Summary Background Most data for treatment of dermatomyositis and juvenile dermatomyositis are from anecdotal, non-randomised case series. We aimed to compare, in a randomised trial, the efficacy and ...safety of prednisone alone with that of prednisone plus either methotrexate or ciclosporin in children with new-onset juvenile dermatomyositis. Methods We did a randomised trial at 54 centres in 22 countries. We enrolled patients aged 18 years or younger with new-onset juvenile dermatomyositis who had received no previous treatment and did not have cutaneous or gastrointestinal ulceration. We randomly allocated 139 patients via a computer-based system to prednisone alone or in combination with either ciclosporin or methotrexate. We did not mask patients or investigators to treatment assignments. Our primary outcomes were the proportion of patients achieving a juvenile dermatomyositis PRINTO 20 level of improvement (20% improvement in three of six core set variables at 6 months), time to clinical remission, and time to treatment failure. We compared the three treatment groups with the Kruskal-Wallis test and Friedman's test, and we analysed survival with Kaplan-Meier curves and the log-rank test. Analysis was by intention to treat. Here, we present results after at least 2 years of treatment (induction and maintenance phases). This trial is registered with ClinicalTrials.gov , number NCT00323960. Findings Between May 31, 2006, and Nov 12, 2010, 47 patients were randomly assigned prednisone alone, 46 were allocated prednisone plus ciclosporin, and 46 were randomised prednisone plus methotrexate. Median duration of follow-up was 35·5 months. At month 6, 24 (51%) of 47 patients assigned prednisone, 32 (70%) of 46 allocated prednisone plus ciclosporin, and 33 (72%) of 46 administered prednisone plus methotrexate achieved a juvenile dermatomyositis PRINTO 20 improvement (p=0·0228). Median time to clinical remission was 41·9 months in patients assigned prednisone plus methotrexate but was not observable in the other two treatment groups (2·45 fold 95% CI 1·2–5·0 increase with prednisone plus methotrexate; p=0·012). Median time to treatment failure was 16·7 months in patients allocated prednisone, 53·3 months in those assigned prednisone plus ciclosporin, but was not observable in patients randomised to prednisone plus methotrexate (1·95 fold 95% CI 1·20–3·15 increase with prednisone; p=0·009). Median time to prednisone discontinuation was 35·8 months with prednisone alone compared with 29·4–29·7 months in the combination groups (p=0·002). A significantly greater proportion of patients assigned prednisone plus ciclosporin had adverse events, affecting the skin and subcutaneous tissues, gastrointestinal system, and general disorders. Infections and infestations were significantly increased in patients assigned prednisone plus ciclosporin and prednisone plus methotrexate. No patients died during the study. Interpretation Combined treatment with prednisone and either ciclosporin or methotrexate was more effective than prednisone alone. The safety profile and steroid-sparing effect favoured the combination of prednisone plus methotrexate. Funding Italian Agency of Drug Evaluation, Istituto Giannina Gaslini (Genoa, Italy), Myositis Association (USA).
Mutations in factor H (CFH), factor I (IF), and membrane cofactor protein (MCP) genes have been described as risk factors for atypical hemolytic uremic syndrome (aHUS). This study analyzed the impact ...of complement mutations on the outcome of 46 children with aHUS. A total of 52% of patients had mutations in one or two of known susceptibility factors (22, 13, and 15% of patients with CFH, IF, or MCP mutations, respectively; 2% with CFH+IF mutations). Age <3 mo at onset seems to be characteristic of CFH and IF mutation-associated aHUS. The most severe prognosis was in the CFH mutation group, 60% of whom reached ESRD or died within <1 yr. Only 30% of CFH mutations were localized in SCR20. MCP mutation-associated HUS has a relapsing course, but none of the children reached ESRD at 1 yr. Half of patients with IF mutation had a rapid evolution to ESRD, and half recovered. Plasmatherapy seemed to have a beneficial effect in one third of patients from all groups except for the MCP mutation group. Only eight (33%) of 24 kidney transplantations that were performed in 15 patients were successful. Graft failures were due to early graft thrombosis (50%) or HUS recurrence. In conclusion, outcome of HUS in patients with CFH mutation is catastrophic, and posttransplantation outcome is poor in all groups except for the MCP mutation group. New therapies are urgently needed, and further research should elucidate the unexplained HUS group.
Observations of a large Dent disease cohort Blanchard, Anne; Curis, Emmanuel; Guyon-Roger, Tiphaine ...
Kidney international,
August 2016, 2016-08-00, 20160801, Letnik:
90, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Dent disease classically combines low-molecular-weight proteinuria, hypercalciuria with nephrocalcinosis, and renal failure. Nephrotic range proteinuria, normal calciuria, and hypokalemia have been ...rarely reported. It is unknown whether the changes in phenotype observed over time are explained by a decrease in glomerular filtration rate (GFR) or whether there is any phenotype-genotype relationship. To answer this we retrospectively analyzed data from 109 male patients with CLCN5 mutations (Dent-1) and 9 patients with mutation of the OCRL gene (Dent-2). In Dent-1 disease, the estimated GFR decreased with age, by 1.0 to 1.6 ml/min per 1.73 m2/yr in the absence and presence of nephrocalcinosis, respectively, with no significant difference. Median values of low-molecular-weight proteinuria were in the nephrotic range and remained at the same level even in late renal disease. End-stage renal disease occurred in 12 patients, at a median age of 40 years. Hypercalciuria decreased with glomerular filtration and was absent in 40% of the patients under 30 and 85% of those over the age of 30. Hypophosphatemia did not resolve with age and calcitriol concentrations were in the upper normal range. Kalemia decreased with age, with half of the patients over the age of 18 presenting with hypokalemia. Thus, no phenotype/genotype correlation was observed in this cohort of patients with Dent disease.
The goal of this study was to describe the spectrum of clinical signs of mevalonate kinase deficiency (MKD).
This was a retrospective French and Belgian study of patients identified on the basis of ...MKD gene mutations.
Fifty patients from 38 different families were identified, including 1 asymptomatic patient. Symptoms began during the first 6 months of life in 30 patients (60%) and before the age of 5 years in 46 patients (92%). Symptoms consisted of febrile diarrhea and/or rash in 23 of 35 patients (66%). Febrile attacks were mostly associated with lymphadenopathy (71%), diarrhea (69%), joint pain (67%), skin lesions (67%), abdominal pain (63%), and splenomegaly (63%). In addition to febrile attacks, 27 patients presented with inflammatory bowel disease, erosive polyarthritis, Sjögren syndrome, and other chronic neurologic, renal, pulmonary, endocrine, cutaneous, hematologic, or ocular symptoms. Recurrent and/or severe infections were observed in 13 patients, hypogammaglobulinemia in 3 patients, and renal angiomyolipoma in 3 patients. Twenty-nine genomic mutations were identified; the p.Val377Ile mutation was the most frequently found (29 of 38 families). Three patients died of causes related to MKD. The disease remained highly active in 17 of the 31 surviving symptomatic patients followed up for >5 years, whereas disease activity decreased over time in the other 14 patients. Interleukin 1 antagonists were the most effective biological agents tested, leading to complete or partial remission in 9 of 11 patients.
MKD is not only an autoinflammatory syndrome but also a multisystemic inflammatory disorder, a possible immunodeficiency disorder, and a condition that predisposes patients to the development of renal angiomyolipoma.
Prenatal forms of autosomal dominant polycystic kidney disease (ADPKD) are rare but can be recurrent in some families, suggesting a common genetic modifying background. Few patients have been ...reported carrying, in addition to the familial mutation, variation(s) in polycystic kidney disease 1 (PKD1) or HNF1 homeobox B (HNF1B), inherited from the unaffected parent, or biallelic polycystic kidney and hepatic disease 1 (PKHD1) mutations. To assess the frequency of additional variations in PKD1, PKD2, HNF1B, and PKHD1 associated with the familial PKD mutation in early ADPKD, these four genes were screened in 42 patients with early ADPKD in 41 families. Two patients were associated with de novo PKD1 mutations. Forty patients occurred in 39 families with known ADPKD and were associated with PKD1 mutation in 36 families and with PKD2 mutation in two families (no mutation identified in one family). Additional PKD variation(s) (inherited from the unaffected parent when tested) were identified in 15 of 42 patients (37.2%), whereas these variations were observed in 25 of 174 (14.4%, P=0.001) patients with adult ADPKD. No HNF1B variations or PKHD1 biallelic mutations were identified. These results suggest that, at least in some patients, the severity of the cystic disease is inversely correlated with the level of polycystin 1 function.
Atypical hemolytic uremic syndrome (aHUS) is a disease of complement dysregulation. In approximately 50% of patients, mutations have been described in the genes encoding the complement regulators ...factor H, MCP, and factor I or the activator factor B. We report here mutations in the central component of the complement cascade, C3, in association with aHUS. We describe 9 novel C3 mutations in 14 aHUS patients with a persistently low serum C3 level. We have demonstrated that 5 of these mutations are gain-of-function and 2 are inactivating. This establishes C3 as a susceptibility factor for aHUS.
Chronic kidney disease (CKD) frequently leads to hyperphosphatemia and hyperparathyroidism, mineral bone disorder (CKD-MBD), ectopic calcifications and cardiovascular mortality. PTH activates the ...osteoanabolic Gαs/PKA and the Gαq/11/PKC pathways in osteoblasts, the specific impact of the latter in CKD-MBD is unknown. We generated osteoblast specific Gαq/11 knockout (KO) mice and established CKD-MBD by subtotal nephrectomy and dietary phosphate load. Bone morphology was assessed by micro-CT, osteoblast function by bone planar scintigraphy at week 10 and 22 and by histomorphometry. Osteoblasts isolated from Gαq/11 KO mice increased cAMP but not IP3 in response to PTH 1-34, demonstrating the specific KO of the PKC signaling pathway. Osteoblast specific Gαq/11 KO mice exhibited increased serum calcium and reduced bone cortical thickness and mineral density at 24 weeks. CKD Gαq/11 KO mice had similar bone morphology compared to WT, while CKD Gαq/11-KO on high phosphate diet developed decreased metaphyseal and diaphyseal cortical thickness and area, as well as a reduction in trabecular number. Gαq/11-KO increased bone scintigraphic tracer uptake at week 10 and mitigated tracer uptake in CKD mice at week 22. Histological bone parameters indicated similar trends. Gαq/11-KO in osteoblast modulates calcium homeostasis, bone formation rate, bone morphometry, and bone mineral density. In CKD and high dietary phosphate intake, osteoblast Gαq/11/PKC KO further aggravates mineral bone disease.
It is well known that the efficiency of peritoneal dialysis (PD) varies with the duration of the dwell and with the prescribed fill volume. Automated PD (APD) is classically given as a series of ...recurrent exchanges, each having the same dwell time and fill volume-that is, conventional APD (APD-C). We propose a new way of giving PD, using a modified version of APD-C. This method first uses a short dwell time with a small fill volume to promote ultrafiltration (UF) and subsequently uses a longer dwell time and a larger fill volume to promote removal of uremic toxins from the blood. We use the term "adapted APD" (APD-A) to describe this modified form of PD.
We designed a multicenter prospective randomized crossover trial to assess the impact of APD-A in comparison with APD-C on the efficacy of dialysis. The parameters investigated were overnight UF; weekly peritoneal Kt/V(urea); weekly peritoneal creatinine clearance corrected to 1.73 m(2) body surface area (K(creat)); and phosphate (PDR) and sodium dialytic removal (SDR) in millimoles per session, corrected for glucose absorption, which provides an estimate of metabolic cost. Blood pressure was also regularly monitored. Initially, 25 patients were identified for inclusion in the study. There were 6 withdrawals in total: 2 at enrolment, 1 at day 75 (transplantation), 2 at day 30 (catheter dysfunction), and 1 for drainage alarms. All patients received the same duration of overnight APD, using the same total volume of dialysate, with the same 1.5% glucose, lactate-buffered dialysate (Balance: Fresenius Medical Care, Bad Homburg, Germany).
Tolerance was good. Compared with APD-C, APD-A resulted in a significant enhancement of Kt/V(urea), K(creat), and PDR. The metabolic cost, in terms of glucose absorption, required to achieve dialytic capacity for urea, creatinine, and phosphate blood purification was significantly lower for APD-A than for APD-C, and UF increased during APD-A. With APD-A, each gram of glucose absorbed contributed to 18.25 ± 15.82 mL UF; in APD-C, each gram of glucose absorbed contributed to 15.79 ± 11.24 mL UF. However, that difference was not found to be significant (p=0.1218). The SDR was significantly higher with APD-A than with APD-C: 35.23 ± 52.00 mmol and 18.35 ± 48.68 mmol per session respectively (p<0.01). The mean blood pressure recorded at the end of each PD period (on day 45) was significantly lower when patients received APD-A than when they received APD-C.
Our study provides evidence that, compared with the uniform dwell times and fill volumes used throughout an APD-C dialysis session, the varying dwell times and fill volumes as described for an APD-A dialysis session result in improved dialysis efficiency in terms of UF, Kt/V(urea), K(creat), PDR, and SDR. Those results were achieved without incurring any extra financial costs and with a reduction in the metabolic cost (assessed using glucose absorption).
Background
We report the case of a patient with Shiga toxin (Stx)-associated hemolytic-uremic syndrome (HUS) (STEC-HUS) with a concomitant heterozygous mutation of the gene coding for complement ...Factor H (
CFH
).
Case diagnosis/treatment
An 18-month-old patient presented with hemolytic anemia and thrombotic microangiopathy in the context of acute gastroenteritis. While the patient did not show kidney or other organ failure, he had persistent hemolysis and complement 3 activation (low C3), leading to the decision to commence immunotherapy with eculizumab (Soliris®) together with transient antibiotic coverage and meningococcal vaccination. Patient outcome was favorable. Diagnostic work-up identified
Escherichia coli
-associated Type 2 Shiga toxin. Complement analysis showed a heterozygous mutation of the
CFH
gene (c.2103 G>A, p. Trp701X) resulting in a quantitative CFH defect.
Conclusions
We report a case of STEC-HUS with a quantitative CFH defect caused by a mutation of the
CFH
gene. To the best of our knowledge, very few cases of STEC-HUS with complement gene mutation have been reported, but none to date with a
CFH
mutation. We therefore suggest that complement analyses be performed in patients diagnosed with STEC-HUS in association with low C3 levels, especially in patients presenting with severe or unexpected clinical symptoms.
Classically, infants with mutations in NPHS1, which encodes nephrin, present with nephrotic syndrome within the first 3 mo of life (congenital nephrotic syndrome of the Finnish-type), and children ...with mutations in NPHS2, which encodes podocin, present later with steroid-resistant nephrotic syndrome. Recently, however, NPHS2 mutations have been identified in children with congenital nephrotic syndrome. Whether NPHS1 mutations similarly account for some cases of childhood steroid-resistant nephrotic syndrome is unknown. In this study, 160 patients who belonged to 142 unrelated families and presented with nephrotic syndrome at least 3 mo after birth were screened for NPHS1 variants once mutations in NPHS2 had been excluded. Compound heterozygous NPHS1 mutations were identified in one familial case and nine sporadic cases. Mutations included protein-truncating nonsense and frameshift mutations, as well as splice-site and missense variants. Mutations were classified as "severe" or "mild" using prediction algorithms and functional assays. Most missense variants trafficked normally to the plasma membrane and maintained the ability to form nephrin homodimers and to heterodimerize with NEPH1, suggesting retained function. The presence of at least one "mild" mutation in these patients likely explains the later onset and milder course of disease. These results broaden the spectrum of renal disease related to nephrin mutations.
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