B cell depletion with rituximab (RTX) is approved for treatment of rheumatoid arthritis (RA) and ANCA-associated vasculitides (AAV). Recently, RTX has been shown to be effective in AAV maintenance ...therapy, but an optimal RTX treatment schedule is unknown and the time to B cell repopulation after RTX has not been studied.
Retrospective single-center analysis of B cell repopulation in patients with AAV, RA or connective tissue disease (CTD) treated with RTX.
Beginning B cell repopulation within the first year after RTX treatment was observed in 93% of RA and 88% of CTD patients. Only 10% of patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) and no patient with eosinophilic granulomatosis with polyangiitis (EGPA) showed B cell repopulation within this time. Median time of B cell depletion was 26 months in GPA/MPA, and 21 months in EGPA compared to 9 months in RA, and 8 months in CTD (p < 0.0001). In 25 AAV-patients B cell depletion lasted for at least 44 months. There was a significant decline in serum immunoglobulin concentrations in GPA/MPA patients, but not in patients with RA or CTD. Significantly more GPA/MPA patients developed hygogammaglobulinemia (IgG <7 g/L) compared to patients with RA or CTD.
In contrast to RA and CTD, in AAV RTX induces long-lasting depletion of B cells that is associated with decreased antibody production. This observation points toward potential defects in the B cell compartment in AAV that are unmasked by immunosuppressive treatment and has important implications for the design of maintenance treatment schedules using RTX.
Standardizing HNF1B-Associated Disease Muench, Johannes; Vasileiou, Georgia; Kowald, Jan ...
Journal of the American Society of Nephrology,
10/2021, Letnik:
32, Številka:
10S
Journal Article
Congenital anomalies of the kidney and urinary tract (CAKUT) represent the most common cause of chronic kidney failure in children. Despite growing knowledge of the genetic causes of CAKUT, the ...majority of cases remain etiologically unsolved. Genetic alterations in roundabout guidance receptor 1 (ROBO1) have been associated with neuronal and cardiac developmental defects in living individuals. Although Slit-Robo signaling is pivotal for kidney development, diagnostic ROBO1 variants have not been reported in viable CAKUT to date. By next-generation-sequencing methods, we identified six unrelated individuals and two non-viable fetuses with biallelic truncating or combined missense and truncating variants in ROBO1. Kidney and genitourinary manifestation included unilateral or bilateral kidney agenesis, vesicoureteral junction obstruction, vesicoureteral reflux, posterior urethral valve, genital malformation, and increased kidney echogenicity. Further clinical characteristics were remarkably heterogeneous, including neurodevelopmental defects, intellectual impairment, cerebral malformations, eye anomalies, and cardiac defects. By in silico analysis, we determined the functional significance of identified missense variants and observed absence of kidney ROBO1 expression in both human and murine mutant tissues. While its expression in multiple tissues may explain heterogeneous organ involvement, variability of the kidney disease suggests gene dosage effects due to a combination of null alleles with mild hypomorphic alleles. Thus, comprehensive genetic analysis in CAKUT should include ROBO1 as a new cause of recessively inherited disease. Hence, in patients with already established ROBO1-associated cardiac or neuronal disorders, screening for kidney involvement is indicated.
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Abstract
BACKGROUND AND AIMS
Congenital anomalies of the kidney and urinary tract (CAKUT) represent the most common cause of chronic kidney failure in children. Despite growing knowledge of the ...genetic causes of CAKUT, the majority of cases remain etiologically unsolved. Genetic alterations in roundabout guidance receptor 1 (ROBO1) have been associated with neuronal and cardiac developmental defects in living individuals. Although Slit-Robo signaling is pivotal for kidney development, diagnostic ROBO1 variants have not been reported in viable CAKUT to date.
METHOD
We collected phenotypic data of all participants. Genetic analysis was conducted by either exome or whole genome sequencing, respectively. We used Sanger sequencing for variant confirmation and segregation analysis and performed in-silico analysis of identified missense variants. In an ENU-induced mouse model, we examined mice with the mutation Robo1Ile270Thr/Ile270Thr.
RESULTS
By next-generation-sequencing methods, we identified six unrelated individuals and two non-viable fetuses from Germany, France, Turkey, Japan and the USA with biallelic truncating or combined missense and truncating variants in ROBO1. Renal and genitourinary manifestation included unilateral or bilateral renal agenesis, vesicoureteral junction obstruction, vesicoureteral reflux, posterior urethral valve, genital malformation and increased renal echogenicity. Further clinical characteristics were remarkably heterogeneous, including neurodevelopmental defects, intellectual impairment, cerebral malformations, eye anomalies, and cardiac defects (Figure 1).
By in-silico analysis, we determined the functional significance of identified missense variants and observed absence of renal ROBO1 expression in both human and murine mutant tissues (Figure 2).
CONCLUSION
This study describes six live-born and two non-viable individuals with syndromic CAKUT due to probably deleterious ROBO1 variants. While its expression in multiple tissues may explain heterogeneous organ involvement, variability of kidney disease suggests gene dosage effects due to a combination of null alleles with mild hypomorphic alleles. In conclusion, comprehensive genetic analysis in CAKUT should include ROBO1 as a new cause of recessively inherited disease. Conversely, in patients with already established ROBO1-associated cardiac or neuronal disorders, screening for renal involvement is indicated.
Following the recent publications of the STAR-study, the ASTRAL trial, the HERCULES trial and the CORAL trial on renal revascularization versus medical therapy in the management of atherosclerotic ...renovascular disease, there has been a near paradigm shift implying the nonutility of revascularization as a useful and necessary therapeutic option. Our recent experience with a patient who underwent an anastomotic bypass revascularization for worsening renal failure and uncontrolled hypertension in bilateral calcific atherosclerotic renal artery stenosis in Burlington, VT rekindled this debate. We posit that in appropriately selected patients, patients with acutely worsening renal failure, uncontrolled hypertension and/or symptomatic pulmonary edema, there is indeed a place for revascularization therapy, especially in the light of improved and safer surgical and anesthesiology techniques. It must be correctly acknowledged that the above well popularized randomized trials recruited mostly patients with otherwise stable chronic kidney disease at the time of enrollment. Similarly, only 12% of the patients in both arms of the ASTRAL trial demonstrated rapidly worsening renal failure prior to enrollment
When Your Patient Needs New Glasses Every Day Prétot, Dominique; Engesser, Katrin Marie; Schlote, Torsten ...
Klinische Monatsblatter fur Augenheilkunde,
04/2023, Letnik:
240, Številka:
4
Journal Article
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