Genetic Characterization of Kidney Failure of Unknown Etiology in Spain: Findings From the GENSEN Study.

RATIONALE & OBJECTIVE: Chronic kidney disease of unknown etiology (CKDUE) is one of the main global causes of kidney failure. Genetic studies may identify an etiology in these patients, but few studies have implemented genetic testing of CKDUE in a population-based series of patients, which was the focus of the GENSEN Study. STUDY DESIGN: Case series. SETTINGS & PARTICIPANTS: 818 patients aged≤45 years at 51 Spanish centers with CKDUE, and either an estimated glomerular filtration rate of<15mL/min/1.73m2 or treatment with maintenance dialysis or transplantation. OBSERVATIONS: Genetic testing for 529 genes associated with inherited nephropathies using high-throughput sequencing (HTS). Pathogenic and/or likely pathogenic (P/LP) gene variants concordant with the inheritance pattern were detected in 203 patients (24.8%). Variants in type IV collagen genes were the most frequent (COL4A5, COL4A4, COL4A3; 35% of total gene variants), followed by NPHP1, PAX2, UMOD, MUC1, and INF2 (7.3%, 5.9%, 2.5%, 2.5%, and 2.5%, respectively). Overall, 87 novel variants classified as P/LP were identified. The top 5 most common previously undiagnosed diseases were Alport syndrome spectrum (35% of total positive reports), genetic podocytopathies (19%), nephronophthisis (11%), autosomal dominant tubulointerstitial kidney disease (7%), and congenital anomalies of the kidney and urinary tract (CAKUT, 5%). A family history of kidney disease was reported by 191 participants (23.3%) and by 65 of 203 patients (32.0%) with P/LP variants. LIMITATIONS: Missing data, and selection bias resulting from voluntary enrollment. CONCLUSIONS: Genomic testing with HTS identified a genetic cause of kidney disease in approximately one quarter of young patients with CKDUE and advanced kidney disease. These findings suggest that genetic studies are a potentially useful tool for the evaluation of people with CKDUE. PLAIN-LANGUAGE SUMMARY: The cause of kidney disease is unknown for 1 in 5 patients requiring kidney replacement therapy, reflecting possible prior missed treatment opportunities. We assessed the diagnostic utility of genetic testing in children and adults aged≤45 years with either an estimated glomerular filtration rate of<15mL/min/1.73m2 or treatment with maintenance dialysis or transplantation. Genetic testing identified the cause of kidney disease in approximately 1 in 4 patients without a previously known cause of kidney disease, suggesting that genetic studies are a potentially useful tool for the evaluation of these patients.

Unresolved aspects in the management of renal anemia, a Delphi consensus of the Anemia Group of the S.E.N.

Anemia is a common complication of chronic kidney disease (CKD) and is associated with a decrease in quality of life and an increased risk of transfusions, morbidity and mortality, and progression of CKD. The Anemia Working Group of the Sociedad Española de Nefrología conducted a Delphi study among experts in anemia in CKD to agree on relevant unanswered questions by existing evidence. The RAND/UCLA consensus methodology was used. We defined 15 questions with a PICO structure, followed by a review in scientific literature databases. Statements to each question were developed based on that literature review. Nineteen experts evaluated them using an iterative Two-Round Delphi-like process. Sixteen statements were agreed in response to 8 questions related to iron deficiency and supplementation with Fe (impact and management of iron deficiency with or without anemia, iron deficiency markers, safety of i.v. iron) and 7 related to erythropoiesis stimulating agents (ESAs) and/or hypoxia-inducible factor stabilizers (HIF), reaching consensus on all of them (individualization of the Hb objective, impact and management of resistance to ESA, ESA in the immediate post-transplant period and HIF stabilizers: impact on ferrokinetics, interaction with inflammation and cardiovascular safety). There is a need for clinical studies addressing the effects of correction of iron deficiency independently of anemia and the impact of anemia treatment with various ESA on quality of life, progression of CKD and cardiovascular events.

Autosomal dominant polycystic kidney disease in young adults.

Background: The clinical manifestations of autosomal dominant polycystic kidney disease (ADPKD) usually appear in adulthood, however pediatric series report a high morbidity. The objective of the study was to analyze the clinical characteristics of ADPKD in young adults. Methods: Family history, hypertension, albuminuria, estimated glomerular filtration rate (eGFR) and imaging tests were examined in 346 young adults (18-30 years old) out of 2521 patients in the Spanish ADPKD registry (REPQRAD). A literature review searched for reports on hypertension in series with more than 50 young (age <30 years) ADPKD patients. Results: The mean age of this young adult cohort was 25.24 (SD 3.72) years. The mean age at diagnosis of hypertension was 21.15 (SD 4.62) years, while in the overall REPQRAD population was aged 37.6 years. The prevalence of hypertension was 28.03% and increased with age (18-24 years, 16.8%; 25-30 years, 36.8%). Although prevalence was lower in women than in men, the age at onset of hypertension (21 years) was similar in both sexes. Mean eGFR was 108 (SD 21) mL/min/1.73 m2, 38.0% had liver cysts and 3.45% of those studied had intracranial aneurysms. In multivariate analyses, hematuria episodes and kidney length were independent predictors of hypertension (area under the curve 0.75). The prevalence of hypertension in 22 pediatric cohorts was 20%-40%, but no literature reports on hypertension in young ADPKD adults were found. Conclusions: Young adults present non-negligible ADPKD-related morbidity. This supports the need for a thorough assessment of young adults at risk of ADPKD that allows early diagnosis and treatment of hypertension.

Association of severe preeclampsia and vascular damage assessed by noninvasive markers of arterial stiffness.

BACKGROUND: Preeclampsia (PE) is a hypertensive disorder of pregnancy associated with high maternal and fetal morbidity and mortality and increased future risk of cardiovascular complications. OBJECTIVE: To analyze whether women who have had PE with severe features in their pregnancy have higher arterial stiffness (AS) parameters than those whose PE course was without signs of severity. METHODS: Sixty-five women who developed PE during their gestation were evaluated, divided into two groups: PE group without severe features or non-severe PE (n=30) and PE group with severe features or severe PE (n=35). Carotid-femoral pulse wave velocity (cfPWV), central augmentation index corrected to a heart rate of 75 beats per minute (AIxc75) and central augmentation pressure (cAP) were determined one month and six months postpartum. Comparison of proportions was carried out using the chi-square test, comparison of means between groups using the Student's t-test or the Mann-Whitney test, and comparison of means of the same group at different evolutionary moments, using the t-test or the Wilcoxon test. Correlation, with and between hemodynamic parameters, was carried out with Spearman's correlation coefficient and the association between demographic variables, personal history and hemodynamic parameters, and altered arterial stiffness parameters was carried out using linear and logistic regression models. RESULTS: Women with severe PE presented, both at 1 and 6 months postpartum, higher values of blood pressure, both central and peripheral, as well as AR and pulse amplification parameters, than those women whose PE was not severe. Central augmentation index (cAIx) values at 1 month and 6 months postpartum were higher, although not significantly, in the severe PE group compared to the non-severe PE group (24.0 (16.5-34.3) vs. 19.0% (14-29) and 24.0 (14.0-30.0) vs. 20.0% (12.3-26.8), respectively). Carotid-femoral pulse wave velocity (cfPWV) was significantly higher at both 1 and 6 months postpartum in the severe PE group compared to the non-severe PE group (10.2 (8.8-10.7) vs. 8.8m/s (8.3-9.6) and 10.0 (8.8-10.6) vs. 8.8m/s (8.3-9.3), respectively). Central systolic pressure and central pulse pressure amplification were also higher, although not significantly, in the severe PE group in comparison with the non-severe PE group. CONCLUSIONS: Women who have had severe PE have more pronounced arterial stiffness parameters than those in whom PE was not particularly severe. The determination of cAIx and cfPWV, as a strategy for the assessment of cardiovascular risk, should be evaluated among women who have had PE.

Increased induction of de novo serum ANCA and ANCA-associated vasculitis after mass vaccination against SARS-CoV-2.

Different immune-mediated diseases have been described after SARS-CoV-2 vaccination, with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) being one of the possible side effects. In this study, a total of 35 patients presented ANCA for the first time during 2021, with the number during 2019 being 15. Twenty-seven out of thirty-five patients developed ANCA after vaccination. Two of them developed these antibodies after receiving the first dose (7.4%), and 25 patients developed ANCA after the second dose of the vaccine (92.6%), with BNT162b2 being the main vaccine received by these patients. In 97.1% of the patients who developed ANCA during 2021, the positivity of ANCA was accompanied by systemic involvement, with renal and respiratory tracts being the main organs affected. Therefore, an increase in the development of AAV has been observed during 2021 in comparison with 2019, which could be due to the administration of SARS-CoV-2 vaccine.

New Insights into Renal Failure in a Cohort of 317 Patients with Autosomal Dominant Forms of Alport Syndrome: Report of Two Novel Heterozygous Mutations in COL4A3.

Alport syndrome (AS) is a clinically and genetically heterogeneous disorder with a wide phenotypic spectrum, onset, and progression. X-linked AS (XLAS) and autosomal recessive AS (ARAS) are severe conditions, whereas the severity of autosomal dominant AS (ADAS) may vary from benign familial hematuria to progressive renal disease with extra-renal manifestations. In this study, we collated information from the literature and analyzed a cohort of 317 patients with ADAS carrying heterozygous disease-causing mutations in COL4A3/4 including four patients from two unrelated families who carried two novel variants in COL4A3. Regarding the age of onset of the disease, 80% of patients presented urinalysis alterations (microhematuria, hematuria, and/or proteinuria) before the age of 40 years. The cumulative probability of suffering adverse renal events was mainly observed between 30 and 70 years, without statistical differences between COL4A3 and COL4A4. We observed statistically significant differences between the sexes in the age of developing ESKD in cases affected by mutations in COL4A3/4 (p value = 0.0097), suggesting that males begin experiencing earlier deterioration of renal function than women. This study supports the importance of follow-up in young patients who harbor pathogenic mutations in COL4A3/4. We update the knowledge of ADAS, highlighting differences in the progression of the disease between males and females.

[Measurement of galactosyl-deficient IgA1 by the monoclonal antibody KM55 contributes to predicting patients with IgA nephropathy with high risk of long-term progression]. / La determinación de IgA1 galactosil deficiente mediante el anticuerpo monoclonal KM55 contribuye a predecir a los pacientes con nefropatía IgA con alto riesgo de progresión a largo plazo.

BACKGROUND AND OBJECTIVE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Measurement of galactosyl-deficient IgA1 by the monoclonal antibody KM55 contributes to predicting patients with IgA nephropathy with high risk of long-term progression.

BACKGROUND AND OBJECTIVE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Non-Criteria Antiphospholipid Antibodies: Risk Factors for Endothelial Dysfunction in Women with Pre-Eclampsia.

The association between unconventional antiphospholipid antibodies and pre-eclampsia in patients without thrombotic manifestations and its relationship with endothelial dysfunction after delivery has been studied poorly. We included 157 pregnant women, 122 of them having developed pre-eclampsia (56 non-severe and 66 severe). The determination of classical and unconventional, as well as pulse wave velocity and ankle-brachial index were performed at three months after delivery. The prevalence of unconventional antiphospholipid antibodies was 22.9% and 54.9% in patients included in control and pre-eclampsia groups, respectively (p = 0.001). The most frequent antiphospholipid antibody was IgM anti-phosphatidylserine/prothrombin in both cohorts. The presence of IgM anti-phosphatidylserine/prothrombin showed an association with the development of pre-eclampsia (OR = 5.4; CI 95% (2.0-14.9), p = 0.001) with an AUC of 0.744 (p < 0.001). Likewise, IgM anti-phosphatidylserine/prothrombin exhibited a positive linear correlation with pulse wave velocity values (rho = 0.830; p < 0.001) and an association with the presence of pulse wave velocity altered values (OR = 1.33; CI95% (1.10-1.59), p = 0.002). With regard to ankle braquial index values, the presence of IgM anti-phosphatidylserine/prothrombin displayed a weak negative correlation (rho = -0.466; p < 0.001) and an association with altered ankle braquial index values (OR = 1.08; CI 95% (1.04-1.13), p < 0.001). In patients who developed preeclampsia, the presence of IgM anti-phosphatidylserine/prothrombin could be associated with endothelial dysfunction, causing alteration of cardiovascular parameters.

Late Plasma Cell Depletion After Thymoglobulin Induction in Kidney Transplant Recipients.

OBJECTIVES: 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. MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Regulatory T-cell Number in Peripheral Blood at 1 Year Posttransplant as Predictor of Long-term Kidney Graft Survival.

BACKGROUND: Regulatory T (Treg) cells play a role in limiting kidney transplant rejection and can potentially promote long-term transplant tolerance. There are no large prospective studies demonstrating the utility of peripheral blood Treg cells as biomarkers for long-term graft outcome in kidney transplantation. The aim of our study was to analyze the influence of the absolute number of peripheral blood Treg cells after transplantation on long-term death-censored graft survival. METHODS: We monitored the absolute numbers of Treg cells by flow cytometry in nonfrozen samples of peripheral blood in 133 kidney transplant recipients, who were prospectively followed up to 2 years after transplantation. Death-censored graft survival was determined retrospectively in January 2017. RESULTS: The mean time of clinical follow-up was 7.4 ± 2.9 years and 24.1% patients suffered death-censored graft loss (DCGL). Patients with high Treg cells 1 year after transplantation and above the median value (14.57 cells/mm3), showed better death-censored graft survival (5-year survival, 92.5% vs 81.4%, Log-rank P = .030). One-year Treg cells showed a receiver operating characteristic - area under curve of 63.1% (95% confidence interval, 52.9-73.2%, P = 0.026) for predicting DCGL. After multivariate Cox regression analysis, an increased number of peripheral blood Treg cells was a protective factor for DCGL (hazard ratio, 0.961, 95% confidence interval, 0.924-0.998, P = 0.041), irrespectively of 1-year proteinuria and renal function. CONCLUSIONS: Peripheral blood absolute numbers of Treg cells 1 year after kidney transplantation predict a better long-term graft outcome and may be used as prognostic biomarkers.

Is it possible to predict the evolution of IgAN? Validation of the IgA nephropathy progression calculator and its relationship with MEST-C score in our population. / ¿Es posible predecir la evolución de la nefropatia IgA? Validamos la calculadora de progresión de nefropatia IgA y su relación con Oxford score en nuestra población.

INTRODUCTION: IgA nephropathy (IgAN) is the most common and heterogeneous glomerular nephropathy. Several strategies have been used to determine the risk of progression to ESRD. We evaluate the prognostic significance and correlate the IgAN progression calculator (IgANPC) and the Oxford/MEST-C score in our population. MATERIAL AND METHODS: We performed a retrospective study of biopsied patients with diagnosis of IgA nephropathy from 1990 to 2015. We classified the biopsies using MEST-C score and we correlated the score to clinical evolution. We also calculated the risk of progression with the online IgANPC at the time of the biopsy. RESULTS: We analysed 48 biopsies, 83% of which were men with a mean age of 45 years at the time of the biopsy. Patients with a biopsy E1 according to MEST-C score had a higher IgANPC score than those with E0 (P=.021). The Pearson's correlation for the percentage of crescents and the IgANPC risk score was statistically significant (P=.014) with r=0.357. The percentage of patients with eGFR above 30 ml/min at 10 years was 100% for the low-risk group (group 1 of IgANPC), and 0% for the high-risk group (group 3), log rank P=0.001. The log rank comparison for variables of the MEST-C score, presented statistically significant results between E (0.036) and S (0.022) and the eGFR time<30 ml/min. A statistically significant relationship was also observed between T1 and eGFR<30 ml/min. The multivariate Cox regression analysis for IgANPC and eGFR<30 ml/min demonstrated a strong correlation (P=.016) between the risk group and eGFR <30 ml/min. CONCLUSION: In our study population, the IgANPC predicts the time to eGFR<30 ml/min, and adds information independent of the MEST. The MEST-C classification and IgANPC are useful and independent ÿolos for prognostic prediction, but more studies are needed to validate its use in the general population.

Epidemiology of hyperkalemia in chronic kidney disease. / Epidemiología de la hiperpotasemia en la enfermedad renal crónica.

BACKGROUND: Hyperkalaemia is a significant electrolyte imbalance in chronic kidney disease (CKD). Renin-angiotensin-aldosterone system inhibitors (RAASi) have beneficial cardio-renal properties, although they can often cause hyperkalaemia. OBJECTIVE: To examine the prevalence of hyperkalaemia in CKD, identify factors associated with its appearance and the relationship between hyperkalaemia and mortality. PATIENTS AND METHODS: Retrospective observational study on patients with CKD in the period 1971-2017. The population was categorised into 3groups: Group 1, patients with CKD without renal replacement therapy; Group 2, patients on haemodialysis; and Group 3, patients on continuous ambulatory peritoneal dialysis. RESULTS: A total of 2,629 patients were evaluated. The prevalence observed in the different groups was: 9.6%, 16.4% and 10.6%, respectively. Risk factors related to the appearance of hyperkalaemia in the CKD group were glomerular filtration rate (GFR) (P<.001), plasma creatinine (P<.001), plasma sodium (P<.001), haemoglobin (P=.028), diastolic blood pressure (P=.012), intake of ACE inhibitors and/or angiotensin ii receptor blockers (P=.008), treatment with metformin (P<.001) and diabetes (P=.045). Treatment with RAASi significantly increased hyperkalaemia as GFR decreased, as well as in patients with diabetes or heart failure. CONCLUSIONS: Hyperkalaemia is a frequent metabolic alteration in CKD patients that increases in the presence of drugs with beneficial cardio-renal properties (RAASi), which means that patients often lose the benefit associated with these drugs. New, recently-appearing non-absorbable compounds, which bind to potassium in the gastrointestinal tract, enhancing faecal excretion and thus maintaining the cardio-renal benefit of the RAASi, could be relevant in the progress of patients with CKD.