Non-renal Solid Organ Transplant Recipients Research Articles

Risk Factors and Outcomes Associated With the Development of Persistent Acute Kidney Injury in Non-Renal Solid Organ Transplant Recipients: Systematic Review and Meta-Analysis.

Persistent acute kidney injury (pAKI), compared with acute kidney injury (AKI) that resolves in <72h, is associated with worse prognosis in critically ill patients. Definitions and prognosis of pAKI are not well characterized in solid organ transplant patients. Our aims were to investigate (a) definitions and incidence of pAKI; (b) association with clinical outcomes; and (c) risk factors for pAKI among heart, lung, and liver transplant recipients. We systematically reviewed the literature including PubMed, Embase, Web of Science, and Cochrane from inception to 8/1/2023 for human prospective and retrospective studies reporting on the development of pAKI in heart, lung, or liver transplant recipients. We assessed heterogeneity using Cochran's Q and I2. We identified 25 studies including 6330 patients. AKI (8%-71.6%) and pAKI (2.7%-55.1%) varied widely. Definitions of pAKI included 48-72h (six studies), 7days (three studies), 14days (four studies), or more (12 studies). Risk factors included age, body mass index (BMI), diabetes, preoperative chronic kidney disease (CKD), intraoperative vasopressor use, and intraoperative circulatory support. pAKI was associated with new onset of CKD (odds ratio [OR] 1.41-11.2), graft dysfunction (OR 1.81-8.51), and long-term mortality (OR 3.01-13.96), although significant heterogeneity limited certainty of CKD and graft dysfunction outcome analyses. pAKI is common and is associated with worse mortality among liver and lung transplant recipients. Standardization of the nomenclature of AKI will be important in future studies (PROSPERO CRD42022371952).

Prospective assessment of pre-existing and de novo anti-HLA IgE in kidney, liver, lung and heart transplantation.

Antibody mediated rejection (ABMR) is a major factor limiting outcome after organ transplantation. Anti-HLA donor-specific antibodies (DSA) of the IgG isotype are mainly responsible for ABMR. Recently DSA of the IgE isotype were demonstrated in murine models as well as in a small cohort of sensitized transplant recipients. In the present study, we aimed to determine the frequency of pre-existing and de novo anti-HLA IgE antibodies in a cohort of 105 solid organ transplant recipients. We prospectively measured anti-HLA IgE antibodies in a cohort of kidney (n=60), liver, heart and lung (n=15 each) transplant recipients before and within one-year after transplantation, employing a single-antigen bead assay for HLA class I and class II antigens. Functional activity of anti-HLA IgE antibodies was assessed by an in vitro mediator release assay. Antibodies of the IgG1-4 subclasses and Th1 and Th2 cytokines were measured in anti-HLA IgE positive patients. Pre-existing anti-HLA IgE antibodies were detected in 10% of renal recipients (including 3.3% IgE-DSA) and in 4.4% of non-renal solid organ transplant recipients (heart, liver and lung cohort). Anti-HLA IgE occurred only in patients that were positive for anti-HLA IgG, and most IgE positive patients had had a previous transplant. Only a small fraction of patients developed de novo anti-HLA IgE antibodies (1.7% of kidney recipients and 4.4% of non-renal recipients), whereas no de novo IgE-DSA was detected. IgG subclass antibodies showed a distinct pattern in patients who were positive for anti-HLA IgE. Moreover, patients with anti-HLA IgE showed elevated Th2 and also Th1 cytokine levels. Serum from IgE positive recipients led to degranulation of basophils in vitro, demonstrating functionality of anti-HLA IgE. These data demonstrate that anti-HLA IgE antibodies occur at low frequency in kidney, liver, heart and lung transplant recipients. Anti-HLA IgE development is associated with sensitization at the IgG level, in particular through previous transplants and distinct IgG subclasses. Taken together, HLA specific IgE sensitization is a new phenomenon in solid organ transplant recipients whose potential relevance for allograft injury requires further investigation.

Does therapeutic drug monitoring (TDM) of trough concentrations suffice for optimizing preemptive therapy with ganciclovir of cytomegalovirus infections in non-renal solid organ transplant recipients?

The aim of this study is to explore the relationship between ganciclovir exposure and clinical efficacy and/or safety in non-renal solid organ transplant (SOT) recipients receiving preemptive therapy with ganciclovir/valganciclovir and undergoing therapeutic drug monitoring (TDM)-guided dosing optimization. Non-renal SOT recipients admitted to IRCCS Azienda Ospedaliero-Universitaria of Bologna receiving preemptive therapy with ganciclovir or valganciclovir for active cytomegalovirus (CMV) infection and who underwent at least one TDM were included. Desired ganciclovir Cmin range was set at 1-3mg/L, and average ganciclovir trough concentrations (Cmin ) were calculated for each patient. Reduced CMV viral load below the lower limit of quantification (LLQ) at 30 days and occurrence of myelotoxicity were selected as the primary outcome. Univariate analysis was performed by comparing patients with average Cmin below or above 1 or 3mg/L. Receiver operating characteristic (ROC) curve analysis was performed to identify the average ganciclovir Cmin cut-off predictive for clinical efficacy or toxicity. Twenty-nine out of 89 retrieved patients met the inclusion criteria, with a median (interquartile [IQR]) baseline CMV viral load of 27,163 copies/mL (IQR 13159.75-151340.25 copies/mL). Reduced CMV viral load below the LLQ at 30 days was found in 17 patients (58.6%). No difference was found in the primary outcome between patients showing average Cmin below or above 1mg/L (100.0%vs. 53.8%; p= .25) and/or 3mg/L (65.2%vs. 33.3%; p = .20). ROC analysis did not allow to identify an average Cmin cut-off predictive of clinical efficacy or toxicity. No clear relationship between ganciclovir Cmin and neither CMV eradication nor safety issues was identified.

BK DNAemia and native kidney polyomavirus nephropathy following lung transplantation.

BK virus DNAemia (BKPyV) and nephropathy are common after kidney transplant; however, there are limited data on BK infections in nonrenal solid organ transplant recipients. We examined the frequency, clinical and pathologic features, and kidney and lung outcomes of BKPyV and BK virus native kidney nephropathy (BKVN) in lung transplant recipients at our center. Among 878 recipients transplanted from 2003 to 2019, 56 (6%) developed BKPyV at a median of 30.1 months after transplant (range, 0.6-213) and 11 (1.3%) developed BKVN at a median of 46 months after transplant (range, 9-213). The incidence of end-stage kidney disease was significantly higher in patients with peak viral load ≥10 000 copies/mL (39% vs 8%, P < .001). All cases of BKVN were in patients with peak viral load of ≥10 000 copies/mL, and 55% of these patients developed end-stage kidney disease. Despite the reduction of immunosuppression to treat BKVN, only 1 patient developed acute rejection, and lung function was stable >1 year. BKPyV and nephropathy are more common after lung transplantation than previously reported. Routine screening for BKPyV should be considered in all lung transplant recipients.

The Role of Peritoneal Dialysis in Different Phases of Kidney Transplantation.

The utilization of peritoneal dialysis (PD) has been increasing in the past decade owing to various government initiatives and recognition of benefits such as better preservation of residual renal function, quality of life, and lower cost. The Advancing American Kidney Health initiative aims to increase the utilization of home therapies such as PD and kidney transplantation to treat end stage kidney disease (ESKD). A natural consequence of this development is that more patients will receive PD, and many will eventually undergo kidney transplantation. Therefore, it is important to understand the effect of pretransplant PD on posttransplant outcomes such as delayed graft function (DGF), rejection, thrombosis, graft, and patient survival. Furthermore, some of these patients may develop DGF, which raises the question of the utility of PD during DGF and its risks. Although transplant is the best renal replacement therapy option, it is not everlasting, and many transplant recipients must go on dialysis after allograft failure. Can PD be a good option for these patients? This is another critical question. Furthermore, a significant proportion of nonrenal solid organ transplant recipients develop ESKD. Is PD feasible in this group? In this review, we try to address all of these questions in the light of available evidence.

PD52-06 MANAGEMENT LANDSCAPE OF RENAL CELL CARCINOMA IN SOLID ORGAN TRANSPLANT RECIPIENTS

You have accessJournal of UrologyKidney Cancer: Epidemiology & Evaluation/Staging/Surveillance II (PD52)1 Sep 2021PD52-06 MANAGEMENT LANDSCAPE OF RENAL CELL CARCINOMA IN SOLID ORGAN TRANSPLANT RECIPIENTS Rishi Sekar, Sara Holt, John Gore, and George Schade Rishi SekarRishi Sekar More articles by this author , Sara HoltSara Holt More articles by this author , John GoreJohn Gore More articles by this author , and George SchadeGeorge Schade More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002079.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Immunosuppression in solid organ transplant recipients (SOTR) is thought to contribute to a higher incidence and adverse outcomes in various malignancies, including renal cell carcinoma (RCC). We evaluate the clinicopathologic characteristics and management landscape of RCC in SOTR. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we identified patients diagnosed with localized RCC (2004-2015) with or without prior history of SOT (kidney, heart, lung, liver, pancreas, and intestine). Demographics, clinicopathological characteristics, and initial management strategies were compared between renal SOTR, non-renal SOTR and non-SOTR. Surgical management was defined as radical (RN) or partial nephrectomy (PN); non-surgical management was defined as cryotherapy/radiofrequency ablation (RFA) or surveillance. Multivariable logistic regression models and Cox proportional hazards models were utilized for group comparisons. RESULTS: We identified 31,195 patients with localized RCC, of whom 335 (1.1%) had a history of SOT. Compared with non-SOTR, SOTR were younger (mean 72.6 vs. 75.2 years, p<0.001), more medically complex (Charlson Comorbidity Index ≥ 3 in 62.7% vs. 18.2%, p<0.001), more likely to present with T1a disease (60.0% vs. 47.9%, p<0.001), and had similar time to definitive intervention (60.4 vs. 51.1 days). There were no significant differences between renal (n=279) and non-renal SOTR (n=56). Initial treatment strategy is presented in Figure 1. Renal SOTR were significantly more to likely to undergo surgery than non-SOTR (HR 1.63, CI 1.21–2.21) and non-renal SOTR (HR 2.06, 1.10–3.99), and significantly more likely to undergo RN versus PN than non-SOTR (HR 3.73, CI 2.47–5.61) and non-renal SOTR (HR 3.46, CI 1.47–8.10). Conversely, when compared to non-SOTR, non-renal SOTR had a trend towards conservative management (HR 0.75, CI 0.42–1.32), and PN versus RN (HR 0. 76, CI 0.37–1.32). CONCLUSIONS: Among Medicare beneficiaries, SOTR presented with RCC at an earlier age and stage. In comparison with non-SOTR, management varied significantly based on transplant type with renal SOTR managed more surgically and with RN, and non-renal SOTR managed more conservatively or with PN. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e912-e913 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Rishi Sekar More articles by this author Sara Holt More articles by this author John Gore More articles by this author George Schade More articles by this author Expand All Advertisement Loading ...

BK virus nephropathy in non-renal solid organ transplant recipients: Are we looking hard enough?

We retrospectively examined the clinical characteristics, pathological features, and outcomes of BK viremia and nephropathy in a population of non-renal solid organ transplant patients (NRSOT) referred for outpatient nephrology consultation over a period of 5years. In the entire cohort of liver, heart, and lung transplant recipients referred to this clinic, 14% percent were found to have BK viremia with a median peak serum BK viral load of 35500 copies/ml (range 250 to 21100000 copies/ml). BK viremia resolved in six of the seventeen patients (35%). Four out of five patients biopsied showed BK virus (BKV) nephropathy. Eleven out of seventeen patients with BK viremia developed advanced (stage 4 or 5) chronic kidney disease. Four patients developed rejection of their solid organ transplant within the first year post detection of BK viremia after immunosuppression reduction. We conclude that a multi-center study is required to evaluate whether implementation of a systematic BK screening program would be effective in early detection and management of this problem in the NRSOT population.

Securing the future of kidney transplantation by addressing the challenges of transplant nephrology.

Kidney transplant is a life-changing procedure, and transplant nephrologists, as part of a larger transplant team, play an important role in the field by managing the complex medical needs of transplant patients. The subspecialty of transplant nephrology, however, faces structural challenges related to its workforce, reporting structures, compensation, research and innovation, and health care information technology. The position of transplant nephrology at the academic and operational intersection of medicine and surgery may limit its access to critical resources, hinder academic promotion, and contribute to physician burnout. The authors provide an overview of the subspecialty transplant nephrology and propose solutions. Collaborative efforts that fortify the subspecialty of transplant nephrology will ultimately improve the lives of patients suffering from kidney disease.

Targeting Asymptomatic Bacteriuria in Antimicrobial Stewardship: the Role of the Microbiology Laboratory.

This minireview focuses on the microbiologic evaluation of patients with asymptomatic bacteriuria, as well as indications for antibiotic treatment. Asymptomatic bacteriuria is defined as two consecutive voided specimens (preferably within 2 weeks) with the same bacterial species, isolated in quantitative counts of ≥105 CFU/ml in women, including pregnant women; a single voided urine specimen with one bacterial species isolated in a quantitative count ≥105 CFU/ml in men; and a single catheterized urine specimen with one or more bacterial species isolated in a quantitative count of ≥105 CFU/ml in either women or men (or ≥102 CFU/ml of a single bacterial species from a single catheterized urine specimen). Any urine specimen with ≥104 CFU/ml group B Streptococcus is significant for asymptomatic bacteriuria in a pregnant woman. Asymptomatic bacteriuria occurs, irrespective of pyuria, in the absence of signs or symptoms of a urinary tract infection. The two groups with the best evidence of adverse outcomes in the setting of untreated asymptomatic bacteriuria include pregnant women and patients who undergo urologic procedures with risk of mucosal injury. Screening and treatment of asymptomatic bacteriuria is not recommended in the following patient populations: pediatric patients, healthy nonpregnant women, older patients in the inpatient or outpatient setting, diabetic patients, patients with an indwelling urethral catheter, patients with impaired voiding following spinal cord injury, patients undergoing nonurologic surgeries, and nonrenal solid-organ transplant recipients. Renal transplant recipients beyond 1 month posttransplant should not undergo screening and treatment for asymptomatic bacteriuria. There is insufficient evidence to recommend for or against screening of renal transplant recipients within 1 month, patients with high-risk neutropenia, or patients with indwelling catheters at the time of catheter removal. Unwarranted antibiotics place patients at increased risk of adverse effects (including Clostridioides difficile diarrhea) and contribute to antibiotic resistance. Methods to reduce unnecessary screening for and treatment of asymptomatic bacteriuria aid in antibiotic stewardship.

Mammalian target of rapamycin (mTOR) inhibitors and skin cancer risk in nonrenal solid organ transplant recipients: systematic review and meta-analysis.

Solid organ transplant recipients have an increased risk of malignancy compared with the general population. Mammalian target of rapamycin (mTOR) inhibitors have been used as immunosuppressants in transplant recipients. There remains a lack of evidence of this treatment in nonrenal solid organ transplantation. We aimed to perform a systematic review and meta-analysis to assess the effects of mTOR inhibitors on secondary nonmelanoma skin cancer(NMSC) malignancies in nonrenal transplant recipients. A systematic review and meta-analysis was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Eligible studies for the present systematic review and meta-analysis included those in which patient cohorts underwent heart, liver, lung, and pancreas (i.e. nonrenal solid organ) transplantation, with treatment group being those treated with an mTOR inhibitor such as sirolimus or everolimus, and control group being placebo, or alternative non-mTOR inhibitor treatment such as calcineurin inhibitors or as per standard treatment protocol. From the six included studies, we found no significant difference in the odds of either primary or secondary NMSC (OR 0.73, 95% CI 0.41-1.29, P=0.28). Pooled analysis of patients with secondary NMSC demonstrated a trend toward significant benefit with mTOR inhibitor treatment (OR 0.61, 95% CI 0.37-1.02, P=0.06) but no protective effect for primary NMSC (OR 0.53, 95% CI 0.03-9.96, P=0.67). Our results suggest that in nonrenal transplant recipients, mTOR inhibitors may have a protective effect against secondary NMSC but not primary NMSC posttransplantation. Extrapolating the findings of reduced NMSC in renal transplant populations to nonrenal transplant cases should be cautioned.

Symptomatic BK virus cystitis in non-renal transplant recipients.

BK virus is implicated most commonly in causing BK virus-associated nephropathy in renal transplant recipients. However, on rare occasions, it can also produce symptomatic cystitis in other solid organ transplant recipients. Retrospective review of 2,149 non-renal solid organ transplant recipients over a 6-year period to evaluate patients for cases of symptomatic BK virus cystitis. Three patients (two heart transplant recipients and one lung transplant recipient) are reported herein with symptomatic BK virus cystitis. These patients responded to reduced immunosuppressive medication with a reduction in viral load in two instances, and the third patient appeared to have an apparent response to prolonged levofloxacin treatment. A high index of suspicion should be exercised in non-renal solid organ transplant recipients (particularly heart and lung transplant recipients) who have symptoms consistent with cystitis but have a negative urine bacterial culture.

Temporal trends of dialysis requiring acute kidney injury after orthotopic cardiac and liver transplant hospitalizations

BackgroundThe epidemiology and outcomes of acute kidney injury (AKI) in prevalent non-renal solid organ transplant recipients is unknown.MethodsWe assessed the epidemiology of trends in acute kidney injury (AKI) in orthotopic cardiac and liver transplant recipients in the United States. We used the Nationwide Inpatient Sample to evaluate the yearly incidence trends (2002 to 2013) of the primary outcome, defined as AKI requiring dialysis (AKI-D) in hospitalizations after cardiac and liver transplantation. We also evaluated the trend and impact of AKI-D on hospital mortality and adverse discharge using adjusted odds ratios (aOR).ResultsThe proportion of hospitalizations with AKI (9.7 to 32.7% in cardiac and 8.5 to 28.1% in liver transplant hospitalizations; ptrend<0.01) and AKI-D (1.63 to 2.33% in cardiac and 1.32 to 2.65% in liver transplant hospitalizations; ptrend<0.01) increased from 2002-2013. This increase in AKI-D was explained by changes in race and increase in age and comorbidity burden of transplant hospitalizations. AKI-D was associated with increased odds of in hospital mortality (aOR 2.85; 95% CI 2.11-3.80 in cardiac and aOR 2.00; 95% CI 1.55-2.59 in liver transplant hospitalizations) and adverse discharge [discharge other than home] (aOR 1.97; 95% CI 1.53-2.55 in cardiac and 1.91; 95% CI 1.57-2.30 in liver transplant hospitalizations).ConclusionsThis study highlights the growing burden of AKI-D in non-renal solid organ transplant recipients and its devastating impact, and emphasizes the need to develop strategies to reduce the risk of AKI to improve health outcomes.

Renal transplantation outcomes following heart and heart-lung transplantation.

Chronic kidney disease is a frequent complication following heart and combined heart-lung transplantation. The aim of this study was to analyse the outcome of a subsequent renal transplant in heart, lung and heart-lung transplantation recipients. All heart, lung and heart-lung transplant recipients who received a subsequent renal transplant over a 27-year period in a national heart and lung transplant centre were included in this study. A total of 18 patients who had previously undergone heart (n=6), lung (n=7) and heart-lung (n=5) transplantation received a renal transplant. The mean duration to development of end-stage kidney disease (ESKD) was 115±45.9months. The most common contributor to ESKD was calcineurin inhibitor nephrotoxicity. The 5-year patient survival and graft survival rates were 91.7 and 85.6%, respectively. The median creatinine level at the most recent follow-up was 123μmol/L, IQR 90.8-147.5. The overall outcome of renal transplantation following previous non-renal solid organ transplantation is excellent considering the medical complexity and co-morbidities of this patient population. Renal transplantation represents an important treatment option for ESKD in non-renal solid organ transplant recipients.

Donor-Specific Antibodies After Starting Hemodialysis in Nonrenal Solid Organ Transplant Recipients: Role of TH17

BackgroundNonrenal transplantation could cause a progressive deterioration in renal function until need dialysis. It is important to know if these patients increased their risk to develop de novo donor-specific anti-HLA antibody (DSA) after starting hemodialysis (HD) and if so, try to find the mechanism. Material and MethodsIn this double-phase study, we first analyzed the incidence of development DSA in nonrenal transplant recipients after starting HD by a retrospective study. Secondly, a prospective study was designed to analyze the pharmacokinetics of immunosuppressive drugs and the cytokine profile of these patients. ResultsOf 179 pancreas transplant recipients, 16 needed to start HD, and 62.5% of these patients developed de novo DSA after starting HD, with 80% of them class I DSA. In the second phase of the study, the plasma levels of the immunosuppressive drugs as measured by a limited sampling strategy of 3 sample time points (C0, C2, and C4) were stable. The cytokine profile showed that there was an increase in Th1 cytokine (interferon gamma of 0.045 ng/mL) and also in Th17 cytokines (transforming growth factor β >10 ng/mL). ConclusionOur data suggest that the development of DSA after starting HD in nonrenal transplant recipients could be mediated by Th17 immune response mechanisms.

The association between polyomavirus BK strains and BKV viruria in liver transplant recipients.

BK virus (BKV) is a polyomavirus that cause of allograft dysfunction among kidney transplant recipients. The role of BKV infection in non-renal solid organ transplant recipients is not well understood neither for the relationship between various BKV strains with occurrence of BKV viral viruria. This study aimed to understand the prevalence of BKV infection and identified of BKV various strains in the urine of liver transplant recipients. There was not significant difference of renal outcome between high BKV viruria and low BKV viruria in the liver transplant recipients. The WW-non-coding control region (NCCR) BKV detected in urine was associated with higher urinary BKV load, whereas the Dunlop-NCCR BKV was detected in the urine of low urinary BKV load. An in vitro cultivation system demonstrated that WW-BKV strain exhibiting the higher viral DNA replication efficiency and higher BKV load. Altogether, this is the first study to demonstrate the impact of BKV strains on the occurrence of BK viruria in the liver transplant recipients.

Acute Kidney Disease After Liver and Heart Transplantation.

After transplantation of nonrenal solid organs, an acute decline in kidney function develops in the majority of patients. In addition, a significant number of nonrenal solid organ transplant recipients develop chronic kidney disease, and some develop end-stage renal disease, requiring renal replacement therapy. The incidence varies depending on the transplanted organ. Acute kidney injury after nonrenal solid organ transplantation is associated with prolonged length of stay, cost, increased risk of death, de novo chronic kidney disease, and end-stage renal disease. This overview focuses on the risk factors for posttransplant acute kidney injury after liver and heart transplantation, integrating discussion of proteinuria and chronic kidney disease with emphasis on pathogenesis, histopathology, and management including the use of mechanistic target of rapamycin inhibition and costimulatory blockade.

Practice recommendations for the monitoring of renal function in pediatric non-renal organ transplant recipients.

The management of non-renal pediatric solid organ transplant recipients has become complex over the last decade with innovations in immunosuppression and surgical techniques. Post-transplantation follow-up is essential to ensure that children have functioning allografts for as long as possible. CKD is highly prevalent in these patients, often under recognized, and has a profound impact on patient survival. These practice recommendations focus on the early detection and management of hypertension, proteinuria, and renal dysfunction in non-renal pediatric solid organ transplant recipients. We present seven practice recommendations. Renal function should be monitored regularly in organ transplant recipients, utilizing assessment of serum creatinine and cystatin C. GFR should be calculated using the new Schwartz formula. Transplant physicians should also monitor blood pressure using automated oscillometric devices and confirm repeated abnormal measures with manual blood pressure readings and ambulatory 24-h blood pressure monitoring. Proteinuria and microalbuminuria should also be assessed regularly. Referrals to a pediatric nephrologist should be made for non-renal organ transplant recipients with repeated blood pressures >95th percentile using the Fourth Task Force reference intervals, microalbumin/creatinine ratio >32.5 mg/g (3.7 mg/mmol) creatinine on repeated testing and/or GFR <90 mL/min/1.73 m(2) .

BK polyoma virus infection and renal disease in non-renal solid organ transplantation.

BK virus (BKV) is a non-enveloped DNA virus of the polyomaviridae family that causes an interstitial nephritis in immunosuppressed patients. BKV nephropathy is now a leading cause of chronic kidney disease and early allograft failure following kidney transplantation. It is also known to cause renal disease with a progressive decline in kidney function in non-renal solid organ transplant (NRSOT) recipients, although the disease may not be recognized nor its impact appreciated in this patient population. In this report, we review the existing literature to highlight our current understanding of its incidence in NRSOT populations, the approaches to diagnosis and the potential treatment options.

Complement Regulatory Gene Mutations in Non-Renal Solid Organ Transplant Recipients with Post-Transplant Thrombotic Microangiopathy

▪Complement dysregulation is central to the pathogenesis of atypical hemolytic uremic syndrome (aHUS). Mutations in genes encoding complement regulatory proteins (CRPs) can be identified in 61% of aHUS patients (Fremeaux-Bacchi 2013). In hematopoietic stem cell transplant (HSCT) recipients, all 6 children who developed post-transplant thrombotic microangiopathy (PT-TMA) were found to have a mutation in complement factor (CF) H related genes and/or the presence of CFH autoantibodies. In contrast, 18 children without evidence of PT-TMA had no mutations detected suggesting a strong role for complement dysregulation in the development of PT-TMA (Jodele 2013). Similarly, 30% of renal transplant patients who develop de novo PT-TMA had a mutation identified in CFH and/or CFI related genes, which were lacking in matched transplanted controls (Le Quintrec 2008).In non-renal solid organ transplant (NRSOT) recipients, the role of complement in PT-TMA is less well-understood. A lack of established diagnostic criteria makes PT-TMA in NRSOT recipients difficult to recognize. The overall rate of renal failure (RF) in NRSOT recipients ranges from 7-21% (Ojo, NEJM 2003). RF is often attributed to endothelial damage triggered by calcineurin inhibitors (CNI), infection, or ischemia, all of which activate the alternative complement pathway. We propose a contributor to NRSOT related RF is PT-TMA, which develops in a subset of patients with underlying mutations in genes encoding CRPs.From January 2012-Novemeber 2013, 10 patients were clinically diagnosed with PT-TMA (8 small bowel (SB), 2 liver) and treated with eculizumab at our institution. The 7 patients remaining on therapy at 1 year underwent testing for mutations in genes encoding CRPs via a commercially available assay at Washington University School of Medicine in St Louis. Identified mutations are depicted in table 1.Table 1Gene MutationsPatient 1SBCFHR3-CFHR1 heterozygous deletion CFH: 2808G>T, 1204C>TCFI: 898A>GPatient 2SBC3: p.T647M (1940C>T) heterozygous CFH: 2808G>T, 1204C>T, 184G>A, CFI: 898A>G, 1217G>ATHBD: 1418C>TPatient 3LCFH: p.Y402H, 1204C>T, 184G>A CFI: 898A>GTHBD: 1418C>TPatient 4SBCFI: 898A>GPatient 5LCFHR3-CFHR1 heterozygous deletion CFI: 898A>GCFB:1693A>G, 95G>APatient 6SBCFB p.I242L (724A>C) heterozygous CFH: 184G>A, 1204C>TCFI: 898A>GPatient 7SBCFH: p.Y402H, 1204C>T, 184G>ACFI: 898A>GCF: Complement Factor, THBD: Thrombomodulin, SB: Small Bowel, L: LiverAll patients clinically diagnosed with PT-TMA had at least one non-synonymous mutation identified in genes encoding CRPs, which supports the role of complement dysregulation in the pathogenesis of PT-TMA in NRSOT patients. CFI898A>G, CFH1204C>T, and the combination of CFH1204C>T and CFH184G>A were found in 100%, 71%, and 57% of our patients, suggesting clinical significance. CFHR3-CFHR1 heterozygous deletion was seen in 29% of our cohort and has been correlated with an increased risk of aHUS and presence of CFH autoantibodies as reported in HSCT-TMA (Zipfel 2007). Two patients were heterozygous for either C3 p.T647M or CFB p.I242, which have been noted in aHUS cohorts (Schramm 2015; Noris 2010). Although seen in 35% of the normal population, CFH p.Y402H was observed in 29% of our cohort. Its presence has been reported to affect CFH related binding and has been associated with complement mediated disorders of the eye and kidney (Mullins 2011; Hageman 2005; Abrera-Abeleda 2006).The identification of one or more CRP mutations in NRSOT patients with PT-TMA strongly suggests they harbor a predisposition to an impaired ability to regulate complement. Upon exposure to complement activating stimuli, these individuals develop PT-TMA or more accurately termed aHUS. We previously linked spontaneous thrombosis, as the underlying cause for SB transplant, to an increased risk of PT-TMA. The 3 patients with spontaneous thrombosis as the etiology for SB transplant that were tested were found to have CRP mutations, supporting our hypothesis that SB ischemia may be the presenting feature of aHUS. To better define the underlying PT-TMA-related risks associated with CRP mutations, we propose a study involving pre-transplant screening of all NRSOT recipients with ongoing prospective evaluation for the development and clinical course of PT-TMA. DisclosuresBroome:Alexion Pharmaceuticals: Consultancy, Honoraria, Research Funding.

Long-Term Management of Atypical Hemolytic Uremic Syndrome after Non-Renal Solid Organ Transplantation with Eculizumab

▪Thrombotic microangiopathy (TMA) defined as microangiopathic hemolytic anemia, thrombocytopenia and end organ damage has been described in the post transplant (PT) setting after solid organ and hematopoietic stem cell transplants (HSCT). The true incidence among non-renal solid organ transplant (NRSOT) recipients is unknown. Reported rates range from 2-30% (Verbiest 2014). Despite standard interventions such as plasma exchange and/or reduction in calcineurin inhibitor (CNI) therapy, 3-month mortality rates remain as high as 40% in NRSOT patients who develop PT-TMA.In HSCT and renal transplant recipients, it has been demonstrated that complement plays a central role in the development of PT-TMA, analogous to atypical hemolytic uremic syndrome (aHUS) (Zuber 2011; Jodele 2013). Based on similar clinical manifestations and etiology, PT-TMA should be defined by the same laboratory criteria as aHUS and treated with eculizumab (ECU), a monoclonal antibody directed against C5 (Sheth, ASH 2014). We previously reported the successful use of ECU for the acute treatment of PT-aHUS in NRSOT patients (Broome, ASH 2013). We report the long-term data on this cohort of patients here.Between January 2012-Novemeber 2013, 10 patients (8 small bowel, 2 liver), were diagnosed with PT-aHUS utilizing established clinical criteria for de novo aHUS. All patients were on CNI therapy at the time of diagnosis. The median time from transplant to TMA diagnosis was 10.5 months (range 1-53 months). All patients received standard aHUS dosing of ECU (with meningococcal vaccinations and antibiotic prophylaxis). By 1 month of ECU therapy, all patients demonstrated normalization of hematologic parameters and 4 of the 5 patients on hemodialysis (HD) at the time of ECU initiation were able to discontinue HD. At a median follow-up of 24 months, 7 patients remain on therapy (range 18-43 months). One patient had ECU discontinued at 3 months by the transplant team. Two patients have died: one at 3 months of therapy due to sepsis/multi-organ failure and the other at 6 months of therapy due to PT lymphoproliferative disorder/graft failure (GF). The 7 patients remaining on ECU had no clinical/laboratory evidence of recurrence of PT-aHUS (Table 1). No new HD has been initiated in the follow-up period. All remained on CNI therapy (tacrolimus) for prevention of transplant rejection. One patient on ECU therapy developed GF. No serious infections have been reported to date.ECU is an effective therapy for the long-term management of PT-aHUS in NRSOT recipients. Prompt initiation of ECU appears to result in an increased likelihood of reversal of end organ damage related to TMA. The 2 patients with GF (240 days, 572 days) and the 1 patient who remained on HD (180 days) had extended intervals from laboratory evidence of PT-aHUS to initiation of ECU, suggesting prolonged complement mediated TMA may contribute to irreversible organ damage. With early ECU therapy, 86% of patients have healthy graft function and 80% of patients were able to discontinue HD. Despite ongoing CNI therapy, renal function, as measured by serum creatinine, has continued to improve demonstrating the benefit of long-term ECU therapy. The observed decline in haptoglobin, an acute phase reactant, at 12 and 18 months suggests a decrease in systemic inflammation with constant complement regulation mediated by ECU, illustrating the systemic nature of PT-aHUS. All patients remained on both CNI and ECU without infectious complications, demonstrating the ability to successfully administer more than one immune mediator in NRSOT patients with PT-aHUS concurrently. The mortality rate in our cohort of NRSOT recipients with PT-aHUS is 20%, significantly less than prior reports of up to 70%. We propose treatment with ECU at the earliest clinical/laboratory signs of aHUS to prevent the morbidity and mortality associated with PT-aHUS in NRSOT patients. Future studies should prospectively evaluate ECU therapy in PT-aHUS to better define the risks and benefits of this therapy in NRSOT patients.Table 1Median Laboratory Values Post ECUAt diagnosis1 month3 months6 months12 months18 monthsPlatelets k/uL86151 p=.01175 p=.04177 p=.01191 p=.04168 p=.07Serum Creatinine mg/dL2.261.54 p=.031.42 p=.051.28 p=.040.97 p=.131.18 p=.13LDH units/L369302 p=.23206 p=.17186 p=.17235 p=.23158 p=.21Haptoglobin mg/dL<8115 p=.00154 p=.01136 p=.0267 p=.0390 p=.04 DisclosuresBroome:Alexion Pharmaceuticals: Consultancy, Honoraria, Research Funding.