Atypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic microangiopathy, and as many as 70% of patients with aHUS have mutations in the genes encoding complement regulatory ...proteins. Eculizumab, a humanized recombinant monoclonal antibody targeting C5, has been used successfully in patients with aHUS since 2009. The standard maintenance treatment requires life-long eculizumab therapy, but the possibility of discontinuation has not yet been tested systematically. We report the safety of discontinuing eculizumab treatment in 10 patients who stopped treatment with the aim of minimizing the risk of adverse reactions, reducing the risk of meningitis, and improving quality of life while also reducing the considerable treatment costs. Disease activity was monitored closely at home by means of urine dipstick testing for hemoglobin. During the cumulative observation period of 95 months, 3 of the 10 patients experienced relapse within 6 weeks of discontinuation, but then immediately resumed treatment and completely recovered. Our experience supports the possibility of discontinuing eculizumab therapy with strict home monitoring for early signs of relapse in patients with aHUS who achieve stable remission.
IgA Nephropathy (IgAN) and Membranous Nephropathy (MN) are primary immune-mediated glomerular diseases with highly variable prognosis. Current guidelines recommend that greater immunologic activity ...and worse prognosis should guide towards the best treatment in an individualized approach. Nevertheless, proteinuria and glomerular filtration rate, the current gold standards for prognosis assessment and treatment guidance in primary glomerular diseases, may be altered with chronic damage and nephron scarring, conditions that are not related to immune activity. In recent years, thanks to the development of new molecular technologies, among them genome-wide genotyping, RNA sequencing techniques, and mass spectrometry, we have witnessed an outstanding improvement in understanding the pathogenesis of IgAN and MN. In addition, recent genome-wide association studies have suggested potential targets for immunomodulating agents, stressing the need for the identification of specific biomarkers of immune activity. In this work, we aim to review current evidence and recent progress, including the more recent use of omics techniques, in the identification of potential biomarkers for immune monitoring in IgAN and MN.
IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide. The disease generally runs an indolent course but may lead to ESRD in 20-30% of patients in 20 years or more after ...diagnosis. Patients with IgA nephropathy are ideal candidates for renal transplant because they are generally relatively young and with few comorbidities. Their graft survival is better or comparable to that of controls at 10 years, though few data are available after 10 years of follow-up. Recurrence of the original disease in the graft is a well-known complication of transplant in IgAN and is a significant cause of deterioration of graft function. Recurrent IgAN rarely manifests clinically before 3 years post transplantation. Recurrence rate is estimated to be around 30% with considerable differences among different series. Despite these factors there is no certain recurrence predictor, young age at renal transplant, rapid progression of the original disease and higher levels of circulating galactose-deficient IgA1 and IgA-IgG immune complexes are all associated with a higher rate of recurrence. Which pathogenetic mechanisms are responsible for the progression of the recurrence to graft function deterioration, and what therapy can prevent or slow down the progression of the disease in the graft, are open questions. The aim of this review is to describe the clinical outcome of renal transplantation in IgA patients with attention to the rate and the predictors of recurrence and to discuss the available therapeutic options for the management of recurrence.
Prednisone and calcineurin inhibitors are the mainstay therapy of idiopathic nephrotic syndrome (INS) in children. However, drug dependence and toxicity associated with protracted use are common. ...Case series suggest that the anti-CD20 monoclonal antibody rituximab (RTX) may maintain disease remission.
This open-label randomized controlled trial was powered to show that a strategy based on RTX and lower doses of prednisone and calcineurin inhibitors was noninferior to standard doses of these agents in maintaining 3-month proteinuria as low as baseline or up to 1 g/d greater (noninferiority margin). Participants were stratified by the presence of toxicity to prednisone/calcineurin inhibitors and centrally assigned to add RTX (Mabthera, 375 mg/m(2) intravenously) to lower doses of standard agents or to continue with current therapy alone. The risk of relapse was a secondary outcome.
Fifty-four children (mean age 11 ± 4 years) with INS dependent on prednisone and calcineurin inhibitors for >12 months were randomized. Three-month proteinuria was 70% lower in the RTX arm (95% confidence interval 35% to 86%) as compared with standard therapy arm (intention-to-treat); relapse rates were 18.5% (intervention) and 48.1% (standard arm) (P = 0.029). Probabilities of being drug-free at 3 months were 62.9% and 3.7%, respectively (P < 0.001); 50% of RTX cases were in stable remission without drugs after 9 months.
Rituximab and lower doses of prednisone and calcineurin inhibitors are noninferior to standard therapy in maintaining short-term remission in children with INS dependent on both drugs and allow their temporary withdrawal.
Background
Shigatoxin-associated hemolytic uremic syndrome (STEC-HUS) is a common thrombotic microangiopathy (TMA) in which central nervous system (CNS) involvement is responsible for the majority of ...deaths and for severe long-term sequelae. We have analyzed the role of hemoconcentration in disease severity.
Methods
This was a retrospective review of the records and laboratory data at presentation of all patients with STEC-HUS cases (
n
= 61) over a 10-year period. The patients were grouped into three severity classes: group A, comprising patients who did not require dialysis; group B, patients who were dialyzed without CNS involvement; group C, patients with CNS involvement.
Results
Patients with CNS involvement (group C) had a higher mean hemoglobin level (11.2 ± 2.3 g/dL) than those of group A or B ( 9.4 ± 2.1 and 7.5 ± 1.9 g/dL, respectively;
p
< 0.0001). We also observed that the higher the initial hemoglobin level, the more severe the long-term renal damage (
p
< 0.007).
Conclusions
In patients with STEC-HUS, hemoconcentration and hypovolemia may be responsible for more severe ischemic organ damage (both short and long term) at disease onset, and these signs should be regarded as risk factors for CNS damage and for more severe TMA. Therefore, we recommend that hydration status should be actively monitored in HUS patients and that dehydration, when diagnosed, should be promptly corrected.
The polyomavirus (PyV), JC virus (JCV), is a small nonenveloped DNA virus that asymptomatically infects about 80% of healthy adults and establishes latency in the kidney tissue. In case of ...immunodeficient hosts, JCV can lytically infect the oligodendrocytes, causing a fatal demyelinating disease, known as progressive multifocal leukoencephalopathy (PML). Although the reactivation of another human PyV, BK virus (BKV), is relatively common and its association with the polyomavirus associated nephropathy (PyVAN) following renal transplantation is proven, JCV replication and its impact on graft function and survival are less well studied. Here we describe the biology of JCV and its pathological features and we review the literature regarding the JCV infection analyzed in the setting of transplantations.
Highlights • We report the frequency of the excretion of human polyomaviruses in urine. • We study adult and pediatric kidney transplant recipients and healthy subjects. • Merkel cell polyomavirus ...(MCPyV) DNA was frequently detected in pediatric subjects. • Despite the rarity of Merkel cell carcinoma, MCPyV is prevalent in the population. • MCPyV likely persists in the kidneys and infects the skin upon reactivation.
The research of novel markers in urinary samples, for the description of renal damage, is of high interest, and several works demonstrated the value of urinary mRNA quantification for the search of ...events related to renal disease or affecting the outcome of transplant kidneys. In the present pilot study, a comparison of the urine mRNA expression of specific podocyte markers among patients who had undergone clinical indication to renal transplanted (RTx, n = 20) and native (N, n = 18) renal biopsy was performed. The aim of this work was to identify genes involved in podocytes signaling and cytoskeletal regulation (NPHS1, NPHS2, SYNPO, WT1, TRPC6, GRM1, and NEUROD) in respect to glomerular pathology. We considered some genes relevant for podocytes signaling and for the function of the glomerular filter applying an alternative normalization approach. Our results demonstrate the WT1 urinary mRNA increases in both groups and it is helpful for podocyte normalization. Furthermore, an increase in the expression of TRPC6 after all kinds of normalizations was observed. According to our data, WT1 normalization might be considered an alternative approach to correct the expression of urinary mRNA. In addition, our study underlines the importance of slit diaphragm proteins involved in calcium disequilibrium, such as TRPC6.
The three yr results of a multicenter trial in de novo pediatric KT treated with a proliferative signal inhibitor and low dose CNI are presented. Thirty‐seven children (9.1 ± 5 yr old) received ...basiliximab, cyclosporine A (CyA C2:1400 ng/mL), (MMF C0:1.5–3 μg/mL), and prednisone. Three wk later everolimus was started (C0:5–10 ng/mL), CyA was reduced (C2:600 ng/mL after 90 days 300 ng/mL), and MMF discontinued. During the three‐yr period patient and graft survivals were 96%. One patient died for causes unrelated to the immunosuppression. Cumulative acute rejection rate including protocol and indication biopsies was 21.9%. None of the patients had signs of chronic humoral rejection. Incidence of dnDSA was 5%, 11%, and 22% at one, two, and three yr post‐transplant, respectively. Mean glomerular filtration rate measured at one yr and three yr post‐transplant was 105.5 ± 31 and 110.7 ± 27 mL/min/1.73 m2, respectively. A growth velocity of 7.7 ± 6.7 cm/yr was achieved with positive catch‐up growth. No malignancy or post‐transplant lymphoproliferative diseases were diagnosed. In conclusion, the treatment based on basiliximab induction, everolimus, low‐dose cyclosporine, and low‐dose prednisone leads to good long‐term efficacy in de novo pediatric KT recipients.
Focal and segmental glomerulosclerosis (FSGS) is a histological pattern clinically characterized by nephrotic proteinuria, hypoalbuminemia, edema and dyslipidemia. Approximately 50% of patients ...progress to end-stage renal disease within 5–10 years, particularly those not responding to the therapies. FSGS pathogenesis is largely unknown and therapy is symptomatic and unspecific. The podocyte is considered as the pathogenetic main target and FSGS is now categorized as a podocytopathy together with minimal change disease, diffuse mesangial proliferation and collapsing glomerulonephritis. This paper provides an overview on the treatment of idiopathic FSGS in adults, citing the latest published trials and the most reliable pathogenetic hypotheses of the disease. A large part of the review then focuses on emerging therapies, specifying for each new drug the assumed mechanism of action and the data available in the literature on the drug’s use in experimental animals and humans.
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