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Nephronophthisis (NPH) is an autosomal-recessive ciliopathy representing one of the most frequent causes of kidney failure in childhood characterized by a broad clinical and genetic heterogeneity. Applied to one of the worldwide largest cohorts of patients with NPH, genetic analysis encompassing targeted and whole exome sequencing identified disease-causing variants in 600 patients from 496 families with a detection rate of 71%. Of 788 pathogenic variants, 40 known ciliopathy genes were identified. However, the majority of patients (53%) bore biallelic pathogenic variants in NPHP1. NPH-causing gene alterations affected all ciliary modules defined by structural and/or functional subdomains. Seventy six percent of these patients had progressed to kidney failure, of which 18% had an infantile form (under five years) and harbored variants affecting the Inversin compartment or intraflagellar transport complex A. Forty eight percent of patients showed a juvenile (5-15 years) and 34% a late-onset disease (over 15 years), the latter mostly carrying variants belonging to the Transition Zone module. Furthermore, while more than 85% of patients with an infantile form presented with extra-kidney manifestations, it only concerned half of juvenile and late onset cases. Eye involvement represented a predominant feature, followed by cerebellar hypoplasia and other brain abnormalities, liver and skeletal defects. The phenotypic variability was in a large part associated with mutation types, genes and corresponding ciliary modules with hypomorphic variants in ciliary genes playing a role in early steps of ciliogenesis associated with juvenile-to-late onset NPH forms. Thus, our data confirm a considerable proportion of late-onset NPH suggesting an underdiagnosis in adult chronic kidney disease.

BACKGROUND AND AIMS Little is known about the long-term outcome during adulthood of childhood onset idiopathic nephrotic syndrome (INS). We aimed to determine which patients require long-term follow up after transition, to identify risk factors of relapse and to analyze treatment strategies. METHOD In this monocentric retrospective study, we included all patients admitted in our adult nephrology department with INS diagnosed during childhood. Patients who reached kidney failure during childhood were excluded. Data regarding the outcome at adult age were obtained through clinical database and medical charts. RESULTS Eighty-two patients (male/female = 2/1) were included, with a median age at diagnosis of 3.9 years (1.2–16.5). Sixty-eight patients had steroid-sensitive INS, including 52 with steroid-dependent nephrotic syndrome or frequently relapsing nephrotic syndrome. Fourteen patients had steroid-resistant nephrotic syndrome. A total of 89% of patients received corticosteroid sparing treatment during childhood. Median follow-up during adulthood was 6.2 (0.3–25) years. A total of 71% of patients experienced at least one relapse during adulthood. The total number of relapses during childhood and the number of relapses per year during childhood, reflecting disease activity, were significantly higher in patients who experienced relapses during adulthood than in patients who did not (Figure 1). The risk of relapse during adulthood was also significantly associated with the need for immunosuppressive regimen at the time of the transition visit (P = 0.002). To promote the successful transition of young people, we propose to organize a transition visit where the adolescent/young adult is seen jointly by pediatric and adult nephrologists, as it was done for 68% of patients in this study. The relapse rate was significantly lower (50%) in the subgroup of patients who had such a transition visit. We also found that relapse during the first two-years of adulthood follow-up was significantly associated with the risk of further relapse, highlighting the need for a close follow-up during the transition period. A total of 45% of patients received corticosteroid sparing treatment during adulthood, mainly mycophenolate mofetil (N = 23), calcineurin inhibitors (N = 21) and rituximab (N = 12). The main complications were high blood pressure (20/82, 26%) and osteopenia (19/26, 73% when bone densitometry was performed). Only one thrombo-embolic event and three severe infections were reported. At last follow-up, median eGFR was 87.1 (23.4–150.8) mL/min/1.73 m². CONCLUSION The incidence of relapses in adulthood is high in patients with active disease during childhood. A long-term follow-up is mandatory in these patients. Whereas renal function remained normal in most patients, high blood pressure and osteopenia were frequent and should be carefully monitored during adulthood. Transition visit should be carefully coordinated to prevent the risk of nonadherence.

Item does not contain fulltext Infantile nephropathic cystinosis (INC) is an inheritable lysosomal storage disorder characterized by lysosomal cystine accumulation, progressive kidney disease, and multiple extrarenal complications (ERCs). Cysteamine postpones the onset of end-stage kidney disease (ESKD) and reduces the incidence of ERCs; however, cysteamine is generally initiated upon establishment of the renal Fanconi syndrome (FS) and partial loss of kidney function, whereas data on long-term effects of cysteamine administered from neonatal age are lacking. An international multicenter retrospective cohort study of siblings with INC was set up to investigate the outcome in relation to age at initiation of cysteamine versus CTNS genotype, with attention to patients treated with cysteamine from neonatal age. None of the siblings treated from neonatal age (n = 9; age 10 ± 6 years) had reached ESKD, while 22% of their index counterparts (n = 9; age 14 ± 5 years) had commenced renal replacement therapy. Siblings treated with cysteamine from the onset of symptoms at a younger age compared with their index counterparts, reached ESKD at a significant older age (13 ± 3 vs. 10 ± 3 years, p = 0.002). In contrast, no significant difference in ERCs was observed between sibling and index patients, independently from the age at initiation of cysteamine. The CTNS genotype had no impact on the overall outcome in this cohort. In INC, presymptomatic treatment with cysteamine results in a better renal outcome in comparison to treatment initiated from the onset of symptoms. This justifies including cystinosis into newborn screening programs. SYNOPSIS: In infantile nephropathic cystinosis, presymptomatic treatment with cysteamine improves the renal outcome which justifies the inclusion of cystinosis into newborn screening programs. 01 januari 2023

Nephropathic cystinosis is a rare disease secondary to recessive mutations of the CTNS gene encoding the lysosomal cystine transporter cystinosin, causing accumulation of cystine in multiple organs. Over the years, the disease has evolved from being a fatal condition during early childhood into a treatable condition, with patients surviving into adulthood. Data on cystinosis are limited by the rarity of the disease. Here, we have investigated factors associated with kidney and growth outcome in a very large cohort of 453 patients born between 1964 and 2016 and followed in Belgium, Germany, Austria, France, Italy, Spain, The Netherlands, Turkey and United Kingdom. From the 1970s to the 1990s, the median increase in kidney survival was 9.1 years. During these years, cysteamine, a cystine-depleting agent, was introduced for the treatment of cystinosis. Significant risk factors associated with early progression to end-stage kidney disease assessed by Cox proportional multivariable analysis included delayed initiation of cysteamine therapy and higher mean leucocyte cystine levels. No significant effect on kidney function was observed for gender, pathogenic variant of the CTNS gene, and the prescription of indomethacin or renin angiotensin system blockers. Significantly improved linear growth was associated with early use of cysteamine and lower leukocyte cystine levels. Thus, our study provides strong evidence in favor of early diagnosis and optimization of cystine depletion therapy in nephropathic cystinosis.

The aim of this study was to estimate the incidence of COVID-19 disease in the French national population of dialysis patients, their course of illness and to identify the risk factors associated with mortality. Our study included all patients on dialysis recorded in the French REIN Registry in April 2020. Clinical characteristics at last follow-up and the evolution of COVID-19 illness severity over time were recorded for diagnosed cases (either suspicious clinical symptoms, characteristic signs on the chest scan or a positive reverse transcription polymerase chain reaction) for SARS-CoV-2. A total of 1,621 infected patients were reported on the REIN registry from March 16th, 2020 to May 4th, 2020. Of these, 344 died. The prevalence of COVID-19 patients varied from less than 1% to 10% between regions. The probability of being a case was higher in males, patients with diabetes, those in need of assistance for transfer or treated at a self-care unit. Dialysis at home was associated with a lower probability of being infected as was being a smoker, a former smoker, having an active malignancy, or peripheral vascular disease. Mortality in diagnosed cases (21%) was associated with the same causes as in the general population. Higher age, hypoalbuminemia and the presence of an ischemic heart disease were statistically independently associated with a higher risk of death. Being treated at a selfcare unit was associated with a lower risk. Thus, our study showed a relatively low frequency of COVID-19 among dialysis patients contrary to what might have been assumed., Graphical abstract

In children, vitamin D deficiency is common after renal transplantation. Besides promoting bone and muscle development, vitamin D has immunomodulatory effects, which could protect kidney allografts. The purpose of this study was to assess the association between vitamin D status and the occurrence of renal rejection.We studied a retrospective cohort of 123 children, who were transplanted at a single institution between September 2008 and April 2019. Patients did not receive vitamin D supplementation systematically. In addition, factors influencing vitamin D status were analyzed using univariate and multivariate analyses.Median 25-hydroxy-vitamin D (25-OH-D) concentration was close to reference values at the time of transplantation (30 ng/mL (min-max 5-100)), but rapidly decreased within the first 3 months to 19 ng/mL (min-max 3-91) (P .001). The overall acute rejection rate was 7%. The clinical rejection rate (5% vs 9%), subclinical rejection (12% vs 36%), and borderline changes (21% vs 28%) were not statistically different during the follow-up between the 3-month 25-OH-D 20 ng/mL and 3-month 25-OH-D 20 ng/mL groups. There was a correlation between the 25-OH-D levels and PTH concentration at 3 months (r = -.2491, P = .01), but no correlation between the 3-month 25-OH-D and the season of the year (F = 0.19, P = .90; F = 1.34, P = .27, respectively). Multivariate analyses revealed that age and mGFR at 3 months, were independent predictors of mGFR at 12 months.Our data show that vitamin D deficiency can develop rapidly after transplantation; vitamin D levels at 3 months are not associated with lower mGFR or a higher rejection rate at 1 year in children as opposed to adult recipients.

Levamisole has been considered the least toxic and least expensive steroid-sparing drug for preventing relapses of steroid-sensitive idiopathic nephrotic syndrome (SSINS). However, evidence for this is limited as previous randomized clinical trials were found to have methodological limitations. Therefore, we conducted an international multicenter, placebo-controlled, double-blind, randomized clinical trial to reassess its usefulness in prevention of relapses in children with SSINS. The efficacy and safety of one year of levamisole treatment in children with SSINS and frequent relapses were evaluated. The primary analysis cohort consisted of 99 patients from 6 countries. Between 100 days and 12 months after the start of study medication, the time to relapse (primary endpoint) was significantly increased in the levamisole compared to the placebo group (hazard ratio 0.22 [95% confidence interval 0.11–0.43]). Significantly, after 12 months of treatment, six percent of placebo patients versus 26 percent of levamisole patients were still in remission. During this period, the most frequent serious adverse event (four of 50 patients) possibly related to levamisole was asymptomatic moderate neutropenia, which was reversible spontaneously or after treatment discontinuation. Thus, in children with SSINS and frequent relapses, levamisole prolonged the time to relapse and also prevented recurrence during one year of treatment compared to prednisone alone. However, regular blood controls are necessary for safety issues., SCOPUS: ar.j, info:eu-repo/semantics/published

Introduction L’evolution a long terme et la prise en charge multidisciplinaire optimale des patients ayant une cystinose restent a determiner. Description ECYSCO est une cohorte multicentrique europeenne retrospective et prospective sur la cystinose du programme Rare Disease Cohort (RaDiCo), sous l’egide de l’ANR, finance par le PIA. L’objectif principal est de decrire l’histoire de la maladie, ses manifestations, sa prise en charge et son impact sur la qualite de vie. Methodes Enfants et adultes avec diagnostic confirme de cystinose et suivis dans 11 centres francais et 3 europeens (Belgique, Italie et Espagne) ont ete inclus. Resultats Cent vingt-six patients (57 enfants, 69 adultes) ont ete inclus. L’âge moyen au diagnostic etait de 1,0 ans [4 j–54 a] et l’âge a l’inclusion de 20,1 ans (enfants : 9,6 ans [1–18], adultes : 29,6 ans [18–60]). Cinquante-huit patients avaient des donnees genetiques disponibles : 25 deletions de 57 kb a l’etat homozygote, 33 deletions heterozygotes. A l’inclusion, 7 % etaient hemodialyses et 41 % transplantes. L’âge moyen a l’insuffisance renale terminale etait de 12,5 ans (4–32 ; n = 46). Le DFG moyen sur rein natif chez les enfants etait de 56 mL/min/1,73 m2 [IC95 % : 36 ; 76] et chez les adultes de 46 mL/min/1,73 m2 [IC95 % : 35 ; 57]. Le taux de cystine intraleucocytaire etait de 1,6 (0,2–9,1) nmol ½ cystine/mg proteine. Vingt-cinq pour cent des patients presentaient une hypothyroidie, 58 % des manifestations squelettiques, 19 % une atteinte musculaire, 15 % une atteinte neurologique et 8 % un diabete. Les traitements specifiques a l’inclusion etaient : Cystagon® 70 %, Procysbi® 28 % et aucun 2 %. Au cours du suivi, en France, 89,6 % ont ete switches pour du Procysbi®. Conclusion La majorite des patients atteints de cystinose sont desormais adultes et la moitie necessite un traitement de suppleance. L’identification et la prise en charge des complications extrarenales sont un enjeu majeur pour les equipes qui suivent les patients.

Background Recommendations for management of Finnish-type congenital nephrotic syndrome (CNS) followed by many teams include daily albumin infusions, early bilateral nephrectomy, dialysis and transplantation. We aimed to assess the treatment and outcome of patients with CNS in France. Methods We conducted a nationwide retrospective study on 55 consecutive children born between 2000 and 2014 treated for non-infectious CNS. Results The estimated cumulative incidence of CNS was 0.5/100 000 live births. The underlying defect was biallelic mutations in NPHS1 (36/55, 65%), NPHS2 (5/55, 7%), PLCE1 (1/55, 2%), heterozygous mutation in WT1 (4/55, 7%) and not identified in nine children (16%). Fifty-three patients (96%) received daily albumin infusions from diagnosis (median age 14 days), which were spaced and withdrawn in 10 patients. Twenty children (35%) were managed as outpatients. Thirty-nine patients reached end-stage kidney disease (ESKD) at a median age of 11 months. The overall renal survival was 64% and 45% at 1 and 2 years of age, respectively. Thirteen children died during the study period including four at diagnosis, two of nosocomial catheter-related septic shock, six on dialysis and one after transplantation. The remaining 13 patients were alive with normal renal function at last follow-up [median 32 months (range 9-52)]. Renal and patient survivals were longer in patients with NPHS1 mutations than in other patients. The invasive infection rate was 2.41/patient/year. Conclusions Our study shows: (i) a survival free from ESKD in two-thirds of patients at 1 year and in one-half at 2 years and (ii) a significant reduction or even a discontinuation of albumin infusions allowing ambulatory care in a subset of patients. These results highlight the need for new therapeutic guidelines for CNS patients.

It is now well established that the podocyte, and in particular the slit diaphragm structure, are critical to the barrier to serum albumin entering glomerular filtrate in large quantities. In minimal change disease there is proteinuria without podocyte death, whereas in focal segmental glomerulosclerosis there is not only podocyte dysfunction but also podocyte loss.

Idiopathic nephrotic syndrome is defined by the combination of massive proteinuria, hypoalbuminaemia, hyperlipidaemia, and oedema, and of non-specific histological abnormalities of the glomeruli. Light microscopy may disclose minimal change disease, diffuse mesangial proliferation, or focal segmental glomerular sclerosis (FSGS). The two main causes of idiopathic nephrotic syndrome are characterized histologically. On electron microscopy the glomerular capillaries show a fusion of visceral epithelial cell (podocyte) foot processes and with the exception of some variants no significant deposits of immunoglobulins or complement by immunofluorescence. In a majority of children only minimal changes are seen on light microscopy. These children are referred to as having ‘minimal change disease’. In adults with idiopathic nephrotic syndrome, lesions of FSGS are more frequent.

Primary focal segmental glomerulosclerosis (FSGS) causes nephrotic syndrome and by definition is not caused by any of the known causes of podocyte toxicity or focal segmental sclerosis such as viral infections or toxins. A number of genetic causes of FSGS are commonly diagnosed in early childhood. Other causes of segmental scarring need to be distinguished. Genotypes in APOL1 of African origin are associated with higher incidence of FSGS and poorer responses to treatment. Cellular and collapsing FSGS are variants of FSGS in which there is overt acute podocytopathy and they have a relatively poor prognosis. A glomerular tip lesion is thought to have a slightly better prognosis than other types. Some cases of primary FSGS respond to high-dose corticosteroids, sometimes only after prolonged therapy. Response to steroids is a good prognostic sign, and without a response, progressive loss of renal function is likely. A circulating factor is implicated by the observation that proteinuria can recur in a donor kidney within hours of transplant. Plasma exchange appears to remove this factor but it is not conclusively identified.

Minimal change disease is characteristically responsive to high-dose corticosteroids. As this is the most common cause of nephrotic syndrome in children, and responses are usually prompt, response to 60 mg/m2/day of oral prednisolone (max. 80 mg) is often used as a diagnostic test. Adults respond more slowly and have a wider differential diagnosis, and often a high risk of side effects, so therapy is not recommended without confirmation by renal biopsy. Then first-line treatment is again prednisolone or prednisone, at 1 mg/kg/day (max. 60 mg). KDIGO and other treatment protocols recommend 6 weeks treatment at full dose then 6 weeks at half dose. Shorter protocols seem to increase the risk of relapse. Children frequently have a relapsing pattern of disease which may be managed by less extreme steroid exposure, but for which second-line therapies may be needed to avoid severe steroid side effects. This can arise in adults too. Some children and adults have steroid-dependent or steroid-resistant disease, leading to earlier initiation of treatment with second-line agents. These include levamisole, calcineurin inhibitors, mycophenolate mofetil, and anti-B cell antibodies. The evidence for these and recommendations for relapsing/resistant disease are given in this chapter.

Familial steroid-sensitive nephrotic syndrome (SSNS) is a rare condition. The disease pathophysiology remains elusive. However, bi-allelic mutations in the EMP2 gene were identified, and specific variations in HLA-DQA1 were linked to a high risk of developing the disease. Clinical data were analyzed in 59 SSNS families. EMP2 gene was sequenced in families with a potential autosomal recessive (AR) inheritance. Exome sequencing was performed in a subset of 13 families with potential AR inheritance. Two variations in HLA-DQA1 were genotyped in the whole cohort. Transmission was compatible with an AR (n = 33) or autosomal dominant (AD, n = 26) inheritance, assuming that familial SSNS is a monogenic trait. Clinical features did not differ between AR and AD groups. All patients, including primary (n = 7) and secondary steroid resistant nephrotic syndrone (SRNS), (n = 13) were sensitive to additional immunosuppressive therapy. Both HLA-DQA1 variations were found to be highly linked to the disease (OR = 4.34 and OR = 4.89; p

MCD represents 95% of all cases of childhood idiopathic nephrotic syndrome (INS) and 30% of INS in adults of all ages and is not exceptional after 60 years. Albuminuria and hypoalbuminemia are accompanied by massive edema without reduction of blood volume. Renal function is moderately altered in 1/3 of patients with MCD, as foot process fusion impairs filtration of small molecules. The GFR returns to normal with remission of proteinuria. Since the early 1960s, a number of publications reported cases of acute oliguric kidney insufficiency complicating the course of MCD in adults. AKI mostly affects older patients with massive proteinuria, severe hypoalbuminemia, a background of hypertension, and arterial/arteriolar lesions on kidney biopsy. Histology reveals ischemic tubular necrosis. AKI may require dialysis for several weeks or months until treatment-induced remission allows resolution of oliguria. In rare cases AKI does not recover. Factors causing AKI in patients with MCD are diuretic-induced hypovolemia, NSAIDs, iodinated contrast media, and nephrotoxic drugs. AKI is not frequent in children with MCD in the absence of intercurrent complications. Conversely when steroid-resistant nephrotic children are hospitalized for an acute episode of hypovolemia, sepsis, peritonitis, and exposure to nephrotoxic medications and/or ACE inhibitors, AKI complicates NS in about half of them. The main goal of supportive therapy is to buy time until corticosteroids obtain a remission of proteinuria. Persistent oliguria may require a long period of dialysis. Prevention is based on early detection and treatment of infection, limited use of diuretics, and avoidance of nephrotoxic agents.

Minimal change disease accounts for 70% to 90% of cases of nephrotic syndrome in children. It also causes nephrotic syndrome in adults, including patients older than age 60. Renal function is altered moderately in approximately 20% to 30% of patients because foot-process fusion impairs filtration of water and solutes. The glomerular filtration rate is reduced by approximately 20% to 30% and returns to baseline with remission of proteinuria. Over the past 50 years, a number of publications have reported cases of acute kidney injury occurring in approximately one-fifth to one-third of adult cases in the absence of prior or concomitant renal disease. Clinical attributes point to a male predominance, age >50, massive proteinuria, severe hypoalbuminemia, a background of hypertension and vascular lesions on kidney biopsy, along with ischemic tubular necrosis. Acute kidney injury may require dialysis for weeks or months until remission of proteinuria allows resolution of oliguria. In some cases, renal function does not recover. An effect of endothelin-1–induced vasoconstriction at the onset of proteinuria has been proposed to explain tubular cell ischemic necrosis. The main factors causing acute kidney injury in patients with minimal change disease are diuretic-induced hypovolemia and nephrotoxic agents. Acute kidney injury is uncommon in children in the absence of intercurrent complications. Infection, nephrotoxic medication, and steroid resistance represent the main risk factors. In all patients, the goal of supportive therapy is essentially to buy time until glucocorticoids obtain remission of proteinuria, which allows resolution of renal failure.

To establish the safety and efficacy of a new gel formulation of cysteamine hydrochloride (CH) eye drops, for the treatment of corneal complications of nephropathic cystinosis.Open label dose response clinical trial.Eight patients with infantile nephropathic cystinosis including 4 children, 3 adolescents, and 1 adult (mean age at inclusion, 12.1 ± 4.6 years) treated with CH 0.1% eye drops.Patients were treated, in both eyes, with the control CH 0.1% eye drop formulation on average 4 times daily for one month and then switched to Cystadrops® at the same dose frequency. Based on clinical ocular findings, the dose regimen was adapted at D30 and D90 in order to decrease the frequency of instillation. After D90, this dose frequency was maintained, except in cases of crystal density worsening. Patients had a follow-up visit every 6 months during 48 months.Safety assessment consisted of adverse event and serious adverse event monitoring and recording at each visit. For the efficacy study, the primary endpoint was the corneal cystine crystal density measured with an in vivo confocal microscopy (IVCM) score.All patients completed the study. During the 4-year study period, neither serious adverse events nor significant adverse events related to the study drug were reported. After switching to Cystadrops®, the IVCM total score decreased from baseline to D90 by a mean of 28.6 ± 17.5% (p0.001). From D90 to M48, the IVCM total score remained stable and significantly decreased as compared to that at D1 despite a reduced dose regimen from D90. At M48, the mean IVCM total score was 8.13 ± 4.15, decreased by a mean 29.9 ± 26.29% from D1 (p = 0.001), with a reduced number of instillations compared to that at D1. The IVCM total score and photophobia were significantly correlated (p = 0.04).This study provides evidence that Cystadrops® gel is superior to the CH 0.1% formulation in terms of efficacy and has a good safety profile over a long follow-up period.

Anti-complement factor H (CFH) autoantibody (Ab)-associated atypical hemolytic uremic syndrome (aHUS) has a poor prognosis, but no consensus exists on its treatment.We report the follow-up of four children with anti-CFH Ab (8,000 to32,000 arbitrary units)-associated aHUS after plasma exchanges (PEs), prednisone, and cyclophosphamide pulse therapy with the evolution of anti-CFH Ab titers and kidney function.Patient 1 received PEs + prednisone + cyclophosphamide pulses after two relapses following PEs and then PEs + rituximab. The other three patients were treated with PEs + prednisone + cyclophosphamide pulses as a first-line therapy. In our four patients, the induction protocol combining PEs + prednisone + cyclophosphamide pulses led to a rapid and sustained remission up to 6 years, 4 years and 4 months without any maintenance therapy. Kidney function was normal and anti-CFH Ab titer decreased, but remained detectable during remission without any clinical or biological signs of relapse.We demonstrate the long-term efficiency and safety of cyclophosphamide pulses combined with PEs and prednisone in anti-CFH Ab-associated aHUS leading to a prolonged decrease in anti-CFH Ab titers and prevention of relapses without the need for maintenance therapy.

Atypical hemolytic uremic syndrome (aHUS) is a rare complement-mediated kidney disease that was first recognized in children but also affects adults. This study assessed the disease presentation and outcome in a nationwide cohort of patients with aHUS according to the age at onset and the underlying complement abnormalities.A total of 214 patients with aHUS were enrolled between 2000 and 2008 and screened for mutations in the six susceptibility factors for aHUS and for anti-factor H antibodies.Onset of aHUS occurred as frequently during adulthood (58.4%) as during childhood (41.6%). The percentages of patients who developed the disease were 23%, 40%, 70%, and 98% by age 2, 18, 40, and 60 years, respectively. Mortality was higher in children than in adults (6.7% versus 0.8% at 1 year) (P=0.02), but progression to ESRD after the first aHUS episode was more frequent in adults (46% versus 16%; P0.001). Sixty-one percent of patients had mutations in their complement genes. The renal outcome was not significantly different in adults regardless of genetic background. Only membrane cofactor protein (MCP) and undetermined aHUS were less severe in children than adults. The frequency of relapse after 1 year was 92% in children with MCP-associated HUS and approximately 30% in all other subgroups.Mortality rate was higher in children than adults with aHUS, but renal prognosis was worse in adults than children. In children, the prognosis strongly depends on the genetic background.

Background Patients with infantile nephropathic cystinosis have progressive accumulation of cystine in tissues leading to delayed extrarenal complications. No simple tool is available to evaluate the level of body cystine accumulation. Objective We sought to determine the value of in vivo reflectance confocal microscopy of the skin in patients with infantile nephrogenic cystinosis. Methods Nine patients and control subjects were recruited for this study. Images were acquired by means of a near-infrared reflectance confocal laser scanning microscope. Results Scattered bright particles within the papillary dermis were observed in all patients but not in control subjects. The density of particles ranged from numerous (+++) to very few (+/–) and their distribution was heterogeneous. Electron microscopy confirmed that these particles corresponded to cystine crystal deposits within dermal fibroblasts. The density of cystine crystals within the dermis was greater in older patients, in patients with a high leukocyte cystine concentration, and with delayed cysteamine therapy. There was no correlation between the density of cystine deposits and renal disease or hypopigmentation but high levels of deposition occurred in association with extrarenal manifestations. Limitations This is a preliminary study on a small sample of patients. Repeated examination and longer follow-up is necessary. Conclusion In vivo reflectance confocal microscopy of the skin appears to be a noninvasive means of assessing body cystine accumulation in infantile cystinosis and could be used as a complementary marker of treatment response in addition to leukocyte cystine measurement.

Resume Les cytopathies mitochondriales sont des maladies genetiques affectant la phosphorylation oxydative consistant en la production d’adenosine triphosphate (ATP), source de l’energie dans les tissus et les organes. La chaine respiratoire mitochondriale comprend plus de 100 polypeptides dont la majorite est codee par des genes nucleaires tandis que 13 sont codes par l’acide desoxyribonucleique (ADN) mitochondrial. L’ADN mitochondrial est transmis par la mere et les mutations sont donc de transmission maternelle. Durant la division cellulaire, les mitochondries sont reparties au hasard dans les cellules filles et le pourcentage de molecules d’ADN mutees et de molecules d’ADN normales dans les cellules filles peut varier au cours du temps. L’atteinte renale au cours des cytopathies mitochondriales est rare. La manifestation la plus frequente est une tubulopathie proximale, responsable d’une forme plus ou moins complete et severe de syndrome de de Toni-Debre-Fanconi. Certains patients presentent un syndrome nephrotique et d’autres une nephropathie tubulo-interstitielle. Les investigations comportent des etudes metaboliques de l’etat d’oxydoreduction dans le plasma, des etudes spectrophotometriques et spectroscopiques de la chaine respiratoire mitochondriale, des etudes histologiques et des etudes genetiques.

The risk of graft failure in young kidney transplant recipients has been found to increase during adolescence and early adulthood. However, this question has not been addressed outside the United States so far. Our objective was to investigate whether the hazard of graft failure also increases during this age period in France irrespective of age at transplantation.Data of all first kidney transplantation performed before 30 years of age between 1993 and 2012 were extracted from the French kidney transplant database. The hazard of graft failure was estimated at each current age using a 2-stage modelling approach that accounted for both age at transplantation and time since transplantation. Hazard ratios comparing the risk of graft failure during adolescence or early adulthood to other periods were estimated from time-dependent Cox models.A total of 5983 renal transplant recipients were included. The risk of graft failure was found to increase around the age of 13 years until the age of 21 years, and decrease thereafter. Results from the Cox model indicated that the hazard of graft failure during the age period 13 to 23 years was almost twice as high as than during the age period 0 to 12 years, and 25% higher than after 23 years.Among first kidney transplant recipients younger than 30 years in France, those currently in adolescence or early adulthood have the highest risk of graft failure.

The most common cause of nephrotic syndrome in children is idiopathic nephrotic syndrome (INS), also called nephrosis [1]. INS is defined by the combination of a nephrotic syndrome (massive proteinuria, hypoalbuminemia, hyperlipidemia, and edema) and nonspecific histological abnormalities of the glomeruli including minimal changes, focal and segmental glomerular sclerosis (FSGS), and diffuse mesangial proliferation. On electron microscopy, glomeruli show an effacement of epithelial cell (podocyte) foot processes and no significant deposits of immunoglobulins or complement by immunofluorescence. In a majority of children, only minimal changes are seen on light microscopy. These children are referred to as having “minimal change disease.” Many authors consider minimal change disease (MCD) and FSGS as separate diseases because of differences in response to corticosteroids and subsequent clinical course. Indeed, these pathologic features carry prognostic significance. Patients with FSGS have more frequently hematuria, are often resistant to corticosteroid treatment, and progress more often to renal failure. Recent data have comforted the belief that MCD and FSGS are different entities. MCD is a functional podocyte disease, whereas FSGS appears to be a structural podocytopathy [2]. The notion of “podocyte dysregulation” [2, 3], the different expression cyclin-dependent kinase inhibitors in MCD and in FSGS, the role of these cell cycle disturbances leading to podocyte proliferation and maturation [4], and the identification of parvovirus B19 in glomeruli of patients with FSGS [5, 6] are in favor of distinct entities. The high circulating levels of the soluble urokinase receptor (suPAR) found in FSGS but not in MCD [7, 8] support the hypothesis that MCD and FSGS as podocytopathies originating from different glomerular permeability factors. In the early stages, FSGS and MCD are indistinguishable [9]. The best illustration of this is the aspect of a transplant biopsy carried out shortly after relapse of proteinuria following transplantation in a patient whose primary renal disease was FSGS. Despite heavy proteinuria, the glomeruli initially show minimal changes. A significant number of patients with FSGS respond to corticosteroids, whereas some steroid-resistant patients have no sclerotic changes on biopsy specimens containing adequate tissue [10]. Therefore, some authors believe that, although histological variants of the INS carry prognostic significance, they cannot at present be considered as separate entities. The term MCD has become synonymous with steroid-responsive nephrotic syndrome although renal biopsy is usually not performed in patients who respond to steroid therapy. Indeed, in many centers, renal biopsy is recommended only for those patients who fail to respond to steroids. Consequently, renal biopsy findings in recent published series are not representative of the true incidence of various histopathological categories seen in INS. It is therefore more appropriate to classify the patients according to their response to steroid therapy. Response to steroid therapy carries a greater prognostic weight than the histological features seen on initial renal biopsy. Thus, two types of INS can be defined: steroid-responsive nephrotic syndrome, in which proteinuria rapidly resolves after starting steroid therapy, and steroid-resistant nephrotic syndrome, in which steroids do not induce remission.

Item does not contain fulltext Nephropathic cystinosis is an autosomal recessive metabolic, lifelong disease characterized by lysosomal cystine accumulation throughout the body that commonly presents in infancy with a renal Fanconi syndrome and, if untreated, leads to end-stage kidney disease (ESKD) in the later childhood years. The molecular basis is due to mutations in CTNS, the gene encoding for the lysosomal cystine-proton cotransporter, cystinosin. During adolescence and adulthood, extrarenal manifestations of cystinosis develop and require multidisciplinary care. Despite substantial improvement in prognosis due to cystine-depleting therapy with cysteamine, no cure of the disease is currently available. Kidney Disease: Improving Global Outcomes (KDIGO) convened a Controversies Conference on cystinosis to review the state-of-the-art knowledge and to address areas of controversies in pathophysiology, diagnostics, monitoring, and treatment in different age groups. More importantly, promising areas of investigation that may lead to optimal outcomes for patients afflicted with this lifelong, systemic disease were discussed with a research agenda proposed for the future.

Resume Ce chapitre a pour but de fournir un ensemble d’indicateur permettant de decrire les specificites de l’insuffisance renale terminale a l’âge pediatrique en France et d’etudier le devenir de ces patients ainsi que les choix fait concernant les modalites de suppleance. En 2011, l’incidence et la prevalence de l’insuffisance renale terminale (IRT) chez les moins de 20 ans sont restees stables a 8 et 53 pmh respectivement. Les premieres causes d’IRT restent les uropathies et hypodysplasies suivies par les glomerulopathies acquises et les maladies genetiques. Concernant les traitements de suppleance, la France se caracterise par un taux d’hemodialyse tres eleve et un faible recourt a la dialyse peritoneale qui est presque exclusivement utilisee chez les jeunes enfants. Le nombre de greffe preemptive en 2011 est de 31 patients soit 27,7% des incidents. Enfin, les donnees de survie confirment que les jeunes enfants (moins de 4 ans) sont les plus a risque de deces (survie de 88% a 2 ans vs 98% pour les patients de plus de 4 ans) et que la modalite de traitement de choix est la transplantation renale puisqu’elle augmente l’esperance de vie de 20 a 40 annees en fonction de l’âge considere.

Boyer O, Noto C, Patey-Mariaud De Serre N, Gubler M-C, Dechaux M, Goulet O, Niaudet P, Lacaille F. Renal function and histology in children after small bowel transplantation. Abstract: CKD is a frequent long-term complication after SBTx. CNIs are a well-known factor, but probably not the only cause. We assessed the incidence, risk factors, and severity of CKD in 27 children with SBTx (15 combined liver/SBTx) and prednisone/TAC-based maintenance immunosuppression. Median follow-up was seven yr (3–21). A renal biopsy was performed in 14 patients, 1–18 yr post-SBTx. A reduced GFR was observed in 17 children (63%) during the follow-up with none requiring dialysis. CNI toxicity was observed in 11/14 biopsies, as early as two yr post-transplant, and could occur with a normal mGFR. The dose of TAC was reduced by 50% in 13 patients with CKD and/or significant kidney histological lesions, and six were also given MMF. This led to a significant improvement in renal function: mGFR normalized in eight patients and improved or stabilized in five. No rejection occurred. At last follow-up, 37% had CKD stage 2 and 15% had CKD stage 3. In conclusion, CKD is frequent in children after SBTx and probably multifactorial. Less nephrotoxic immunosuppressive protocols may improve mGFR and should be further considered. The kidney histology helps in designing personalized immunosuppression strategies for patients.

Dense deposit disease and glomerulonephritis with isolated C3 deposits are glomerulopathies characterized by deposits of C3 within or along the glomerular basement membrane. Previous studies found a link between dysregulation of the complement alternative pathway and the pathogenesis of these diseases. We analyzed the role of acquired and genetic complement abnormalities in a cohort of 134 patients, of whom 29 have dense deposit disease, 56 have glomerulonephritis with isolated C3 deposits, and 49 have primary membranoproliferative glomerulonephritis type I, with adult and pediatric onset. A total of 53 patients presented with a low C3 level, and 65 were positive for C3 nephritic factor that was significantly more frequently detected in patients with dense deposit disease than in other histological types. Mutations in CFH and CFI genes were identified in 24 patients associated with a C3 nephritic factor in half the cases. We found evidence for complement alternative pathway dysregulation in 26 patients with membranoproliferative glomerulonephritis type I. The complement factor H Y402H variant was significantly increased in dense deposit disease. We identified one at-risk membrane cofactor protein (MCP) haplotype for glomerulonephritis with isolated C3 deposits and membranoproliferative glomerulonephritis type I. Thus, our results suggest a critical role of fluid-phase alternative pathway dysregulation in the pathogenesis of C3 glomerulopathies as well as in immune complex–mediated glomerular diseases. The localization of the C3 deposits may be under the influence of MCP expression.

Summary Background and objectives Immediate-release cysteamine bitartrate (Cystagon; Mylan Pharmaceuticals, Canonsburg, PA) may prevent or delay kidney transplantation and other serious outcomes in patients with cystinosis, but has never been subjected to a prospective clinical trial. Cystagon efficacy requires strict lifelong dosing every 6 hours. Such a dosing schedule and Cystagon-associated side effects are often cited by patients as reasons for nonadherence. Design, setting, participants, & measurements This open-label, randomized, controlled, crossover trial was powered to show that a new delayed-release formulation of cysteamine bitartrate, RP103, taken every 12 hours, was noninferior to Cystagon for maintenance of white blood cell (WBC) cystine at levels associated with optimal outcomes in the disease. Results Forty-three patients were randomized. Using a mixed-effects statistical analysis model, the least-squares mean peak value of WBC cystine level was 0.6260.05 nmol 1/2 cystine/mg protein after 12 hours under RP103 and 0.5460.05 nmol 1/2 cystine/mg protein after 6 hours under Cystagon, a difference of 0.0860.04 nmol 1/2 cystine/mg protein (95.8% confidence interval, 0–0.16). The average steady-state total daily dose of RP103 was 82% of the incoming steady-state total daily dose of Cystagon. There were three-fold more gastrointestinal side effects compared with using Cystagon. Conclusions A new delayed-release Q12H formulation of cysteamine bitartrate is not inferior to the Q6H formulation (Cystagon) in maintaining low WBC cystine levels in patients with cystinosis but at a lower total daily dose. Clin J Am Soc Nephrol 7: ccc–ccc, 2012. doi: 10.2215/CJN.12321211

We report the first observation of successful kidney transplantation under pre-emptive eculizumab treatment in a 7-year-old boy with atypical hemolytic uremic syndrome (aHUS) and a known hybrid CFH/CFHR1 gene, who was dependent on plasma therapy during the 3-year dialysis period. The hybrid CFH/CFHR1 protein has an altered C3b/C3d binding, is incapable to protect cells from complement attack and is directly implicated in aHUS pathogenesis. There was no evidence of recurrence during the first 16-month follow-up period. We conclude that eculizumab alone, without plasma therapy (plasma infusion and/or plasma exchange), is sufficient to prevent recurrence of aHUS and to maintain long-term graft function.

Systemic-onset juvenile idiopathic arthritis is an inflammatory disease of unknown cause and is not commonly associated with kidney involvement. We describe 3 patients with systemic-onset juvenile idiopathic arthritis with high disease activity who developed antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis 1-6 years after the onset of systemic-onset juvenile idiopathic arthritis. Renal and systemic-onset juvenile idiopathic arthritis remission occurred in one patient under anti-interleukin 1 (anti-IL-1) treatment associated with immunosuppressive drugs. The other 2 patients developed end-stage renal disease, and one of those patients died. This report suggests that the diagnosis of ANCA-associated glomerulonephritis must be considered in patients with systemic-onset juvenile idiopathic arthritis with persistently active systemic disease who present with proteinuria. Furthermore, use of an anti-IL-1 agent might be an effective therapeutic option.

Chronic shortage of available donor organs has led to re-evaluation of the use of en bloc kidney transplants. Although excellent results have been reported in adult patients, experience in pediatric patients remains limited because of potential early complications and poor long-term graft outcome. We report 14 pediatric en bloc renal transplantations into 14 pediatric recipients, performed between 1990 and 2007 in France. We retrospectively analyzed demographic data, postoperative complications, and graft function with a median follow-up of five yr. Donor age ranged from four to 54 months. Complications were vascular graft thrombosis in four patients, leading to graft loss in two cases, and to excellent long-term graft function in the two others. Two hemorrhagic complications resulted in death in one case and in graft loss in the other. Six acute rejection episodes occurred in four patients. Median glomerular filtration rate at three months, one, five, and 10 yr was 90.8, 106, 87.8, and 66.1 mL/1.73 m(2) /min. We believe that en bloc transplantation may be an option for children with end-stage kidney disease.

Nephropathic cystinosis is a multisystem autosomal recessive disease caused by cystine accumulation, which is usually treated by oral cysteamine. In order to determine long-term effects of this therapy, we enrolled 86 adult patients (mean age 26.7 years) diagnosed with nephropathic cystinosis, 75 of whom received cysteamine. Therapy was initiated at a mean age of 9.9 years with a mean duration of 17.4 years. By last follow-up, 78 patients had end-stage renal disease (mean age 11.1 years), 62 had hypothyroidism (mean age 13.4), 48 developed diabetes (mean age 17.1 years), and 32 had neuromuscular disorders (mean age 23.3 years). Initiating cysteamine therapy before 5 years of age significantly decreased the incidence and delayed the onset of end-stage renal disease, and significantly delayed the onset of hypothyroidism, diabetes, and neuromuscular disorders. The development of diabetes and hypothyroidism was still significantly delayed, however, in patients in whom therapy was initiated after 5 years of age, compared with untreated patients. The life expectancy was significantly improved in cysteamine-treated versus untreated patients. Thus, cysteamine decreases and delays the onset of complications and improves life expectancy in cystinosis. Hence, cysteamine therapy should be introduced as early as possible during childhood and maintained lifelong.

Summary Background: There are few data regarding perioperative adverse events in children with nephrotic syndrome. Objectives: The aim of this study was to describe the nature and frequency of perioperative adverse events in children with nephrotic syndrome. Materials and Methods: This is a retrospective study from a large university pediatric hospital. All procedures under general anesthesia in children with nephrotic syndrome between January 1995 and May 2007 were included, with the exception of renal transplantation. Data were collected on demographics, etiology of nephrotic syndrome and related treatments, surgical procedures and anesthetic techniques, and pre- and postoperative treatments. Adverse events occurring during the intraoperative period and up to the fifth postoperative day were recorded. Results: Data on eight patients who underwent 24 surgical or interventional procedures under general anesthesia over the study period were reviewed. Three patients had steroid-resistant nephrotic syndrome and five patients had congenital or infantile nephrotic syndrome. Five patients had progressed to end-stage renal failure requiring dialysis. General anesthesia was performed for: nephrectomy (n = 9), central venous catheter insertion (n = 8), peritoneal dialysis catheter insertion (n = 5), and emergency surgery in two cases (acute intestinal intussusception and hemodialysis catheter insertion). Three patients were receiving aspirin and one anticoagulant therapy. No postoperative thrombosis or infections, bleeding, peripheral edema or ascites, and increase in kalemia were noted. There was no significant postoperative increase in median serum creatinine level. Conclusions: Surgical procedures were seldom associated with the occurrence of perioperative adverse events. However, larger studies are needed to confirm these results.

Mycophenolate mofetil (MMF) has emerged as a new therapeutic option in steroid-dependent nephrotic syndrome (SDNS). We conducted a phase II Bayesian trial of MMF in children with SDNS. Phase II trials, usually single-arm studies, investigate the effect of new treatments. Standard Fleming's procedure relies on observed results (relapse rate during the trial), whereas Bayesian approach combines observed results with prior information (expected relapse rate according to prior studies and clinical experience). All patients were required to have received prior alkylating-agent treatment. Sixty-seven percent of them had also received levamisole. Patients received MMF (1,200 mg/m(2)/day) and prednisone according to a defined schedule [reduction of alternate-day (e.o.d) dose to 50% of pre-MMF dose at 3 months, 25% at 6 months]. Twenty-four children (median age 6.0 years, 2.8-14.4) entered the study and 23 completed it. Bayesian analysis showed that adding four patients would not change significance of results, allowing stopping inclusions. Four patients relapsed during the first 6 months (estimated probability 17.6%, 95% credibility interval: 5.4-35.0%) and two at months 8 and 11.5. In the 19 patients free of relapse during the first 6 months, median (Q1-Q3) prednisone maintenance dose decreased from 25 (10-44) to 9 (7.5-11.2) mg/m(2) e.o.d (p0.001) and cumulative dose from 459 (382-689) to 264 (196-306) mg/m(2)/month (p0.001) before and on MMF respectively. Pre-MMF patient characteristics and MMF pharmacokinetics did not differ between patients with or without relapse. MMF reduces relapse rate and steroid dose in children with SDNS and should be proposed before cyclosporine and cyclophosphamide.

The M-type phospholipase A(2) receptor (PLA(2)R) was recently identified as a candidate antigen in 70% of cases of idiopathic membranous nephropathy, a common form of the nephrotic syndrome. The nature of antigens involved in other idiopathic and secondary membranous nephropathies remains unclear.We searched for antibodies against bovine serum albumin and circulating bovine serum albumin by means of enzyme-linked immunosorbent assay and Western blotting in serum specimens obtained from 50 patients with membranous nephropathy and 172 controls. The properties of immunopurified circulating bovine serum albumin obtained from serum specimens were analyzed with the use of two-dimensional sodium dodecyl sulfate-polyacrylamide-gel electrophoresis. We detected bovine serum albumin in glomerular deposits and analyzed the reactivity of eluted IgG.Eleven patients, including four children, had high levels of circulating anti-bovine serum albumin antibodies, of both the IgG1 and IgG4 subclasses. These patients also had elevated levels of circulating bovine serum albumin, without an increase in circulating immune complex levels. Bovine serum albumin immunopurified from the serum specimens of these four children migrated in the basic range of pH, whereas the bovine serum albumin from adult patients migrated in neutral regions as native bovine serum albumin. Bovine serum albumin was detected in subepithelial immune deposits only in the children with both high levels of cationic circulating bovine serum albumin and bovine serum albumin-specific antibodies, and it colocalized with IgG in the absence of PLA(2)R. IgG eluted from such deposits was specific for bovine serum albumin.Some patients with childhood membranous nephropathy have both circulating cationic bovine serum albumin and anti-bovine serum albumin antibodies. Bovine serum albumin is present in immune deposits, suggesting that cationic bovine serum albumin is pathogenic through binding to the anionic glomerular capillary wall and in situ formation of immune complexes, as shown in experimental models.

We report the case of a 4-year-old boy, diagnosed with atypical hemolytic uremic syndrome (HUS) due to a hybrid factor H. He progressed to end-stage renal failure despite plasmatherapy and underwent bilateral nephrectomy because of uncontrolled hypertension. Three days after, he had partial complex seizures with normal blood pressure, normal blood count and normal magnetic resonance imaging (MRI), which recurred 1 month later. Eight months later, he had a third episode of seizures, with hemoglobin of 10 g/dl without schizocytes, low haptoglobin of 0.18 g/l, and moderate thrombocytopenia (platelets 98 × 10(9)/l). He remained hypertensive and deeply confused for 2 days. The third MRI showed bilateral symmetrical hyperintensities of the cerebral pedunculas, caudate nuclei, putamens, thalami, hippocampi, and insulae suggesting thrombotic microangiopathy secondary to a relapse of HUS rather than reversible posterior leukoencephalopathy syndrome (RPLS), usually occipital and asymmetrical. Plasmatherapy led to a complete neurological recovery within 2 days although hypertension had remained uncontrolled. The fourth MRI 10 weeks after, on maintenance plasmatherapy, was normal and clinical examination remained normal, except for high blood pressure. In conclusion, brain MRI allows differentiating thrombotic microangiopathy lesions from RPLS in atypical HUS, which is crucial since lesions may be reversible with plasmatherapy.

We report 3 children with atypical hemolytic uremic syndrome associated with anti-complement factor H (CFH) autoantibodies who presented with sustained remission with low antibody titers and normal kidney function after plasma exchanges (PEs) and cyclophosphamide pulses. The 3 children initially presented with acute vomiting, fatigue, gross hematuria, hypertension, hemolytic anemia, thrombocytopenia, nephrotic syndrome, and acute kidney injury. C3 levels were normal in patients 1 and 3 and low in patient 2 (0.376 mg/mL [0.376 g/L]). CFH antibody titers were increased (15,000 to32,000 arbitrary units [AU]). Patient 1, an 11-year-old boy, was treated with 12 PEs, leading to a decrease in CFH antibody titer (to 800 AU). A first relapse 1 month later was treated with 6 PEs and 4 rituximab infusions. A second relapse 3 months later required 5 PEs, and the patient received oral steroids (0.5 mg/d/kg body weight) and 5 cyclophosphamide pulses (1 g/1.73 m(2)), leading to sustained remission with normal kidney function (estimated glomerular filtration rate [eGFR], 120 mL/min/1.73 m(2) [2.0 mL/s/1.73 m(2)]) and a stable decrease in CFH antibody titer (to 2,000 AU) 3 years later. Patient 2, a 5-year-old boy, required dialysis therapy for 2 weeks. He received 3 plasma infusions without remission. Six PEs associated with 2 cyclophosphamide pulses (0.5 g/1.73 m(2)) and steroids (1 mg/d/kg body weight) led to rapid remission, with eGFR of 107 mL/min/1.73 m(2) [1.78 mL/s/1.73 m(2)] and a prolonged decrease in CFH antibody titer after 15 months (1,300 AU). Patient 3, a 16-month-old boy, was treated with oral steroids (1 mg/d/kg body weight), 2 PEs, and 2 cyclophosphamide pulses (0.5 g/1.73 m(2)), resulting in a stable decrease in CFH antibody titer to 276 AU. Kidney function quickly normalized (eGFR, 110 mL/min/1.73 m(2) [1.83 mL/s/1.73 m(2)]) and has remained normal after 14 months. All 3 patients show a homozygous deletion mutation of the CFHR1 and CFHR3 genes. Cyclophosphamide pulses with PE may lead to a prolonged decrease in CFH antibody titers and a favorable outcome of atypical hemolytic uremic syndrome and kidney function.

PurposeIfosfamide is widely used in pediatric oncology but its nephrotoxicity may become a significant issue in survivors. This study is aimed at evaluating the incidence of late renal toxicity of ifosfamide and its risk factors.Patients and MethodsOf the 183 patients prospectively investigated for renal function, 77 treated for rhabdomyosarcoma, 39 for other soft tissue sarcoma, 39 for Ewing's sarcoma, and 28 for osteosarcoma were investigated at least 5 years after treatment. No patients had received cisplatin and/or carboplatin. Glomerular and tubular functions were graded according to the Skinner system.ResultsThe median dose of ifosfamide was 54 g/m2(range, 18 to 117 g/m2). After a median follow-up of 10 years, 89.5% of patients had normal tubular function, and 78.5% had normal glomerular function rate (GFR). Serum bicarbonate and calcium were normal in all patients. Hypomagnesemia was observed in 1.2% and hypophosphatemia in 1%. The tubular threshold for phosphate was reduced in 24% of the patients (grade 1 in 15%, grade 2 in 8%, and grade 3 in 0.5%). Glycosuria was detected in 37% of the patients but was more than 0.5 g/24 hours in only 5%. Proteinuria was observed in 12%. Ifosfamide dose and interval from therapy to investigations were predictors of tubulopathy in univariate and multivariate analysis. In a multivariate analysis, an older age at diagnosis and the length of interval since treatment had independent impacts on the risk of abnormal GFR.ConclusionRenal toxicity is moderate with a moderate dose of ifosfamide. However, since it can be permanent and can get worse with time, repeated long-term evaluations are important, and this risk should be balanced against efficacy.