A randomized clinical trial indicates that levamisole increases the time to relapse in children with steroid-sensitive idiopathic nephrotic syndrome.

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.

The glomerular permeability factors in idiopathic nephrotic syndrome.

It is currently postulated that steroid-sensitive idiopathic nephrotic syndrome (SSNS) and steroid-resistant idiopathic nephrotic syndrome (SRNS), which are not related to the mutation of a gene coding for podocyte structures or for glomerular basement membrane proteins, result from a circulating factor affecting podocyte shape and function. T lymphocytes have for a long time been suspected to be involved in the pathophysiology of these diseases. The successful treatment of steroid-dependant nephrotic syndrome with rituximab suggests a potential role for B lymphocytes. Clinical and experimental data indicate roles for cytokines IL-13, TNFα, circulating cardiotrophin-like cytokine factor 1 (member of the IL-6 family), circulating hemopexin, radical oxygen species, and the soluble urokinase-type plasminogen activator receptor (suPAR) in the development of nephrotic syndrome. Podocyte metabolism modifications-leading to the overexpression of the podocyte B7-1antigen (CD 80), hypoactivity of the podocyte enzyme sphingomyelin phosphodiesterase acid-like 3 b (SMPDL3b), and to the podocyte production of a hyposialylated form of the angiopoietin-like 4 (Angptl4)-are mechanisms possibly involved in the changes in the podocyte cytoskeleton leading to SSNS and or SRNS. Different multifactorial pathophysiological mechanisms can be advocated for SSNS and SRNS. The present paper reviews the experimental and clinical data upon which the different hypotheses are based and reports their possible clinical applications.

The difficulty in considering modifiable pathology risk factors in children with IgA nephropathy: crescents and timing of renal biopsy.

The need for an early diagnosis of primary IgA nephropathy (IgAN) is particularly felt in children since they have a long life expectancy. However, IgAN has a slowly progressive course and renal function can even remain unchanged for decades. The long-term predictive value of modifiable risk factors, such as proteinuria and proliferative/inflammatory lesion at renal biopsy, remains unknown. Interest has focused on crescents, which represent a clear risk factor for renal vasculitides. A number of rare cases of extracapillary IgAN involving >40 % of glomeruli have been reported, but in most cases of IgAN crescents involve <10 % of glomeruli. The long-term effect of small non-circumferential crescents detected by chance or without a clinical picture of progressive IgAN is still unknown. The Oxford study failed to find a predictive value of crescents in either children or adults, and these results were confirmed by the recent VALIGA study on 1,147 patients with IgAN (174 children). A recent study reports a correlation between the time elapsed from the diagnosis of urinary abnormalities and renal biopsy which suggests that crescents are associated with disease onset and then likely undergo a healing process into sclerotic lesions, which are commonly detected in biopsies performed years after onset. The authors of this study propose that primary IgAN may have similarities with Henoch-Schoenlein purpura nephritis, which presents with acute glomerular damage, mesangial proliferation, endocapillary leucocyte infiltration and crescent formations, and that these lesions can undergo resolution with sclerotic healing. This hypothesis is highly suggestive of the silent progression of several cases of IgAN without clear clinical changes, stressing once more the need for a combined clinical and pathological evaluation of children with IgAN that considers both the underlying pathogenetic event and its possible evolution.

Prevention of steroid-induced low bone mineral density in children with renal diseases: a systematic review.

BACKGROUND: Children with renal diseases who are treated with glucocorticoids are at increased risk of developing osteoporosis and fractures. However, there is no common strategy for prevention of corticosteroid-induced osteoporosis. The present systematic review was performed to determine whether prevention of bone loss by calcium (Ca), vitamin D (vit D) and/or bisphosphonates is justified, safe and efficacious in children treated with steroids for various renal diseases. DATA SOURCES: Medline, Embase, Central were searched from 1961 up to 2012. Randomized controlled trials (RCTs) and observational studies concerning children ≤18 years with renal diseases requiring steroids were included. RESULTS: The search strategy retrieved 2482 studies. Four RCTs including 166 patients and one observational study including 100 children met our eligibility criteria. One RCT and the observational study concerned treatment with Ca/vit D, one RCT with bisphosphonates and two RCTs with a combination of both therapies. All described a significant improvement in bone mineral density (BMD) in the treatment group compared with the control group. CONCLUSIONS:  Ca combined with vit D is recommended to prevent bone disease in children with renal diseases treated with steroids. Because of side effects, bisphosphonates should be reserved for the treatment of severe osteoporosis when Ca and/or vit D supplementation has failed.

Atypical hemolytic uremic syndrome in children: complement mutations and clinical characteristics.

BACKGROUND: Mutations in complement factor H (CFH), factor I (CFI), factor B (CFB), thrombomodulin (THBD), C3 and membrane cofactor protein (MCP), and autoantibodies against factor H (αFH) with or without a homozygous deletion in CFH-related protein 1 and 3 (∆CFHR1/3) predispose development of atypical hemolytic uremic syndrome (aHUS). METHODS: Different mutations in genes encoding complement proteins in 45 pediatric aHUS patients were retrospectively linked with clinical features, treatment, and outcome. RESULTS: In 47% of the study participants, potentially pathogenic genetic anomalies were found (5xCFH, 4xMCP, and 4xC3, 3xCFI, 2xCFB, 6xαFH, of which five had ∆CFHR1/3); four patients carried combined genetic defects or a mutation, together with αFH. In the majority (87%), disease onset was preceeded by a triggering event; in 25% of cases diarrhea was the presenting symptom. More than 50% had normal serum C3 levels at presentation. Relapses were seen in half of the patients, and there was renal graft failure in all except one case following transplant. CONCLUSIONS: Performing adequate DNA analysis is essential for treatment and positive outcome in children with aHUS. The impact of intensive initial therapy and renal replacement therapy, as well as the high risk of recurrence of aHUS in renal transplant, warrants further understanding of the pathogenesis, which will lead to better treatment options.

Maintenance of kidney function following treatment with eculizumab and discontinuation of plasma exchange after a third kidney transplant for atypical hemolytic uremic syndrome associated with a CFH mutation.

Kidney transplant in patients with atypical hemolytic uremic syndrome (aHUS) is associated with a poor outcome because of recurrent disease, especially in patients known to have a factor H mutation. Long-term prophylactic plasma exchange and combined liver-kidney transplant have prevented graft loss caused by recurrence. However, the mortality associated with liver transplant is not negligible, and prophylactic plasma exchange requires permanent vascular access and regular hospitalization and exposes the patient to potential allergic reactions to plasma. Eculizumab is a high-affinity humanized monoclonal antibody that binds to C5 and thus prevents generation of C5a and the membrane attack complex. We report the case of a 17-year-old girl with aHUS associated with a mutation in the gene for complement factor H (CFH; c.3572C>T, Ser1191Leu) who was highly dependent on plasma exchange. Because of severe allergic reactions to plasma after the third renal graft, eculizumab was introduced in place of plasma exchange without problems. This and other reports suggest that the promise of complement inhibitors in the management of aHUS is going to be fulfilled.

Non-atheromatous arterial stenoses in atypical haemolytic uraemic syndrome associated with complement dysregulation.

BACKGROUND: A child, who presented atypical haemolytic uraemic syndrome (aHUS) at the age of 1 month, developed cerebral ischaemic events at the age of 10 years. RESULTS: Stenoses of both carotid arteries, left subclavian and vertebral arteries, several intracranial, right humeral, several coronary, and all pulmonary arteries were demonstrated. At the age of 13 years, left subclavian and right cervical carotid arteries were occluded. Right carotid recanalization induced intracranial dissection and death. The child had a Lys350Asp factor B mutation. CONCLUSION: Arterial steno-occlusive lesions appear as potential complications of dysregulated complement activation in aHUS. Endovascular treatment should be considered cautiously in this setting.

Prophylactic plasma exchange in CD46-associated atypical haemolytic uremic syndrome.

Patients with atypical haemolytic uremic syndrome (aHUS) with a mutation in the gene encoding membrane cofactor protein (CD46) are known to have a better prognosis than those with mutations in factor H (CFH) or factor I (CFI), but a small number of the former still proceed to end-stage renal failure. Plasma therapy (PE) is the recommended approach to treat both acute episodes and prevent recurrences in aHUS, but studies have yet to show PE efficacy in aHUS associated with a CD46 mutation. The factors determining failure to treatment are not clear and may be related to the mutation involved or to insufficient treatment. Our experience of PE in a family of three sisters with CFH-associated aHUS suggests that intensive and prophylactic PE allows renal function to be maintained in both native kidneys and allografts. The success of this strategy has led us to use it in all cases of aHUS. Here, we describe the effect of this strategy in a child with aHUS and a CD46 mutation. The initial episode was treated with daily PE, resulting in the recovery of renal function. However, over the next 4 years, there was a progressive decline in renal function to end-stage renal failure, with evidence of an on-going thrombotic microangiopathy despite continuous prophylactic PE. Prophylactic PE does not influence the natural course of aHUS and CD46 mutation.

Pulmonary complaints and lung function after pediatric kidney transplantation.

Recently four of 38 children with a kidney transplant were diagnosed with bronchiectasis. The aim of the current study was to identify patients with increased risk for pulmonary damage. In this cross-sectional observational study, children with a functioning kidney graft in the Netherlands and Antwerp, Belgium, were screened with the use of a symptom checklist and spirometry. Maximum score for upper airway complaints was 21 (normal: <8), for lower airway complaints 28 (<10). Results of FVC, FEV(1) and MEF(25) were expressed as percentage predicted for height and sex. One hundred and thirty-five patients completed the interview (122) and/or spirometry (103); 91 did both. Lower airways symptoms were above acceptable levels in 18 (14%) patients. Forty-nine patients (48%) had an abnormal lung function test: in 12 concerning FVC%, in 11 FEV(1)%, in 24 MEF(25)% and in 36 FEV(1)/FVC. Of correlations between symptomatology or spirometry data, and clinical parameters, only that between GFR and MEF(25)% was statistically significant. Children with a kidney transplant are at increased risk for obstructive lung disease. We recommend to monitor lung function during the follow-up after renal transplantation.

Maintenance immunosuppression with mycophenolate mofetil and corticosteroids in pediatric kidney transplantation: temporary benefit but not without risk.

BACKGROUND: Aiming at reducing cyclosporine toxicity, we investigated safety and efficacy of mycophenolate mofetil (MMF) as an immunosuppressive drug in pediatric kidney transplantation compared with cyclosporine (CsA), both in combination with corticosteroids. METHODS: One year after kidney transplantation, children on triple immunosuppression, having experienced no more than one, steroid-sensitive, acute rejection episode, were randomized to withdrawal of either CsA or MMF and were followed for 2 yr. RESULTS: In each group, two patients had an acute rejection episode during withdrawal. Treatment failure occurred in 3 of 21 MMF and 5 of 23 CsA patients. Final analysis was for 18 patients in either group. A larger than 10 mL/min 1.73 m decrease in glomerular filtration rate was observed in more patients on CsA than on MMF (73% vs. 29%, P=0.019). No differences in blood pressure or nightly decrease of blood pressure were noted. Hypercholesterolism improved in the MMF (-16%), but not the CsA group (+5%, P<0.05), over the first, but not over both study years. Differences in triglycerid levels between groups were not shown. At study end, MMF patients tended to have lower hemoglobin levels than patients on CsA. Two MMF patients experienced a first acute rejection episode during the second study year, resulting in chronic transplant glomerulopathy with graft loss in one and deterioration of kidney function in the other. CONCLUSION: In pediatric kidney transplantation, maintenance immunosuppression with MMF together with corticosteroids has short-term benefits for kidney function and lipid pattern compared with CsA but is not without risk of complications.

Henoch Schonlein purpura in children: an epidemiological study among Dutch paediatricians on incidence and diagnostic criteria.

BACKGROUND: The aim of the present study on the occurrence of Henoch-Schönlein Purpura (HSP) in Dutch children is to give some insight into the epidemiology of HSP in the Netherlands, to record the diagnostic criteria used by Dutch paediatricians and to evaluate the accuracy of the latter using the presence of IgA in the skin when biopsies are available. METHODS: Each month in 2004, all Dutch paediatricians received an electronic card asking them to mention new diagnosed HSP. Paediatricians reporting one or more new patients with HSP were sent a list of questions concerning various parameters. RESULTS: 232 patients from 0 to 18 years of age (6.1/10(5)) were reported as having contracted HSP in 2004. 29% presented renal symptoms. In accordance with the classification criteria of the American College of Rheumatology, 80% of paediatricians consider that isolated purpura (without haematological abnormalities) is sufficient to allow the diagnosis of HSP in children. From the 17 skin biopsies performed, only 9 (53%) presented IgA deposits. The follow-up duration, considered as necessary, was longer in case of renal symptoms at presentation. However, 45% of patients without renal symptoms would be followed for more than 1 year. CONCLUSION: Considering the recent (2006) EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides, HSP should have been diagnosed in only 160 of the 179 patients of our study. The use of isolated non-thrombocytopenic purpura as the only criterion to diagnose HSP in children might therefore lead to over diagnosis and unnecessary follow-up.

Takayasu arteritis in children: preliminary experience with cyclophosphamide induction and corticosteroids followed by methotrexate.

OBJECTIVE: To review the results of our treatment protocol in the last 7 years. STUDY DESIGN: Six patients (4 girls, 2 boys) with an age range of 12 to 17 years were diagnosed with Takayasu arteritis (TA) during this period. Patients were allocated to receive (1) oral steroids and methotrexate (MTX) (12.5 mg/m(2)/week) if they had disease limited to one side of the diaphragm only without pulmonary disease involvement (two patients); and (2) oral steroids and oral cyclophosphamide (CYC) (maximum total dose 150 mg/kg) followed by oral MTX for maintenance as above if the disease was more widespread (four patients). RESULTS: One patient died of pulmonary vasculitis during the first month of therapy. The remaining three patients with involvement of both the thoracic and abdominal aorta and branches received the second protocol for 12 to 18 months. All entered remission. Aortic bypass, aortorenal bypass, balloon dilatation, and unilateral nephrectomy were performed in these patients. CONCLUSIONS: The presented single-center experience suggests that CYC induction and corticosteroids followed by MTX is an effective and safe treatment for childhood TA.

Complement factor H-associated atypical hemolytic uremic syndrome in monozygotic twins: concordant presentation, discordant response to treatment.

Hemolytic uremic syndrome not associated with diarrhea (diarrhea negative, atypical) is less common than the diarrhea-positive typical form, but frequently results in end-stage renal failure. Although there are anecdotal cases of successful treatment with fresh frozen plasma alone, the value of this treatment compared with plasma exchange (PE) is difficult to assess. We describe monozygotic female twins who presented at 5 years of age with factor H-related (c.3572 > T; Ser1191Leu) atypical hemolytic uremic syndrome within months of each other. In the first twin to present, 10 sessions of PE with fresh frozen plasma replacement (40 mL/kg) resulted in resolution of hemolysis and improvement in plasma creatinine level (1.9 to 1.5 mg/dL [166 to 137 micromol/L]). Subsequently, 17 infusions of fresh frozen plasma were administered during a 4-month period for recurrent thrombocytopenia. However, within 4 months, plasma creatinine level increased to 5.1 mg/dL (450 micromol/L), necessitating peritoneal dialysis. When the second twin presented with the same disease, an extended PE regimen was instituted. After 10 daily sessions, PE was continued once every 2 weeks. Two recurrences were treated successfully with daily PE for 7 days. After 44 months of follow-up, kidney function is normal (plasma creatinine, 0.6 mg/dL [53 micromol/L]; creatinine clearance, 119 mL/min/1.73 m2 [1.98 mL/s/1.73 m2]) on maintenance PE therapy. In conclusion, the response to treatment of these monozygotic twins suggests that long-term PE may have benefits over plasma infusion alone.

Posttransplantation cytomegalovirus-induced recurrence of atypical hemolytic uremic syndrome associated with a factor H mutation: successful treatment with intensive plasma exchanges and ganciclovir.

Atypical hemolytic uremic syndrome (HUS) can recur after renal transplantation and often leads to graft loss. In some series of familial HUS, the risk of early graft loss due to recurrence of HUS approaches 100% despite any therapy. This led some authors to claim that kidney transplantation is contraindicated in those patients. The authors describe an 8-year-old girl with end-stage renal failure owing to familial atypical HUS with a factor H mutation who underwent successful transplantation using continuous prophylactic plasma exchange (PE). Twenty-four months after transplantation, plasma creatinine level is 1.2 mg/dL (106 micromol/L) despite 2 recurrences of HUS contemporaneous to 2 cytomegalovirus infections, which resolved with PE intensification and ganciclovir. This strongly suggests that cytomegalovirus infection may trigger posttransplant recurrent HUS. The feasibility of kidney transplantation in case of atypical HUS related to factor H mutation using continuous prophylactic PE intensified during relapses should be confirmed in prospective studies.