Sirolimus plus prednisone for Erdheim-Chester disease: an open-label trial.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, to whose pathogenesis neoplastic and immune-mediated mechanisms contribute. Mammalian target of rapamycin (mTOR)-inhibitors have antiproliferative and immunosuppressive properties. We tested in this study, the efficacy and safety of the mTOR-inhibitor sirolimus (SRL) plus prednisone (PDN) in patients with ECD. PDN was given initially at 0.75 mg/kg per day, tapered to 5 to 2.5 mg per day by month 6. Target SRL blood levels were 8 to 12 ng/mL. Treatment was continued for at least 24 months in patients who showed disease stabilization or improvement. Ten patients were enrolled; 8 achieved stable disease or objective responses, whereas 2 had disease progression. Responses were mainly observed at the following sites: retroperitoneum in 5/8 patients (62.5%), cardiovascular in 3/4 (75%), bone in 3/9 (33.3%), and central nervous system (CNS) in 1/3 (33.3%). The median follow-up was 29 months (interquartile range, 16.5-74.5); 2 patients died of progressive CNS disease and small-cell lung cancer, respectively. Treatment-related toxicity was mild. Using immunohistochemistry and immunofluorescence on ECD biopsies, we detected expression in foamy histiocytes of the phosphorylated forms of mTOR and of its downstream kinase p70S6K, which indicated mTOR pathway activation. In conclusion, SRL and PDN often induce objective responses or disease stabilization and may represent a valid treatment of ECD. The trial is registered at the Australia-New Zealand Clinical Trial Registry as #ACTRN12613001321730.

Recurrent exercise-induced acute renal failure in a young Pakistani man with severe renal hypouricemia and SLC2A9 compound heterozygosity.

BACKGROUND: Familial renal hypouricemia (RHUC) is a hereditary disease characterized by hypouricemia, high renal fractional excretion of uric acid (FE-UA) and can be complicated by acute kidney failure and nephrolithiasis. Loss-of-function mutations in the SLC22A12 gene cause renal hypouricemia type 1 (RHUC1), whereas renal hypouricemia type 2 (RHUC2) is caused by mutations in the SLC2A9 gene. CASE PRESENTATION: We describe a 24-year-old Pakistani man who was admitted twice to our hospital for severe exercise-induced acute renal failure (EIARF), abdominal pain and fever; he had very low serum UA levels (0.2 mg/dl the first time and 0.09 mg/dl the second time) and high FE-UA (200% and 732% respectively), suggestive of RHUC. Mutational analyses of both urate transporters revealed a new compound heterozygosity for two distinct missense mutations in the SLC2A9 gene: p.Arg380Trp, already identified in heterozygosity, and p.Gly216Arg, previously found in homozygosity or compound heterozygosity in some RHUC2 patients. Compared with previously reported patients harbouring these mutations, our proband showed the highest FE-UA levels, suggesting that the combination of p.Arg380Trp and p.Gly216Arg mutations most severely affects the renal handling of UA. CONCLUSIONS: The clinical and molecular findings from this patient and a review of the literature provide new insights into the genotype-phenotype correlation of this disorder, supporting the evidence of an autosomal recessive inheritance pattern for RHUC2. Further investigations into the functional properties of GLUT9, URAT1 and other urate transporters are required to assess their potential research and clinical implications.

Grange syndrome: an identifiable cause of stroke in young adults.

Grange syndrome is a disorder characterized by arterial occlusive disease, hypertension, congenital cardiac defects, bone fragility, brachysyndactyly, and learning disabilities. It was first described in four members of the same family and in two sporadic cases thereafter, suggesting the possibility of various patterns of inheritance. We report on the case of an 18-year-old female presenting with subarachnoid hemorrhage due to the rupture of a basilar artery aneurysm, and with distinctive systemic features including extensive vasculopathy, facial dysmorphisms and brachysyndactyly, consistent with the diagnosis of Grange syndrome. Although rare and not fully characterized, Grange syndrome should be included in the differential diagnosis of stroke at young age.

Effect of post-dilutional on-line haemodiafiltration on serum calcium, phosphate and parathyroid hormone concentrations in uraemic patients.

BACKGROUND: Strict control of serum calcium and phosphate concentrations is paramount to prevent secondary hyperparathyroidism in haemodialysis (HD) patients. Standard intermittent low-flux HD (Lf-HD) is not sufficient to reach this goal. The aim of this study was to evaluate the effect of on-line haemodiafiltration (Ol-HDF) on serum calcium (sCa), phosphate (sPO4) and parathyroid hormone (PTHint) concentrations. METHODS: Of the 220 patients screened, 65 met the inclusion criteria for the study; 30 of whom agreed to participate in the study (Study group), the others were considered as the control group (Controls). Protocol for Study the group consisted of 6 months conventional Lf-HD (Period 1) and 6 months of post-dilutional Ol-HDF (Period 2). Controls continued their usual Lf-HD and were followed for 12 months. The main variables evaluated at the start and at the end of each period were sCa, sPO(4) and PTHint. RESULTS: The switchover from Lf-HD to Ol-HDF resulted in a significant reduction of sPO4 (from 5.1 ± 1.0 to 4.0 ± 0.7; P < 0.0001) and PTHint concentrations (from 307 ± 167 to 194 ± 98; P < 0.0001), no significant changes were found in both sCa concentrations (from 9.1 ± 0.7 to 8.9 ± 0.6) and phosphate binder dose. Kt/Vurea increased significantly, and beta(2) microglobulin concentrations decreased significantly. In the Controls, no significant variations of the same variables were observed over time, except for a significant increase in sevelamer intake. CONCLUSION: This study supports the idea that Ol-HDF could be better than Lf-HD in controlling mineral metabolism in HD patients.

Prognostic Factors and Long-Term Outcome with ANCA-Associated Kidney Vasculitis in Childhood.

BACKGROUND AND OBJECTIVES: ANCA-associated vasculitis is extremely rare in children. We report the clinicopathologic features, long-term outcomes, and prognostic factors of a large pediatric cohort of patients with ANCA-associated kidney vasculitis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective study included 85 consecutive patients with kidney biopsy specimen-proven ANCA-associated vasculitis from tertiary referral centers in Italy and Canada. Kidney biopsy specimens were categorized as focal, crescentic, sclerotic, or mixed, according to the Berden classification. The prognostic significance of baseline clinical, laboratory, and histologic findings was analyzed with respect to kidney failure or CKD stage 3-5/kidney failure. RESULTS: A total of 53 patients had microscopic polyangiitis (62%), and 32 had granulomatosis with polyangiitis (38%). Rapidly progressive GN was the most frequent presentation (39%); a third of the patients also had nephrotic-range proteinuria. Kidney biopsy specimens were classified as focal in 21% of the patients, crescentic in 51%, sclerotic in 15%, and mixed in 13%. Remission-induction therapies included cyclophosphamide in 78% of patients. A total of 25 patients (29%) reached kidney failure. The median (interquartile range) time to kidney failure or last follow-up was 35 (6-89) months in the whole cohort, and 73 (24-109) months among the patients who did not reach this outcome. Patients whose biopsy specimens showed sclerotic histology had significantly shorter kidney survival (hazard ratio, 11.80; 95% confidence interval, 2.49 to 55.99) and survival free of CKD stage 3-5 (hazard ratio, 8.88; 95% confidence interval, 2.43 to 32.48), as compared with those with focal/mixed histology. Baseline eGFR, low serum albumin, hypertension, central nervous system complications, and sclerotic histology, which reflected severe kidney involvement, were associated with both kidney failure and CKD stage 3-5/kidney failure at unadjusted analysis; no independent prognostic factors emerged at multivariable analysis. CONCLUSIONS: Children with ANCA-associated kidney vasculitis often have aggressive presentation; a third of such children progress to kidney failure and this usually occurs early during follow-up. A severe clinical presentation is associated with the development of CKD or kidney failure.

Cholesterol crystal embolism (atheroembolism).

Cholesterol crystal embolism, known as atheroembolic disease, is caused by showers of cholesterol crystals from an atherosclerotic plaque that occludes small arteries. Embolization can occur spontaneously or as an iatrogenic complication from an invasive vascular procedure (angiography or vascular surgery) and after anticoagulant therapy. The atheroembolism can give rise to different degrees of renal impairment. Some patients show a moderate loss of renal function, others severe renal failure requiring dialysis. Renal outcome can be variable: some patients deteriorate or remain on dialysis, some improve and some remain with chronic renal impairment. Clinically, three types of atheroembolic renal disease have been described: acute, subacute or chronic. More frequently a progressive loss of renal function occurs over weeks. Atheroembolization can involve the skin, gastrointestinal system and central nervous system. The diagnosis is difficult and controversial for the protean extrarenal manifestations. In the past, the diagnosis was often made post-mortem. In the last 10 yrs, awareness of atheroembolic renal disease has improved. The correct diagnosis requires the clinician to be alert. The typical patient is a white male aged >60 yrs with a history of hypertension, smoking and arterial disease. The presence of a classic triad (precipitating event, renal failure and peripheral cholesterol crystal embolization) suggests the diagnosis. This can be confirmed by a biopsy of the target organs. A specific treatment is lacking; however, it is an important diagnosis to make because an aggressive therapeutic approach can be associated with a more favorable clinical outcome.