Marta Calatroni

ANCA-associated vasculitis in childhood: recent advances

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides are rare systemic diseases that usually occur in adulthood. They comprise granulomatosis with polyangiitis (GPA, Wegener’s), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome). Their clinical presentation is often heterogeneous, with frequent involvement of the respiratory tract, the kidney, the skin and the joints. ANCA-associated vasculitis is rare in childhood but North-American and European cohort studies performed during the last decade have clarified their phenotype, patterns of renal involvement and their prognostic implications, and outcome. Herein, we review the main clinical and therapeutic aspects of childhood-onset ANCA-associated vasculitis, and provide preliminary data on demographic characteristics and organ manifestations of an Italian multicentre cohort.

Renal involvement in mushroom poisoning: The case of Orellanus syndrome

Although mushroom poisoning is a rare cause of acute renal injury, in some cases it may lead to the development of a severe and irreversible renal failure. Orellanus syndrome is the most important example of organic renal damage related to mushroom consumption. It is caused by the ingestion of orellanine, the main toxin of different types of Cortinarius mushrooms (Cortinarius speciosissimus, C. orellanus, C. orellanoides, etc.), and it is characterized by progressive clinical phases with a predominant kidney involvement, finally requiring renal replacement therapy in about 10% of cases. Renal damage is often late and associated with a histological picture of interstitial nephritis. Diagnosis is essentially clinical and no specific therapy has been shown to be effective in preventing and treating renal damage. Here, we describe the case of a patient with mixed wild mushroom poisoning, presenting the typical clinical signs and course of the Orellanus syndrome. This case offers us the opportunity to review the main clinical features of this severe and little‐known intoxication.

Severe cyclophosphamide-related hyponatremia in a patient with acute glomerulonephritis

Cyclophosphamide is frequently used to treat cancer, autoimmune and renal diseases, such as rapidly progressive glomerulonephritis. Its side effects are well-known, including bone marrow depression, infections, alopecia, sterility, bladder malignancy and hemorrhagic cystitis. Moreover, in some cases cyclophosphamide use has been related to the onset of hyponatremia, by development of a syndrome of inappropriate antidiuresis. Indeed, severe hyponatremia has been previously reported in patients treated with high-dose or moderate-dose of intravenous cyclophosphamide, while only few cases have been reported in patients treated with low dose. Here, we discuss a case of a syndrome of inappropriate antidiuresis followed to a single low-dose of intravenous cyclophosphamide in a patient with a histological diagnosis of acute glomerulonephritis, presenting as acute kidney injury. After cyclophosphamide administration (500 mg IV), while renal function gradually improved, the patient developed confusion and headache. Laboratory examinations showed serum sodium concentration dropped to 122 mmol per liter associated with an elevated urinary osmolality of 199 mOsm/kg, while common causes of acute hyponatremia were excluded. He was successfully treated with water restriction and hypertonic saline solution infusion with the resolution of the electrolyte disorder. This case, together with the previous ones already reported, highlights that electrolyte profile should be strictly monitored in patients undergoing cyclophosphamide therapy in order to early recognize the potentially life-threatening complications of acute water retention.

Modulation of Myostatin/Hepatocyte Growth Factor Balance by Different Hemodialysis Modalities

Background. In this study we investigated the relevance of myostatin and Hepatocyte Growth Factor (HGF) in patients undergoing hemodialysis HD and the influence of different HD modalities on their levels. Methods. We performed a prospective crossover study in which HD patients were randomized to undergo 3-month treatment periods with bicarbonate hemodialysis (BHD) followed by online hemodiafiltration (HDF). Clinical data, laboratory parameters, and myostatin and HGF serum levels were collected and compared. Results. Ten patients and six controls (C) were evaluated. In any experimental condition myostatin and HGF levels were higher in HD than in C. At enrollment and after BHD there were not significant correlations, whereas at the end of the HDF treatment period myostatin and HGF were inversely correlated (r  −0.65, p < 0.05), myostatin serum levels inversely correlated with transferrin (r  −0.73, p < 0.05), and HGF levels that resulted positively correlated with BMI (r 0.67, p < 0.05). Moving from BHD to HDF, clinical and laboratory parameters were unchanged, as well as serum HGF, whereas myostatin levels significantly decreased (6.3 ± 4.1 versus 4.3 ± 3.1 ng/ml, p < 0.05). Conclusions. Modulation of myostatin levels and myostatin/HGF balance by the use of different HD modalities might represent a novel approach to the prevention and treatment of HD-related muscle wasting syndrome.

The evolving paradigm of cancer risk related to cyclophosphamide therapy in granulomatosis with polyangiitis

Granulomatosis with polyangiitis (GPA) is a potentially lifethreatening ANCA-associated vasculitis (AAV) that typically involves the respiratory tract and the kidney. The introduction of glucocorticoid and CYC therapy in the 1960s dramatically improved the prognosis of affected patients, with 78% surviving at 5 years compared with a 1-year mortality in 80% of untreated patients [1]. No conventional immunosuppressants have emerged as valid alternatives to CYC for the induction treatment of AAV, except for MTX in early systemic disease. The introduction of biologics such as rituximab has offered an exciting perspective for AAV treatment; however, trials comparing rituximab and CYC as initial therapy for AAV demonstrated that the former is not superior in inducing remission and that its short-term toxicity is also not negligible [2]. Thus, CYC still remains a cornerstone of AAV therapy and is unlikely to become of historical interest only. CYC has severe side effects, including bone marrow suppression, impaired fertility, haemorrhagic cystitis and increased susceptibility to infections and cancer. While some of these (e.g. leucopenia) usually occur early, others—particularly malignancies—are more frequent in the long term and their risk is related to the cumulative dose of CYC. This is particularly relevant for GPA patients, who are more prone to relapse than patients with other vasculitides and therefore require repeat treatment courses. Thus, several attempts have been made to minimize CYC exposure in AAV. In initial studies [1], CYC was used as both induction and maintenance treatment, which resulted in a considerable cumulative dose. The adoption of a staged approach based on an induction-of-remission phase (with high-dose glucocorticoids and CYC) followed by a maintenance period (where CYC is replaced by AZA or MTX) has reduced the cumulative amount of CYC. Subsequent studies have also demonstrated that CYC exposure can be reduced if a pulse i.v. regimen is used instead of daily oral administration. Finally, preventive measures such as the use of mesna are now recommended to limit the occurrence of haemorrhagic cystitis, which is associated with an increased risk of bladder cancer [3]. Changes in the way CYC is used in AAV have probably influenced its long-term cancer risk. To address this point, we searched PubMed without any date limits for full papers on CYC-related toxicity using the search terms ANCA-associated vasculitis, Wegener, treatment, cyclophosphamide, and cancer risk. Early studies covering observation periods that dated back to the 1970s to 1980s indicated that CYC-treated GPA patients had a 2.0to 2.4-fold increase in overall cancer incidence as compared with control populations [1, 4]. Cancer-typespecific analyses showed a significant excess risk for bladder cancer, non-melanoma skin cancer (NMSC) [1 , 4, 5], lymphoma and leukaemia [4]. More recent studies, reflecting treatment periods spanning the 1990s to 2000s, have provided more reassuring findings, showing standardized incidence ratios (SIRs) (i.e. observed number of cancers divided by the expected number) of 1.6 2.1 for all cancer types [6, 7]. These studies have also shown that lymphoma is no longer over-represented in the patient population [7]. Interestingly, in a recent work with 535 AAV patients enrolled in four trials conducted by the European Vasculitis Study Group, the SIR for non-NMSC dropped to 1.3 (95% CI 0.90, 1.80) and was not significantly increased; thus, the excess cancer risk observed in AAV was driven mainly by NMSC [6]. Cancer risk is also determined by other immunosuppressants, although their influence is difficult to assess because AAV is seldom treated with these agents alone. AZA used for >12 months was associated with a 3-fold increase in all-cancer incidence after 5 years of follow-up [5]. In a long-term follow-up study, cancer incidence in AAV patients treated with MTX for induction was comparable to that of patients who received pulse CYC [8]. Cancer risk attributable to MMF seems lower than with other agents, as demonstrated in renal transplantation; in a study comparing MMF with AZA in AAV, malignancies tended to be more frequent in the latter group [9]. In this issue of Rheumatology, Faurschou and colleagues [10] report the results of a registry-based study on the long-term cancer risk following conventional immunosuppressive therapy in GPA. The authors had previously shown a greater-than-expected occurrence of NMSC among CYC-exposed patients and an increased incidence of bladder cancer and myeloid leukaemia among patients treated with high cumulative CYC doses

Adverse events linked with the use of chimeric and humanized anti-CD20 antibodies in children with idiopathic nephrotic syndrome

Anti‐CD20 antibodies are increasingly being used to treat idiopathic nephrotic syndrome (INS) in children. While they may allow steroid and calcineurin inhibitor withdrawal, repeated infusions of anti‐CD20 antibodies are often required to maintain remission. Data on their potential toxicity in INS are needed, to consider repeated infusions.

Global Performance Status Score: A New Tool to Assess Physical Performance in Kidney Transplant Patients

BACKGROUND Information on physical performance in renal transplantation is limited because of the shortage of specifically designed evaluation instruments. Therefore, we elaborated and validated the Global Performance Status (GloPerSta) score to provide a new and comprehensive tool, exploring the different components of physical performance in kidney transplant patients. METHODS We elaborated the GloPerSta score on the basis of the data obtained from a cross-sectional study, in which we evaluated the physical performance of a cohort of kidney transplant patients. The results of these analyses were weighted to describe the different contribution of any single test, via the generation of a structural equation model, resulting in the definition of the GloPerSta. Then, to internally validate this score, we studied its correlation with clinical parameters and quality of life (evaluated as KDQOL-SF, Kidney Disease Quality of Life-Short Form) in the same patient population. RESULTS We enrolled 132 patients in whom the functional tests revealed a great heterogeneity. GloPerSta allowed the stratification of the patients in 3 different physical performance categories (low: score 0-11; medium: 12-22; high: 23-33). Internal validation showed that GloPerSta was directly and significantly correlated with the quality of life and allograft function, independent of the time from transplantation. CONCLUSIONS The GloPerSta is a reliable tool to assess physical performance in a kidney transplant population. Its application might be of help in identifying patients needing intensive and personalized rehabilitation programs.