Transplant Onconephrology in Patients With Kidney Transplants.

Cancer is a leading cause of death in patients with kidney transplantation. Patients with kidney transplants are 10- to 200-times more likely to develop cancers after transplant than the general population, depending on the cancer type. Recent advances in cancer therapies have dramatically improved survival outcomes; however, patients with kidney transplants face unique challenges of immunosuppression management, cancer screening, and recurrence of cancer after transplant. Patients with a history of cancer tend to be excluded from transplant candidacy or are required to have long cancer-free wait time before wait-listing. The strategy of pretransplant wait time management may need to be revisited as cancer therapies improve, which is most applicable to patients with a history of multiple myeloma. In this review, we discuss several important topics in transplant onconephrology: the current recommendations for pretransplant wait times for transplant candidates with cancer histories, cancer screening post-transplant, post-transplant lymphoproliferative disorder, strategies for transplant patients with a history of multiple myeloma, and novel therapies for patients with post-transplant malignancies. With emerging novel cancer treatments, it is critical to have multidisciplinary discussions involving patients, caregivers, transplant nephrologists, and oncologists to achieve patient-oriented goals.

Cohort and nested case-control study of cutaneous squamous cell carcinoma in solid organ transplant recipients, by medication.

BACKGROUND: Knowledge is needed about the risk of cutaneous squamous cell carcinoma (cSCC) in solid organ transplant recipients (SOTRs) using contemporary immunosuppressive regimens. OBJECTIVE: Evaluate the risk of cSCC in relation to medications used by SOTRs. METHODS: The cohort and nest case-control study included 3308 SOTRs and 65,883 persons without transplantation during 2009-2019. Incident cSCC was identified from pathology data, and medications were identified from pharmacy data. Adjusted hazard ratios and 95% confidence intervals (CIs) were estimated using Cox proportional hazards analysis, with voriconazole examined as a time-dependent variable. RESULTS: The annual incidence of cSCC was 1.69% in SOTRs and 0.30% in persons without transplantation. The adjusted hazard ratio of cSCC associated with lung transplant was 14.83 (95% CI, 9.85-22.33) for lung and 6.53-10.69 for other organs. Risk in Latinx persons was higher than in other non-White groups. Among lung recipients, the hazard ratio was 1.14 for each month of voriconazole use (95% CI, 1.04-1.26). Azathioprine use for ≥7 months, relating to mycophenolate mofetil intolerance, was associated with a 4.22-fold increased risk of cSCC (95% CI, 1.90-9.40). Belatacept and other immunsuppressive medications were not associated with risk. LIMITATION: The number of events was somewhat small. CONCLUSIONS: The knowledge of risks and benefits in diverse patients can translate to improvements in care.

Outcomes of kidney transplant recipients with ESKD due to plasma cell dyscrasia: A case series.

Transplant centers have historically been reluctant to proceed with kidney transplantation in individuals with plasma cell dyscrasias (PCDs) due to concern for high rates of PCD recurrence and PCD-related mortality. As novel therapies for PCDs have improved hematologic outcomes, strategies to optimize kidney transplantation in individuals with PCD-mediated kidney disease are needed. In this single-center case series we discuss our protocol for the transplantation of individuals with ESKD attributed to PCD as well as the hematologic and allograft outcomes of 12 kidney transplant recipients with ESKD attributed to PCD. Median follow-up time after kidney transplantation was 44 months (IQR 36, 84). All patients had a functioning allograft 1 year after kidney transplantation. 9/12 patients were alive and had a functioning allograft 5 years after kidney transplantation. Five patients experienced relapse of PCD (of whom three responded well to subsequent therapies) and four patients developed secondary malignancies, including three patients with urologic malignancies. This case series demonstrates that patients with kidney disease attributed to PCD have favorable outcomes with kidney transplantation. Transplant evaluation in patients with PCDs should involve a multidisciplinary team of transplant nephrologists and oncologists to select appropriate candidates. Providers should consider screening for urologic malignancies pre- and post-transplantation.

The effect of kidney transplantation on left ventricular remodeling and global diastolic strain rate in end-stage renal disease.

BACKGROUND: Diastolic dysfunction is an early marker of cardiac pathology in end-stage kidney disease (ESKD) patients. The ratio of transmitral filling velocity (E) to early diastolic strain rate (E/e'sr) is a novel non-invasive marker of early left ventricular (LV) filling pressure obtained using two-dimensional speckle tracking echocardiography (2DSTE). METHODS: In a prospective cohort of kidney transplant (KTX) recipients with echocardiograms performed pre-transplant we obtained repeat echocardiograms at 6 months following transplant. All echocardiograms were analyzed using 2DSTE where E/e'sr and global longitudinal strain were obtained. Paired tests were used to assess changes to cardiac structure and function following KTX. RESULTS: A total of 33 patients were included in the study (mean age was 46.6 ± 13.7 years and 42% were males). The primary causes of ESKD in the cohort were glomerular disease (33%), hypertension (30%), and polycystic kidney disease (12%). The median (IQR) time spent on dialysis was 5.4 years [2.9, 7.7 years]. A reverse remodeling of the LV was observed following KTX as LV mass decreased (189.2 ± 57.5 g vs 171.1 ± 56.8 g, P = 0.014). LV filling pressure decreased as assessed by E/e'sr (103.7 ± 51.1 cm vs 72.6 ± 35.5 cm, P = 0.009). E to early diastolic mitral annular tissue velocity (E/e') did not change following KTX (9.9 ± 4.5 vs 10.3 ± 4.1, P = 0.54). Additionally, both LV internal diastolic and systolic diameter decreased significantly. CONCLUSION: Reverse cardiac remodeling following KTX was observed as improvements in LV mass and LV dimensions. LV filling pressure improved as assessed by E/e'sr decreased following KTX, whereas E/e' did not change.

COVID-19 and Abdominal Transplant: A Stepwise Approach to Practice During Pandemic Conditions.

BACKGROUND: The novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) disease has transformed innumerable aspects of medical practice, particularly in the field of transplantation. MAIN BODY: Here we describe a single-center approach to creating a generalizable, comprehensive, and graduated set of recommendations to respond in stepwise fashion to the challenges posed by these conditions, and the underlying principles guiding such decisions. CONCLUSIONS: Creation of a stepwise plan will allow transplant centers to respond in a dynamic fashion to the ongoing challenges posed by the COVID-19 pandemic.

A Virtual Crossmatch-based Strategy Facilitates Sharing of Deceased Donor Kidneys for Highly Sensitized Recipients.

BACKGROUND: It is estimated that 19.2% of kidneys exported for candidates with >98% calculated panel reactive antibodies are transplanted into unintended recipients, most commonly due to positive physical crossmatch (PXM). We describe the application of a virtual crossmatch (VXM) that has resulted in a very low rate of transplantation into unintended recipients. METHODS: We performed a retrospective review of kidneys imported to our center to assess the reasons driving late reallocation based on the type of pretransplant crossmatch used for the intended recipient. RESULTS: From December 2014 to October 2017, 254 kidneys were imported based on our assessment of a VXM. Of these, 215 (84.6%) were transplanted without a pretransplant PXM. The remaining 39 (15.4%) recipients required a PXM on admission using a new sample because they did not have an HLA antibody test within the preceding 3 months or because they had a recent blood transfusion. A total of 93% of the imported kidneys were transplanted into intended recipients. There were 18 late reallocations: 9 (3.5%) due to identification of a new recipient medical problem upon admission, 5 (2%) due to suboptimal organ quality on arrival, and only 4 (1.6%) due to a positive PXM or HLA antibody concern. A total of 42% of the recipients of imported kidneys had a 100% calculated panel reactive antibodies. There were no hyperacute rejections and very infrequent acute rejection in the first year suggesting no evidence for immunologic memory response. CONCLUSIONS: Seamless sharing is within reach, even when kidneys are shipped long distances for highly sensitized recipients. Late reallocations can be almost entirely avoided with a strategy that relies heavily on VXM.

Nuclear Factor of Activated T Cell-regulated Cytokine Gene Expression for Adjustment of Tacrolimus in Kidney Transplant Recipients: A Randomized Controlled Pilot Trial.

BACKGROUND: The aim of this pilot study was to assess the feasibility of a pharmacodynamics assay that measures Nuclear Factor of Activated T Cell-dependent cytokines expressed as % mean residual expression (MRE) to adjust tacrolimus (tac) dose (intervention [INT] arm) in comparison with the standard of care of tac trough levels (control [CTL] arm). METHODS: We conducted a single-center randomized controlled trial involving 40 stable kidney transplant recipients over 1 year. In the INT arm, the dose of tac was reduced by 15% if the MRE was less than 20% and was increased by 15% if the MRE was greater than 60%. Controls were adjusted based on tac trough levels. RESULTS: There was a median of 2 tac dose changes per arm. Ten subjects had 1 or more infections in the INT arm and 6 subjects had 1 or more infection in the CTL arm. Rates for hospitalizations, rejections, malignancies and death were similar in both arms. In subjects whose tac dose was not adjusted in the first 6 months, those with infections had a lower MRE at enrollment compared with those without infections (P = 0.049). This was not true for tac trough levels (P = 0.80). There was no correlation between MRE and rejection. CONCLUSIONS: Our study suggests that adjusting tac based on this pharmacodynamics assay is feasible. Quantitative analysis of nuclear factor of activated T-regulated gene expression may serve as a reliable assay to lower tac dosing. Further studies with larger populations are needed.

Kidney Transplantation for Kidney Failure Due to Multiple Myeloma: Case Reports.

Transplantation centers have historically considered a history of multiple myeloma as a contraindication to kidney transplantation due to high recurrence rates and poor transplant survival. However, there have been significant advances in the treatment of multiple myeloma, with improved patient survival, which may allow for successful kidney transplantation in these patients. We report on 4 patients who underwent kidney transplantation at our institution between 2009 and 2015 after having achieved a very good partial response or better with chemotherapy and autologous stem cell transplantation. All 4 patients received kidneys from living donors; 2 underwent induction therapy with basiliximab, and 2, with thymoglobulin. One patient had progression of myeloma, which responded well to therapy. All had functioning transplants at 1 year after kidney transplantation. No patients experienced a rejection episode or infections with BK polyomavirus or cytomegalovirus, with follow-up ranging from 16 to 58 months after kidney transplantation. Our experience suggests that kidney transplantation is feasible in a subset of patients with multiple myeloma. Future studies are necessary to compare outcomes in these patients with other high-risk patients undergoing kidney transplantation.

An Update on Calcineurin Inhibitor-Free Regimens: The Need Persists, but the Landscape has Changed.

Calcineurin inhibitors (CNIs) have failed to improve long-term renal allograft survival. Their association with cardiovascular morbidity in addition to their suboptimal inhibition of a chronic alloimmune response has shifted investigative efforts toward CNI-free regimens. Sotrastaurin, a small molecule targeting protein kinase C isoforms, failed to provide adequate immunosuppression, whereas the Janus kinase 3 inhibitor tofacitinib's success in the treatment of rheumatoid arthritis led to biopharma's abandonment of it as a transplant agent. Like tofacitinib, tocilizumab, a biologic targeting the IL-6 pathway, has been approved for use in rheumatoid arthritis and interest in transplantation has been confined to several investigator-initiated trials. Belatacept, a second-generation, higher avidity variant of CTLA4Ig (abatacept), was approved by the Food and Drug Administration for prophylaxis of transplant rejection in 2011. Long-term follow-up of recipients on belatacept has demonstrated superior glomerular filtration rates as compared with CNIs, albeit with an increased risk of early and histologically severe rejection. Focus on optimizing belatacept-inclusive regimens has led to studies using lymphocyte depletion as induction and maintenance therapy with target of rapamycin inhibitors. ASKP1240, the most advanced of the anti-CD40 antibodies targeting the CD40/CD154 costimulatory pathway has just completed a phase II trial with a CNI-free arm. Animal models suggest that its highest efficacy may be in combination with belatacept. Finally, nonagonistic CD28 antibodies, which would allow CTLA4 and PD-LI binding of CD80/CD86 and activation of inhibitory pathways, have re-emerged with 2 anti-CD28 candidates in preclinical development. A reliable nontoxic CNI-free regimen may ultimately require the combination of biologic agents that provide efficacy as well as safety.

Prediabetic living kidney donors have preserved kidney function at 10 years after donation.

BACKGROUND: Potential living kidney donors with prediabetes are often excluded from donation because of concerns about the development of type 2 diabetes mellitus (DM) and progression to end-stage renal disease (ESRD). This strategy may be unnecessarily restrictive. Previous studies of living kidney donors have not specifically examined subsets with prediabetes. METHODS: We ascertained the vital status and development of ESRD in 143 living kidney donors from 1994 to 2007 with predonation impaired fasting glucose (IFG). We then compared the development of DM, the estimated glomerular filtration rate, and the level of albumin excretion in 45 of these IFG donors to 45 matched controls with normal predonation fasting glucose. RESULTS: The majority (57.8%) of IFG donors had reverted to normal fasting glucose at a mean follow-up of 10.4 years. Compared with donors with normal fasting glucose, a higher proportion of IFG donors had developed DM (15.56% vs. 2.2%, P=0.06). Predonation characteristics including age, sex, and body mass index did not correlate with the risk of developing DM. At follow- up, estimated glomerular filtration rate by the Modification of Diet in Renal Disease equation (70.7±16.1 mL/min/1.73 m vs. 67.3±16.6 mL/min/1.73 m, P=0.21) and albumin excretion (urine albumin/ creatinine 9.76±23.6 mg/g vs. 5.91±11 mg/g, P=0.29) were similar in IFG and normal glucose donors. CONCLUSION: Carefully screened prediabetic living kidney donors often revert to normal fasting glucose and do not seem to have a significantly increased risk of impaired kidney function in the short term.

Fatal transplant-associated west nile virus encephalitis and public health investigation-california, 2010.

BACKGROUND: In December 2010, a case of West Nile virus (WNV) encephalitis occurring in a kidney recipient shortly after organ transplantation was identified. METHODS: A public health investigation was initiated to determine the likely route of transmission, detect potential WNV infections among recipients from the same organ donor, and remove any potentially infected blood products or tissues. Available serum, cerebrospinal fluid, and urine samples from the organ donor and recipients were tested for WNV infection by nucleic acid testing and serology. RESULTS: Two additional recipients from the same organ donor were identified, their clinical and exposure histories were reviewed, and samples were obtained. WNV RNA was retrospectively detected in the organ donor's serum. After transplantation, the left kidney recipient had serologic and molecular evidence of WNV infection and the right kidney recipient had prolonged but clinically inapparent WNV viremia. The liver recipient showed no clinical signs of infection but had flavivirus IgG antibodies; however, insufficient samples were available to determine the timing of infection. No remaining infectious products or tissues were identified. CONCLUSIONS: Clinicians should suspect WNV as a cause of encephalitis in organ transplant recipients and report cases to public health departments for prompt investigation of the source of infection. Increased use of molecular testing and retaining pretransplantation sera may improve the ability to detect and diagnose transplant-associated WNV infection in organ transplant recipients.

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.

Mean arterial blood pressure while awaiting kidney transplantation is associated with the risk of primary nonfunction.

BACKGROUND: Primary nonfunction (PNF) is a devastating outcome after kidney transplantation and is more common with kidneys from donors without a heartbeat or expanded criteria donors, or both. We investigated recipient-based risk factors for PNF independent of organ donor source. METHODS: We used a case-control study design and matched for the source of organ and year of transplantation; for each recipient with PNF, two recipients without PNF (controls) were randomly selected. We identified 20 PNF cases and 40 controls from our pool of 993 kidney transplant recipients who all received their transplants at our center between 2003 and 2008. The association between PNF and immune risk factors and blood pressure (BP) levels during the 3 months before transplantation was analyzed. RESULTS: Among the factors analyzed, the mean systolic BP (P=0.003, Wilcoxon test), diastolic BP (P=0.02), and mean arterial pressure (MAP) (P=0.006) during the 3 months before transplantation were significantly lower in the PNF cases compared with the controls without PNF. In a multivariable model, only MAP remained as a significant risk factor for PNF and each 10 mm Hg decrease in MAP was associated with a 43% increased odds for PNF (P=0.01). The odds ratio for PNF in those with MAP less than or equal to 80 mm Hg was 4.32 (95% confidence interval, 1.41-13.2, P=0.008), compared with the group with MAP more than 100 mm Hg. CONCLUSIONS: Our findings support the hypothesis that the average MAP less than or equal to 80 mm Hg during the 3 months before kidney transplantation is a risk factor for PNF.

Novel strategies in immunosuppression: issues in perspective.

Recent findings suggest that a chronic alloimmune response is playing the dominant role in late allograft loss, challenging the notion that most grafts are lost due to the inexorable progression of calcineurin inhibitor (CNI) nephrotoxicity. CNIs have failed to improve long-term outcomes and are associated with multiple metabolic derangements. Thus, improvement in long-term allograft outcomes may depend on new agents with novel mechanisms of action, devoid of the toxicities associated with CNIs. To meet this need, inhibitors of novel pathways in B cell and plasma cell activation have emerged to combat the humoral immune response including belimumab and atacicept, both promising targets of B-cell survival factors and bortezomib and eculizumab, agents currently in trials for desensitization protocols and treatment of antibody-mediated rejection. Promising agents for maintenance immunosuppression, used as monotherapy or synergistically, include monoclonal antibodies and fusion receptor proteins targeting the CD40-CD154 pathway (multiple anti-CD40 antibodies), the CD28-CD80/86 pathway (i.e., belatacept), the LFA3-CD2 pathway (i.e., alefacept), and small molecules such as tofacitinib, a janus kinase 1/3 inhibitor. The induction of allograft tolerance has been attempted with some success with simultaneous bone marrow/kidney transplantation from the same donor, albeit, limited by its associated toxicites. Finally, the exciting fields of tissue engineering and stem cell biology with the repopulation of decellularized organs is ushering in a new paradigm for transplantation. The era of simplified immunosuppression regimens devoid of toxicities is upon us with the promise of dramatic improvement in long term survival.

Managing the atazanavir-tacrolimus drug interaction in a renal transplant recipient.

PURPOSE: The management of the drug interaction between atazanavir and tacrolimus in a renal transplant recipient is described. SUMMARY: A 53-year-old African-American man with human immunodeficiency virus (HIV) received a renal transplant and was treated in accordance with a corticosteroid-sparing immunosuppressive protocol and maintenance immunosuppression with mycophenolate mofetil and tacrolimus. His highly active antiretroviral therapy included atazanavir 400 mg daily, abacavir 600 mg daily, and lamivudine 100 mg daily. Because of the potential for a significant interaction between tacrolimus and atazanavir, the tacrolimus dosage was to be based on serum tacrolimus concentrations. The patient was initially administered one dose of tacrolimus 0.5 mg on the morning of postoperative day 2. Evaluation of the tacrolimus profiles revealed that a higher dosage was necessary because serum tacrolimus levels decreased to subtherapeutic levels by 6 hours after dose administration. In an attempt to minimize tacrolimus toxicity and limit the duration of a subtherapeutic tacrolimus level, dosing was adjusted to 1 mg every 8 hours. After 48 hours of this regimen, peak serum tacrolimus levels were lower, and the drug concentrations remained at a relatively steady level throughout the dosing interval. One final dosage adjustment (1.5 mg every 12 hours) was performed to optimize serum tacrolimus levels and patient compliance. CONCLUSION: In a 53-year-old man with HIV infection who underwent renal transplantation, the drug interaction between atazanavir and tacrolimus was managed by modifying the tacrolimus dosage regimen after determining the patient's blood tacrolimus concentration profile.