En torno al 25% de los pacientes con nefropatía IgA (NIgA) progresa hacia el estadio 5 de la enfermedad renal crónica tras años de evolución. En los últimos años se han desarrollado diversas ...herramientas diseñadas para predecir qué pacientes evolucionan peor. El valor de IgA1 galactosil-deficiente (Gd-IgA1) circulante se ha relacionado con una peor evolución de la NIgA en algunos estudios. También hay varios trabajos que relacionan valores más elevados de APRIL con una peor evolución. Recientemente se ha desarrollado un método que permite medir el valor de Gd-IgA1 circulante de una manera más sencilla que los previamente disponibles. El objetivo de este estudio es analizar la influencia de la Gd-IgA1 circulante, medida por este método, en la progresión de la NIgA.
Se seleccionaron 49 pacientes con diagnóstico de NIgA demostrado mediante biopsia renal en nuestro centro, sin haber recibido tratamiento inmunosupresor previo, de los que se dispusiera de suero congelado. La mediana de seguimiento fue de cuatro años. Se midió Gd-IgA1 mediante ELISA independiente de lectina con el anticuerpo monoclonal KM55 (IgA1 kit Cat. No 30111694. IBL Int., Hamburgo, Alemania). Así mismo también se midieron los niveles de APRIL en estos pacientes.
19 (38,8%) pacientes alcanzaron ERC estadio 5. El cuarto cuartil de Gd-IgA1 circulante se relacionaba con un mayor riesgo acumulado de llegar a ERC estadio 5 en el análisis de Kaplan-Meier (riesgo al 5 año 39,4% vs. 24,3%; log rank p = 0,019). El valor de Gd-IgA1 se relacionaba con un mayor riesgo de ERC estadio 5 (HR 1,147; IC 95%: 1,035-1,270; p = 0,009), independientemente del filtrado glomerular, la proteinuria, el porcentaje de glomérulos esclerosados y el valor de esclerosis segmentaria. No encontramos diferencias significativas en los valores de APRIL.
El valor de Gd-IgA1 circulante medido mediante el anticuerpo monoclonal KM55 se relaciona con una peor evolución de los pacientes con NIgA independientemente de otras variables, por lo que se podría incluir en el estudio de los pacientes para mejorar la predicción del riesgo de progresión de la enfermedad.
About 25% of patients with IgA nephropathy (IgAN) progress to stage 5 chronic kidney disease (CKD) after years of evolution. Various tools have been developed in recent years designed to predict which of the patients will had poorer outcomes. The value of circulating galactosyl-deficient IgA1 (Gd-IgA1) has been related to a worse evolution of IgAN in several studies. There are also some publications that relate higher APRIL values with a worse evolution. Recently, a new method has been developed that allows measuring the value of circulating Gd-IgA1 in a simpler way than those previously available. The objective of this study is to analyze the influence of circulating Gd-IgA1, measured by this method, on the progression of IgAN.
Forty-nine patients with a diagnosis of IgAN demonstrated by renal biopsy were selected in our center, without having received prior immunosuppressive treatment, for whom frozen serum was available. The median follow-up was 4 years. Gd-IgA1 was measured by lectin-independent ELISA with the monoclonal antibody KM55 (IgA1 kit Cat. No. 30111694. IBL Int., Hamburg, Germany). Likewise, APRIL levels were also measured in these patients.
19 (38.8%) patients reached stage 5 CKD. The fourth quartile of circulating Gd-IgA1 was related to a higher cumulative risk of reaching stage 5 CKD in the Kaplan–Meier analysis (risk at the 5th year 39.4% vs. 24.3%, log rank p=0.019). The Gd-IgA1 value was related to an increased risk of CKD stage 5 (HR 1.147, 95% CI 1.035–1.270, p=0.009), regardless of glomerular filtration rate, proteinuria, the percentage of sclerosed glomeruli and the value of segmental sclerosis. We did not find significant differences in the APRIL values.
The value of circulating Gd-IgA1 measured by the monoclonal antibody KM55 is related to a worse evolution of patients with IgAN independently of other variables, so it could be included in the study of patients to improve the prediction of the risk of disease progression.
Background
IgA nephropathy (IgAN) may recur in kidney transplant recipients. B‐cell‐activating factor (BAFF), a proliferation‐inducing ligand (APRIL), and α‐defensins are involved in the pathogenesis ...of native IgAN; however, their role on IgAN recurrence has not been previously analyzed.
Methods
Thirty‐five patients with IgAN who received a kidney transplant in our center between January 1, 1993, and December 31, 2015, were included. Recurrence was diagnosed and ruled out in 14 and 11 patients, respectively, by indication biopsies. Pre‐transplant, 6‐month, 1‐, 3‐, and 5‐year sera selected to measure BAFF, APRIL, and defensin by ELISA.
Results
Six months post‐transplantation, APRIL levels (300.1 vs 1203.8 pg/mL, P = 0.033) and the mean APRIL values from 6 months to 3 years (409.8 vs 1258.0 pg/mL, P = 0.003) were higher in recurrent patients. Both 6‐month APRIL levels (AUC‐ROC 0.753, P = 0.033) and mean APRIL values (AUC‐ROC 0.844, P = 0.004) discriminated patients with recurrence risk. By logistic regression, APRIL at 6 months (P = 0.044) and mean APRIL (P = 0.021) related to the risk of IgAN recurrence independently. Neither BAFF nor defensin related to recurrence.
Conclusions
Serum APRIL increased at 6 months and mean APRIL remained higher the first 3 years in patients in whom IgAN was going to recur.
Deficient recovery from acute kidney injury (AKI) has immediate and long-term health, clinical and economic consequences. Pre-emptive recovery estimation may improve nephrology referral, optimize ...decision making, enrollment in trials, and provide key information for subsequent clinical handling and follow-up. For this purpose, new biomarkers are needed that predict outcome during the AKI episode. We hypothesized that damage pattern-specific biomarkers are expected to more closely associate to outcome within distinct subpopulations (i.e. those affected by specific pathological processes determining a specific outcome), as biomarker pleiotropy (i.e. associated to phenomena unrelated to AKI) introduced by unselected, heterogeneous populations may blur statistics. A panel of urinary biomarkers was measured in patients with AKI and their capacity to associate to normal or abnormal recovery was studied in the whole cohort or after sub-classification by AKI etiology, namely pre-renal and intrinsic AKI. A combination of urinary GM2AP and TCP1-eta best associates with recovery from AKI, specifically within the sub-population of renal AKI patients. This two-step strategy generates a multidimensional space in which patients with specific characteristics (i.e. renal AKI patients with good or bad prognosis) can be identified based on a collection of biomarkers working serially, applying pathophysiology-driven criteria to estimate AKI recovery, to facilitate pre-emptive and personalized handling.
In patients with chronic kidney disease (CKD), the main cause of morbidity and mortality is cardiovascular disease (CVD). Both coronary artery calcium scoring by computed tomography (CT) and optical ...coherence tomography (OCT) are used to identify patients at increased risk for ischemic heart disease, thereby indicating a higher cardiovascular risk profile. Our study aimed to investigate the utility of these techniques in the CKD population. In patients with CKD, OCT was used to measure the choroidal thickness (CHT) and the thickness of the peripapillary retinal nerve fiber layer (pRNFL). A total of 127 patients were included, including 70 men (55%) with an estimated glomerular filtration rate (eGFR) of 39 ± 30 mL/min/1.73 m
. Lower pRNFL thickness was found to be related to high-sensitivity troponin I (r = -0.362,
< 0.001) and total coronary calcification (r = -0.194,
= 0.032). In a multivariate analysis, pRNFL measurements remained associated with age (β = -0.189; -0.739--0.027;
= 0.035) and high-sensitivity troponin I (β = -0.301; -0.259--0.071;
< 0.001). Severe coronary calcification (Agatston score ≥ 400 HU) was related to a worse eGFR (
= 0.008), a higher grade of CKD (
= 0.036), and a thinner pRNFL (
= 0.011). The ROC curve confirmed that the pRNFL measurement could determine the patients with an Agatston score of ≥400 HU (AUC 0.638; 95% CI 0.525-0.750;
= 0.015). Our study concludes that measurement of pRNFL thickness using OCT is related to the markers associated with ischemic heart disease, such as coronary calcification and high-sensitivity troponin I, in the CKD population.
About 25% of patients with IgA nephropathy (IgAN) progress to stage 5 chronic kidney disease (CKD) after years of evolution. Various tools have been developed in recent years designed to predict ...which of the patients will had poorer outcomes. The value of circulating galactosyl-deficient IgA1 (Gd-IgA1) has been related to a worse evolution of IgAN in several studies. There are also some publications that relate higher APRIL values with a worse evolution. Recently, a new method has been developed that allows measuring the value of circulating Gd-IgA1 in a simpler way than those previously available. The objective of this study is to analyze the influence of circulating Gd-IgA1, measured by this method, on the progression of IgAN.
Forty-nine patients with a diagnosis of IgAN demonstrated by renal biopsy were selected in our center, without having received prior immunosuppressive treatment, for whom frozen serum was available. The median follow-up was 4 years. Gd-IgA1 was measured by lectin-independent ELISA with the monoclonal antibody KM55 (IgA1 kit Cat. No. 30111694. IBL Int., Hamburg, Germany). Likewise, APRIL levels were also measured in these patients.
19 (38.8%) patients reached stage 5 CKD. The fourth quartile of circulating Gd-IgA1 was related to a higher cumulative risk of reaching stage 5 CKD in the Kaplan–Meier analysis (risk at the 5th year 39.4% vs. 24.3%, log rank p=0.019). The Gd-IgA1 value was related to an increased risk of CKD stage 5 (HR 1.147, 95% CI 1.035–1.270, p=0.009), regardless of glomerular filtration rate, proteinuria, the percentage of sclerosed glomeruli and the value of segmental sclerosis. We did not find significant differences in the APRIL values.
The value of circulating Gd-IgA1 measured by the monoclonal antibody KM55 is related to a worse evolution of patients with IgAN independently of other variables, so it could be included in the study of patients to improve the prediction of the risk of disease progression.
En torno al 25% de los pacientes con nefropatía IgA (NIgA) progresa hacia el estadio 5 de la enfermedad renal crónica tras años de evolución. En los últimos años se han desarrollado diversas herramientas diseñadas para predecir qué pacientes evolucionan peor. El valor de IgA1 galactosil-deficiente (Gd-IgA1) circulante se ha relacionado con una peor evolución de la NIgA en algunos estudios. También hay varios trabajos que relacionan valores más elevados de APRIL con una peor evolución. Recientemente se ha desarrollado un método que permite medir el valor de Gd-IgA1 circulante de una manera más sencilla que los previamente disponibles. El objetivo de este estudio es analizar la influencia de la Gd-IgA1 circulante, medida por este método, en la progresión de la NIgA.
Se seleccionaron 49 pacientes con diagnóstico de NIgA demostrado mediante biopsia renal en nuestro centro, sin haber recibido tratamiento inmunosupresor previo, de los que se dispusiera de suero congelado. La mediana de seguimiento fue de cuatro años. Se midió Gd-IgA1 mediante ELISA independiente de lectina con el anticuerpo monoclonal KM55 (IgA1 kit Cat. No 30111694. IBL Int., Hamburgo, Alemania). Así mismo también se midieron los niveles de APRIL en estos pacientes.
19 (38,8%) pacientes alcanzaron ERC estadio 5. El cuarto cuartil de Gd-IgA1 circulante se relacionaba con un mayor riesgo acumulado de llegar a ERC estadio 5 en el análisis de Kaplan–Meier (riesgo al 5 año 39,4% vs. 24,3%; log rank p=0,019). El valor de Gd-IgA1 se relacionaba con un mayor riesgo de ERC estadio 5 (HR 1,147; IC 95%: 1,035–1,270; p=0,009), independientemente del filtrado glomerular, la proteinuria, el porcentaje de glomérulos esclerosados y el valor de esclerosis segmentaria. No encontramos diferencias significativas en los valores de APRIL.
El valor de Gd-IgA1 circulante medido mediante el anticuerpo monoclonal KM55 se relaciona con una peor evolución de los pacientes con NIgA independientemente de otras variables, por lo que se podría incluir en el estudio de los pacientes para mejorar la predicción del riesgo de progresión de la enfermedad.
Measuring the non-pathogenic Torque Teno Virus (TTV) load allows assessing the net immunosuppressive state after kidney transplantation (KTx). Currently, it is not known how exposure to maintenance ...immunosuppression affects TTV load. We hypothesized that TTV load is associated with the exposure to mycophenolic acid (MPA) and tacrolimus. We performed a prospective study including 54 consecutive KTx. Blood TTV load was measured by an in-house PCR at months 1 and 3. Together with doses and trough blood levels of tacrolimus and MPA, we calculated the coefficient of variability (CV), time in therapeutic range (TTR) and concentration/dose ratio (C/D) of tacrolimus, and the MPA-area under the curve (AUC-MPA) at the third month. TTV load at the first and third month discriminated those patients at risk of developing opportunistic infections between months 1 and 3 (AUC-ROC 0.723, 95%CI 0.559-0.905,
= 0.023) and between months 3 and 6 (AUC-ROC 0.778, 95%CI 0.599-0.957,
= 0.028), respectively, but not those at risk of acute rejection. TTV load did not relate to mean tacrolimus blood level, CV, TTR, C/D and AUC-MPA. To conclude, although TTV is a useful marker of net immunosuppressive status after KTx, it is not related to exposure to maintenance immunosuppression.
Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the clonal expansion of hematopoietic stem cells carrying certain genes associated with an increased risk of hematological ...malignancies. Our study analyzes the influence of CHIP on the risk of heart disease and cardiovascular events in a population with chronic kidney disease (CKD). A total of 128 patients were prospectively followed up for 18 months to detect major cardiovascular events (MACE). To detect the presence of silent heart disease, troponin I, NT-Pro-BNP, and coronary calcification were measured. A massive sequencing was performed to detect CHIP. A total of 24.2% of the patients presented CHIP, including that which was only pathogenic. The most frequently affected gene was TET2 (21.1%). Using multivariate logistic regression analysis, the presence of CHIP was not related to coronary calcification (OR 0.387, 95% CI 0.142–1.058, p = 0.387), nor was it related to troponin I or NT-Pro-BNP. A total of nine patients developed major cardiovascular events. Patients with CHIP did not have a higher risk of major cardiovascular events, although patients with DNMT3A did have a higher risk (HR 6.637, 95% CI 1.443–30.533, p = 0.015), independent of other variables. We did not find that CHIP was associated with a greater risk of silent heart disease or cardiovascular events, although those affected by DNMT3a, analyzed independently, were associated with a greater number of cardiovascular events.
Induction therapy with rabbit antithymocyte globulin is frequently used in kidney transplant recipients and contributes to regulating the humoral alloantibody response. However, the effect of rabbit ...antithymocyte globulin on B-cell subpopulations, including plasma cells, has not been previously studied in humans in vivo.
We prospectively studied a cohort of 39 adult kidney transplant recipients. Twenty patients received rabbit antithymocyte globulin as induction therapy. Peripheral blood samples were obtained pretransplant and at 6 and 12 months posttransplant. T and B cells were acquired by flow cytometry.
Total lymphocytes and CD3 and CD4 cells significantly decreased at 6 and 12 months only in patients who received rabbit antithymocyte globulin. In contrast, the CD19 population did not change after rabbit antithymocyte globulin induction. One-year circulating plasma cells remained significantly lower than pretransplant levels in patients who received rabbit antithymocyte globulin. We observed sig-nificant differences in plasma cell numbers at 12 months after transplant between patients who received rabbit antithymocyte globulin and those patients who did not receive it (median of 5 and interquartile range of 3-17 vs median of 25 and interquartile range of 12-35; P = .001).
Rabbit antithymocyte globulin induction leads to a late reduction in the number of circulating plasma cells at 1 year after kidney transplant. This effect can contribute to down-regulation of the humoral alloantibody response.
Acute kidney injury (AKI) poses an increased risk factor for new AKI episodes, progression to chronic kidney disease, and death. A worsened evolution has been linked to an incomplete renal repair ...beyond the apparent functional recovery based on plasma creatinine (pCr) normalization. However, structural sequelae pass largely unnoticed due to the absence of specific diagnostic tools. The urinary kidney injury molecule 1 (KIM-1) participates in renal tissue damage and repair and is proposed as a biomarker of early and subclinical AKI. Thus, we study in this paper the evolution of KIM-1 urinary excretion alongside renal tissue sequelae after an intrinsic AKI episode induced by cisplatin in Wistar rats. Creatinine clearance, pCr, proteinuria and the fractional excretion of Na
and glucose were used to monitor renal function. Renal tissue damage was blindly scored in kidney specimens stained with hematoxylin-eosin and periodic acid-Schiff. KIM-1 urinary excretion and renal mRNA expression were also assessed. Finally, we analyzed urinary KIM-1 in patients apparently recovered from AKI. Our results show that, after the normalization of the standard markers of glomerular filtration and tubular function, the extent of persistent histological findings of tissue repair correlates with the renal expression and urinary level of KIM-1 in rats. In addition, KIM-1 is also elevated in the urine of a significant fraction of patients apparently recovered from an AKI. Besides its potential utility in the early and subclinical diagnosis of renal damage, this study suggests a new application of urinary KIM-1 in the non-invasive follow-up of renal repair after AKI.
Maternal smoking during pregnancy is associated with a variety of adverse neonatal outcomes including altered reproductive performance. Herein we provide molecular evidence for a pathway involved in ...the elimination of the female germline due to prepregnancy and/or lactational exposure to polycyclic aromatic hydrocarbons (PAHs), environmental toxicants found in cigarette smoke. We show that ovaries of offspring born to mice exposed to PAHs contained only a third of the ovarian follicle pool compared with offspring of unexposed female mice. Activation of the cell death pathway in immature follicles of exposed females was mediated by the aryl hydrocarbon receptor (Ahr), as ovarian reserve was fully rescued by maternal cotreatment with the Ahr antagonist, resveratrol, or by inactivation of the Ahr gene. Furthermore, in response to PAHs, Ahr-mediated activation of the harakiri, BCL2 interacting protein (contains only BH3 domain), was necessary for execution of cell death. This pathway appeared to be conserved between mouse and human, as xenotransplanted human ovarian cortex exposed to PAHs responded by activation of the identical cell death cascade. Our data indicate that maternal exposure to PAHs prior to pregnancy and/or during lactation compromises ovarian reserve of female offspring, raising the concern about the transgenerational impact of maternal smoking on ovarian function in the human.
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