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BACKGROUND: An unmet need exists for focal segmental glomerulosclerosis (FSGS) treatment. In an 8-week, phase 2 trial, sparsentan, a dual endothelin-angiotensin receptor antagonist, reduced proteinuria in patients with FSGS. The efficacy and safety of longer-term treatment with sparsentan for FSGS are unknown. METHODS: In this phase 3 trial, we enrolled patients with FSGS (without known secondary causes) who were 8 to 75 years of age; patients were randomly assigned to receive sparsentan or irbesartan (active control) for 108 weeks. The surrogate efficacy end point assessed at the prespecified interim analysis at 36 weeks was the FSGS partial remission of proteinuria end point (defined as a urinary protein-to-creatinine ratio of ≤1.5 [with protein and creatinine both measured in grams] and a >40% reduction in the ratio from baseline). The primary efficacy end point was the estimated glomerular filtration rate (eGFR) slope at the time of the final analysis. The change in eGFR from baseline to 4 weeks after the end of treatment (week 112) was a secondary end point. Safety was also evaluated. RESULTS: A total of 371 patients underwent randomization: 184 were assigned to receive sparsentan and 187 to receive irbesartan. At 36 weeks, the percentage of patients with partial remission of proteinuria was 42.0% in the sparsentan group and 26.0% in the irbesartan group (P = 0.009), a response that was sustained through 108 weeks. At the time of the final analysis at week 108, there were no significant between-group differences in the eGFR slope; the between-group difference in total slope (day 1 to week 108) was 0.3 ml per minute per 1.73 m2 of body-surface area per year (95% confidence interval [CI], -1.7 to 2.4), and the between-group difference in the slope from week 6 to week 108 (i.e., chronic slope) was 0.9 ml per minute per 1.73 m2 per year (95% CI, -1.3 to 3.0). The mean change in eGFR from baseline to week 112 was -10.4 ml per minute per 1.73 m2 with sparsentan and -12.1 ml per minute per 1.73 m2 with irbesartan (difference, 1.8 ml per minute per 1.73 m2; 95% CI, -1.4 to 4.9). Sparsentan and irbesartan had similar safety profiles, and the frequency of adverse events was similar in the two groups. CONCLUSIONS: Among patients with FSGS, there were no significant between-group differences in eGFR slope at 108 weeks, despite a greater reduction in proteinuria with sparsentan than with irbesartan. (Funded by Travere Therapeutics; DUPLEX ClinicalTrials.gov number, NCT03493685.).
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Glomeruloesclerosis Focal y Segmentaria , Irbesartán , Proteinuria , Humanos , Biomarcadores , Creatinina , Tasa de Filtración Glomerular , Glomeruloesclerosis Focal y Segmentaria/complicaciones , Glomeruloesclerosis Focal y Segmentaria/tratamiento farmacológico , Glomeruloesclerosis Focal y Segmentaria/fisiopatología , Irbesartán/administración & dosificación , Irbesartán/efectos adversos , Irbesartán/uso terapéutico , Proteinuria/tratamiento farmacológico , Proteinuria/etiología , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Inducción de RemisiónRESUMEN
Focal segmental glomerular sclerosis (FSGS) is 1 of the primary causes of nephrotic syndrome in both pediatric and adult patients, which can lead to end-stage kidney disease. Recurrence of FSGS after kidney transplantation significantly increases allograft loss, leading to morbidity and mortality. Currently, there are no consensus guidelines for identifying those patients who are at risk for recurrence or for the management of recurrent FSGS. Our work group performed a literature search on PubMed/Medline, Embase, and Cochrane, and recommendations were proposed and graded for strength of evidence. Of the 614 initially identified studies, 221 were found suitable to formulate consensus guidelines for recurrent FSGS. These guidelines focus on the definition, epidemiology, risk factors, pathogenesis, and management of recurrent FSGS. We conclude that additional studies are required to strengthen the recommendations proposed in this review.
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Glomeruloesclerosis Focal y Segmentaria , Trasplante de Riñón , Síndrome Nefrótico , Adulto , Humanos , Niño , Glomeruloesclerosis Focal y Segmentaria/diagnóstico , Glomeruloesclerosis Focal y Segmentaria/epidemiología , Glomeruloesclerosis Focal y Segmentaria/etiología , Esclerosis/complicaciones , Trasplante de Riñón/efectos adversos , Trasplante Homólogo/efectos adversos , Síndrome Nefrótico/diagnóstico , Síndrome Nefrótico/etiología , Síndrome Nefrótico/terapia , Recurrencia , PlasmaféresisRESUMEN
BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Travere Therapeutics.
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Glomerulonefritis por IGA , Adulto , Humanos , Adolescente , Irbesartán/uso terapéutico , Glomerulonefritis por IGA/tratamiento farmacológico , Creatinina/orina , Proteinuria/tratamiento farmacológico , Método Doble Ciego , Resultado del TratamientoRESUMEN
BACKGROUND: Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. METHODS: PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin-angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850. FINDINGS: Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6-110) was -2·7 mL/min per 1·73 m2 per year versus -3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1-week 110) was -2·9 mL/min per 1·73 m2 per year versus -3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI -0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (-42·8%, 95% CI -49·8 to -35·0, with sparsentan versus -4·4%, -15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. INTERPRETATION: Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function. FUNDING: Travere Therapeutics.
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Glomerulonefritis por IGA , Fallo Renal Crónico , Femenino , Humanos , Masculino , Antagonistas de Receptores de Angiotensina/efectos adversos , Método Doble Ciego , Glomerulonefritis por IGA/tratamiento farmacológico , Irbesartán/efectos adversos , Proteinuria/tratamiento farmacológico , Resultado del Tratamiento , AdultoRESUMEN
BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have demonstrated benefit in patients with heart failure, but minimal data exist concerning the use of these medications in amyloid light-chain cardiomyopathy (AL-CM). We performed a retrospective study to assess the safety and efficacy of SGLT2is in AL-CM. METHODS: We queried our institutional registry and identified 27 patients with AL-CM who received SGLT2is. The safety analysis included all 27 patients and assessed SGLT2i-associated adverse events, hospitalizations and deaths. To decrease confounding, the efficacy analysis included only a subset of patients with stable disease (on stable anti-plasma cell therapy for ≥ 2 months prior to baseline and had achieved at least a hematologic Very Good Partial Response) and compared disease-marker changes in these patients (nâ¯=â¯17) with those of a contemporaneous untreated control cohort from our registry (nâ¯=â¯21). RESULTS: The mean age of the overall population was 68.6 (standard deviation 9.4) years. Of the patients, 7 (14.6%) had diabetes, and 19 (39.6%) had chronic kidney disease. In the safety analysis, the median follow-up time was 10.9 (interquartile range 7.2) months. Two (7.4%) patients discontinued SGLT2is due to hypovolemia and genital irritation, and 6 (22.2%) additional patients temporarily held SGLT2is due to an adverse event that is commonly related to volume depletion. There were 13 hospitalizations, all considered unrelated to SGLT2i use, and no deaths occurred. In the efficacy analysis, SGLT2i-treated patients had more severe disease at baseline than controls, demonstrating significantly higher median troponin-T and loop diuretic dosage (P < 0.05). Compared with controls, SGLT2i treatment was associated with significantly greater reductions in loop diuretic dosage (P < 0.001) and NTproBNP levels (Pâ¯=â¯0.033) across 3-, 6- and 12-month follow-up timepoints. SGLT2i treatment was also associated with a significantly greater reduction in mean arterial pressure at 12 months (Pâ¯=â¯0.031) but not at other timepoints. No significant differences were observed in changes in weight, eGFR, troponin-T, proteinuria, or albumin levels. CONCLUSIONS: In this small-scale retrospective study, we demonstrate that SGLT2is are well tolerated by most patients with AL-CM, but volume depletion symptoms may limit continuous use. SGLT2is may aid management of congestion in AL-CM, as evidenced by reduced diuretic dosage and NTproBNP levels without adverse renal effects. Larger long-term studies are needed to build on our findings.
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SIGNIFICANCE STATEMENT: Congenital obstructive uropathy (COU) is a prevalent human developmental defect with highly heterogeneous clinical presentations and outcomes. Genetics may refine diagnosis, prognosis, and treatment, but the genomic architecture of COU is largely unknown. Comprehensive genomic screening study of 733 cases with three distinct COU subphenotypes revealed disease etiology in 10.0% of them. We detected no significant differences in the overall diagnostic yield among COU subphenotypes, with characteristic variable expressivity of several mutant genes. Our findings therefore may legitimize a genetic first diagnostic approach for COU, especially when burdening clinical and imaging characterization is not complete or available. BACKGROUND: Congenital obstructive uropathy (COU) is a common cause of developmental defects of the urinary tract, with heterogeneous clinical presentation and outcome. Genetic analysis has the potential to elucidate the underlying diagnosis and help risk stratification. METHODS: We performed a comprehensive genomic screen of 733 independent COU cases, which consisted of individuals with ureteropelvic junction obstruction ( n =321), ureterovesical junction obstruction/congenital megaureter ( n =178), and COU not otherwise specified (COU-NOS; n =234). RESULTS: We identified pathogenic single nucleotide variants (SNVs) in 53 (7.2%) cases and genomic disorders (GDs) in 23 (3.1%) cases. We detected no significant differences in the overall diagnostic yield between COU sub-phenotypes, and pathogenic SNVs in several genes were associated to any of the three categories. Hence, although COU may appear phenotypically heterogeneous, COU phenotypes are likely to share common molecular bases. On the other hand, mutations in TNXB were more often identified in COU-NOS cases, demonstrating the diagnostic challenge in discriminating COU from hydronephrosis secondary to vesicoureteral reflux, particularly when diagnostic imaging is incomplete. Pathogenic SNVs in only six genes were found in more than one individual, supporting high genetic heterogeneity. Finally, convergence between data on SNVs and GDs suggest MYH11 as a dosage-sensitive gene possibly correlating with severity of COU. CONCLUSIONS: We established a genomic diagnosis in 10.0% of COU individuals. The findings underscore the urgent need to identify novel genetic susceptibility factors to COU to better define the natural history of the remaining 90% of cases without a molecular diagnosis.
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Hidronefrosis , Obstrucción Ureteral , Reflujo Vesicoureteral , Humanos , Variaciones en el Número de Copia de ADN , Obstrucción Ureteral/complicaciones , Obstrucción Ureteral/genética , Reflujo Vesicoureteral/diagnóstico , Reflujo Vesicoureteral/genética , Pelvis Renal/patologíaRESUMEN
Although Dara-VCD (daratumumab-bortezomib-cyclophosphamide-dexamethasone) has revolutionized the treatment of newly diagnosed Amyloid Light chain (AL) amyloidosis, patients with stage IIIb disease were excluded in the pivotal trial. We performed a multicentre retrospective cohort study to investigate the outcomes of 19 consecutive patients treated with Dara-VCD front-line therapy who had stage IIIb AL at diagnosis. More than two thirds presented with New York Heart Association Class III/IV symptoms, and had a median of two organs involved (range, 2-4). The haematologic overall response rate was 100%, with 17/19 patients (89.5%) achieving a very good partial response (VGPR) or better. Haematologic responses were achieved rapidly, as evidenced by 63% of evaluable patients with involved serum free light chains (iFLC) < 2 mg/dl and the difference between involved and uninvolved serum free light chains (dFLC) <1 mg/dl at three months. Among 18 evaluable patients, 10 (56%) achieved a cardiac organ response and six (33%) cardiac VGPR or better. The median time to first cardiac response was 1.9 months (range, 0.4-7.3). At a median follow-up of 12 months for surviving patients, estimated one-year overall survival was 67.5% [95% confidence interval (CI), 43.8-84.7]. The incidence of grade 3 or higher infections was 21%, with no infection-related mortality thus far. In summary, Dara-VCD has a promising efficacy and safety profile in stage IIIb AL, and should be studied in prospective trials.
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Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Humanos , Bortezomib/efectos adversos , Ciclofosfamida/efectos adversos , Dexametasona/efectos adversos , Estudios Prospectivos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
RATIONALE & OBJECTIVE: The clinical implications of the discrepancy between cystatin C (cysC)- and serum creatinine (Scr)-estimated glomerular filtration rate (eGFR) in patients with heart failure (HF) and reduced ejection fraction (HFrEF) are unknown. STUDY DESIGN: Post-hoc analysis of randomized trial data. SETTING & PARTICIPANTS: 1,970 patients with HFrEF enrolled in PARADIGM-HF with available baseline cysC and Scr measurements. EXPOSURE: Intraindividual differences between eGFR based on cysC (eGFRcysC) and Scr (eGFRScr; eGFRdiffcysC-Scr). OUTCOMES: Clinical outcomes included the PARADIGM-HF primary end point (composite of cardiovascular [CV] mortality or HF hospitalization), CV mortality, all-cause mortality, and worsening kidney function. We also examined poor health-related quality of life (HRQoL), frailty, and worsening HF (WHF), defined as HF hospitalization, emergency department visit, or outpatient intensification of therapy between baseline and 8-month follow-up. ANALYTICAL APPROACH: Fine-Gray subdistribution hazard models and Cox proportional hazards models were used to regress clinical outcomes on baseline eGFRdiffcysC-Scr. Logistic regression was used to investigate the association of baseline eGFRdiffcysC-Scr with poor HRQoL and frailty. Linear regression models were used to assess the association of WHF with eGFRcysC, eGFRScr, and eGFRdiffcysC-Scr at 8-month follow-up. RESULTS: Baseline eGFRdiffcysC-Scr was higher than +10 and lower than-10mL/min/1.73m2 in 13.0% and 35.7% of patients, respectively. More negative values of eGFRdiffcysC-Scr were associated with worse outcomes ([sub]hazard ratio per standard deviation: PARADIGM-HF primary end point, 1.18; P=0.008; CV mortality, 1.34; P=0.001; all-cause mortality, 1.39; P<0.001; worsening kidney function, 1.31; P=0.05). For a 1-standard-deviation decrease in eGFRdiffcysC-Scr, the prevalences of poor HRQoL and frailty increased by 29% and 17%, respectively (P≤0.008). WHF was associated with a more pronounced decrease in eGFRcysC than in eGFRScr, resulting in a change in 8-month eGFRdiffcysC-Scr of-4.67mL/min/1.73m2 (P<0.001). LIMITATIONS: Lack of gold-standard assessment of kidney function. CONCLUSIONS: In patients with HFrEF, discrepancies between eGFRcysC and eGFRScr are common and are associated with clinical outcomes, HRQoL, and frailty. The decline in kidney function associated with WHF is more marked when assessed with eGFRcysC than with eGFRScr. PLAIN-LANGUAGE SUMMARY: Kidney function assessment traditionally relies on serum creatinine (Scr) to establish an estimated glomerular filtration rate (eGFR). However, this has been challenged with the introduction of an alternative marker, cystatin C (cysC). Muscle mass and nutritional status have differential effects on eGFR based on cysC (eGFRcysC) and Scr (eGFRScr). Among ambulatory patients with heart failure enrolled in PARADIGM-HF, we investigated the clinical significance of the difference between eGFRcysC and eGFRScr. More negative values (ie, eGFRScr>eGFRcysC) were associated with worse clinical outcomes (including mortality), poor quality of life, and frailty. In patients with progressive heart failure, which is characterized by muscle loss and poor nutritional status, the decline in kidney function was more pronounced when eGFR was estimated using cysC rather than Scr.
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Systemic immunoglobulin light-chain amyloidosis is characterized by pathologic deposition of immunoglobulin light chains as amyloid fibrils in vital organs, leading to organ impairment and eventual death. That the process is reversible was evidenced in an in vivo experimental model in which fibril-reactive chimeric monoclonal antibody (mAb) 11-1F4 directly targeted human light-chain amyloid deposits and affected their removal via a phagocyte-mediated response. To determine the tolerability and potential amyloidolytic effect of this agent (now designated mAb CAEL-101), we conducted a phase 1a/b study involving 27 patients, most of whom had manifestations of organ involvement. This was an open-label study in which phase 1a patients received mAb CAEL-101 as a single intravenous infusion with escalating dose levels from 0.5 mg/m2 to 500 mg/m2 to establish the maximum tolerated dose (MTD). In phase 1b, the antibody was administered as a graded series of 4 weekly infusions. For both phases, there were no drug-related serious adverse events or dose-limiting toxicities among recipients, and the MTD was not reached. The majority of patients had deep hematologic responses but persistent organ disease prior to treatment. Fifteen of 24 patients (63%) who manifested cardiac, renal, hepatic, gastrointestinal, or soft tissue involvement had a therapeutic response to mAb CAEL-101 as evidenced by serum biomarkers or objective imaging modalities with a median time to response of 3 weeks. Infusions of mAb CAEL-101 were well tolerated and, for the majority, resulted in improved organ function, notably for those with cardiac impairment. This trial was registered at www.clinicaltrials.gov as #NCT02245867.
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Anticuerpos Monoclonales/uso terapéutico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/sangre , Femenino , Humanos , Infusiones Intravenosas , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
BACKGROUND: In the context of kidney transplantation, genomic incompatibilities between donor and recipient may lead to allosensitization against new antigens. We hypothesized that recessive inheritance of gene-disrupting variants may represent a risk factor for allograft rejection. METHODS: We performed a two-stage genetic association study of kidney allograft rejection. In the first stage, we performed a recessive association screen of 50 common gene-intersecting deletion polymorphisms in a cohort of kidney transplant recipients. In the second stage, we replicated our findings in three independent cohorts of donor-recipient pairs. We defined genomic collision as a specific donor-recipient genotype combination in which a recipient who was homozygous for a gene-intersecting deletion received a transplant from a nonhomozygous donor. Identification of alloantibodies was performed with the use of protein arrays, enzyme-linked immunosorbent assays, and Western blot analyses. RESULTS: In the discovery cohort, which included 705 recipients, we found a significant association with allograft rejection at the LIMS1 locus represented by rs893403 (hazard ratio with the risk genotype vs. nonrisk genotypes, 1.84; 95% confidence interval [CI], 1.35 to 2.50; P = 9.8×10-5). This effect was replicated under the genomic-collision model in three independent cohorts involving a total of 2004 donor-recipient pairs (hazard ratio, 1.55; 95% CI, 1.25 to 1.93; P = 6.5×10-5). In the combined analysis (discovery cohort plus replication cohorts), the risk genotype was associated with a higher risk of rejection than the nonrisk genotype (hazard ratio, 1.63; 95% CI, 1.37 to 1.95; P = 4.7×10-8). We identified a specific antibody response against LIMS1, a kidney-expressed protein encoded within the collision locus. The response involved predominantly IgG2 and IgG3 antibody subclasses. CONCLUSIONS: We found that the LIMS1 locus appeared to encode a minor histocompatibility antigen. Genomic collision at this locus was associated with rejection of the kidney allograft and with production of anti-LIMS1 IgG2 and IgG3. (Funded by the Columbia University Transplant Center and others.).
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Proteínas Adaptadoras Transductoras de Señales/genética , Variaciones en el Número de Copia de ADN , Rechazo de Injerto/genética , Trasplante de Riñón , Proteínas con Dominio LIM/genética , Proteínas Adaptadoras Transductoras de Señales/inmunología , Estudios de Cohortes , Estudios de Asociación Genética , Genotipo , Antígenos HLA/genética , Prueba de Histocompatibilidad , Humanos , Inmunoglobulina G/sangre , Proteínas con Dominio LIM/inmunología , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Polimorfismo de Nucleótido Simple , Donantes de TejidosRESUMEN
BACKGROUND: Exome sequencing is emerging as a first-line diagnostic method in some clinical disciplines, but its usefulness has yet to be examined for most constitutional disorders in adults, including chronic kidney disease, which affects more than 1 in 10 persons globally. METHODS: We conducted exome sequencing and diagnostic analysis in two cohorts totaling 3315 patients with chronic kidney disease. We assessed the diagnostic yield and, among the patients for whom detailed clinical data were available, the clinical implications of diagnostic and other medically relevant findings. RESULTS: In all, 3037 patients (91.6%) were over 21 years of age, and 1179 (35.6%) were of self-identified non-European ancestry. We detected diagnostic variants in 307 of the 3315 patients (9.3%), encompassing 66 different monogenic disorders. Of the disorders detected, 39 (59%) were found in only a single patient. Diagnostic variants were detected across all clinically defined categories, including congenital or cystic renal disease (127 of 531 patients [23.9%]) and nephropathy of unknown origin (48 of 281 patients [17.1%]). Of the 2187 patients assessed, 34 (1.6%) had genetic findings for medically actionable disorders that, although unrelated to their nephropathy, would also lead to subspecialty referral and inform renal management. CONCLUSIONS: Exome sequencing in a combined cohort of more than 3000 patients with chronic kidney disease yielded a genetic diagnosis in just under 10% of cases. (Funded by the National Institutes of Health and others.).
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Exoma , Predisposición Genética a la Enfermedad , Mutación , Insuficiencia Renal Crónica/genética , Análisis de Secuencia de ADN/métodos , Adulto , Anciano , Estudios de Cohortes , Variación Genética , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia Renal Crónica/etnología , Adulto JovenRESUMEN
Coronary artery disease is highly prevalent in patients with end-stage renal disease (ESRD), and cardiovascular complications remain the most common cause of death in this patient population. Accordingly, many cardiac surgical procedures requiring cardiopulmonary bypass support are performed on these patients each year, with morbidity and mortality rates far exceeding patients without ESRD. Anuric patients lack the normal renal homeostatic functions which typically allow for physiologic protection from challenges during the operation, such as volume overload, hyperkalemia, and acidemia. Careful preoperative planning and coordination to provide pre-, intra-, and postoperative renal replacement therapies for such patients are imperative. Many different strategies have been reported in the literature. Zero-balance ultrafiltration is a newer strategy which utilizes convective ultrafiltration much like pre-filter continuous renal replacement therapy and utilizes pre-existing connections on the cardiopulmonary bypass pump performed by the perfusion team. This allows for control of potassium concentration throughout the operation with existing personnel and minimal additional equipment. Here, we describe the unique challenges caring for patients receiving renal replacement therapy undergoing cardiac surgical procedures requiring cardiopulmonary bypass.
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Hydralazine, a widely used therapy for hypertension and heart failure, can elicit autoimmune disease, including anti-neutrophil cytoplasmic antibody associated glomerulonephritis (ANCA-GN). We identified 80 cases of ANCA-GN complicating treatment with hydralazine, accounting for 4.3% (80/1858 biopsies) of ANCA-GN diagnosed between 2006 and 2019. Over three-fourths of patients were on hydralazine for at least one year, with mean daily dose of approximately 250 mg/day. ANCA testing revealed p-ANCA/myeloperoxidase-ANCA seropositivity in 98%, including 39% with dual p-ANCA/myeloperoxidase-ANCA and cANCA/anti-protinase 3-ANCA positivity, often accompanied by anti-nuclear antibody (89%), anti-histone antibody (98%), and hypocomplementemia (58%). Kidney biopsy revealed necrotizing and crescentic glomerulonephritis, similar to primary ANCA-GN, but significantly less frequently pauci-immune (77 vs. 100%) and more commonly associated with mesangial hypercellularity (30 vs. 5%), electron dense deposits (62 vs. 20%), and endothelial tubuloreticular inclusions (11 vs. 0%); all significant differences. On follow-up, 42 of 51 patients received induction immunosuppression: 19 reached the combined end-points of kidney failure or death and 32 had mean creatinine of 1.49 mg/dL at last follow-up. Thus, hydralazine-associated ANCA-GN often exhibits overlapping clinical and pathologic features of mild immune complex glomerulonephritis resembling lupus nephritis. With discontinuation of hydralazine and immunosuppression, outcomes are similar to primary ANCA-GN.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Glomerulonefritis , Hipertensión , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inducido químicamente , Anticuerpos Anticitoplasma de Neutrófilos , Glomerulonefritis/inducido químicamente , Humanos , Hidralazina/efectos adversos , PeroxidasaRESUMEN
Outcomes relevant to treatment decision-making are inconsistently reported in trials involving glomerular disease. Here, we sought to establish a consensus-derived set of critically important outcomes designed to be reported in all future trials by using an online, international two-round Delphi survey in English. To develop this, patients with glomerular disease, caregivers and health professionals aged 18 years and older rated the importance of outcomes using a Likert scale and a Best-Worst scale. The absolute and relative importance was assessed and comments were analyzed thematically. Of 1198 participants who completed Round 1, 734 were patients/caregivers while 464 were health care professionals from 59 countries. Of 700 participants that completed Round 2, 412 were patients/caregivers and 288 were health care professionals. Need for dialysis or transplant, kidney function, death, cardiovascular disease, remission-relapse and life participation were the most important outcomes to patients/caregivers and health professionals. Patients/caregivers rated patient-reported outcomes higher while health care professionals rated hospitalization, death and remission/relapse higher. Four themes explained the reasons for their priorities: confronting death and compounded suffering, focusing on specific targets in glomerular disease, preserving meaning in life, and fostering self-management. Thus, consistent reporting of these critically important outcomes in all trials involving glomerular disease is hoped to improve patient-centered decision-making.
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Cuidadores , Diálisis Renal , Adulto , Técnica Delphi , Humanos , Evaluación de Resultado en la Atención de Salud , Encuestas y CuestionariosRESUMEN
The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Glomerular Diseases is an update to the KDIGO 2012 guideline. The aim is to assist clinicians caring for individuals with glomerulonephritis (GN), both adults and children. The scope includes various glomerular diseases, including IgA nephropathy and IgA vasculitis, membranous nephropathy, nephrotic syndrome, minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), infection-related GN, antineutrophil cytoplasmic antibody (ANCA) vasculitis, lupus nephritis, and anti-glomerular basement membrane antibody GN. In addition, this guideline will be the first to address the subtype of complement-mediated diseases. Each chapter follows the same format providing guidance related to diagnosis, prognosis, treatment, and special situations. The goal of the guideline is to generate a useful resource for clinicians and patients by providing actionable recommendations based on evidence syntheses, with useful infographics incorporating views from experts in the field. Another aim is to propose research recommendations for areas where there are gaps in knowledge. The guideline targets a broad global audience of clinicians treating GN while being mindful of implications for policy and cost. Development of this guideline update followed an explicit process whereby treatment approaches and guideline recommendations are based on systematic reviews of relevant studies, and appraisal of the quality of the evidence and the strength of recommendations followed the "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) approach. Limitations of the evidence are discussed, with areas of future research also presented.
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Glomerulonefritis por IGA , Glomerulonefritis Membranosa , Glomerulonefritis , Nefrosis Lipoidea , Adulto , Niño , Glomerulonefritis/diagnóstico , Glomerulonefritis/terapia , Glomerulonefritis por IGA/diagnóstico , Glomerulonefritis por IGA/terapia , Glomerulonefritis Membranosa/diagnóstico , Glomerulonefritis Membranosa/tratamiento farmacológico , Humanos , RiñónRESUMEN
RATIONALE & OBJECTIVE: Anti-glomerular basement membrane (GBM) disease is a rapidly progressive glomerulonephritis which, in some instances, occurs concurrently with other diseases such as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Rarely, it also occurs with membranous nephropathy (MN). We report a series of such patients, characterizing their long-term follow up. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Twelve patients referred to 1 medical center between 2001 and 2019 with anti-GBM disease and MN whose clinical characteristics and course were described. RESULTS: Patients' ages ranged from 20 to 81 years old, and all presented with severe acute kidney injury requiring dialysis on presentation or shortly thereafter. Only 1 patient had pulmonary findings on presentation. The predominant pathology was crescentic and necrotizing glomerulonephritis with linear staining for immunoglobulin G along the GBM associated with epimembranous electron-dense immune-type deposits. All 11 patients who were tested had significant titers of anti-GBM antibodies, but only 1 of the 5 tested for phospholipase A2 receptor (PLA2R) on biopsy was positive. Eight patients received therapy with cyclophosphamide, prednisone, and plasmapheresis; 2 patients with prednisone and plasmapheresis; and 2 with rituximab-based regimens. Progression to a requirement for kidney replacement therapy occurred in all 12 patients, but 2 patients later recovered kidney function. Recurrence of anti-GBM disease did not occur for any of the patients studied. LIMITATIONS: Incomplete testing for PLA2R in biopsy and serum, limited sample size, and lack of uniform treatment regimen. CONCLUSIONS: In this case series, the presentation of concurrent anti-GBM disease and MN was characterized by rapidly progressive glomerulonephritis and poor kidney outcomes. These findings suggest possible value from earlier diagnosis and the need for identification of more effective treatment regimens.
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Enfermedad por Anticuerpos Antimembrana Basal Glomerular/complicaciones , Glomerulonefritis Membranosa/complicaciones , Lesión Renal Aguda/etiología , Lesión Renal Aguda/terapia , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/inmunología , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/terapia , Autoanticuerpos/inmunología , Ciclofosfamida/uso terapéutico , Femenino , Membrana Basal Glomerular/inmunología , Glomerulonefritis Membranosa/terapia , Glucocorticoides/uso terapéutico , Humanos , Inmunoglobulina G/inmunología , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Plasmaféresis , Prednisona/uso terapéutico , Diálisis Renal , Adulto JovenRESUMEN
BACKGROUND: AKI is common among hospitalized patients with coronavirus disease 2019 (COVID-19) and is an independent risk factor for mortality. Although there are numerous potential mechanisms underlying COVID-19-associated AKI, our current knowledge of kidney pathologic findings in COVID-19 is limited. METHODS: We examined the postmortem kidneys from 42 patients who died of COVID-19. We reviewed light microscopy findings in all autopsies and performed immunofluorescence, electron microscopy, and in situ hybridization studies for SARS-CoV-2 on a subset of samples. RESULTS: The cohort had a median age of 71.5 years (range, 38-97 years); 69% were men, 57% were Hispanic, and 73% had a history of hypertension. Among patients with available data, AKI developed in 31 of 33 patients (94%), including 6 with AKI stage 1, 9 with stage 2, and 16 with stage 3. The predominant finding correlating with AKI was acute tubular injury. However, the degree of acute tubular injury was often less severe than predicted for the degree of AKI, suggesting a role for hemodynamic factors, such as aggressive fluid management. Background changes of hypertensive arterionephrosclerosis and diabetic glomerulosclerosis were frequent but typically mild. We identified focal kidney fibrin thrombi in 6 of 42 (14%) autopsies. A single Black patient had collapsing FSGS. Immunofluorescence and electron microscopy were largely unrevealing, and in situ hybridization for SARS-CoV-2 showed no definitive positivity. CONCLUSIONS: Among a cohort of 42 patients dying with COVID-19, autopsy histologic evaluation revealed acute tubular injury, which was typically mild relative to the degree of creatinine elevation. These findings suggest potential for reversibility upon resolution of SARS-CoV-2 infection.
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Betacoronavirus , Infecciones por Coronavirus/patología , Riñón/patología , Neumonía Viral/patología , Lesión Renal Aguda/patología , Adulto , Anciano , Anciano de 80 o más Años , Autopsia , COVID-19 , Femenino , Humanos , Riñón/ultraestructura , Túbulos Renales/patología , Masculino , Persona de Mediana Edad , Pandemias , SARS-CoV-2RESUMEN
BACKGROUND: The relative immunosuppression and high prevalence of comorbidities in patients with ESKD on dialysis raise concerns that they may have an elevated risk of severe coronavirus disease 2019 (COVID-19), but outcomes for COVID-19 in such patients are unclear. METHODS: To examine presentation and outcomes of COVID-19 in patients with ESKD on dialysis, we retrospectively collected clinical data on 59 patients on dialysis who were hospitalized with COVID-19. We used Wilcoxon rank sum and Fischer exact tests to compare patients who died versus those still living. RESULTS: Two of the study's 59 patients were on peritoneal dialysis, and 57 were on hemodialysis. Median age was 63 years, with high prevalence of hypertension (98%) and diabetes (69%). Patients who died were significantly older than those still living (median age, 75 versus 62 years) and had a higher median Charlson comorbidity index (8 versus 7). The most common presenting symptoms were fever (49%) and cough (39%); initial radiographs most commonly showed multifocal or bilateral opacities (59%). By end of follow-up, 18 patients (31%) died a median 6 days after hospitalization, including 75% of patients who required mechanical ventilation. Eleven of those who died had advanced directives against intubation. The remaining 41 patients (69%) were discharged home a median 8 days after admission. The median initial white blood cell count was significantly higher in patients who died compared with those still living (7.5 versus 5.7×103/µl), as was C-reactive protein (163 versus 80 mg/L). CONCLUSIONS: The association of COVID-19 with high mortality in patients with ESKD on dialysis reinforces the need to take appropriate infection control measures to prevent COVID-19 spread in this vulnerable population.
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Infecciones por Coronavirus/epidemiología , Control de Infecciones/organización & administración , Fallo Renal Crónico/epidemiología , Evaluación de Resultado en la Atención de Salud , Neumonía Viral/epidemiología , Diálisis Renal/métodos , Adulto , Factores de Edad , Anciano , COVID-19 , Causas de Muerte , Estudios de Cohortes , Comorbilidad , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/terapia , Femenino , Mortalidad Hospitalaria/tendencias , Hospitalización/estadística & datos numéricos , Hospitales Universitarios , Humanos , Unidades de Cuidados Intensivos/organización & administración , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Ciudad de Nueva York , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/terapia , Prevalencia , Diálisis Renal/mortalidad , Estudios Retrospectivos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Factores Sexuales , Estadísticas no Paramétricas , Análisis de Supervivencia , Poblaciones Vulnerables/estadística & datos numéricosRESUMEN
RATIONALE & OBJECTIVES: Posttransplantation membranous nephropathy (MN) represents a rare complication of kidney transplantation that can be classified as recurrent or de novo. The clinical, pathologic, and immunogenetic characteristics of posttransplantation MN and the differences between de novo and recurrent MN are not well understood. STUDY DESIGN: Multicenter case series. SETTING & PARTICIPANTS: We included 77 patients from 5 North American and European medical centers with post-kidney transplantation MN (27 de novo and 50 recurrent). Patients with MN in the native kidney who received kidney allografts but did not develop recurrent MN were used as nonrecurrent controls (n = 43). To improve understanding of posttransplantation MN, we compared de novo MN with recurrent MN and then contrasted recurrent MN with nonrecurrent controls. FINDINGS: Compared with recurrent MN, de novo MN was less likely to be classified as primary MN (OR, 0.04; P < 0.001) and had more concurrent antibody-mediated rejection (OR, 12.0; P < 0.001) and inferior allograft survival (HR for allograft failure, 3.2; P = 0.007). HLA-DQ2 and HLA-DR17 antigens were more common in recipients with recurrent MN compared with those with de novo MN; however, the frequency of these recipient antigens in recurrent MN was similar to that in nonrecurrent MN controls. Among the 93 kidney transplant recipients with native kidney failure attributed to MN, older recipient age (HR per each year older, 1.03; P = 0.02), recipient HLA-A3 antigen (HR, 2.5; P = 0.003), steroid-free immunosuppressive regimens (HR, 2.84; P < 0.001), and living related allograft (HR, 1.94; P = 0.03) were predictors of MN recurrence. LIMITATIONS: Retrospective case series, limited sample size due to rarity of the disease, nonstandardized nature of data collection and biopsies. CONCLUSIONS: De novo and recurrent MN likely represent separate diseases. De novo MN is associated with humoral alloimmunity and guarded outcome. Potential predisposing factors for recurrent MN include recipients who are older, recipient HLA-A3 antigen, steroid-free immunosuppressive regimen, and living related donor kidney.