Impact of OPTN policy 3.7D providing waiting time modification for candidates affected by race-inclusive eGFR calculations: Early results from a single center.

INTRODUCTION: OPTN Policy 3.7D, implemented January 5, 2023, mandates that all kidney transplant programs modify waiting time for candidates affected by race-inclusive eGFR calculations. We report the early impact of this policy change. METHODS: Our transplant program reviewed all listed transplant candidates and identified patients potentially eligible for waiting time modification. Eligible candidates received waiting time modification after submission of supporting evidence to the OPTN. We reviewed the impact on waiting time and transplant activity through October 1, 2023. RESULTS: Forty-six adult patients on our center's active waiting list self-identified as Black/African American. 25 (54.3%) candidates qualified for waiting time modification. A median 451 (321, 1543.5) additional days of waiting time was added for qualifying patients. Of the 25 patients who qualified for waiting time modification, 11 patients received a deceased donor kidney in the early period following waiting time modification, including 5 patients transplanted within 1 month after modification. CONCLUSIONS: Policy 3.7D is one of few national mandates to address specifically structural racism within transplantation. Implementation has yielded near immediate effects with greater than 40% of time-adjusted patients at our center receiving a deceased donor kidney transplant in the initial months after policy enactment. Early assessment demonstrates great potential impact for this policy.

Factors Associated With Persistent Post-transplant Hyperparathyroidism After Index Renal Transplantation.

INTRODUCTION: Secondary hyperparathyroidism (SHP) is common in end-stage renal disease and may progress to persistent post-transplant hyperparathyroidism (PTHP) following renal transplantation (RT). We sought to describe the frequency and determine factors associated with the incidence of PTHP for patients undergoing RT at a single institution that restricts RT for patients with uncontrolled SHP with a parathyroid hormone (PTH) of >800pg/mL at time of initial transplant evaluation. METHODS: We conducted a single-institution retrospective study of adults undergoing index RT from 2012 to 2020 who had a calcium and PTH level within 12 mo prior to RT and at least 6 mo following RT. PTHP was defined as calcium of >10 mg/dL with an elevated PTH > 88pg/mL at six or more months following RT. Univariate analysis and multivariable logistic regression were performed for factors associated with developing PTHP. RESULTS: We identified 1110 patients with RT, 65 were excluded for prior RT, 549 did not have a pre-RT and post-RT calcium, and PTH laboratories for inclusion, yielding 496 for analysis. Following RT, 39 patients (7.9%) developed PTHP, compared to those who did not develop PTHP; these patients had significantly higher pre-RT PTH, pre-RT calcium, and frequency of calcimimetic therapy. In multivariable logistic regression factors significantly associated with PTHP were pre-RT calcium of more than 10 mg/dL with an odds ratio (OR) of 3.57 (95% confidence interval [CI] 1.52-8.39, P = 0.003) and pre-RT calcimimetic therapy with an OR 1.30 (95% CI 1.06-2.85, P = 0.041). Compared with patients who had a pre-RT PTH of less than 200 pg/mL, a PTH of 200-399 pg/mL increased risk of PTHP with an OR of 4.52 (95% CI 1.95-21.5, P = 0.048) and a PTH of > 400 pg/mL increased risk of PTHP with an OR of 7.17 (95% CI 1.47-34.9, P = 0.015). In this cohort, 11 patients (28.2%) with PTHP underwent parathyroidectomy (PTx) at a mean of 1.4 y post-RT (standard deviation 0.87). CONCLUSIONS: For patients required to have a PTH < 800pg/mL for initial transplant candidacy, the subsequent incidence of PTHP is relatively low at 7.9%. Risk factors for PTHP include higher pre-RT calcium and PTH levels and pre-RT calcimimetic therapy. PTx remains underused in the treatment of PTHP. Further study is warranted to determine the optimal PTH cutoff for transplant candidacy and recommendation for PTx in patients requiring calcimimetic therapy for SHP.

Kidney injury and status 1 liver transplantation: Outcomes, kidney function, and listing for kidney transplantation.

BACKGROUND: Effects of kidney injury (KI) at the time of liver transplantation (LT) for acute liver failure (ALF) remain poorly described. We hypothesized that patients with ALF and KI who undergo LT have persistent post-transplant KI, inferior survival, and increased rate of kidney transplantation (KT). METHODS: The US Scientific Registry of Transplant Recipients database was queried for patients transplanted with status 1 listing for LT between 2002 and 2021. KI was defined as estimated glomerular filtration rate (eGFR) ≤ 30 mL/min/1.73 m2 or dialysis in the week prior to LT. Outcomes evaluated were post-LT eGFR, listing for subsequent KT, and overall survival (OS) after LT. RESULTS: A total of 2984 patients underwent LT for ALF with 1241 (41.6%) having KI. KI patients had lower eGFR at 6 months post-LT (57.8 vs. 68.7, p < .001) that persisted out to 5 years (59.9 vs. 69.7, p < .001). KI patients were more likely to be listed for KT (4.3% vs. 1.9%, p < .001) and undergo listing sooner after LT (.8 vs. 3.7 years, p < .001). Patients without KI had higher adjusted post-transplant OS compared to those with KI (HR .75, p < .001). CONCLUSION: KI in the setting of ALF portends a worse prognosis for both kidney recovery and OS.

Emerging biomarkers in kidney transplantation and challenge of clinical implementation.

PURPOSE OF REVIEW: Despite improvement in short-term outcomes after kidney transplantation, long-term outcomes remain suboptimal. Conventional biomarkers are limited in their ability to reliably identify early immunologic and nonimmunologic injury. Novel biomarkers are needed for noninvasive diagnosis of subclinical injury, prediction of response to treatment, and personalization of the care of kidney transplant recipients. RECENT FINDINGS: Recent biotechnological advances have led to the discovery of promising molecular biomarker candidates. However, translating potential biomarkers from bench to clinic is challenging, and many potential biomarkers are abandoned prior to clinical implementation. Despite these challenges, several promising urine, blood, and tissue novel molecular biomarkers have emerged and are approaching incorporation into clinical practice. SUMMARY: This article highlights the challenges in adopting biomarker-driven posttransplant management and reviews several promising emerging novel biomarkers that are approaching clinical implementation.

A multi-center study on safety and efficacy of immune checkpoint inhibitors in cancer patients with kidney transplant.

Immune checkpoint inhibitors (ICIs) are widely used for various malignancies. However, their safety and efficacy in patients with a kidney transplant have not been defined. To delineate this, we conducted a multicenter retrospective study of 69 patients with a kidney transplant receiving ICIs between January 2010 and May 2020. For safety, we assessed the incidence, timing, and risk factors of acute graft rejection. For efficacy, objective response rate and overall survival were assessed in cutaneous squamous cell carcinoma and melanoma, the most common cancers in our cohort, and compared with stage-matched 23 patients with squamous cell carcinoma and 14 with melanoma with a kidney transplant not receiving ICIs. Following ICI treatment, 29 out of 69 (42%) patients developed acute rejection, 19 of whom lost their allograft, compared with an acute rejection rate of 5.4% in the non-ICI cohort. Median time from ICI initiation to rejection was 24 days. Factors associated with a lower risk of rejection were mTOR inhibitor use (odds ratio 0.26; 95% confidence interval, 0.09-0.72) and triple-agent immunosuppression (0.67, 0.48-0.92). The objective response ratio was 36.4% and 40% in the squamous cell carcinoma and melanoma subgroups, respectively. In the squamous cell carcinoma subgroup, overall survival was significantly longer in patients treated with ICIs (median overall survival 19.8 months vs. 10.6 months), whereas in the melanoma subgroup, overall survival did not differ between groups. Thus, ICIs were associated with a high risk of rejection in patients with kidney transplants but may lead to improved cancer outcomes. Prospective studies are needed to determine optimal immunosuppression strategies to improve patient outcomes.

The impact of multi-organ transplant allocation priority on waitlisted kidney transplant candidates.

Kidney-alone transplant (KAT) candidates may be disadvantaged by the allocation priority given to multi-organ transplant (MOT) candidates. This study identified potential KAT candidates not receiving a given kidney offer due to its allocation for MOT. Using the Organ Procurement and Transplant Network (OPTN) database, we identified deceased donors from 2002 to 2017 who had one kidney allocated for MOT and the other kidney allocated for KAT or simultaneous pancreas-kidney transplant (SPK) (n = 7,378). Potential transplant recipient data were used to identify the "next-sequential KAT candidate" who would have received a given kidney offer had it not been allocated to a higher prioritized MOT candidate. In this analysis, next-sequential KAT candidates were younger (p < .001), more likely to be racial/ethnic minorities (p < .001), and more highly sensitized than MOT recipients (p < .001). A total of 2,113 (28.6%) next-sequential KAT candidates subsequently either died or were removed from the waiting list without receiving a transplant. In a multivariable model, despite adjacent position on the kidney match-run, mortality risk was significantly higher for next-sequential KAT candidates compared to KAT/SPK recipients (hazard ratio 1.55, 95% confidence interval 1.44, 1.66). These results highlight implications of MOT allocation prioritization, and potential consequences to KAT candidates prioritized below MOT candidates.

Public health service increased risk donor kidney grafts for transplant into children, a survey of pediatric nephrologists.

BACKGROUND: Kidney transplant is the best treatment for end-stage renal disease (ESRD); however, access is limited by severe organ shortage. Public Health Service increased risk donors (PHS-IRD) represent a significant portion of available organs which are discarded at disproportional rates. METHODS: Pediatric nephrologists were surveyed regarding PHS-IRD kidneys to understand attitudes and perceived barriers to the use of these grafts in children. We sought to elucidate what methods may help increase the likelihood of PHS-IRD acceptance. RESULTS: Twenty-two responses were received from United States pediatric nephrologists representing 11 UNOS regions (response rate 5.9%). Of respondents, 50% had been practicing for 20+ years, 77% in academic hospitals, and 63% in cities with over 1 000 000 people. All respondents worked in an institution with a kidney transplant program. 41% reported that they would not accept PHS-IRD kidneys under any circumstance, 45% would accept depending on the candidate's medical status, and 14% routinely accepted PHS-IRD kidneys. Infectious transmission was the biggest disincentive reported (59%), with only 55% of respondents feeling comfortable counseling families on the associated risks. 82% of respondents did not perceive all PHS-IRD as the same, and 90% supported stratifying PHS-IRD into tiers based on risk, which would increase the likelihood of organ acceptance (82%) and assist in counseling families (91%). CONCLUSIONS: With improved utilization, PHS-IRD kidneys offer a step toward decreasing the organ shortage. These findings suggest hesitance in use of PHS-IRD kidneys for pediatric recipients. Further stratification of risk could aid in provider organ acceptance and counseling patients.

Eculizumab in post-transplant C3 glomerulonephritis caused by a C3 mutation
.

C3 glomerulonephritis (C3GN) is a disorder of excess alternative complement activation leading to glomerular injury. Following kidney transplantation, C3GN has a high recurrence rate, and the overall prognosis is poor without treatment. However, treatment efficacy is highly variable. Eculizumab, a humanized monoclonal antibody that targets complement C5 to inhibit terminal complement activity, has emerged as a potential treatment option for C3G, although data regarding its clinical utility remains limited. In this report, we describe the successful use of eculizumab to treat a patient with recurrent post-transplant C3GN caused by a C3 gene gain-of-function mutation, and also review the published literature regarding the use of eculizumab for the treatment of recurrent C3 glomerulopathy.

BK viremia surveillance and outcomes in simultaneous pancreas-kidney transplant recipients.

BACKGROUND: While screening for asymptomatic BK viremia (BKV) has been well studied in isolated kidney transplant recipients, there is a paucity of published outcomes in simultaneous pancreas-kidney (SPK) transplant recipients who underwent BKV screening followed by pre-emptive reduction in immunosuppression. METHODS: This is a single-center, retrospective review of 31 consecutive SPK recipients who were transplanted over a 5-year period following the initiation of a serum BKV screening protocol. RESULTS: BK viremia developed in 11 (35.5%) patients, and all patients achieved complete viral clearance following reduction in immunosuppression. Two patients (6.5%) developed BK virus nephropathy, but both had preserved allograft function. One patient developed mild rejection of the kidney allograft following clearance of BKV, and two patients developed mild rejection of the pancreas allograft after reduction in immunosuppression, but there were no kidney or pancreas allograft losses due to rejection. The development of BK viremia did not impact overall patient survival or kidney and pancreas allograft survival. CONCLUSION: Screening asymptomatic SPK recipients for BKV followed by reduction in maintenance immunosuppression appears to be an effective strategy to prevent kidney allograft dysfunction and graft loss due to BK virus nephropathy, without compromising pancreas allograft outcomes.

Iatrogenic Baclofen Neurotoxicity in ESRD: Recognition and Management.

Baclofen is an oral derivative of gamma-aminobutyric acid (GABA) used to treat muscular spasticity from disorders of the central nervous system. However, it is also being used for a variety of other conditions such as musculoskeletal pain, myoclonus, and alcohol withdrawal. The elimination of baclofen is heavily dependent on intact renal function, and the contraindication for use in patients with insufficient renal function is not well recognized by healthcare providers. Here, the authors report a series of mild to severe cases of baclofen intoxication in patients with end-stage renal disease. In all cases, baclofen was initiated by either inpatient or outpatient healthcare providers and the patients generally presented with altered mentation, somnolence, and/or respiratory depression. All patients were treated with aggressive hemodialysis and made a full recovery. This paper will briefly review the literature regarding baclofen intoxication, safety of baclofen use in renal disease, and efficacy of extracorporeal therapy in the treatment of baclofen intoxication.

Improved Early Post-Transplant Outcomes and Organ Use in Kidney Transplant Using Normothermic Regional Perfusion for Donation after Circulatory Death: National Experience in the US.

BACKGROUND: Normothermic regional perfusion (NRP) is a technique that is intended to enhance organ transplant outcomes from donation circulatory death (DCD) donors. STUDY DESIGN: A retrospective analysis of data from the Scientific Registry of Transplant Recipients was performed. DCD donors were screened for inclusion based on date of donation 2020 or later, and whether the heart was also recovered for transplantation. We grouped donors as either donation after brain death or DCD. DCD donors were further divided into groups including those in which the heart was not recovered for transplant (Non-Heart DCD) and those in which it was, based on recovery technique (thoracoabdominal-NRP [TA-NRP] Heart DCD and Super Rapid Recovery Heart DCD). RESULTS: A total of 219 kidney transplant recipients receiving organs from TA-NRP Heart DCD donors were compared to 436 SRR Super Rapid Recovery DCD, 10,630 Super Rapid Recovery non-heart DCD, and 27,820 donations after brain death recipients. Kidney transplant recipients of TA-NRP DCD allografts experienced shorter length of stay, lower rates of delayed graft function, and lower serum creatinine at the time of discharge when compared with recipients of other DCD allografts. CONCLUSIONS: Our analysis demonstrates superior early kidney allograft function when TA-NRP is used for DCD organ recovery.

Current State of Multiorgan Transplantation and Implications for Future Practice and Policy.

The incidence of kidney dysfunction has increased in liver transplant and heart transplant candidates, reflecting a changing patient population and allocation policies that prioritize the most urgent candidates. A higher burden of pretransplant kidney dysfunction has resulted in a substantial rise in the utilization of multiorgan transplantation (MOT). Owing to a shortage of available deceased donor kidneys, the increased use of MOT has the potential to disadvantage kidney-alone transplant candidates, as current allocation policies generally provide priority for MOT candidates above all kidney-alone transplant candidates. In this review, the implications of kidney disease in liver transplant and heart transplant candidates is reviewed, and current policies used to allocate organs are discussed. Important ethical considerations pertaining to MOT allocation are examined, and future policy modifications that may improve both equity and utility in MOT policy are considered.

Liposuction used to treat deep vascular accesses for hemodialysis.

BACKGROUND: Oftentimes, obese dialysis patients develop a viable dialysis access but the access is too deep for cannulation and needs a superficialization procedure. METHODS: We present our 14-patient cohort in whom we performed liposuction to superficialize viable but deep vascular accesses. Out of 14 patients, 12 had arteriovenous fistulas and 2 arteriovenous grafts. The primary end points were the ability to superficialize a completely unusable access and to remove the hemodialysis catheter (3patients), or to significantly extend the useful length of a deep access in which only a very short segment was used and to continue to use the access post-surgery without the need to place a dialysis catheter (11 patients). RESULTS: The study goal was met in 13 out of 14 patients. In two of three patients, the catheters were removed and their access usable length was 14 and 13 cm, respectively. The accesses could be used immediately after liposuction in all patients in which this applied-11 patients. The usable access length increased from a mean of 5 to 12.7 cm. The access mean depth decreased from 10.8 mm pre-surgery to 7 mm post-surgery and 5.3 mm 4 weeks after surgery. The mean volume of fat removed was 43.8 cc. We had only one surgical complication: bleeding that was readily controlled with manual pressure. All patients were discharged to home the same day. Postoperative pain was mild. CONCLUSION: Liposuction is effective, safe, and seems to be the least invasive technique of superficialization.

Opportunistic Infections After Induction With Alemtuzumab or Basiliximab: A 3-Year Kidney Transplantation Experience.

BACKGROUND: Antibody induction immunosuppression is commonly used in kidney transplantation to decrease the risk of early acute rejection. However, infectious complications may arise in patients treated with higher intensity induction immunosuppression. In this study, we compared the rate of opportunistic infections during the 3 years after kidney transplantation in recipients who received either alemtuzumab or basiliximab for induction therapy. METHODS: All renal transplant recipients from our center who received induction with alemtuzumab between 2011 and 2016 were included and matched 1:2 (by age and date of transplant) to renal transplant recipients who received basiliximab. The primary outcome was the rate of opportunistic infections. RESULTS: Twenty-seven patients received alemtuzumab (mean age = 50.8 years; SD ±12), and 54 received basiliximab (mean age = 50.8 years; SD ±11.8). Infections within 3 years posttransplant were not different between groups: BK viremia (P = .99), BK nephritis (P = .48), cytomegalovirus infection (P = .13), varicella zoster virus (P = .22), and all infections (P = .87). Time to infection (P = .67), patient survival (P = .21), and time to rejection (P = .098) were similar in both groups. There were also no group differences in delayed graft function (P = .76), graft loss (P = .97), or rejection (P = .2). CONCLUSION: The rate of infection was not significantly increased in recipients receiving lymphocyte-depleting alemtuzumab compared to recipients receiving basiliximab induction therapy, despite receiving similar maintenance immunosuppression. Although the immunologic risks differed between the 2 groups, there was no observable difference in clinical outcomes.

Simultaneous Liver-Kidney Transplantation: Impact on Liver Transplant Patients and the Kidney Transplant Waiting List.

PURPOSE: The number of simultaneous liver-kidney transplants (SLKT) performed in the USA has been rising. The Organ Procurement and Transplantation Network implemented a new policy governing SLKT that specifies eligibility criteria for candidates to receive a kidney with a liver, and creates a kidney waitlist "safety net" for liver recipients with persistent renal failure after transplant. This review explores potential impacts for liver patients and the kidney waitlist. RECENT FINDINGS: Factors that have contributed to the rise in SLKT including Model for End-stage Liver Disease (MELD)-based allocation, regional sharing for high MELD candidates, and the rising incidence of non-alcoholic steatohepatitis will continue to increase the number of liver transplant candidates with concurrent renal insufficiency. The effect of center behavior based on the new policy is harder to predict, given wide historic variability in SLKT practice. SUMMARY: Continued increase in combined liver/kidney failure is likely, and SLKT and kidney after liver transplant may both increase. Impact of the new policy should be carefully monitored, but influences beyond the policy need to be accounted for.

Transgenic biosynthesis of trypanothione protects Escherichia coli from radiation-induced toxicity.

Trypanothione is a unique diglutathionyl-spermidine conjugate found in abundance in trypanosomes but not in other eukaryotes. Because trypanothione is a naturally occurring polyamine thiol reminiscent of the synthetic drug amifostine, it may be a useful protector against radiation and oxidative stress. For these reasons we hypothesized that trypanothione might serve as a radioprotective agent when produced in bacteria. To accomplish this objective, the trypanothione synthetase and reductase genes from T. cruzi were introduced into E. coli and their expression was verified by qPCR and immunoblotting. Trypanothione synthesis in bacteria, detected by HPLC, resulted in decreased intracellular levels of reactive oxygen species as determined by H(2)DCFDA oxidation. Moreover, E. coli genomic DNA was protected from radiation-induced DNA damage by 4.6-fold in the presence of trypanothione compared to control bacteria. Concordantly, the transgenic E. coli expressing trypanothione were 4.3-fold more resistant to killing by (137)Cs gamma radiation compared to E. coli devoid of trypanothione expression. Thus we have shown for the first time that E. coli can be genetically engineered to express the trypanothione biosynthetic pathway and produce trypanothione, which results in their radioresistance. These results warrant further research to explore the possibility of developing trypanothione as a novel radioprotective agent.

The brain Renin-angiotensin system controls divergent efferent mechanisms to regulate fluid and energy balance.

The renin-angiotensin system (RAS), in addition to its endocrine functions, plays a role within individual tissues such as the brain. The brain RAS is thought to control blood pressure through effects on fluid intake, vasopressin release, and sympathetic nerve activity (SNA), and may regulate metabolism through mechanisms which remain undefined. We used a double-transgenic mouse model that exhibits brain-specific RAS activity to examine mechanisms contributing to fluid and energy homeostasis. The mice exhibit high fluid turnover through increased adrenal steroids, which is corrected by adrenalectomy and attenuated by mineralocorticoid receptor blockade. They are also hyperphagic but lean because of a marked increase in body temperature and metabolic rate, mediated by increased SNA and suppression of the circulating RAS. ß-adrenergic blockade or restoration of circulating angiotensin-II, but not adrenalectomy, normalized metabolic rate. Our data point to contrasting mechanisms by which the brain RAS regulates fluid intake and energy expenditure.