The outcome of SARS-CoV2 infection in patients who have received a kidney allograft and are being treated with immunosuppression is unclear. We describe 20 kidney transplant recipients (median age 59 ...years inter quartile range 51-64 years, median age of transplant 13 years 9-20 years, baseline eGFR 36.5 23-47.5) with SARS-CoV2 induced pneumonia. At admission, all had immunosuppression withdrawn and were started on methylprednisolone 16 mg/day, all but one was commenced on antiviral therapy and hydroxychloroquine with doses adjusted for kidney function. At baseline, all patients presented fever but only one complained of difficulty in breathing. Half of patients showed chest radiographic evidence of bilateral infiltrates while the other half showed unilateral changes or no infiltrates. During a median follow-up of seven days, 87% experienced a radiological progression and among those 73% required escalation of oxygen therapy. Six patients developed acute kidney injury with one requiring hemodialysis. Six of 12 patients were treated with tocilizumab, a humanized monoclonal antibody to the IL-6 receptor. Overall, five kidney transplant recipients died after a median period of 15 days 15-19 from symptom onset. These preliminary findings describe a rapid clinical deterioration associated with chest radiographic deterioration and escalating oxygen requirement in renal transplant recipients with SARS-Cov2 pneumonia. Thus, in this limited cohort of long-term kidney transplant patients, SARS-CoV-2 induced pneumonia is characterized by high risk of progression and significant mortality.
Display omitted
A cyclic corticosteroid-cyclophosphamide regimen is the first-line therapy for membranous nephropathy. Compared with this regimen, rituximab therapy might have a more favorable safety profile, but a ...head-to-head comparison is lacking.
We randomly assigned 74 adults with membranous nephropathy and proteinuria >3.5 g/d to rituximab (1 g) on days 1 and 15, or a 6-month cyclic regimen with corticosteroids alternated with cyclophosphamide every other month. The primary outcome was complete remission of proteinuria at 12 months. Other outcomes included determination of complete or partial remission at 24 months and occurrence of adverse events.
At 12 months, six of 37 patients (16%) randomized to rituximab and 12 of 37 patients (32%) randomized to the cyclic regimen experienced complete remission (odds ratio OR, 0.4; 95% CI, 0.13 to 1.23); 23 of 37 (62%) receiving rituximab and 27 of 37 (73%) receiving the cyclic regimen had complete or partial remission (OR, 0.61; 95% CI, 0.23 to 1.63). At 24 months, the probabilities of complete and of complete or partial remission with rituximab were 0.42 (95% CI, 0.26 to 0.62) and 0.83 (95% CI, 0.65 to 0.95), respectively, and 0.43 (95% CI, 0.28 to 0.61) and 0.82 (95% CI, 0.68 to 0.93), respectively, with the cyclic regimen. Serious adverse events occurred in 19% of patients receiving rituximab and in 14% receiving the cyclic regimen.
This pilot trial found no signal of more benefit or less harm associated with rituximab versus a cyclic corticosteroid-cyclophosphamide regimen in the treatment of membranous nephropathy. A head-to-head, pragmatic comparison of the cyclic regimen versus rituximab may require a global noninferiority trial.
Rituximab versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO), NCT03018535.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as coronavirus disease (COVID-19), is a major pandemic challenging health care systems around the world. The optimal ...management of patients infected with COVID-19 is still unclear, although the consensus is moving toward the need of a biphasic approach. During the first phase of the disease (from onset of the symptoms up to 7–10 days) viral-induced effects are prominent, with the opportunity to institute antiviral therapy. In the second inflammatory phase of the disease, immunosuppressive strategies (for example with glucocorticoids or anticytokine drugs) may be considered. This latter stage is characterized by the development of progressive lung involvement with increasing oxygen requirements and occasionally signs of the hemophagocytic syndrome. The management of the disease in patients with kidney disease is even more challenging, especially in those who are immunosuppressed or with severe comorbidities. Here we present the therapeutic approach used in Brescia (Italy) for managing patients infected with COVID-19 who underwent kidney transplantation and are receiving hemodialysis. Furthermore, we provide some clinical and physiopathological background, as well as preliminary outcome data of our cohort, to better clarify the pathogenesis of the disease and clinical management.
The SARS-CoV-2 epidemic is pressuring healthcare systems worldwide. Disease outcomes in certain subgroups of patients are still scarce, and data are needed. Therefore, we describe here the experience ...of four dialysis centers of the Brescia Renal COVID Task Force. During March 2020, within an overall population of 643 hemodialysis patients, SARS-CoV-2 RNA positivity was detected in 94 (15%). At disease diagnosis, 37 of the 94 (39%) patients (group 1) were managed on an outpatient basis, whereas the remaining 57 (61%) (group 2) required hospitalization. Choices regarding management strategy were made based on disease severity. In group 1, 41% received antivirals and 76% hydroxychloroquine. Eight percent died and 5% developed acute respiratory distress syndrome (ARDS). In group 2, 79% received antivirals and 77% hydroxychloroquine. Forty two percent died and 79% developed ARDS. Overall mortality rate for the entire cohort was 29%. History of ischemic cardiac disease, fever, older age (over age 70), and dyspnea at presentation were associated with the risk of developing ARDS, whereas fever, cough and a C-reactive protein higher than 50 mg/l at disease presentation were associated with the risk of death. Thus, in our population of hemodialysis patients with SARS-CoV-2 infection, we documented a wide range of disease severity. The risk of ARDS and death is significant for patients requiring hospital admission at disease diagnosis.
Display omitted
Abstract
Background and Aims
Rituximab (RTX) has emerged as the first-line treatment to maintain remission in ANCA-Associated Vasculitis (AAV). However, the ideal strategy to RTX re-dosing is still ...unclear 1.
Method
In this monocentric and retrospective study we evaluated the efficacy and safety of two RTX-based maintenance regimens in patients with AAV. Fixed-dose (FD) RTX dosing, consisting of at least 3 pre-emptive RTX administrations every 6 months, was preferred in patients judged to be at high relapse risk. Instead, a biomarker-guided on-demand (OD) RTX dosing strategy was preferred for patients deemed at lower risk of relapse; this consisted in RTX re-treatment only in case of B-cell repopulation or rise in ANCA titer. The single patient relapse risk was assessed according to the disease phenotype (granulomatous vs vasculitic), the ANCA specificity and the disease status (onset vs relapse). Relapses were defined as increase of disease activity requiring escalation of immunosuppression; major relapses were defined in case of life/organ-threatening manifestations.
Results
The study included 100 patients followed for a median of 24 months (IQR 20-30), 51% treated with an OD and 49% with a FD strategy. The main baseline characteristics of our cohort are shown in the Table; patients treated with a FD strategy were more often GPA, PR3-ANCA positive, with relapsing disease and ENT involvement and less frequent renal involvement. The FD group received a median of 4 (IQR 4-4) administrations of RTX for a median cumulative dose of 2 g (IQR 2-2). Only 6 (11.8%) patients in the OD group received RTX as maintenance therapy with a median of 1 (IQR 1-3) administration of RTX for a median cumulative dose of 0.75 g (IQR 0.5-1.75). Thirteen relapses occurred, 6 in the FD group and 7 in the OD one. Remission rates were comparable in the two cohorts, with respectively 87.6% and 85.9% of the patients in remission at 24 months (Figure 1 - panel A). No significant differences in remission rates across the 2 groups were observed after considering only major flares or after stratification according to clinical diagnosis (MPA/GPA) and ANCA specificity (Figure 1 - panel B to F). Ten and 20 severe infections (p = 0.383) and 3 and 1 cancer (p = 0.581) occurred respectively in the FD and OD group.
Conclusion
In our case series, a phenotypic-driven approach to RTX maintenance showed comparable efficacy and safety between fixed and on-demand dosing, despite different baseline characteristics between the two groups. These results suggest that personalizing RTX maintenance may be a feasible and safe strategy.
Despite the increasing use of rituximab in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), it remains unclear what the optimal dosing is, especially for maintenance of ...remission. A deeper understanding of post-rituximab B-cell repopulation patterns may aid better-tailored treatment.
This is a monocentric, retrospective study including ANCA-positive AAV patients receiving a single course of rituximab induction. CD19+ B cells were longitudinally monitored with flow cytometry. B-cell repopulation was defined as CD19+ >10 cells/μL.
Seventy-one patients were included, the majority with microscopic polyangiitis (75%), myeloperoxidase-ANCA positivity (75%) and with renal involvement (79%). During a median follow-up of 54 months since the first rituximab infusion, 44 patients (62%) repopulated B cells, with a median time to repopulation of 39 months (range 7-102). Patients experiencing B-cell depletion lasting longer than the overall median time to repopulation (39 months) exhibited a lower risk of flare and higher risk of serious infection. In multivariate Cox regression, higher estimated glomerular filtration rate (eGFR) hazard ratio (HR) 1.84, 95% confidence interval (CI) 1.13-2.98 per 30 mL/min/1.73 m2 eGFR and female sex (HR 2.70, 95% CI 1.37-5.31) were independent predictors of increased rate of B-cell repopulation.
A subset of AAV patients develop sustained post-rituximab B-cell depletion, which associates with reduced risk of flare and increased risk of serious infection in the long term. Preserved renal function and female sex are associated with faster B-cell repopulation. These observations further highlight the need to personalize immunosuppression to improve clinical outcomes.
Abstract
Background and Aims
Discordant affected relative-pairs are seen in ∼10% of families with Autosomal Dominant Polycystic Kidney Disease (ADPKD); <1% of patients exhibit very early onset (VEO) ...disease. Complex genotypes may result in renal disease variability beyond that predicted by the sole effect of a single PKD mutant allele, leading to the discovery of biallelic or digenic disease. Here we illustrate such complexity in 6 ADPKD pedigrees.
Method
Among our single-center ADPKD cohort (186 index patients), we selected pedigrees (P) in which marked familial phenotypic variability or severe and early onset disease was investigated by NGS and MLPA analysis of PKD1 and PKD2 genes and NGS analysis of other cystogenes. Segregation analysis by Sanger sequencing of PKD variants was performed in available affected and unaffected family members.
Results
In P1 and P2, the index cases (IC), presented with very early onset (VEO) disease characterized by prenatal/neonatal enlarged and hyperechogenic kidneys mimicking autosomal recessive polycystic kidney disease (ARPKD). In P1, with neonatal onset, the ADPKD affected father transmitted a PKD1 PT variant p.Gln4231*, whereas the mother, without renal cystic phenotype, transmitted a PKD1 hypomorphic variant p.Asp1332Asn.
In P2, the ADPKD-PKD2 mother’s pregnancy was complicated by Potter sequence. Parent’s PKHD1 gene analysis was negative. Two missense NT variants in PKD1/PKD2 genes were detected in the healthy father, respectively p.Gly1944Arg and p.Thr203Ile. Therefore, a complex PKD inheritance was supposed in the fetus. Fetus DNA was not available.
In P3 early onset (EO) ADPKD in two monozygous twins was underpinned by a PKD1 NT variant (p.Arg1951Gln) inherited by the ADPKD mild affected father and worsened by a de novo PKD1 truncating variant p.Arg2402*.
In P4 and P5 a digenic ADPKD (PKD1 +PKD2 and PKD1 +PKHD1) was diagnosed in severe ADPKD IC. In P4 the two most severely affected siblings carried a PKD2 T variant (p.Ala365fs) and a PKD1 NT variant p-Cys259Tyr.
In P5 the IC presented with EO ADPKD, a de novo splicing variant c.2097 + 5_+6insT in PKD1 gene was discovered but the phenotype was probably worsened by the presence of biallelic variant in a second cystogene PKHD1: one paternally inherited: p.Gly1712Arg and one maternally inherited: p.Asp3088Asn .
Elderly parents in P6 had mild ADPKD with bilateral few kidney cysts and preserved eGFR, whereas IC showed moderate/severe CKD due to ADPKD biallelic variants. The IC carried a homozygous PKD1 NT variant (p.Arg4154Cys): each mutant allele inherited from the mild ADPKD affected parents.
Conclusion
Our study illustrates the genetic complexity in an otherwise “simple” Mendelian disorder, providing insights into the genetic basis of severity of ADPKD cases and into ADPKD intrafamilial disease variability. In our pedigree all cases with more severe clinical picture in the family presented at least two PKD variants. In P5 we found for the first time an EO ADPKD due to both PKD1 and PKHD1 variants.
PKD1 and PKD2 sequence analysis together with cystic kidney disease gene panel analysis is recommended in those patients with discordant phenotype compared to family members. Molecular study of PKD patients is expected to be a good prognostic tool together with clinical and renal imaging data to better manage disease therapy, follow-up and reproductive issues.
Figure:
Background
Causative mutations in the GANAB gene have been described in only 14 families, 9 diagnosed with late-onset Autosomal Dominant Polycystic Kidney Disease (ADPKD) and 5 with Autosomal ...Dominant Polycystic Liver Disease (ADPLD).
Case
Diagnosis of ADPKD was made in a 45-year old man during screening for hernia repair. CT scan showed enlarged cystic kidneys, nephrolithiasis and normal-sized liver with multiple cysts. Hematuria, hypertension and aortic root dilatation were also documented. Renal function was normal. Molecular analysis of PKD genes disclosed a heterozygous p.R839W GANAB variant inherited from the mother. Both his elderly parents presented normal-sized bilateral cystic kidneys but normal renal function. The GANAB-ADPKD mother had no liver cysts. The father was screened for PKD-related genes and no variant was found.
Genetic analysis
We describe a new family with late-onset ADPKD due to the p.R839W GANAB variant, previously reported in a severe ADPLD patient, requiring liver transplantation.
Discussion
Since ADPKD-GANAB is an ultrarare, recently described disease, reporting further patients may help unraveling gene-related phenotype. In our patients the p.R839W GANAB variant was not related to severe ADPLD, as previously reported, but with mild ADPKD and a plethora of renal and extrarenal manifestations, usually described in PKD1/PKD2 patients. The evidence that the GANAB variant may cause both ADPKD and ADPLD of variable severity supports that renal and hepatic cystogenesis are the result of a common defective polycystin-1 pathway.
Graphic abstract
PDF
