Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura.

BACKGROUND: Congenital thrombotic thrombocytopenic purpura (TTP) results from severe hereditary deficiency of ADAMTS13. The efficacy and safety of recombinant ADAMTS13 and standard therapy (plasma-derived products) administered as routine prophylaxis or on-demand treatment in patients with congenital TTP is not known. METHODS: In this phase 3, open-label, crossover trial, we randomly assigned patients in a 1:1 ratio to two 6-month periods of prophylaxis with recombinant ADAMTS13 (40 IU per kilogram of body weight, administered intravenously) or standard therapy, followed by the alternate treatment; thereafter, all the patients received recombinant ADAMTS13 for an additional 6 months. The trigger for this interim analysis was trial completion by at least 30 patients. The primary outcome was acute TTP events. Manifestations of TTP, safety, and pharmacokinetics were assessed. Patients who had an acute TTP event could receive on-demand treatment. RESULTS: A total of 48 patients underwent randomization; 32 completed the trial. No acute TTP event occurred during prophylaxis with recombinant ADAMTS13, whereas 1 patient had an acute TTP event during prophylaxis with standard therapy (mean annualized event rate, 0.05). Thrombocytopenia was the most frequent TTP manifestation (annualized event rate, 0.74 with recombinant ADAMTS13 and 1.73 with standard therapy). Adverse events occurred in 71% of the patients with recombinant ADAMTS13 and in 84% with standard therapy. Adverse events that were considered by investigators to be related to the trial drug occurred in 9% of the patients with recombinant ADAMTS13 and in 48% with standard therapy. Trial-drug interruption or discontinuation due to adverse events occurred in no patients with recombinant ADAMTS13 and in 8 patients with standard therapy. No neutralizing antibodies developed during recombinant ADAMTS13 treatment. The mean maximum ADAMTS13 activity after recombinant ADAMTS13 treatment was 101%, as compared with 19% after standard therapy. CONCLUSIONS: During prophylaxis with recombinant ADAMTS13 in patients with congenital TTP, ADAMTS13 activity reached approximately 100% of normal levels, adverse events were generally mild or moderate in severity, and TTP events and manifestations were rare. (Funded by Takeda Development Center Americas and Baxalta Innovations; ClinicalTrials.gov number, NCT03393975.).

Primary hyperoxaluria in adults and children: a nationwide cohort highlights a persistent diagnostic delay.

Background: Primary hyperoxalurias (PH) are extremely rare genetic disorders characterized by clinical heterogeneity. Delay in diagnosing these conditions can have detrimental effects on patient outcomes. The primary objective of this study is to assess the current diagnostic delay for PH. Methods: This nationwide, observational and retrospective study included patients who received a genetic diagnosis of PH types 1, 2 and 3 between 1 January 2015 and 31 December 2019. Diagnostic delay was defined as the duration between the onset of symptoms and the time of genetic diagnosis. Results: A total of 52 patients (34 children and 18 adults) were included in the study, with 40 PH1 (77%), 3 PH2 (6%) and 9 PH3 (17%). At the time of diagnosis, 12 patients (23%) required dialysis. Among the PH1 patients, the predominant symptom at onset in adults was renal colic (79% of cases), whereas symptoms in children were more diverse (renal colic in 17% of cases). The diagnostic delay was significantly shorter in children compared with adults [median (interquartile range)]: 1.2 (0.1-3.0) versus 30 (17-36) years, respectively (P < .0001). RNA interference was utilized in 23 patients (58%). Five individuals (13%) underwent double liver-kidney transplantation, and five (13%) received isolated kidney transplantation, with lumasiran therapy in four patients. For PH2 and PH3 patients, the diagnostic delay ranges from 0 to 3 years, with renal colic as first symptom in 33% of cases. Conclusion: This extensive and recent cohort of PH underscores the considerable delay in diagnosing PH, particularly in adults, even in a country with a dedicated organization for enhancing the overall management of rare diseases. These findings reinforce the imperative for increased awareness among relevant specialties regarding the evaluation of urolithiasis.

Is withdrawal of nocturnal hyperhydration possible in children with primary hyperoxaluria treated with RNAi?

Primary hyperoxaluria type 1 is a rare genetic disorder caused by bi-allelic pathogenic variants in the AGXT gene leading to an overproduction of oxalate which accumulates in the kidneys in the form of calcium oxalate crystals. Thus, patients may present with recurrent nephrocalcinosis and lithiasis, with progressive impairment of the  renal function and eventually kidney failure.  There is no specific treatment besides liver-kidney transplantation, and pre-transplantation management by 24 h-hyperhydration, crystallisation inhibitors and high-dose pyridoxine has a high negative impact on quality of life, especially because of the discomfort due to nocturnal hyperhydration. Since 2020, lumasiran, an RNA-interfering therapy, has been approved for the treatment of primary hyperoxaluria type 1 in adults and children. However, to date, there are no recommendations regarding the discontinuation of other supportive measures during RNAi therapy. In this report, we present two patients with primary hyperoxaluria type 1 who were treated with lumasiran and stopped nocturnal hyperhydration with positive outcomes, i.e. normal urinary oxalate, absence of crystalluria, stable kidney function and improved well-being. These data suggest that discontinuing nocturnal hydration may be safe in children responding to lumasiran, and may have a positive impact on their quality of life. Additional data are needed to update treatment recommendations.

Induction therapy for pediatric onset class IV lupus nephritis: Mycophenolate Mofetil versus Cyclophosphamide.

OBJECTIVES: Class IV lupus nephritis (LN) is one of the most frequent and severe types of involvement in pediatric systemic lupus erythematosus. Gold standard treatment consists of intravenous (i.v.) Cyclophosphamide (CYC) associated with corticosteroids. Recent studies in adults have shown similar efficacy of oral Mycophenolate Mofetil (MMF) with fewer adverse events. Our aim was to compare the efficacy and tolerance of CYC and MMF as induction therapy in children with class IV LN. METHODS: We conducted a retrospective study of children diagnosed with class IV LN who started oral MMF or i.v. CYC treatment at Necker Enfants Malades Hospital (Paris, France). RESULTS: The study included 33 patients, 17 treated with oral MMF (51%) and 16 with i.v. CYC (48%). The characteristics at treatment induction did not significantly differ between the two groups except for the neurological involvement, that was only present in the CYC group. Complete remission was obtained in 9/17 (53%) children treated with MMF versus 10/16 (71%) treated with CYC (p = 0.46). Relapse was observed in 59% of patients receiving MMF versus 50% receiving CYC (p = 0.87), after a median of 3.4 years and 4.7 years after the beginning of treatment, respectively (p = 0.41). During the 6.5 years of follow-up, we observed no significant difference regarding the number of treatment-related adverse events between the two groups (p = 0.48). CONCLUSION: We report similar efficacy and tolerance of MMF or CYC as induction therapy of class IV LN in children. However, the long-term adverse events such as infertility could not be systematically evaluated in this retrospective pediatric study. Overall, however, considering the long-term safety profile reported in the literature, we suggest that MMF may be used as first-line induction therapy in LN.

Human kidney-derived hematopoietic stem cells can support long-term multilineage hematopoiesis.

Long-term multilineage hematopoietic donor chimerism occurs sporadically in patients who receive a transplanted solid organ enriched in lymphoid tissues such as the intestine or liver. There is currently no evidence for the presence of kidney-resident hematopoietic stem cells in any mammal species. Graft-versus-host-reactive donor T cells promote engraftment of graft-derived hematopoietic stem cells by making space in the bone marrow. Here, we report full (over 99%) multilineage, donor-derived hematopoietic chimerism in a pediatric kidney transplant recipient with syndromic combined immune deficiency that leads to transplant tolerance. Interestingly, we found that the human kidney-derived hematopoietic stem cells took up long-term residence in the recipient's bone marrow and gradually replaced their host counterparts, leading to blood type conversion and full donor chimerism of both lymphoid and myeloid lineages. Thus, our findings highlight the existence of human kidney-derived hematopoietic stem cells with a self-renewal ability able to support multilineage hematopoiesis.

The spectrum of kidney function alterations in adolescents with a solitary functioning kidney.

BACKGROUND: A precise assessment of glomerular filtration rate is key to delineate the care of children with a solitary functioning kidney (SFK). Data regarding measured GFR (mGFR) in this population is restricted to a single study of 77 individuals, which suggested that a GFR estimation (eGFR) method based on creatinine and cystatin C (eGFR-CKiD2) performed better than Schwartz's equation (eGFR-Schwartz). METHODS: We measured GFR in 210 consecutive adolescents (7 to 22 years old) with an SFK referred to our institution between 2014 and 2019 and in 43 young candidates for kidney donation (18 to 25 years old). We compared the distribution of mGFR in both groups and determined the factors associated with reduced mGFR in adolescents with an SFK. We further compared different eGFR formulas with mGFR and assessed the association of mGFR and eGFRs with PTH and FGF23, two early indicators of GFR reduction. RESULTS: While adolescents with an SFK had a similar median mGFR to healthy controls (103 ± 24ml/min/1.73m2 vs. 107 ± 12 ml/min/1.73m2), the fraction of individuals with an mGFR below 90 ml/min/1.73m2 was higher in patients with SFK (23% vs. 5% in controls; P = 0.005). Multiple linear regression identified older age, ipsilateral abnormalities of the urinary tract, lack of compensatory hypertrophy, and treated hypertension as independent factors associated with reduced mGFR. A smaller bias using eGFR-Schwartz (95% confidence interval (95%CI): 3 to 7) was revealed when compared to other eGFR. Compared to eGFR-Schwartz, mGFR showed a stronger correlation with PTH (r = 0.04 vs. r = 0.1) and FGF23 (r = 0.03 vs. r = 0.05). CONCLUSION: SFK is not a benign condition, since 20% of the patients display altered kidney function. Our results raise caution regarding the use of the cystatin-based equation. mGFR shows a better ability than eGFR-Schwartz to differentiate patients showing early homeostatic adaptation to GFR reduction.

Long-term kidney and liver outcome in 50 children with autosomal recessive polycystic kidney disease.

BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is a rare ciliopathy characterized by congenital hepatic fibrosis and cystic kidney disease. Lack of data about long-term follow-up makes it difficult to discuss timing and type of organ transplantation. Our objectives were to evaluate long-term evolution and indications for transplantation, from birth to adulthood. METHODS: Neonatal survivors and patients diagnosed in postnatal period with ARPKD between 1985 January and 2017 December from 3 French pediatric centers were retrospectively enrolled in the study. RESULTS: Fifty patients with mean follow-up 12.5 ± 1 years were enrolled. ARPKD was diagnosed before birth in 24%, and at mean age 1.8 years in others. Thirty-three patients were < 1 year of age at first symptoms, which were mostly kidney-related. These most often presented high blood pressure during follow-up. Portal hypertension was diagnosed in 29 patients (58%), 4 of them with bleeding from esophageal varices. Eight patients presented cholangitis (> 3 episodes in three children). Liver function was normal in all patients. Nine children received a kidney transplant without liver complications. A 20-year-old patient received a combined liver-kidney transplant (CLKT) for recurrent cholangitis, and a 15-year-old boy an isolated liver transplant for uncontrollable variceal bleeding despite portosystemic shunt. CONCLUSIONS: Long-term outcome in patients with ARPKD is heterogeneous, and in this cohort did not depend on age at diagnosis except for blood pressure. Few patients required liver transplantation. Indications for liver or combined liver-kidney transplantation were limited to recurrent cholangitis or uncontrollable portal hypertension. Liver complications after kidney transplantation were not significant.

Donor-targeted serotherapy as a rescue therapy for steroid-resistant acute GVHD after HLA-mismatched kidney transplantation.

Acute graft-versus-host disease (GVHD) is a rare but frequently lethal complication after solid organ transplantation. GVHD occurs in unduly immunocompromised hosts but requires the escalation of immunosuppression, which does not discriminate between host and donor cells. In contrast, donor-targeted therapy would ideally mitigate graft-versus-host reactivity while sparing recipient immune functions. We report two children with end-stage renal disease and severe primary immune deficiency (Schimke syndrome) who developed severe steroid-resistant acute GVHD along with full and sustained donor T cell chimerism after isolated kidney transplantation. Facing a therapeutic dead end, we used a novel strategy based on the adoptive transfer of anti-HLA donor-specific antibodies (DSAs) through the transfusion of highly selected plasma. After approval by the appropriate regulatory authority, an urgent nationwide search was launched among more than 3800 registered blood donors with known anti-HLA sensitization. Adoptively transferred DSAs bound to and selectively depleted circulating donor T cells. The administration of DSA-rich plasma was well tolerated and notably did not induce antibody-mediated rejection of the renal allografts. Acute GVHD symptoms promptly resolved in one child. This report provides a proof of concept for a highly targeted novel therapeutic approach for solid organ transplantation-associated GVHD.

Influenza vaccination among children with idiopathic nephrotic syndrome: an investigation of practices.

BACKGROUND: Annual influenza vaccination is recommended for all children with idiopathic nephrotic syndrome (INS) in France. Consequently, the Social Security automatically sends prescriptions to all patients suffering from a chronic disease. The aim of this study was to evaluate the follow-up to these recommendations. METHODS: We conducted a monocentric retrospective investigation of practices. We included all children with steroid-sensitive INS in remission who attended our clinics from January 1st 2015 to January 1st 2017, resided in France and had a valid phone number. Data were collected from May 2017 to June 2017 through a phone interview and review of clinical charts. RESULTS: 75 patients met the inclusion criteria. The parents of 57 children could be reached by phone and agreed to participate to the survey. 35/57 (61.4%) declared having received a prescription during the 2016-2017 campaign. Only 14 children (24.6%) were vaccinated. 17/43 (39.5%) parents of unvaccinated children had concerns about the safety of the vaccine, 16/43 (37.2%) were not aware of the recommendations, 5/43 (11.6%) had been recommended by their physician not to vaccinate their child, 3/43 (7%) forgot to have them vaccinated and 2/43 (4.6%) reported no reason. 13/43 (30%) unvaccinated children presented a relapse during the flu season - 2/13 during an influenza-like illness - whereas 1/14 (7%) immunized children presented a relapse during the six months of post-vaccination follow-up. Relapse rates were not increased in vaccinated children compared to unvaccinated children (p = 0.15), nor in the 6 months following vaccination compared to the 6 months prior (1/14 vs 5/14, p = 0.20). CONCLUSIONS: 1) < 2/3 patients were properly prescribed the recommended yearly influenza vaccination at our center 2) only 1/4 were vaccinated and most of their parents were misinformed. Physicians must be aware of this and should make every effort to better inform their patients on the risks of flu illness and the benefits and safety of the vaccination.

ADAMTS13 Gene Mutations Influence ADAMTS13 Conformation and Disease Age-Onset in the French Cohort of Upshaw-Schulman Syndrome.

BACKGROUND: Congenital thrombotic thrombocytopaenic purpura (TTP) or Upshaw-Schulman syndrome (USS) is a rare, life-threatening, inherited thrombotic microangiopathy (TMA). USS is mostly due to bi-allelic recessive sequence variations of the a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13) gene inducing a severe ADAMTS13 deficiency (activity < 10 IU/dL). In healthy individuals, ADAMTS13 circulates in a folded conformation where CUB domains interact with the spacer domain. The spacer-CUB interaction is abrogated when ADAMTS13 is conformationally activated. OBJECTIVE: This article evaluates the influence of ADAMTS13 sequence variations on both clinical/biological phenotype and ADAMTS13 conformation in USS. PATIENTS AND METHODS: All USS patients from the French registry for TMAs (1 January 2000 to 1 June 2017) were investigated for ADAMTS13 genotype, phenotype (activity, antigen and autoantibodies) and conformation. Clinical records were analysed (inaugural acute TTP and follow-up). Child-onset USS was compared with adult-onset USS. RESULTS: Fifty-six USS patients from 51 families (34 child-onset and 22 adult-onset cases) were enrolled. Child-onset USS was characterized by a large panel of ADAMTS13 sequence variations (n = 43), spread all over ADAMTS13 gene and not correlated with either clinical features or plasmatic ADAMTS13 parameters. In contrast, adult-onset USS, consisting exclusively in pregnancy-induced TTP, included a smaller and distinct panel of ADAMTS13 sequence variations (n = 20) because of one mutation (p.Arg1060Trp) present in 82% of patients. ADAMTS13 conformation was studied in 16 USS patients (5 child-onset and 11 adult-onset USS, encompassing 16 distinct ADAMTS13 sequence variations) whose ADAMTS13 antigen levels were detectable: 14 of 16 patients (87.5%) exhibited abnormalities of ADAMTS13 conformation. CONCLUSION: In USS, age-onset defines two entities and ADAMTS13 sequence variations modify ADAMTS13 conformation.

Nephrological abnormalities in patients with transaldolase deficiency.

BACKGROUND: Transaldolase deficiency (OMIM 606003) is a multisystem disorder first described in 2001. Transaldolase is an enzyme of the reversible part of the pentose phosphate pathway. Affected patients have abnormal polyol concentrations in body fluids, mostly in urine. The clinical presentation is variable. The leading symptoms are coagulopathy, thrombocytopenia, hepatosplenomegaly, hepatic fibrosis and dysmorphic features. The objective of our study was to attempt to characterize the renal phenotype of patients with transaldolase deficiency. METHODS: Clinical and laboratory data of all nine patients with transaldolase deficiency presently known were gathered by retrospective chart analysis. RESULTS: Nephrological abnormalities were present in seven of the nine patients. The most common findings were low molecular weight (LMW) proteinuria and hypercalciuria. The two oldest patients had moderate chronic kidney failure. In two patients, generalized aminoaciduria was found, two patients had renal phosphate wasting and three patients had hyperchloremic metabolic acidosis. Three patients had anatomical abnormalities. CONCLUSIONS: Renal tubular dysfunction is present in the majority of patients with transaldolase deficiency and may lead to chronic renal failure. The combination of unexplained liver dysfunction with LMW proteinuria should prompt metabolic screening for transaldolase deficiency by measuring urinary polyols. In patients with transaldolase deficiency, monitoring of kidney function is mandatory.

A murine model of Denys-Drash syndrome reveals novel transcriptional targets of WT1 in podocytes.

The Wilms tumor-suppressor gene WT1, a key player in renal development, also has a crucial role in maintenance of the glomerulus in the mature kidney. However, molecular pathways orchestrated by WT1 in podocytes, where it is highly expressed, remain unknown. Their defects are thought to modify the cross-talk between podocytes and other glomerular cells and ultimately lead to glomerular sclerosis, as observed in diffuse mesangial sclerosis (DMS) a nephropathy associated with WT1 mutations. To identify podocyte WT1 targets, we generated a novel DMS mouse line, performed gene expression profiling in isolated glomeruli and identified excellent candidates that may modify podocyte differentiation and growth factor signaling in glomeruli. Scel, encoding sciellin, a protein of the cornified envelope in the skin, and Sulf1, encoding a 6-O endosulfatase, are shown to be expressed in wild-type podocytes and to be strongly down-regulated in mutants. Co-expression of Wt1, Scel and Sulf1 was also found in a mesonephric cell line, and siRNA-mediated knockdown of WT1 decreased Scel and Sulf1 mRNAs and proteins. By ChIP we show that Scel and Sulf1 are direct WT1 targets. Cyp26a1, encoding an enzyme involved in the degradation of retinoic acid, is shown to be up-regulated in mutant podocytes. Cyp26a1 may play a role in the development of glomerular lesions but does not seem to be regulated by WT1. These results provide novel clues in our understanding of normal glomerular function and early events involved in glomerulosclerosis.

Complement factor H deficiency and posttransplantation glomerulonephritis with isolated C3 deposits.

We report the first cases of atypical hemolytic and uremic syndrome associated with complement factor H (CFH) deficiency in native kidneys and glomerulonephritis with isolated C3 deposits after kidney transplantation. Two boys developed atypical hemolytic and uremic syndrome at 16 and 11 months of age, associated with low C3 and CFH levels. Both rapidly progressed to end-stage renal failure and received a kidney transplant. Patient 1 had combined CFH and complement factor I (CFI) heterozygous mutations and a membrane cofactor protein (gene symbol, CD46) gene polymorphism. Five years posttransplantation, an allograft biopsy specimen showed numerous mesangial and extramembranous C3 deposits, although the patient had no biological sign of glomerulopathy. Nine years after transplantation, he was well with stable kidney function. Patient 2, who had a homozygous CFH mutation, developed glomerulonephritis with isolated C3 deposits 5 months after kidney transplantation while he was treated for early recurrence of hemolytic anemia. Four years later, the second kidney transplant biopsy specimen showed recurrence of thrombotic microangiopathy. Six years posttransplantation, kidney function was stable and complete blood cell count was normal with regular plasma therapy. These observations suggest that constitutional dysregulation of the alternative pathway is associated with a wide spectrum of kidney diseases, and glomerulonephritis with isolated C3 deposits and thrombotic microangiopathy may be different expressions of the same condition. Several factors could influence the disease, such as degree of CFH haploinsufficiency and other complement alternative pathway regulator abnormalities, such as a membrane cofactor protein polymorphism.

Prognosis of autosomal dominant polycystic kidney disease diagnosed in utero or at birth.

The use of prenatal ultrasonography has resulted in increased numbers of fetuses being diagnosed with autosomal dominant polycystic kidney disease (ADPKD), but the long-term prognosis is still not well-known. Between 1981 and 2006 we followed 26 consecutive children with enlarged hyperechoic kidneys detected between the 12th week of pregnancy and the first day of life (Day 1) as well as one affected parent. Three other fetuses were excluded following the termination of the pregnancy. The mother was the transmitting parent in 16 of the 26 children (ns, p=0.1). Clinical features that presented during follow-up were oligoamnios (5/26), neonatal pneumothorax (3/26), pyelonephritis (5/26), gross hematuria (2/26), hypertension (5/26), proteinuria (2/26) and chronic renal insufficiency (CRI) (2/26). At the last follow-up (mean duration of follow-up: 76 months; range: 0.5-262 months), 19 children (mean age: 5.5 years) were asymptomatic, five (mean age: 8.5 years) had hypertension, two (mean age: 9.7 years) had proteinuria and two (mean age: 19 years) had CRI. Children presenting enlarged kidneys postnatally tended to have more clinical manifestations than their counterparts who did not. Of 25 siblings of the patients, seven had renal cysts; these were detected during childhood in five siblings and in utero in two siblings. In conclusion, prognosis is favourable in most children with prenatal ADPKD, at least during childhood. The sex of the transmitting parent is not a risk factor of prenatal ADPKD. A high proportion of siblings develop early renal cysts. Abnormalities visualized by ultrasonography appear to be associated to more clinical manifestations.