylaxis in kidney transplant recipients reduces BK virus infection at 3 months but not at 1 year.

Background BK polyomavirus (BKV) infection remains a significant cause of nephropathy and graft loss. Fluoroquinolones inhibit BKV replication in vitro, and small studies suggest in vivo benefit. A strategy of fluoroquinolone prophylaxis directed specifically against BKV has not been formally tested against a control group in kidney transplant recipients. Methods We retrospectively compared the impact of a change in antibiotic prophylaxis practice from no BKV prophylaxis (Group 1, n=106, July–December 2009) to BKV prophylaxis with ciprofloxacin 250 mg twice daily for 30 days (Group 2, n=130, January–June 2010) on the rate of BKV infection during the first 12 months after kidney transplantation. Results Baseline demographics, transplant characteristics, induction immunosuppression, and 1-year incidence of acute rejection were similar between groups. Group 1 had fewer patients on maintenance corticosteroids (65.1% vs. 83.2%, P=0.002). At 3 months, Group 1 had a significantly higher risk of developing BK viremia (0.161 vs. 0.065, P=0.0378) and viruria (0.303 vs. 0.146, P=0.0067) compared with Group 2, but this difference disappeared at 12 months for both viremia (0.297 vs. 0.261, P=0.6061) and viruria (0.437 vs. 0.389, P=0.5363). Adjusting for the difference in steroid use did not change the results. There was a trend toward higher incidence of biopsy-proven BKV nephropathy in Group 1 (4.7% vs. 0.8%, P=0.057). Conclusion Thirty-day ciprofloxacin prophylaxis in kidney transplant recipients is associated with a lower rate of BKV infection at 3 months but not at 12 months. The long-term effectiveness and optimal duration of fluoroquinolone prophylaxis against BKV infection remain unknown.

Belatacept in kidney transplantation.

Purpose of reviewIn June 2011 the US Food and Drug Administration approved belatacept (Nulojix; Bristol-Myers Squibb, Princeton, New Jersey, USA) for the prophylaxis of organ rejection in adult kidney transplant recipients. This review will discuss the use of belatacept for the prevention of acute rejection as part of a maintenance immunosuppression regimen. Recent findingsBelatacept is a selective costimulation blocker designed to provide effective immunosuppression while avoiding the toxicities associated with calcineurin inhibitors. Phase 3 trial data have demonstrated that belatacept is noninferior to cyclosporine in 1-year patient and allograft survival. Three-year data demonstrate an ongoing improvement in mean measured glomerular filtration rate in belatacept-treated versus cyclosporine-treated patients. Overall, there seemed to be an improvement in cardiometabolic parameters in patients treated with belatacept compared with cyclosporine. There was a trend toward higher rates of early rejection episodes in patients treated with belatacept. One safety issue that must be considered when using belatacept is the potential for increased risk of posttransplant lymphoproliferative disease, especially in Epstein–Barr virus-seronegative recipients or patients treated with lymphocyte-depleting agents. SummaryBelatacept is the first new agent available in kidney transplant that may achieve the goal of improved long-term renal function.

Targeting JAK3 in kidney transplantation: current status and future options.

Purpose of reviewThis review will discuss the mechanism of action and important clinical trial data in renal transplantation for the small molecule Janus kinase (JAK) 3 inhibitor tofacitinib, formerly known as CP-690,550 and tasocitinib. Recent findingsJAKs are cytoplasmic tyrosine kinases that participate in the signaling of a broad range of cell surface receptors, particularly members of the cytokine receptor common gamma (c&ggr;) chain family. JAK3 inhibition has immunosuppressive effects and treatment with tofacitinib in clinical trials has demonstrated efficacy in autoimmune disorders such as psoriasis and rheumatoid arthritis. Nonhuman primate models of renal transplantation demonstrated prolonged graft survival with tofacitinib compared with vehicle control. Renal transplant clinical trials in humans have demonstrated tofacitinib to be noninferior to cyclosporine in terms of rejection rates and graft survival. There was also a lower rate of new-onset diabetes after transplant. However, there was a trend toward more infections, including cytomegalovirus and BK virus nephritis. SummaryTofacitinib may be a promising alternative to calcineurin inhibitors. The optimal therapeutic window is still being determined.

Challenges and opportunities in targeting the costimulation pathway in solid organ transplantation

Signaling through the costimulatory pathway is critical in the regulation of T cell activation. Abatacept, a selective costimulatory antagonist FDA approved for the treatment of moderate to severe rheumatoid arthritis, binds to CD80 and CD86 on antigen presenting cells, blocking the interaction with CD28 on T cells. Belatacept, a second generation CTLA4-Ig with 2 amino acid substitutions, has shown considerable promise in clinical transplantation as part of a maintenance immunosuppression regimen. This review will summarize the role of costimulation in T cell activation, detail the development of costimulation antagonists and highlight the pertinent clinical trials completed and ongoing utilizing belatacept as part of an immunosuppressive regimen in organ transplantation.

Effect of ciprofloxacin combined with sulfamethoxazole-trimethoprim prophylaxis on the incidence of urinary tract infections after kidney transplantation.

Background Urinary tract infections (UTIs) are common after kidney transplantation, with limited data to guide antibiotic prophylaxis. Methods Retrospective single-center study comparing sulfamethoxazole-trimethoprim 800/160 mg (SMZ/TMP) daily for 30 days followed by Monday, Wednesday, Friday for an additional 5 months (Group 1) versus SMZ/TMP Monday, Wednesday, Friday for 6 months plus ciprofloxacin 250 mg twice daily for 30 days (Group 2) on UTI incidence after kidney transplantation. Results There were 106 and 130 patients in Groups 1 and 2, respectively. Demographics and transplant characteristics were well matched, except for more patients in Group 2 on corticosteroid maintenance. At 1 year, more patients in Group 1 developed UTIs (23.6% vs. 10.8%; P=0.01) and the mean time to first UTI was shorter (96.6±79.5 vs. 168±89.7 days; P=0.01). UTIs caused by Enterococcus species were higher in Group 2 (28.6% vs. 4%; P=0.047) with enteric gram-negative bacilli accounting for the remaining infections. There was a similar incidence of enteric gram-negative antibiotic resistance to SMZ/TMP (75% vs. 80%; P=1.00) and ciprofloxacin (16.7% vs. 30%; P=0.39) in Groups 1 and 2. For Groups 1 and 2, the proportion of first UTIs requiring hospitalization was 48.9% vs. 40.6%, respectively (P=0.62). Female gender was a UTI risk factor (hazard ratio, 3.5; 95% confidence interval, 1.78–6.8; P=0.0003). Conclusions The addition of a 30-day course of ciprofloxacin lowered the incidence of UTI; randomized prospective studies are needed to confirm the safety and efficacy of this approach.

Tofacitinib in kidney transplantation.

Introduction: This review will discuss the mechanism of action and important kidney transplant clinical trial data for the small molecule Janus kinase (JAK) 3 inhibitor tofacitinib, formerly known as CP-690,550 and tasocitinib. Areas covered: Successful kidney transplantation requires adequate immunosuppression. Current maintenance immunosuppressive protocols which rely on calcineurin inhibitors have long-term nephrotoxicity and negative impact on cardiometabolic risk factors. JAKs are cytoplasmic tyrosine kinases that participate in the signaling of a broad range of cell surface receptors, particularly members of the cytokine receptor common gamma (cγ) chain family. JAK3 inhibition has immunosuppressive effects and treatment with tofacitinib in clinical trials has demonstrated efficacy in autoimmune disorders such as psoriasis and rheumatoid arthritis. Nonhuman primate models of renal transplantation demonstrated prolonged graft survival with tofacitinib compared to control. Renal transplant clinical trials in humans have demonstrated tofacitinib to be noninferior to cyclosporine in terms of rejection rates and graft survival. There was also a lower rate of new onset diabetes after transplant. However, there was a trend toward more infections, including cytomegalovirus and BK virus nephritis. Expert opinion: Tofacitinib may be a promising alternative to calcineurin inhibitors. The optimal therapeutic window is still being determined.

Evaluation and Treatment of Resistant or Difficult-to-Control Hypertension

An observational study was conducted in 164 patients with resistant or difficult‐to‐control hypertension. Treatment was adjusted to achieve blood pressure recommendations from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7). Patients were mostly male (95.73%) and African American (86.59%) and had an average age of 63.68 years. Comorbidities included diabetes (42.07%) and chronic kidney disease, with an average estimated glomerular filtration rate of 83.55 mL/min/1.73 m2. At the time of referral, average blood pressure was 160/87 mm Hg. The average number of antihypertensive medications per patient at baseline was 3.43, which increased to 4.06 and 4.18 at 3 and 6 months, respectively (P≤.0008), with about 80% of patients receiving a diuretic prior to intervention. Blood pressure decreased to 135.55/74.55 and 137.62/74.03 mm Hg at 3 and 6 months, respectively (P<.0001). By month 6, the blood pressure goal was reached in 45.10% of patients. At months 3 and 6, 100% of patients were now receiving a diuretic. The average estimated glomerular filtration rate at month 6 was 79.36 mL/min/1.73 m2 (P=NS). Patients referred for resistant or difficult‐to‐control hypertension may be controlled by making targeted adjustments to their medical regimen.

A Case of Cocaine-Induced Acute Interstitial Nephritis

D cute interstitial nephritis (AIN) is a well known but often overlooked cause of acute idney injury (AKI). AIN is discovered on 15% f biopsy samples obtained in the evaluation of cute renal failure. AIN may occur because of a ariety of conditions, including systemic infecions and immune or immune-like inflammation nd as a drug reaction. We present a case of rug-induced AIN secondary to a cocaine binge.

Trends in the Management and Outcomes of Kidney Transplantation for Autosomal Dominant Polycystic Kidney Disease

Background. Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder leading to end-stage renal failure. The objective of this study was to evaluate a longitudinal experience of kidney transplantation for ADPKD. Methods. A single center retrospective review of patients undergoing kidney transplantation was conducted, with comparisons across two time periods: early (02/2000–04/2007, n = 66) and late (04/2007–08/2012, n = 67). Results. Over the 13.5-year study period, 133 patients underwent transplantation for ADPKD. Overall, no significant difference between the early and late group with regard to intraoperative complications, need for reoperation, readmissions within 30 days, delayed graft function, and mortality was noted. There was a trend towards increase in one-year graft survival (early 93.1% versus late 100%, P = 0.05). In the early group, 67% of recipients had undergone aneurysm screening, compared to 91% of recipients in the late group (P < 0.001). Conclusions. This study demonstrates consistent clinical care with a trend towards improved rates of one-year graft survival. Interestingly, we also note a significantly higher use of cerebral imaging over time, with the majority that were detected requiring surgical intervention which may justify the current practice of nonselective radiological screening until improved screening criteria are developed.

Belatacept for prevention of acute rejection in adult patients who have had a kidney transplant: an update

In June 2011, the US Food and Drug Administration approved belatacept for the prophylaxis of organ rejection in adult kidney transplant recipients. This review discusses the use of belatacept for the prevention of acute rejection as part of a maintenance immunosuppression regimen. Belatacept is a selective costimulation blocker designed to provide effective immunosuppression while avoiding the toxicities associated with calcineurin inhibitors. Phase III trial data have demonstrated that belatacept is noninferior to cyclosporine in 1-year patient and allograft survival. Three-year data demonstrate an ongoing improvement in mean measured glomerular filtration rate in belatacept-treated versus cyclosporine-treated patients. However, the rate of acute rejection was higher in belatacept-treated patients compared with cyclosporine. Specifically, there was a higher incidence of Banff type II rejections in patients treated with belatacept. Despite the higher Banff grade, rejections on belatacept were not associated with other factors associated with poor outcomes, such as the development of donor-specific antibodies or reduced estimated glomerular filtration rate. One safety issue that must be considered when using belatacept is the potential for increased risk of post-transplant lymphoproliferative disease. There were more cases of post-transplant lymphoproliferative disease in belatacept-treated patients, especially in recipients seronegative for Epstein–Barr virus or patients treated with lymphocyte-depleting agents. Therefore, belatacept can be recommended for use in Epstein–Barr virus antibody-positive recipients.