Non-renal Solid Organ Transplant Research Articles

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.

Race, Calcineurin Inhibitor Exposure, and Renal Function After Solid Organ Transplantation

BackgroundCalcineurin-inhibitor (CNI)–induced nephrotoxicity frequently complicates transplantation. African-Americans are at a greater risk of renal failure than the general population. We investigated whether race was an effect modifier of the relationship between CNI exposure and kidney function after nonrenal solid organ transplantation. MethodsThis is a retrospective cohort study of 1609 patients who underwent initial nonrenal solid organ transplantation between January 2000 and June 2012. A central repository administrative database was queried electronically for demographics, comorbidities, and serial levels of tacrolimus, cyclosporine, and serum creatinine. Predictors of interest were total drug exposure of tacrolimus and cyclosporine (area under the concentration–time curve) and self-reported race. The outcome of interest was cumulative change in estimated glomerular filtration rate (GFR). ResultsThere were 1109 patients treated with tacrolimus (271 African-Americans) and 500 patients treated with cyclosporine (113 African Americans). A decline in GFR over time was seen with total tacrolimus exposure (−1.3 mL/min/1.73 m2 for every 5 ng/mL·year increase in tacrolimus) and total cyclosporine exposure (−1.1 mL/min/1.73 m2 for every 50 ng/mL·year increase in cyclosporine). However, total CNI exposure effect on estimated GFR changes did not vary by race (P interaction was 0.9 for tacrolimus and 0.6 for cyclosporine). ConclusionsTotal CNI exposure is associated with worsening kidney function among patients with nonrenal solid organ transplantation. However, African-American patients are not more vulnerable to chronic CNI-induced nephrotoxicity when compared to white patients.

Adenovirus disease in six small bowel, kidney and heart transplant recipients; pathology and clinical outcome.

Adenoviruses are emerging as important viral pathogens in hematopoietic stem cell and solid organ transplant recipients, impacting morbidity, graft survival, and even mortality. The risk seems to be highest in allogeneic hematopoietic stem cell transplant recipients as well as heart, lung, and small bowel transplant recipients. Most of the adenovirus diseases develop in the first 6 months after transplantation, particularly in pediatric patients. Among abdominal organ recipients, small bowel grafts are most frequently affected, presumably due to the presence of a virus reservoir in the mucosa-associated lymphoid tissue. Management of these infections may be difficult and includes the reduction of immunosuppression, whenever possible, combined with antiviral therapy, if necessary. Therefore, an awareness of the pathology associated with such infections is important in order to allow early detection and specific treatment. We reviewed six transplant recipients (small bowel, kidney, and heart) with adenovirus graft involvement from two institutions. We sought to compare the diagnostic morphology and the clinical and laboratory findings. The histopathologic features of an adenovirus infection of the renal graft and one native kidney in a heart transplant recipient included a vaguely granulomatous mixed inflammatory infiltrate associated with rare cells showing a cytopathic effect (smudgy nuclei). A lymphocytic infiltrate, simulating T cell rejection, with admixture of eosinophils was also seen. In the small bowel grafts, there was a focal mixed inflammatory infiltrate with associated necrosis in addition to cytopathic effects. In the heart, allograft adenovirus infection was silent with no evidence of inflammatory changes. Immunohistochemical stain for adenovirus was positive in all grafts and in one native kidney. All patients were subsequently cleared of adenovirus infection, as evidenced by follow-up biopsies, with no loss of the grafts. Adenovirus infection can involve allografts as well as native organs in solid organ transplant recipients. Infection is associated with variable necrosis and acute inflammation, in addition to a rejection-like infiltrate. Hematuria in non-renal solid organ transplant recipients may be associated with adenovirus nephritis and clinically silent graft involvement. Prompt diagnosis (aided by immunohistochemistry (IHC) and serology), with specific treatment, can prevent graft loss.

Generic immunosuppression in solid organ transplantation: systematic review and meta-analysis

Objective To compare the clinical efficacy and bioequivalence of generic immunosuppressive drugs in patients with solid organ transplants.Design Systematic review and meta-analysis of all studies comparing generic with innovator immunosuppressive...

The prevalence and implications of BK virus replication in non-renal solid organ transplant recipients: A systematic review.

The significance of BK viruria and viremia in non-renal solid organ transplants is poorly understood. A systematic review was performed reviewing the incidence and implications of BK virus replication in non-renal solid organ transplants. Ninety-seven studies were identified, of which 18 including lung, heart, liver and pancreas transplants were included. The overall incidence of BK viruria and viremia was 20% and 3% respectively and 17 cases of BK nephropathy were identified. Heart transplant recipients had a higher overall incidence of BK viremia than other non-renal organ types, and the majority of cases of BK virus-associated nephropathy were in heart transplant recipients. The incidence of BK viremia was significantly lower in non-renal solid organ transplants than that of renal transplant recipients and BK virus-associated nephropathy was rare. BK virus-associated nephropathy may be considered in heart transplant recipients who have unexplained and persistent renal dysfunction not attributable to other causes.

Risk Factors for Chronic Renal Insufficiency Following Cardiac Transplantation.

Although previous publications have discussed kidney disease in nonrenal solid-organ transplantation, none has reviewed thoroughly the potential predictors of long-term renal impairment in cardiac recipients. Thus, the purpose of this review article is to summarize the current state of knowledge on risk factors of chronic renal insufficiency in heart transplant patients. An English language Medline literature search (1946-April 2014) was conducted using the search terms renal insufficiency, kidney failure, kidney diseases, nephrotoxi$ ($ for truncation), creatinine, glomerular filtration rate, heart transplantation and organ transplantation. Additional references were identified from a review of literature citations. A total of 74 articles discussing key risk factors were included in the manuscript. The existing literature reveals that several recipient characteristics (age, female sex, pretransplant/early post-transplant kidney impairment, diabetes, and hypertension) increase the risk of renal insufficiency after transplantation. Current data also indicate that, while cyclosporine and tacrolimus are most likely major determinants of post-transplant kidney failure, the effects of calcineurin inhibitor doses and concentrations remain unclear. A small number of studies suggest that tacrolimus could possibly induce less nephrotoxicity than cyclosporine, but meta-analyses of randomized controlled trials show the opposite with comparable incidences of dialysis after cardiac transplantation. Finally, the role of genetic variations has only been explored to a limited extent in heart transplant patients. This growing body of evidence should ultimately lead to a better risk prediction regarding chronic renal insufficiency following cardiac transplantation and a more personalized tailoring of immunosuppressive regimens.

Eculizumab Reduces Red Blood Cell Transfusions in Non-Renal Solid Organ Transplant Patients Diagnosed with Post Transplant Atypical Hemolytic Uremic Syndrome (PT-aHUS)

INTRODUCTIONPatients who receive non-renal solid organ transplants have a reported 4-30% incidence of post transplant thrombotic microangiopathy (PT-TMA). The development of PT- TMA is associated with a significant increase in early mortality when compared to patients with no PT-TMA. Mortality rates as high as 70% are associated with PT-TMA in spite of plasma exchange therapy. The factors which contribute to this high mortality are poorly understood. New findings suggest that this form of TMA is complement mediated and can be classified as PT-aHUS. We and others have reported the clinical and laboratory benefits of treating PT-aHUS with eculizumab. There are suggestions of a link between PT-TMA and decreased graft survival although the mechanism is not well understood. Theories include: 1) chronic ischemia from TMA, 2) chronic/low grade antibody mediated rejection (perhaps contributed to by alloimmunization from transfusions) and 3) direct damage to graft mediated by complement. The role that multiple post transplant transfusions plays in poor overall and/or poor graft survival in these patients has not been evaluated, but is intriguing. MATERIALS and METHODSWe report our experience with 9 patients who underwent non renal solid organ transplantation (7 small bowel and 2 orthotopic liver) in 2011 - 2013 at our institution who were diagnosed clinically with PT-aHUS and treated with eculizumab. Blood component use was evaluated from the date of transplant (DOT) to the date of initiation of eculizumab therapy 1-53 months (mean: 11 months) and after initiation of eculizumab therapy 6-24 months (mean: 13 months). Criteria for transfusions and the clinical team were unchanged during the study period. RESULTSRed blood cell (RBC) transfusions from the DOT to the date of eculizumab initiation 5-53 units (mean: 31 units), PRBC transfusions post initiation of eculizumab therapy 0-41 units (mean: 11 units). Apheresis platelet (PLT) transfusions from the DOT to the date of eculizumab initiation 0-7 units (mean: 3 units), PLT transfusions post initiation of eculizumab therapy 0-16 units (mean: 2units). Fresh frozen plasma (FFP) infusions from the DOT to the date of eulizumab initiation 0-272 units (mean: 43 units) FFP infusions post initiation of eculizumab therapy 1-10 units (mean: 2units). CONCLUSIONSThe significant reduction in RBC transfusions after the initiation of eculizumab demonstrates a previously unreported clinical benefit of the complement inhibitory effects of eculizumab in patients with PT-aHUS. While long term results remain to be determined continued monitoring of both overall patient and graft survival in these patients will be interesting. We hypothesize that early treatment of PT-aHUS with eculizumab minimizing the need for transfusion therapy will have a beneficial effect on overall patient as well as graft survival. DisclosuresBroome:Alexion Pharmaceuticals: Honoraria.

Value of serum cystatin C in estimating renal function in children with non‐renal solid organ transplantation

Children with non-renal solid organ transplants are surviving longer, but outcome is complicated by CKD. Accurate and frequent renal function monitoring is imperative to recognize and institute measures early to reverse, prevent, or arrest progression. This study of 59 children determined the accuracy (P30), bias, sensitivity and specificity between measured renal function by NM-GFR, and estimated GFR by three formulas: Filler (serum cystatin C), mSchwartz (serum creatinine), and CKiD (serum cystatin C, creatinine, urea, and height). Mean GFR by all formulas differed significantly from NM-GFR. Filler and mSchwartz formulas significantly increased the proportion of patients with GFR≥90mL/min/1.73m(2) (CKD stage 1) while decreasing those with GFR 60-89mL/min/1.73m(2) (CKD stage 2). All formulas overestimated GFR. CKiD showed the highest P30 and lowest bias (79.7%; 6.9mL/min/1.73m(2) ) followed by Filler (67.7%; 19.9mL/min/1.73m(2) ) and Schwartz (57.6%; 26.8mL/min/1.73m(2) ) for all GFR values. All formulas performed best with GFR≥90mL/min/1.73m(2) , but CKiD was the only formula to achieve 91.1% accuracy. All formulas showed high sensitivities, but low specificities at NM-GFR cutoff at 90. Thus, GFR estimated by CKiD followed by Filler formula is an adequate method to monitor renal function closely and frequently in these children.

De novo thrombotic microangiopathy after non-renal solid organ transplantation

Thrombotic microangiopathy (TMA) is a rare but serious complication of organ transplantation. This article presents the first literature review on TMA following non-renal solid organ transplantation (SOT). Ischemia–reperfusion, immunosuppressive drugs, acute interfering disease and a relative deficiency of the von Willebrand factor (vWF) cleaving protease (ADAMTS13) appear to play a major role in its pathogenesis. De novo TMA occurs in 4.0% of liver and 2.3% of lung transplant recipients, whereas the incidence remains unknown after intestinal transplantation. The median time of onset is 2, 37 and 8weeks after liver, lung and intestinal transplantations respectively, with a three month survival of about 70%. In heart transplantation TMA is rare, occurrence is late and prognosis is poor. In TMA early after liver transplantation an elevated vWF/ADAMTS13 ratio may show diagnostic value. Early withdrawal of calcineurin inhibitors (CNI) proves to be lifesaving. Conversion to another CNI and rechallenge after resolution are generally safe, except after heart transplantation. The value of plasma exchange therapy remains controversial.

A 13-Year Retrospective Analysis of Acute Kidney Injury Requiring Renal Replacement Therapy in Non Renal Solid Organ Transplantation.

Acute kidney injury (AKI) requiring renal replacement therapy (RRT) is associated with high mortality and progression toward chronic kidney disease (CKD). A few studies analyzed the impact of AKI in non renal solid organ transplant (NRSOT) recipients. The aim of this study was a 13-year retrospective analysis of AKI in NRSOT recipients identifying its clinical relevance on outcome and progression toward CKD. We analyzed (2001-2013) the percentage of NRSOT in the AKI population treated by RRT in our University Hospital. For each NRSOT recipient, we evaluated RIFLE, SOFA and the severity index ATN_ISS at RRT start. The percentage of AKI requiring RRT in the NRSOT population and for distinct transplanted organ (liver, heart or lung graft) was studied. Renal function (eGFR) was evaluated at the end of observation (30 days). We treated by RRT 2648 critically ill patients with AKI for a total of 20932 sessions performed: 291/2648 (10.99%) were NRSOT recipients. In the study period, 1673 liver, 317 heart and 34 lung transplantations were performed. We treated by RRT 174/1673 (10.4 %) liver, 83/317 (26.2 %) heart and 34/110 (30.9%) lung transplanted patients. NRSOT patients’ characteristics were: age 59.8±7.6 yrs, male 67.7%, serum creatinine 3.88±1.27 mg/dl, SOFA 12.8±3.1, RIFLE (Risk 12%, Injury 17.2%, Failure 70.8%) and ATN_ISS score 0.8±0.11. The prevalent cause of AKI was sepsis (44%). Mortality rate of NRSOT patients treated by RRT was 44.3% (129/291), 42.5% (74/174) for liver, 49.4% (41/83) for heart and 41.2% (14/34) for lung recipients, respectively. AKI was a complication of the early post-transplantation period since the need for RRT occurred in the first 30 days after surgery in 69.1% of NRSOT recipients (64.9% for liver, 60.2% for heart and 82.3% for lung, respectively). In survivors, mean serum creatinine at the end of the study period was 2.37±0.82 mg/dl (1.88±0.94 mg/dl in liver, 2.42±0.75 mg/dl in heart and 2.81±0.92 mg/dl in lung graft recipients, respectively). Our retrospective analysis revealed an increased incidence of AKI mainly due to sepsis in the NRSOT population. The occurrence of AKI requiring RRT in the first 30 days after transplantation was associated with a worse outcome and with progression toward CKD in survivors.

Pediatric Kidney Transplantation Following Nonrenal Organ Transplantation: A Single Center Experience.

Renal insufficiency is a known comorbidity in solid organ transplantation that can have significant morbidity and mortality. We retrospectively reviewed and present the outcomes of 22 patients who underwent an isolated kidney transplantation following a non-renal organ transplant at our center. Between 1990 and 2012, a total of 23 kidney transplants were performed in nonrenal organ transplant recipients (1 lung, 2 intestine, 4 heart, 5 multivisceral, and 11 liver transplants) with one patient lost to follow-up. We will present the underlying medical condition, estimated glomerular filtration rate at initial transplant, cause of kidney disease, time to kidney transplant, rejection incidence after kidney transplant, and infectious complications following kidney transplantation. The overall 1 year patient survival following kidney transplant is 95% and graft survival is 91%. The overall 5 year patient survival is 84% following kidney transplant and graft survival is 89%.Table: No Caption available.Conclusion: Kidney allograft survival following nonrenal solid organ transplant is comparable to that of an isolated kidney transplant. Preliminary review indicates there does not appear to be higher rates of complication in kidney after non-renal solid organ transplantation than isolated kidney transplants.

Risk Factors for Chronic Kidney Disease in Pediatric Non-Renal Solid Organ Transplant Recipients.

Background: Chronic kidney disease (CKD) is a significant cause of morbidity and mortality in non-renal solid organ transplant (NRSOT; liver, heart, lung, and multiple organs) recipients. Risk factors associated with incident CKD after pediatric NRSOT remain uncertain. Objective:Determine risk factors associated with CKD development among childhood recipients of non-renal NRSOTs. Methods: The study cohort included 344 children who received their first NRSOT between January 1st, 2002 and January 1st, 2012 at the Hospital for Sick Children and were followed until the time of transfer (at age of 18 years) or death. CKD was defined as two consecutive estimated glomerular filtration rates (eGFR) of < 60 ml/min/1.73m2 over 2 months using the modified Schwartz formula. Cox regression model was used to examine the risk factors of age, gender, organ type, eGFR at transplant, use of induction medication, and angiotensin converting enzyme inhibitors used in year 1 post-transplant. Results: The population included liver (48%), heart (41%), lung (8%), and multiple organ (3%) transplant recipients. During a mean follow-up of 4.2 years (median: 3.9 years), 63 (18%) recipients developed CKD. The relative hazard for CKD was 3.78 higher in lung, 2.08 in heart, and 1.67 in multi-organ transplant compared to liver recipients (Table 1). For every 1 mL/min/1.73m2 increase in eGFR at the time of transplant, the hazard ratio for CKD decreased by 3%. Another significant risk factor for CKD was induction medication use.Table: No Caption available.Conclusion: CKD is common among children after NRSOT. The highest risk was observed among recipients of lung and heart, while the lowest risk was seen in liver recipients. Early implementation of strategies to maximize preservation of renal function in pediatric NRSOT population is warranted. DISCLOSURES:Kim, S.: Grant/Research Support, Astellas Pharma Canada, Novartis Pharma Canada, Genzyme.

Successful Management of CNI-Induced Atypical Hemolytic Uremic Syndrome With Eculizumab After Non-Renal Solid Organ Transplantation.

Successful Management of CNI-Induced Atypical Hemolytic Uremic Syndrome With Eculizumab After Non-Renal Solid Organ Transplantation.

Renal Failure Associated With Intestinal Transplantation: Our Experience in Spain

BackgroundRenal failure (RF) is a frequent complication in non-renal solid organ transplants. In the present study, we analyze our experience with intestinal transplants (ITx). MethodsBetween 2004 and 2012, we performed 21 ITx in 19 adult patients. Alemtuzumab was used as an induction agent followed by tacrolimus. Renal function was assessed before ITx and during the perioperative period. ResultsThe main cause for transplants was non-resectable desmoids tumors (33.3%), followed by vascular thrombosis (19%) and others. Medical complications were frequent, especially infectious diseases, which were the most common (51%). Surgical complications were also frequent, but most of them (>50%) were mild but leading to a great number of re-operations and prolonged stays in hospital. Acute rejection is very frequent (66.6%) but mild in more than 70% of the cases. Finally, RF was very frequent (68.4%; 13/19 patients) and accounted for 15.6% of all medical complications. Causes were multiple. One patient is awaiting a kidney transplant, but no other patients need renal replacement therapy at the moment. Ileostomy closure was performed in 5 of 12 patients alive, showing improved renal function in 3 of them. ConclusionsRF is a problem in ITx and is always multifactorial. Increases in hospital stay, higher morbidity and is a cause for hospital readmission. Almost all patients had an impaired renal function when discharged. Immunosuppressants and ileostomy closure as soon as possible might prevent RF.

Solid Organ Transplant Patients Experience High Rates of Infection and Other Complications After Total Knee Arthroplasty

Survival after solid organ transplants in the United States is increasing, and there is a need to understand the complications in knee arthroplasty patients who underwent organ transplantation. A retrospective study was conducted from 1993–2008 on 19 patients (23 knee arthroplasties) with previous successful solid organ transplants. Eleven knee arthroplasties were performed after renal transplantation, and 12 after nonrenal solid organ transplant (seven liver, four heart, one lung). Complications occurred in 9/23 patients (39.1%) and infections occurred in 4/23 patients (17.3%). Of the infected knees, two had MRSA, one had MSSA, and one Escherichia coli. Noninfectious complications (5/24, 21.7%) include aseptic loosening, quadriceps rupture, femoral fracture, hemarthrosis, and arthrofibrosis. All patients with complications were on immunosuppressant medications at the time of arthroplasty. There was a significantly higher rate of infection in the renal group compared to the non-renal group (P = 0.022). There was also a higher overall complication rate in the renal group however this did not reach significance.

Collapsing FSGS Post Non Renal Solid Organ Transplantation

Introduction: Collapsing focal and segmental glomerulosclerosis (cFSGS) is a rare and aggressive form of FSGS. It occurs in a variety of clinical settings and is usually associated with a heavy proteinuria and very poor renal outcome. We describe the clinical and histological characteristics of 10 cases of cFSGS occurring at our institution after non-renal solid organ transplantation. Methods: We performed a retrospective review of all cases of biopsy proven cFSGS occurring post non-renal solid organ transplantation at our institution. Results are given as mean ±SEM. Results: We identified 10 cases of cFSGS post non-renal solid organ transplantation occurring over the last 20 years at our institution. 5 cases occurred post heart transplantation, 3 cases post combined heart and lung transplantation, 1 case post liver transplantation and 1 post lung transplantation. Two patients were female, the rest (8) were male. All had well preserved renal function and minimal proteinuria prior to transplantation. 3/10 of the patients had been smokers prior to transplantation, 5/10 patients had developed diabetes post transplantation and 7/10 were being treated for hypertension at the time of renal biopsy. 9/10 patients were treated with a calcineurin inhibitor (CNI) based immunosuppressive regimen post transplantation and 1/10 was treated with an everolimus based immunosuppressive regimen without CNI. The mean age of patients at the time of renal biopsy was 44±4.73. Mean time in years between transplantation and renal biopsy was 8.1±1.81. Mean serum creatinine at the time of biopsy was 261±30μmol/L. Mean proteinuria at the time of renal biopsy was 6.6±1.35g/24hours and mean serum albumin at the time of biopsy was 31.1±1.88g/L. On biopsy the mean percentage of glomeruli with global sclerosis was 45±7%. Remaining glomeruli showed changes constant with cFSGS. All biopsies showed moderate to severe interstitial fibrosis and atrophy, mostly in a striped pattern consistent with chronic CNI nephrotoxicity. At diagnosis many patients were converted to non-CNI based immunosuppressive regimens. Despite this all but 1 patient progressed to end-stage renal failure (ESRF) within a mean of 20±8.3 months of diagnosis. The only patient not to progress to ESRF has had only 4 months follow-up. Conclusion: cFSGS is a rare complication occurring late post non-renal solid organ transplantation. It occurs in the setting of prolonged exposure to CNIs and in association with other vascular risk factors. It presents with heavy proteinuria and moderate degrees of renal failure. The prognosis, as with most forms of FSGS, is almost universally poor. Late amendment to immunosuppressive therapy, in particular withdrawal of CNIs has little effect on the progression of disease which is characterised by chronic and irreversible biopsy changes. Close monitoring of renal parameters in the post transplant period, particularly regular monitoring for the onset of proteinuria may allow earlier detection of the lesion and improve outcome with earlier changes to immunosuppressive regimens.

Collapsing FSGS Post Non Renal Solid Organ Transplantation

Introduction: Collapsing focal and segmental glomerulosclerosis (cFSGS) is a rare and aggressive form of FSGS. It occurs in a variety of clinical settings and is usually associated with a heavy proteinuria and very poor renal outcome. We describe the clinical and histological characteristics of 10 cases of cFSGS occurring at our institution after non-renal solid organ transplantation. Methods: We performed a retrospective review of all cases of biopsy proven cFSGS occurring post non-renal solid organ transplantation at our institution. Results are given as mean ±SEM. Results: We identified 10 cases of cFSGS post non-renal solid organ transplantation occurring over the last 20 years at our institution. 5 cases occurred post heart transplantation, 3 cases post combined heart and lung transplantation, 1 case post liver transplantation and 1 post lung transplantation. Two patients were female, the rest (8) were male. All had well preserved renal function and minimal proteinuria prior to transplantation. 3/10 of the patients had been smokers prior to transplantation, 5/10 patients had developed diabetes post transplantation and 7/10 were being treated for hypertension at the time of renal biopsy. 9/10 patients were treated with a calcineurin inhibitor (CNI) based immunosuppressive regimen post transplantation and 1/10 was treated with an everolimus based immunosuppressive regimen without CNI. The mean age of patients at the time of renal biopsy was 44±4.73. Mean time in years between transplantation and renal biopsy was 8.1±1.81. Mean serum creatinine at the time of biopsy was 261±30μmol/L. Mean proteinuria at the time of renal biopsy was 6.6±1.35g/24hours and mean serum albumin at the time of biopsy was 31.1±1.88g/L. On biopsy the mean percentage of glomeruli with global sclerosis was 45±7%. Remaining glomeruli showed changes constant with cFSGS. All biopsies showed moderate to severe interstitial fibrosis and atrophy, mostly in a striped pattern consistent with chronic CNI nephrotoxicity. At diagnosis many patients were converted to non-CNI based immunosuppressive regimens. Despite this all but 1 patient progressed to end-stage renal failure (ESRF) within a mean of 20±8.3 months of diagnosis. The only patient not to progress to ESRF has had only 4 months follow-up. Conclusion: cFSGS is a rare complication occurring late post non-renal solid organ transplantation. It occurs in the setting of prolonged exposure to CNIs and in association with other vascular risk factors. It presents with heavy proteinuria and moderate degrees of renal failure. The prognosis, as with most forms of FSGS, is almost universally poor. Late amendment to immunosuppressive therapy, in particular withdrawal of CNIs has little effect on the progression of disease which is characterised by chronic and irreversible biopsy changes. Close monitoring of renal parameters in the post transplant period, particularly regular monitoring for the onset of proteinuria may allow earlier detection of the lesion and improve outcome with earlier changes to immunosuppressive regimens.

Renal failure and transplantation following nonrenal solid-organ transplantation

To review the challenges and complications related to the native kidney following nonrenal solid-organ transplantation (NRSOT). Deterioration of renal function has been reported as an independent predictor of mortality following NRSOT. The incidence of pediatric end-stage renal disease (ESRD) after nonrenal transplantation is at least 3%, according to the 2011 United States Renal Data System Annual Report. Although calcineurin toxicity is a leading cause of renal insufficiency, other pathologic changes can be seen. Calcineurin inhibitor nephrotoxicity in nonrenal allograft recipients can lead to ESRD and the need for kidney transplantation. There is increased morbidity and mortality associated with chronic kidney disease (CKD) following nonrenal transplantation, but few large-scale studies have been conducted in pediatric patients. Challenges exist in monitoring renal function in chronically ill pediatric patients and estimating equations using creatinine overestimate glomerular filtration rates. Collaborative research is needed to define further the incidence of CKD following NRSOT.