ABSTRACT
Background
Genetic causes are increasingly recognized in patients with focal segmental glomerulosclerosis (FSGS), but it remains unclear which patients should undergo genetic study. Our ...objective was to determine the frequency and distribution of genetic variants in steroid-resistant nephrotic syndrome FSGS (SRNS-FSGS) and in FSGS of undetermined cause (FSGS-UC).
Methods
We performed targeted exome sequencing of 84 genes associated with glomerulopathy in patients with adult-onset SRNS-FSGS or FSGS-UC after ruling out secondary causes.
Results
Seventy-six patients met the study criteria; 24 presented with SRNS-FSGS and 52 with FSGS-UC. We detected FSGS-related disease-causing variants in 27/76 patients (35.5%). There were no differences between genetic and non-genetic causes in age, proteinuria, glomerular filtration rate, serum albumin, body mass index, hypertension, diabetes or family history. Hematuria was more prevalent among patients with genetic causes. We found 19 pathogenic variants in COL4A3–5 genes in 16 (29.3%) patients. NPHS2 mutations were identified in 6 (16.2%) patients. The remaining cases had variants affecting INF2, OCRL, ACTN4 genes or APOL1 high-risk alleles. FSGS-related genetic variants were more common in SRNS-FSGS than in FSGS-UC (41.7% vs 32.7%). Four SRNS-FSGS patients presented with NPHS2 disease-causing variants. COL4A variants were the most prevalent finding in FSGS-UC patients, with 12 patients carrying disease-causing variants in these genes.
Conclusions
FSGS-related variants were detected in a substantial number of patients with SRNS-FSGS or FSGS-UC, regardless of age of onset of disease or the patient's family history. In our experience, genetic testing should be performed in routine clinical practice for the diagnosis of this group of patients.
Lay Summary
Prevalence of genetic causes in patients with a histological diagnosis of focal segmental glomerulosclerosis (FSGS) is probably underestimated due to the diagnostic challenges in its diagnosis. The criteria for genetic testing in adult patients with FSGS remains unclear. In this study, we found that there is a high prevalence of genetic forms in FSGS with steroid-resistant nephrotic syndrome (41.7%) and FSGS of undetermined cause (32.7%). The most common genetic variants in adult-onset FSGS steroid-resistant nephrotic syndrome were NPHS2 gene mutations, whereas in FSGS of undetermined cause the most frequent genetic mutations were in COL4A genes. The age of onset of disease and the presence of a positive family history did not discriminate between genetic and non-genetic forms of FSGS. In conclusion, genetic testing should be performed in patients with FSGS and steroid-resistant nephrotic syndrome or FSGS of undetermined cause, regardless of the age of onset or family history of kidney disease.
Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report ...the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety.
PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to <60 mL/min per 1·73 m2 and ≥60 mL/min per 1·73 m2) and urine protein excretion at screening (≤1·75 g/day and >1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein–creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850.
Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein–creatinine ratio was statistically significantly greater in the sparsentan group (–49·8%) than the irbesartan group (–15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51–0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups.
Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan.
Travere Therapeutics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pathologic complete response (pCR) after multimodal treatment for locally advanced rectal cancer (LARC) is used as surrogate marker of success as it is assumed to correlate with improved oncologic ...outcome. However, long-term oncologic data are scarce.
This retrospective, multicentre study updated the oncologic follow-up of prospectively collected data from the Spanish Rectal Cancer Project database. pCR was described as no evidence of tumour cells in the specimen. Endpoints were distant metastases-free survival (DMFS) and overall survival (OS). Multivariate regression analyses were run to identify factors associated with survival.
Overall, 32 different hospitals were involved, providing data on 815 patients with pCR. At a median follow-up of 73.4 (IQR 57.7–99.5) months, distant metastases occurred in 6.4% of patients. Abdominoperineal excision (APE) (HR 2.2, 95%CI 1.2–4.1, p = 0.008) and elevated CEA levels (HR = 1.9, 95% CI 1.0–3.7, p = 0.049) were independent risk factors for distant recurrence. Age (years) (HR 1.1; 95%-CI 1.05–41.09; p < 0.001) and ASA III-IV (HR = 2.0; 95%-CI 1.4–2.9; p < 0.001), were the only factors associated with OS. The estimated 12, 36 and 60-months DMFS rates were 96.9%, 91.3%, and 86.8%. The estimated 12, 36 and 60-months OS rates were 99.1%, 94.9% and 89.3%.
The incidence of metachronous distant metastases is low after pCR, with high rates of both DMFS and OS. The oncologic prognosis in LARC patients that achieve pCR after neoadjuvant chemo-radiotherapy is excellent in the long term.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
La encefalitis necrotizante focal por Toxoplasma Gondii es una de las infecciones oportunistas más frecuente en pacientes con síndrome de inmunodeficiencia adquirida. (SIDA). El tratamiento de ...elección consiste en la combinación de Pirimetamida y Sulfadiacina. Uno de los principales efectos adversos de la Sulfadiazina es su precipitación en el sistema urinario. Presentamos a una paciente con SIDA y encefalitis por Toxoplasma Gondii que desarrolla insuficiencia renal aguda reversible por depósito de cristales de sulfadiacina a nivel renal. La ecografía mostró múltiples calcificaciones en el seno renal, que desaparecieron tras hidratación y administración de bicarbonato sódico endovenoso. Estos pacientes y otros inmunodeprimidos, presentan factores favorecedores de la precipitación de éste y otros fármacos, siendo necesario una adecuada monitorización de la función renal y del sedimento urinario, junto con medidas profilácticas como el aumento de la ingesta de líquidos y la alcalinización urinaria.
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