Rebecca Sberro-Soussan

New insights into postrenal transplant hemolytic uremic syndrome

After renal transplantation, hemolytic uremic syndrome (HUS) may occur either as a recurrent or de novo form. Over the past decade, much effort has been devoted to elucidating the pathogenesis of atypical HUS (aHUS). Approximately 60–70% patients with aHUS have mutations in regulatory factors of the complement system or antibodies against complement factor H. The risk of post-transplant recurrence of aHUS depends on the genetic abnormality involved, and ranges from 15% to 20% in patients with mutations in the gene that encodes membrane cofactor protein and from 50% to 100% in patients with mutations in the genes that encode circulating regulators of complement. Given the poor outcomes associated with recurrence, isolated renal transplantation had been contraindicated in patients at high risk of aHUS recurrence. However, emerging therapies, including pre-emptive plasma therapy and anti-C5 component monoclonal antibody (eculizumab) treatment have provided promising results and should further limit indications for the risky procedure of combined liver–kidney transplantation. Studies from the past 2 years have demonstrated genetic abnormalities in complement regulators in 30% of renal transplant recipients who experienced de novo HUS after renal transplantation. This finding suggests that the burden of endothelial injury in a post-transplantation setting may trigger de novo HUS in the presence of mild genetic susceptibility to HUS.

Successful treatment of acute thrombotic microangiopathy by eculizumab after combined lung and kidney transplantation.

Thrombotic microangiopathy (TMA) can be frequently observed after lung transplantation with various causes, for example, calcineurin inhibitor (CNI) toxicity or infectious disease (1). Atypical hemolytic-uremic syndrome (aHUS) is a disease related to unregulated complement progression also associated with TMA lesions (2). Plasma exchange or infusion was used to control the progression of the disease, but this therapy is invasive and not effective in all patients. The treatment and the prognosis of aHUS and its recurrence on the renal graft have been modified by the use of eculizumab, a monoclonal antibody that targets complement factor C5 and blocks the activation of the terminal complement cascade. This humanized monoclonal antibody used for the treatment of paroxysmal nocturnal hemoglobinuria has been recently approved for the treatment of aHUS or its recurrence (3, 4). We report here on the efficacy of eculizumab in a combined lung and kidney transplant recipient who presented TMA in the initial period after transplantation. The patient was a 45-yearfemale who developed end-stage lung disease because of pulmonary fibrosis related to sarcoidosis. She presented an end-stage renal disease (ESRD) with TMA lesion on the renal biopsies of her native kidney performed in 1998 and 2006. The initial nephropathy was considered to be aHUS. However, screening for regulatory factors of the complement system mutations or antibodies against complement factor H was negative. Hemodialysis therapy was initiated in 2008 and she was enlisted for a combined lung and kidney transplantation in 2010. She received a lung and kidney transplant from a deceased donor aged 22. She was not sensitized. Initial immunosuppressive regimen associated polyclonal antithymocyte antibodies, cyclosporine, mycophenolate mofetil, and steroids. The evolution of the lung transplant was uneventful. The initial evolution of kidney transplant was excellent with a serum creatinine at 72 Kmol/L on day 5. From day 3, the platelet count falls to reach 22,000/mm, the hemoglobin was 11.4 g/dL, the lactate dehydrogenase level was 857 UI/mL, haptoglobin was decreased to 0.07 g/L, and the creatinine was 91 Kmol/L. The suspected etiologies of this TMA were either a recurrence of aHUS or acute CNI toxicity, although the cyclosporine through levels were within target (145 ng/mL). The renal evolution was unfavorable leading to the initiation of dialysis at performed with no improvement of renal function or platelet count. Eculizumab therapy was started consisting in 900 mg on day 15 and weekly thereafter until day 36. She had received prior meningococcal vaccine and antibioprophylaxis by oracillin maintained during the whole period of treatment. Hemolysis resolved, haptoglobin, and platelet count increased to normal limits and progressively renal graft recovered function leading to dialysis interruption. A renal biopsy was performed on day 20. It revealed no TMA lesion but acute tubular necrosis compatible with CNI toxicity. Histologically, we cannot definitely discriminate between aHUS recurrence and CNI toxicity. The ESRD occurred frequently after transplantation because of CNI nephrotoxicity. On native kidney biopsies in lung transplant recipients, CNI nephrotoxicity is present in 93.3% associated with TMA in 46.7% (1). We know that genetic polymorphisms of complement increased susceptibility to CNI toxicity (5). In our case, we postulate that CNI toxicity could induce an inappropriate regulation of the alternative complement pathway and so an aHUS recurrence. Our observation suggests the positive effect of eculizumab when ESRD occurs after transplantation secondary to CNI toxicity. In this context, eculizumab may be an interesting therapeutic option. FIGURE 1. Treatment effects on posttransplantation TMA: platelet count and haptoglobin evolution with treatment. LETTERS TO THE EDITOR

Prevalence and Predictors of Early Cardiovascular Events after Kidney Transplantation: Evaluation of Pre-Transplant Cardiovascular Work-Up

Introduction Cardiovascular disease is the leading cause of mortality after renal transplantation. The purpose of this study was to analyze cardiovascular risk factors at transplantation, occurrence of cardiovascular events in the first year after transplantation and evaluate pre-transplant work-up. Material and Method In total, 244 renal transplant recipients older than 50 years were included. The results of pre-transplant work-up, including clinical evaluation, electrocardiogram, echocardiography, myocardial perfusion testing and coronary angiography were analyzed. Results Patients had multiple risk factors at inclusion on renal transplantation waiting list as high blood pressure (94.7%), dyslipidemia (81.1%), smoking (45.3%), diabetes (23.6%), past history of cardiovascular disease (21.3%) and obesity (12.7%). Following transplantation, 15.5% (n = 38) of patients experienced a cardiovascular event, including 2.8% (n = 7) acute coronary syndrome, 5.8% (n = 14) isolated increase in troponin level and 5.3% (n = 13) new onset atrial fibrillation. The pre-transplant parameters associated with a cardiovascular event were a past medical history of cardiovascular disease (HR = 2.06 [1.06–4.03], p = 0.03), echocardiographic left ventricular hypertrophy (HR = 2.04 [1.04–3.98], p = 0.037) and abnormal myocardial perfusion testing (HR = 2.25 [1.09 –5.96], p = 0.03). Pre-transplantation evaluation allowed the diagnosis of unknown coronary artery lesions in 8.9% of patients.

Sirolimus therapy may cause cardiac tamponade.

The side‐effects associated with the immunosuppressive drug sirolimus are numerous and constitute a major limitation for its use in renal transplantation. In this study, we describe two cases of renal transplant recipients treated with sirolimus who developed pericardial tamponade associated with interstitial pneumonia, proteinuria, microcytic anemia and, in one case, lymphocytic meningitidis. An extensive search for infectious agents was negative, and all symptoms disappeared after sirolimus interruption. Therefore, this case demonstrates for the first time that sirolimus can cause pericardial tamponade as well as lymphocytic meningitidis.

Home and Office Blood Pressure Monitoring in Renal Transplant Recipients

Background. Arterial hypertension in renal transplant recipients (RTR) is associated with increased morbid mortality. In the general population, home blood pressure monitoring (HBPM) was found to be superior to office blood pressure (OBP) in identifying true hypertensive patients. The aim of this study was to investigate HBPM for the assessment of blood pressure profile in RTR. Methodology and Principal Findings. We included prospectively 87 stable RTR. Sitting OBP was measured during the outpatient clinic. HBPM was performed by measuring BP every morning and night for 4 days. The accepted limits for the OBP and HBPM, were respectively, 140/90 mmHg and 135/85 mmHg. Patients were classified as “normotensive,” “uncontrolled,” “white-coat hypertensive” and “masked hypertensive”, (OBP below the limit and HBPM above). During the study, 81 patients (55 males, age 48.5 ± 14 years) were available for analysis. The mean OBP and HBP were 138/83 ± 14/10 mmHg and 133/79 ± 14/8 mmHg; 29% of patients were uncontrolled, 28% normotensive, 21% white coat, and 21% masked hypertensive. Age, glycemia, and number of antihypertensive drugs were associated with hypertension. Conclusion and Significance. In RTR, HBPM is well accepted and better define BP profile since there is 42% discrepancy between OBPM and HBPM. Whether this discrepancy is associated with worst outcome in the long term remains to be demonstrated.

Midterm Outcomes of 12 Renal Transplant Recipients Treated With Eculizumab to Prevent Atypical Hemolytic Syndrome Recurrence

Background Atypical hemolytic uremic syndrome (aHUS) is an orphan disease with a high rate of recurrence after kidney transplantation. However, reports of successful prevention of posttransplant aHUS recurrence with eculizumab emerged a few years ago. To further delineate its optimal use, we describe the largest series of kidney transplant recipients treated with prophylactic eculizumab. Methods Twelve renal transplant recipients with aHUS-related end-stage renal disease received eculizumab: 10 from day 0 and 2 at the time of recurrence (days 6 and 25). Clinical and histological features, complement assessment, and free eculizumab measurements were analyzed. The median follow-up was 24.6 months. Results Five patients had failed at least 1 previous renal transplant from aHUS. A genetic mutation was identified in 9 patients, anti-H antibodies were found in 2. No patient demonstrated biological recurrence of thrombotic microangiopathy under treatment. Three antibody-mediated rejections (AMRs) occurred without detectable C5 residual activity. AMR was associated with subclinical thrombotic microangiopathy in 2 patients. One patient lost his graft after several complications, including AMR. One patient experienced posttransplant C3 glomerulonephritis. The last median serum creatinine was 128.2 ± 40.8 &mgr;mol/L. Conclusions These data confirm that eculizumab is highly effective in preventing posttransplantation aHUS recurrence, yet may not fully block AMR pathogenesis.

Prognosis of Invasive Aspergillosis in Kidney Transplant Recipients: A Case-Control Study.

Background Invasive aspergillosis (IA) is a major cause of invasive fungal infection in kidney transplant recipients (KTR), and it has a high mortality rate. However, its impact on patients and graft survival has not been well defined in the current era of voriconazole first-line therapy. Methods We retrospectively collected all cases of KTR-associated IA occurring at Necker Enfants Malades Hospital, Paris, from 2003 to 2013. These cases were compared with a group of controls (1:3) who were matched by age, year of kidney transplantation, and sex. The characteristics of IA were also studied. Results Sixteen patients developed IA after KTR. Most IA cases were limited to the lungs (81.3%), with mild respiratory symptoms in only 53% of the patients. The patients were administered voriconazole (n = 15, 94%) and/or posaconazole (n = 2, 13%). The 12-week and 1-year postinfection survival rates were 94% and 81%, respectively. Compared with the controls (n = 46), patients and death-censored graft survivals rates were significantly lower after IA (P = 0.017 and 0.001, respectively). In the patients with IA, the occurrences of cardiovascular diseases before transplantation (P < 0.0001), delayed graft function (P < 0.0001), and infectious complications (0.0018) were significantly more frequent. Conclusions Even with voriconazole therapy, the prognosis of patients with IA after kidney transplantation is still poor. When the patients survive to IA, they have a high risk of graft loss.

Long-term outcomes of kidney transplantation in patients with high levels of preformed DSA: the Necker high-risk transplant program.

Background There is an increasing number of anti-HLA sensitized and highly sensitized renal transplant candidates on waiting lists, and the presence of donor-specific alloantibodies (DSAs) at the time of transplantation leads to acute and chronic antibody-mediated rejection (AMR). Acceptable short-term outcomes have been described, notably because of desensitization protocols, but mid- and long-term data are still required. Methods Our high immunologic risk program included 95 patients with high peak or day 0 DSA levels (mean fluorescence intensity [MFI] > 3000) with a complement-dependent cytotoxicity-negative crossmatch, who received a posttransplant desensitization protocol starting at day 0 with high-dose intravenous immunoglobulin, plasma exchanges, and eventually rituximab. Their characteristics were compared with a control group including 39 patients with a lower immunologic risk (MFI between 500 and 3000 at day 0) who received the same posttransplant desensitization. Results The median MFI of the immunodominant class I or II DSA in the peak or day 0 serum was 9421 (interquartile range, 4959-12 610). An AMR occurred during the first posttransplant year in 31 patients (32.6%), and at one year, the rate of chronic AMR was 39.5%. The 1-, 3-, 5- and 7-year death-censored allograft survival rates were 98%, 91%, 86%, and 78%, respectively, with concomitant recipient survival rates of 97%, 93%, 85%, and 79%, respectively. Conclusions These results suggest that DSA-sensitized patients with high MFI levels can receive transplantation across the HLA-barrier, with the use of an intensified posttransplant immunosuppressive therapy starting at day 0 combined with close clinical, immunologic, and histologic monitoring.

Identification of genetic causes for sporadic steroid-resistant nephrotic syndrome in adults

Monogenic forms of Steroid-Resistant Nephrotic Syndrome (SRNS) have been widely characterized, but genetic screening paradigms preferentially address congenital, infantile onset, and familial cases. Our aim was to characterize the distribution of disease-causing gene mutations in adults with sporadic SRNS or focal segmental glomerulosclerosis (FSGS). We selected adult patients with non-syndromic, biopsy-proven FSGS or SRNS in the absence of known family history. Strict clinical criteria included lack of response to glucocorticoids and cyclosporine, and no recurrence after kidney transplantation. Mutations in SRNS genes were detected using a targeted gene panel. Sixteen of 135 tested participants (11.8%) carried pathogenic mutations in monogenic SRNS genes, and 14 others (10.4%) carried two APOL1 high-risk alleles. Autosomal recessive disease was diagnosed in 5 participants, autosomal dominant disease in 9, and X-linked disease in 2. Four participants carried a de novo heterozygous mutation. Among the 16 participants with identified mutations in monogenic SNRS genes, 7 (43.7%) had type IV collagen mutations. Mutations in monogenic SNRS genes were identified primarily in participants with proteinuria onset before 25 years of age, while the age at disease onset was variable in those with APOL1 high-risk genotype. Mean age at diagnosis was lower and renal survival was worse in participants with identified mutations in SNRS genes than in those without mutations. We found a significant rate of pathogenic mutations in adults with SRNS, with Type IV collagen mutations being the most frequent. These findings may have immediate impact on clinical practice.