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1.
Am J Kidney Dis ; 83(2): 229-240, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37742867

RESUMEN

IgA nephropathy (IgAN) is the most common glomerular disease in the world. However, the approach to treatment remains controversial. There has been an explosion of clinical trials over the past decade both to further examine corticosteroid use and usher in additional treatment considerations, including 2 newly approved therapies for IgAN. Sodium glucose cotransporter 2 inhibitors are proving to be effective therapy across proteinuric chronic kidney diseases, and IgAN is not likely to be an exception. Further supportive agents are looking highly promising and so are novel agents that specifically focus on the pathophysiology of this disease, including endothelin blockade, complement inhibition, and B-cell targeted strategies. We suggest a present-day approach to treatment of individuals with IgAN, expose the limitations in our knowledge, and discuss new treatments that may arise, hoping they come with evidence about optimal utilization. Change appears to be inevitable for our approach to the treatment of IgA nephropathy. This is truly an exciting and optimistic time.


Asunto(s)
Glomerulonefritis por IGA , Insuficiencia Renal Crónica , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Glomerulonefritis por IGA/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico
2.
Kidney Int ; 104(2): 254-264, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37263354

RESUMEN

Many patients with immunoglobulin A nephropathy (IgAN) progress to kidney failure even with optimal supportive care. An improved understanding of the pathophysiology of IgAN in recent years has led to the investigation of targeted therapies with acceptable tolerability that may address the underlying causes of IgAN or the pathogenesis of kidney injury. The complement system-particularly the lectin and alternative pathways of complement-has emerged as a key mediator of kidney injury in IgAN and a possible target for investigational therapy. This review will focus on the lectin pathway. The examination of kidney biopsies has consistently shown glomerular deposition of mannan-binding lectin (1 of 6 pattern-recognition molecules that activate the lectin pathway) together with IgA1 in up to 50% of patients with IgAN. Glomerular deposition of pattern-recognition molecules for the lectin pathway is associated with more severe glomerular damage and more severe proteinuria and hematuria. Emerging research suggests that the lectin pathway may also contribute to tubulointerstitial fibrosis in IgAN and that collectin-11 is a key mediator of this association. This review summarizes the growing scientific and clinical evidence supporting the role of the lectin pathway in IgAN and examines the possible therapeutic role of lectin pathway inhibition for these patients.


Asunto(s)
Glomerulonefritis por IGA , Humanos , Glomerulonefritis por IGA/patología , Lectinas/metabolismo , Glomérulos Renales/patología , Riñón/patología , Inmunoglobulina A/metabolismo
3.
Kidney Int ; 103(3): 565-579, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36442540

RESUMEN

The diagnosis of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies, but not specific to underlying pathobiology. Consequently, there are variable rates of progression and response to therapy within diagnoses. Here, an unbiased transcriptomic-driven approach was used to identify molecular pathways which are shared by subgroups of patients with either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). Kidney tissue transcriptomic profile-based clustering identified three patient subgroups with shared molecular signatures across independent, North American, European, and African cohorts. One subgroup had significantly greater disease progression (Hazard Ratio 5.2) which persisted after adjusting for diagnosis and clinical measures (Hazard Ratio 3.8). Inclusion in this subgroup was retained even when clustering was limited to those with less than 25% interstitial fibrosis. The molecular profile of this subgroup was largely consistent with tumor necrosis factor (TNF) pathway activation. Two TNF pathway urine markers were identified, tissue inhibitor of metalloproteinases-1 (TIMP-1) and monocyte chemoattractant protein-1 (MCP-1), that could be used to predict an individual's TNF pathway activation score. Kidney organoids and single-nucleus RNA-sequencing of participant kidney biopsies, validated TNF-dependent increases in pathway activation score, transcript and protein levels of TIMP-1 and MCP-1, in resident kidney cells. Thus, molecular profiling identified a subgroup of patients with either MCD or FSGS who shared kidney TNF pathway activation and poor outcomes. A clinical trial testing targeted therapies in patients selected using urinary markers of TNF pathway activation is ongoing.


Asunto(s)
Glomeruloesclerosis Focal y Segmentaria , Nefrología , Nefrosis Lipoidea , Síndrome Nefrótico , Humanos , Glomeruloesclerosis Focal y Segmentaria/patología , Nefrosis Lipoidea/diagnóstico , Inhibidor Tisular de Metaloproteinasa-1 , Síndrome Nefrótico/diagnóstico , Factores de Necrosis Tumoral/uso terapéutico
4.
N Engl J Med ; 381(1): 36-46, 2019 07 04.
Artículo en Inglés | MEDLINE | ID: mdl-31269364

RESUMEN

BACKGROUND: B-cell anomalies play a role in the pathogenesis of membranous nephropathy. B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition. METHODS: We randomly assigned patients who had membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 ml per minute per 1.73 m2 of body-surface area and had been receiving angiotensin-system blockade for at least 3 months to receive intravenous rituximab (two infusions, 1000 mg each, administered 14 days apart; repeated at 6 months in case of partial response) or oral cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed for 24 months. The primary outcome was a composite of complete or partial remission of proteinuria at 24 months. Laboratory variables and safety were also assessed. RESULTS: A total of 130 patients underwent randomization. At 12 months, 39 of 65 patients (60%) in the rituximab group and 34 of 65 (52%) in the cyclosporine group had a complete or partial remission (risk difference, 8 percentage points; 95% confidence interval [CI], -9 to 25; P = 0.004 for noninferiority). At 24 months, 39 patients (60%) in the rituximab group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; P<0.001 for both noninferiority and superiority). Among patients in remission who tested positive for anti-phospholipase A2 receptor (PLA2R) antibodies, the decline in autoantibodies to anti-PLA2R was faster and of greater magnitude and duration in the rituximab group than in the cyclosporine group. Serious adverse events occurred in 11 patients (17%) in the rituximab group and in 20 (31%) in the cyclosporine group (P = 0.06). CONCLUSIONS: Rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months. (Funded by Genentech and the Fulk Family Foundation; MENTOR ClinicalTrials.gov number, NCT01180036.).


Asunto(s)
Ciclosporina/uso terapéutico , Glomerulonefritis Membranosa/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Rituximab/uso terapéutico , Administración Oral , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Ciclosporina/efectos adversos , Esquema de Medicación , Femenino , Humanos , Factores Inmunológicos/uso terapéutico , Inmunosupresores/efectos adversos , Infusiones Intravenosas , Análisis de Intención de Tratar , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Proteinuria/tratamiento farmacológico , Inducción de Remisión , Rituximab/efectos adversos , Insuficiencia del Tratamiento , Adulto Joven
5.
Kidney Int ; 100(4): 881-893, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-33964313

RESUMEN

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.


Asunto(s)
Cuidadores , Diálisis Renal , Adulto , Técnica Delphi , Humanos , Evaluación de Resultado en la Atención de Salud , Encuestas y Cuestionarios
6.
Pediatr Nephrol ; 36(9): 2747-2757, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33646395

RESUMEN

BACKGROUND: The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1's natural absence in laboratory animals makes studying its pathobiology challenging. METHODS: In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes. RESULTS: Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR <0.1) with decreased global mesangial hypercellularity, decreased condensation of cytoskeleton, and increased tubular microcysts. No significant correlations were detected in MCD cohort. Independent of risk alleles, glomerular APOL1 expression in FSGS patients was not correlated with morphologic features. CONCLUSIONS: While APOL1-associated FSGS is associated with two risk alleles, both one and two risk alleles are associated with cellular/tissue changes in this study of FSGS patients. Our lack of discovery of a large group of tissue differences in FSGS and no significant difference in MCD may be due to the lack of power but also supports investigating whether machine learning methods may more sensitively detect APOL1-associated changes.


Asunto(s)
Apolipoproteína L1/genética , Glomeruloesclerosis Focal y Segmentaria , Alelos , Genotipo , Glomeruloesclerosis Focal y Segmentaria/genética , Humanos , Síndrome Nefrótico/genética
7.
Eur Heart J ; 40(11): 887-898, 2019 03 14.
Artículo en Inglés | MEDLINE | ID: mdl-30085056

RESUMEN

AIMS: End-stage renal disease (ESRD) is a strong cardiovascular risk factor. We aimed to determine the extent to which cause of kidney disease independently contributes to this risk. METHODS AND RESULTS: Using a national US ESRD registry, we selected patients with eight different causes of ESRD who initiated dialysis 1997-2014. We used proportional sub-distribution hazard models, with non-cardiovascular death or kidney transplantation as competing risks, to estimate hazard ratios (HRs) for a first composite cardiovascular event (myocardial infarction, ischaemic stroke, or cardiovascular or cerebrovascular death), by cause of ESRD. The population was restricted to those using Medicare insurance at Day 91 after dialysis initiation (when most patients become Medicare eligible). Outcomes were ascertained from Medicare claims or Death Notifications. Among the 658 168 patients identified, composite event rates ranged from 3.5/100 person-years in IgA nephropathy to 14.6/100 person-years in diabetic nephropathy (DN). After adjusting for demographics, socioeconomic factors, comorbidities, dialysis modality, and laboratory values, cardiovascular event HRs differed significantly by cause of ESRD. Comparing to IgA nephropathy, the adjusted HR was highest for DN [aHR = 2.97, 95% confidence interval (CI) 2.77-3.20], next highest for lupus nephritis (aHR = 1.86, 95% CI 1.71-2.03), and thereafter ranged from 1.29 (95% CI 1.19-1.39) in autosomal dominant polycystic kidney disease to 1.67 (95% CI 1.52-1.83) in membranous nephropathy. CONCLUSION: High cardiovascular event rates in dialysis patients vary considerably by cause of ESRD. Determining underlying reasons for these differences might provide new insights in to cardiovascular disease mechanisms as well as inform future drug development and clinical trial design.


Asunto(s)
Nefropatías Diabéticas/complicaciones , Diálisis/efectos adversos , Glomerulonefritis por IGA/complicaciones , Enfermedades Renales/complicaciones , Fallo Renal Crónico/etiología , Adulto , Muerte Encefálica/fisiopatología , Isquemia Encefálica/fisiopatología , Estudios de Cohortes , Comorbilidad , Muerte , Nefropatías Diabéticas/epidemiología , Diálisis/métodos , Diálisis/tendencias , Femenino , Glomerulonefritis por IGA/epidemiología , Humanos , Enfermedades Renales/epidemiología , Fallo Renal Crónico/terapia , Masculino , Medicare/normas , Persona de Mediana Edad , Infarto del Miocardio/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Accidente Cerebrovascular/epidemiología , Estados Unidos/epidemiología
8.
Blood ; 130(7): 900-902, 2017 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-28615223

RESUMEN

The majority of patients with immunoglobulin light chain amyloidosis (AL) fail to achieve a complete response (CR) to standard light chain suppressive chemotherapy, and almost all patients eventually experience hematologic relapse and progression of organ involvement. Additional well-tolerated treatment options are needed. We present our retrospective experience of 25 consecutive previously treated AL patients who received daratumumab, a CD38-directed monoclonal antibody approved for the treatment of multiple myeloma. Daratumumab was administered at 16 mg/kg weekly for 8 weeks, then every 2 weeks for 8 doses, and then every 4 weeks. Patients had received a median of 3 prior lines of therapy, with a previous hematologic CR in only 5 patients. The overall hematologic response rate to daratumumab was 76%, including CR in 36% and very good partial response in 24%. Median time to response was 1 month. Therapy was well tolerated, even among the 72% of patients with cardiac AL involvement. Grade 1-2 infusion reactions occurred in 15 patients, but no grade 3 or 4 reactions were observed. Daratumumab is a highly effective agent that produced rapid and deep hematologic responses without unexpected toxicity in our cohort of heavily pretreated AL patients.


Asunto(s)
Amiloidosis/sangre , Amiloidosis/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Cadenas Ligeras de Inmunoglobulina/metabolismo , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad
9.
Int J Mol Sci ; 20(18)2019 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-31510053

RESUMEN

Standard methods for detecting and monitoring of IgA nephropathy (IgAN) have conventionally required kidney biopsies or suffer from poor sensitivity and specificity. The Kidney Injury Test (KIT) Assay of urinary biomarkers has previously been shown to distinguish between various kidney pathologies, including chronic kidney disease, nephrolithiasis, and transplant rejection. This validation study uses the KIT Assay to investigate the clinical utility of the non-invasive detection of IgAN and predicting the progression of renal damage over time. The study design benefits from longitudinally collected urine samples from an investigator-initiated, multicenter, prospective study, evaluating the efficacy of corticosteroids versus Rituximab for preventing progressive IgAN. A total of 131 urine samples were processed for this study; 64 urine samples were collected from 34 IgAN patients, and urine samples from 64 demographically matched healthy controls were also collected; multiple urinary biomarkers consisting of cell-free DNA, methylated cell-free DNA, DMAIMO, MAMIMO, total protein, clusterin, creatinine, and CXCL10 were measured by the microwell-based KIT Assay. An IgA risk score (KIT-IgA) was significantly higher in IgAN patients as compared to healthy control (87.76 vs. 14.03, p < 0.0001) and performed better than proteinuria in discriminating between the two groups. The KIT Assay biomarkers, measured on a spot random urine sample at study entry could distinguish patients likely to have progressive renal dysfunction a year later. These data support the pursuit of larger prospective studies to evaluate the predictive performance of the KIT-IgA score in both screening for non-invasive diagnosis of IgAN, and for predicting risk of progressive renal disease from IgA and utilizing the KIT score for potentially evaluating the efficacy of IgAN-targeted therapies.


Asunto(s)
Biomarcadores/orina , Glomerulonefritis por IGA/orina , Monitoreo Fisiológico/métodos , Corticoesteroides/uso terapéutico , Adulto , Creatinina/orina , Progresión de la Enfermedad , Femenino , Glomerulonefritis por IGA/diagnóstico , Glomerulonefritis por IGA/tratamiento farmacológico , Humanos , Inmunoglobulina A/orina , Factores Inmunológicos/uso terapéutico , Riñón/patología , Riñón/fisiopatología , Pruebas de Función Renal/métodos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteinuria/orina , Rituximab/uso terapéutico , Sensibilidad y Especificidad , Adulto Joven
10.
Kidney Int ; 94(4): 795-808, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30093081

RESUMEN

Focal segmental glomerular sclerosis (FSGS) is a devastating disease with limited treatment options and poor prognosis. Activated JAK-STAT signaling has been implicated in other kidney diseases. Since new technologies allow us to better evaluate changes in systemic and renal JAK-STAT activity as it relates to kidney function, we examined this in 106 patients with biopsy-proven FSGS compared to 47 healthy control individuals. Peripheral immune function was assessed in peripheral blood mononuclear cells by phosphoflow studies before and after cytokine stimulation. Kidney JAK-STAT activity was measured by immunofluorescence and by transcriptomics. A STAT1 activity score was calculated by evaluating message status of downstream targets of pSTAT 1. Peripheral blood mononuclear cells were found to be upregulated in terms of pSTAT production at baseline in FSGS and to have limited reserve to respond to various cytokines. Increased staining for components of the JAK-STAT system in FSGS by microscopy was found. Furthermore, we found transcriptomic evidence for activation of JAK-STAT that increased pSTAT 1 and pSTAT 3 in glomerular and tubulointerstitial sections of the kidney. Some of these changes were associated with the likelihood of remission of proteinuria and progression of disease. JAK-STAT signaling is altered in patients with FSGS as compared to healthy controls with activated peripheral immune cells, increased message in the kidney and increased activated proteins in the kidney. Thus, our findings support immune activation in this disease and point to the JAK-STAT pathway as a potential target for treatment of FSGS.


Asunto(s)
Glomeruloesclerosis Focal y Segmentaria/genética , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Janus Quinasa 1/metabolismo , Janus Quinasa 2/metabolismo , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT3/metabolismo , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Perfilación de la Expresión Génica , Glomeruloesclerosis Focal y Segmentaria/sangre , Glomeruloesclerosis Focal y Segmentaria/inmunología , Humanos , Janus Quinasa 1/sangre , Janus Quinasa 1/genética , Janus Quinasa 2/sangre , Janus Quinasa 2/genética , Glomérulos Renales/metabolismo , Leucocitos Mononucleares/inmunología , Masculino , Persona de Mediana Edad , Fosforilación , Factor de Transcripción STAT1/sangre , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT3/sangre , Transducción de Señal , Transcriptoma , Adulto Joven
11.
Am J Nephrol ; 47 Suppl 1: 43-52, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29852501

RESUMEN

BACKGROUND: Immunoglobulin A (IgA) nephropathy is the most common form of primary glomerulonephritis and has clinical associations with a wide range of inflammatory and infectious diseases. There is a substantial variation in clinical course and outcomes, with many patients not diagnosed until they present with sequelae, which may include gross hematuria, hypertension, renal insufficiency, and/or significant proteinuria. Treatment options are currently limited and directed mainly toward control of these sequelae and have limited ability to reduce the incidence of end-stage renal disease or treat the primary IgA defect. SUMMARY: Growing knowledge about the pathogenesis of IgA nephropathy and research into its genetic basis are helping to elucidate the course of this widely variable disease. IgA accumulation in the kidneys is thought to be the result of a number of different pathways in a "multi-hit" process that includes an initial traumatic trigger (often infection related) and subsequent memory responses that are amplified in those with a genetic predisposition to the disease and lead to an inflammatory response in susceptible individuals. Genome-wide association studies are providing new insights into the genetic variance of this autoimmune disease and are yielding information that may address both its causes and consequences. Key Messages: New treatment approaches are urgently required for the management of patients with IgA nephropathy. Novel interventions based around its inflammatory nature and "multi-hit" pathogenesis are being investigated to potentially limit disease progression.


Asunto(s)
Glomerulonefritis por IGA/tratamiento farmacológico , Glomerulonefritis por IGA/etiología , Glomerulonefritis por IGA/diagnóstico , Glomerulonefritis por IGA/genética , Humanos
12.
BMC Nephrol ; 19(1): 355, 2018 12 12.
Artículo en Inglés | MEDLINE | ID: mdl-30541482

RESUMEN

BACKGROUND: Renal thrombotic microangiopathy (TMA) is occasionally seen in biopsies with pauci-immune necrotizing crescentic glomerulonephritis (PCGN). Recent study indicated that the complement activation is more prominent in the ANCA-negative glomerulonephritis. CASE PRESENTATION: We report a case of concurrent TMA and PCGN without ANCA positivity. Interestingly, our patient also had biopsy features supportive of Alport syndrome (AS). Genetic studies identified variants and polymorphisms in alternative complement pathway genes that confer substantial risk of developing atypical hemolytic uremic syndrome (aHUS). CONCLUSIONS: Abnormal activation in complement pathway may represent a common pathogenic link between these three distinct entities.


Asunto(s)
Síndrome Hemolítico Urémico Atípico/complicaciones , Síndrome Hemolítico Urémico Atípico/patología , Glomerulonefritis/complicaciones , Glomerulonefritis/patología , Nefritis Hereditaria/complicaciones , Nefritis Hereditaria/patología , Adulto , Anticuerpos Anticitoplasma de Neutrófilos/sangre , Síndrome Hemolítico Urémico Atípico/genética , Vía Clásica del Complemento/genética , Femenino , Humanos , Riñón/patología
13.
J Am Soc Nephrol ; 28(2): 632-644, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27432742

RESUMEN

Differences in kidney transplantation outcomes across GN subtypes have rarely been studied. From the US Renal Data System, we identified all adult (≥18 years) first kidney transplant recipients (1996-2011) with ESRD attributed to one of six GN subtypes or two comparator kidney diseases. We computed hazard ratios (HRs) for death, all-cause allograft failure, and allograft failure excluding death as a cause (competing risks framework) using Cox proportional hazards regression. Among the 32,131 patients with GN studied, patients with IgA nephropathy (IgAN) had the lowest mortality rates and patients with IgAN or vasculitis had the lowest allograft failure rates. After adjusting for patient- and transplant-related factors, compared with IgAN (referent), FSGS, membranous nephropathy, membranoproliferative GN, lupus nephritis, and vasculitis associated with HRs (95% confidence intervals) for death of 1.57 (1.43 to 1.72), 1.52 (1.34 to 1.72), 1.76 (1.55 to 2.01), 1.82 (1.63 to 2.02), and 1.56 (1.34 to 1.81), respectively, and with HRs for allograft failure excluding death as a cause of 1.20 (1.12 to 1.28), 1.27 (1.14 to 1.41), 1.50 (1.36 to 1.66), 1.11 (1.02 to 1.20), and 0.94 (0.81 to 1.09), respectively. Considering external comparator groups, and comparing with IgAN, autosomal dominant polycystic kidney disease (ADPKD) and diabetic nephropathy associated with higher HRs for mortality [1.22 (1.12 to 1.34) and 2.57 (2.35 to 2.82), respectively], but ADPKD associated with a lower HR for allograft failure excluding death as a cause [0.85 (0.79 to 0.91)]. Reasons for differential outcomes by GN subtype and cause of ESRD should be examined in future research.


Asunto(s)
Glomerulonefritis/clasificación , Glomerulonefritis/complicaciones , Fallo Renal Crónico/etiología , Fallo Renal Crónico/cirugía , Trasplante de Riñón , Adulto , Anciano , Femenino , Glomerulonefritis/mortalidad , Humanos , Fallo Renal Crónico/mortalidad , Masculino , Persona de Mediana Edad , Tasa de Supervivencia , Resultado del Tratamiento , Estados Unidos
14.
J Am Soc Nephrol ; 28(4): 1306-1313, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27821627

RESUMEN

IgA nephropathy frequently leads to progressive CKD. Although interest surrounds use of immunosuppressive agents added to standard therapy, several recent studies have questioned efficacy of these agents. Depleting antibody-producing B cells potentially offers a new therapy. In this open label, multicenter study conducted over 1-year follow-up, we randomized 34 adult patients with biopsy-proven IgA nephropathy and proteinuria >1 g/d, maintained on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers with well controlled BP and eGFR<90 ml/min per 1.73 m2, to receive standard therapy or rituximab with standard therapy. Primary outcome measures included change in proteinuria and change in eGFR. Median baseline serum creatinine level (range) was 1.4 (0.8-2.4) mg/dl, and proteinuria was 2.1 (0.6-5.3) g/d. Treatment with rituximab depleted B cells and was well tolerated. eGFR did not change in either group. Rituximab did not alter the level of proteinuria compared with that at baseline or in the control group; three patients in each group had ≥50% reduction in level of proteinuria. Serum levels of galactose-deficient IgA1 or antibodies against galactose-deficient IgA1 did not change. In this trial, rituximab therapy did not significantly improve renal function or proteinuria assessed over 1 year. Although rituximab effectively depleted B cells, it failed to reduce serum levels of galactose-deficient IgA1 and antigalactose-deficient IgA1 antibodies. Lack of efficacy of rituximab, at least at this stage and severity of IgA nephropathy, may reflect a failure of rituximab to reduce levels of specific antibodies assigned salient pathogenetic roles in IgA nephropathy.


Asunto(s)
Glomerulonefritis por IGA/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Rituximab/uso terapéutico , Adulto , Femenino , Glomerulonefritis por IGA/complicaciones , Glomerulonefritis por IGA/inmunología , Glomerulonefritis por IGA/fisiopatología , Humanos , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Proteinuria/etiología , Adulto Joven
16.
Am J Kidney Dis ; 67(4): 638-47, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26774466

RESUMEN

BACKGROUND: The type of vascular access used for hemodialysis affects patient morbidity and mortality. Whether vascular access types differ by glomerulonephritis (GN) subtype in the US hemodialysis population has not been investigated. STUDY DESIGN: Cross-sectional observational study. SETTING & PARTICIPANTS: We identified all adult (aged ≥ 18 years) patients within the US Renal Data System who initiated hemodialysis therapy from July 2005 through December 2011 with a diagnosis of end-stage renal disease attributed to any of 4 primary (focal segmental glomerulosclerosis, immunoglobulin A nephropathy [reference group], membranous nephropathy, and membranoproliferative GN) or 2 secondary (lupus nephritis and vasculitis) GN subtypes. PREDICTOR: GN subtype. OUTCOMES: ORs with 95% CIs for arteriovenous fistula versus central venous catheter (CVC) use and for arteriovenous graft versus CVC use were computed using multinomial logistic regression, with adjustment for demographic, socioeconomic, comorbidity, and duration of nephrology care covariates. RESULTS: Among 29,015 patients, CVC use at initiation of hemodialysis therapy was substantially higher in patients with lupus nephritis (89.2%) or vasculitis (91.2%) compared with patients with primary GN subtypes (72.7%-79.8%). After adjustment and compared with patients with immunoglobulin A nephropathy, patients with lupus nephritis or vasculitis were as likely to have used an arteriovenous graft (ORs of 0.94 [95% CI, 0.70-1.27] and 0.80 [95% CI, 0.56-1.13], respectively) but significantly less likely to have used an arteriovenous fistula (ORs of 0.66 [95% CI, 0.57-0.76] and 0.54 [95% CI, 0.45-0.63], respectively), whereas patients with any comparator primary GN subtype were at least as likely to have used either of these 2 access types. LIMITATIONS: Potential misclassification of exposure; residual confounding by unmeasured covariates; inability to determine causes of observed associations; lacking longitudinal data for vascular access use. CONCLUSIONS: Significant differences in vascular access distributions at initiation of hemodialysis therapy are apparent among GN subtypes. The unacceptably high use of CVCs in patients with lupus nephritis and vasculitis is particularly concerning. Further studies are needed to identify any potentially modifiable factors underlying these findings.


Asunto(s)
Derivación Arteriovenosa Quirúrgica , Glomerulonefritis/clasificación , Fallo Renal Crónico/terapia , Diálisis Renal/métodos , Adulto , Catéteres Venosos Centrales , Estudios Transversales , Femenino , Glomerulonefritis/complicaciones , Humanos , Fallo Renal Crónico/complicaciones , Masculino , Persona de Mediana Edad
17.
Am J Nephrol ; 43(5): 348-56, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27166157

RESUMEN

BACKGROUND: Little is known about the endoplasmic reticulum stress (ERS) marker glucose regulated protein 78 (GRP78) and calcineurin in the kidney in primary membranous nephropathy (PMN) and if they could predict post-cyclosporine treatment outcome. METHODS: This is a retrospective study using a dataset of biopsy-confirmed PMN from Peking Union Medical College Hospital from 1996 to 2014. Seventy-six adult patients treated with cyclosporine as primary immunosuppression for at least 6 months were studied. Immunohistochemistry was used to detect GRP78 and calcineurin in the kidney. Serum calcineurin was assayed by ELISA. Patients were grouped into no-remission (NR, n = 17), partial remission (PR, n = 39), or complete remission (CR, n = 20) at the end of 6 months of treatment. RESULTS: There was no difference of initial dose of cyclosporine among NR, PR, and CR groups. Kidney calcineurin expression in PMN was significantly increased compared to that in controls (p < 0.0083). The glomerular GRP78 in NR PMN was higher than that in control, CR and PR patients (p < 0.0083). Kidney calcineurin expression and GRP78 expression was positively correlated. However, there were no differences in either serum calcineurin levels or kidney calcineurin expressions among NR, PR or CR groups. There was a negative correlation between serum calcineurin activity and whole kidney calcineurin expression (p = 0.034) or glomerular calcineurin expression (p = 0.007). Neither kidney calcineurin nor GRP78 expression was correlated with proteinuria. CONCLUSIONS: ERS marker GRP78 in the glomeruli but not serum or kidney calcineurin expression could be a useful marker in PMN to negatively predict the response to cyclosporine treatment at the sixth month.


Asunto(s)
Inhibidores de la Calcineurina/uso terapéutico , Ciclosporina/uso terapéutico , Estrés del Retículo Endoplásmico , Glomerulonefritis Membranosa/tratamiento farmacológico , Adulto , Anciano , Calcineurina/sangre , Chaperón BiP del Retículo Endoplásmico , Femenino , Glomerulonefritis Membranosa/metabolismo , Proteínas de Choque Térmico/metabolismo , Humanos , Riñón/metabolismo , Masculino , Persona de Mediana Edad , Estudios Retrospectivos
18.
Nephrol Dial Transplant ; 31(2): 290-8, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26610594

RESUMEN

BACKGROUND: Kidney transplantation is the preferred treatment for end-stage renal disease (ESRD), while peritoneal dialysis affords certain benefits over hemodialysis. Distributions and determinants of first ESRD treatment modality have not been compared across glomerulonephritis (GN) subtypes. METHODS: We identified all adult (18-75 years) patients with ESRD attributed to any of six GN subtypes [focal segmental glomerulosclerosis (FSGS), IgA nephropathy (IgAN), membranous nephropathy (MN), membranoproliferative GN (MPGN), lupus nephritis (LN) and vasculitis] who were first registered in the US Renal Data System (USRDS) between 1996 and 2011. We used multinomial logistic regression--adjusting for temporal, geographic, demographic, socioeconomic and comorbid factors--to determine odds ratios (ORs) with 95% confidence intervals (CIs) for transplantation versus hemodialysis, and for peritoneal dialysis versus hemodialysis, comparing other GN subtypes to IgAN. RESULTS: Among the 75 278 patients studied, patients with comparator GN subtypes were significantly less likely than those with IgAN to receive either transplantation or peritoneal dialysis. After adjusting for potentially confounding covariates, patients with comparator primary GN subtypes (FSGS, MN, MPGN) were at least as likely to receive transplantation [FSGS OR 0.98 (95% CI 0.93-1.15), MN OR 1.19 (95% CI 1.01-1.39), MPGN OR 1.08 (95% CI 0.93-1.26)] or peritoneal dialysis [FSGS OR 1.05 (95% CI 0.98-1.12), MN OR 1.30 (95% CI 1.18-1.43), MPGN OR 0.95 (95% CI 0.85-1.06)] as patients with IgAN. Conversely, patients with the secondary GN subtypes LN and vasculitis remained significantly less likely to receive either modality [transplantation OR 0.49 (95% CI 0.43-0.56) for LN and 0.27 (95% CI 0.22-0.34) for vasculitis, peritoneal dialysis OR 0.76 (95% CI 0.70-0.82) for LN and 0.54 (95% CI 0.48-0.60) for vasculitis]. CONCLUSIONS: Significant differences in ESRD treatment practice patterns are apparent among GN subtypes. To ensure equitable care for all patients, regardless of GN subtype, reasons for observed disparities should be elucidated and-if appropriate-eliminated.


Asunto(s)
Glomerulonefritis/complicaciones , Fallo Renal Crónico/terapia , Trasplante de Riñón , Diálisis Renal/métodos , Adolescente , Adulto , Anciano , Femenino , Glomerulonefritis/terapia , Glomerulonefritis por IGA/complicaciones , Humanos , Incidencia , Fallo Renal Crónico/epidemiología , Fallo Renal Crónico/etiología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Estados Unidos/epidemiología , Adulto Joven
19.
Pharmacoepidemiol Drug Saf ; 24(6): 654-62, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25903095

RESUMEN

PURPOSE: In recent years, the use of red blood cell (RBC) transfusion for the treatment of chronic kidney disease (CKD)-related anemia has increased. We used the OptumInsight medical claims database to study the association between receiving a transfusion and hyperkalemia and heart failure events. METHODS: Persons 18-64 years of age with diagnosed stage 4 or 5 CKD (not requiring dialysis) between 2006 and 2010 were followed until their first hospitalization or emergency room visit with a diagnosis of hyperkalemia or heart failure, termination of insurance coverage, or death. We used a case-only design and conditional logistic regression to estimate rate ratios (RR) and 95% confidence intervals (CIs) describing associations between RBC transfusion and the risks of hyperkalemia or heart failure. We used single (1:1) and variable (1:m) self-control matching intervals, with adjustment for time-varying confounders. RESULTS: Seven thousand eight hundred twenty-nine individuals met our inclusion criteria; two-thirds were age 50 years or older; 43% were women and 51% had diabetes. Rates of hyperkalemia and heart failure were 7.9/100 person-years (95%CI: 7.3, 8.5) and 16.3/100 person-years (95%CI: 15.5, 17.2), respectively. RBC transfusion was associated with an increased risk of both hyperkalemia (single interval matched RR = 12.0, 95%CI: 1.3, 109; multiple interval matched RR = 6.1, 95%CI: 2.5, 15.1) and heart failure (single interval matched RR = 1.7, 95%CI: 0.3, 9.2; multiple interval matched RR = 3.8, 95%CI: 1.4, 10.3). CONCLUSION: In patients with advanced CKD, RBC transfusion appears to be associated with an elevated risk of hyperkalemia and heart failure; further investigation into these risks is warranted.


Asunto(s)
Transfusión de Eritrocitos/estadística & datos numéricos , Insuficiencia Cardíaca/epidemiología , Hiperpotasemia/epidemiología , Insuficiencia Renal Crónica/epidemiología , Adolescente , Adulto , Anciano , Bases de Datos Factuales , Femenino , Insuficiencia Cardíaca/complicaciones , Humanos , Hiperpotasemia/complicaciones , Revisión de Utilización de Seguros , Masculino , Persona de Mediana Edad , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/mortalidad , Estados Unidos/epidemiología , Adulto Joven
20.
Clin Nephrol ; 84(6): 323-30, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26445002

RESUMEN

BACKGROUND: A recent classification of membranoproliferative glomerulonephritis (MPGN) utilizes the presence of immunoglobulin and complements to simplify diagnosis and point towards disease etiology. Here, we evaluate a historic cohort of patients with idiopathic MPGN using the new classification system and correlate it with clinical outcome. METHODS: We identified 281 patients diagnosed with MPGN at Stanford from 2000 to 2012. Patients with hepatitis, systemic lupus erythematosis, lymphomas, and plasma cell dyscrasias were excluded. The clinicopathologic findings of the remaining 71 patients were further analyzed and differences between immunoglobulin dominant (IM) and complement dominant (CM) disease were evaluated. RESULTS: Using the new classification system, 51 subjects were characterized as CM MPGN and 20 as IM MPGN. In the CM MPGN group, there was a non-significant trend towards lower proteinuria but higher serum creatinine values. At biopsy, most subjects had less than 50% global sclerosis or cortical scarring. The majority of subjects in the CM MPGN group (41%) had C3 nephropathy while 60% of subjects in IM MPGN group had C3 dominant disease. Treatment and outcomes: During follow-up (median 2 years), 20 patients reached a clinical end point of dialysis or death. The mean creatinine was significantly higher while the baseline proteinuria also trended slightly higher. Prednisone use was statistically higher in the survivor group. CONCLUSIONS: Our study highlights the clinicopathological features of patients with biopsy proven MPGN with no known etiological factors and sheds some light on the incidence and outcomes of various categories of MPGN under the new criteria, including MPGN with "dominant C3" deposits, rapidly becoming a descriptive diagnosis.


Asunto(s)
Glomerulonefritis Membranoproliferativa/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Albúminas/análisis , Antiinflamatorios/uso terapéutico , Biopsia/métodos , Niño , Preescolar , Estudios de Cohortes , Complemento C1q/análisis , Complemento C3/análisis , Creatinina/sangre , Femenino , Fibrinógeno/análisis , Estudios de Seguimiento , Glomerulonefritis Membranoproliferativa/clasificación , Humanos , Inmunoglobulina A/análisis , Inmunoglobulina G/análisis , Inmunoglobulina M/análisis , Cadenas kappa de Inmunoglobulina/análisis , Cadenas lambda de Inmunoglobulina/análisis , Corteza Renal/patología , Masculino , Persona de Mediana Edad , Prednisona/uso terapéutico , Proteinuria/orina , Adulto Joven
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