1. Investigación

Chronic kidney disease (CKD) has been increasing over the last years, with a rate between 0.49% to 0.87% new cases per year. Currently, the number of affected people is around 850 million worldwide. CKD is a slowly progressive disease that leads to irreversible loss of kidney function, end-stage kidney disease, and premature death. Therefore, CKD is considered a global health problem, and this sets the alarm for necessary efficient prediction, management, and disease prevention. At present, modern computer analysis, such as in silico medicine (ISM), denotes an emergent data science that offers interesting promise in the nephrology field. ISM offers reliable computer predictions to suggest optimal treatments in a case-specific manner. In addition, ISM offers the potential to gain a better understanding of the kidney physiology and/or pathophysiology of many complex diseases, together with a multiscale disease modeling. Similarly, -omics platforms (including genomics, transcriptomics, metabolomics, and proteomics), can generate biological data to obtain information on gene expression and regulation, protein turnover, and biological pathway connections in renal diseases. In this sense, the novel patient-centered approach in CKD research is built upon the combination of ISM analysis of human data, the use of in vitro models, and in vivo validation. Thus, one of the main objectives of CKD research is to manage the disease by the identification of new disease drivers, which could be prevented and monitored. This review explores the wide-ranging application of computational medicine and the application of -omics strategies in evaluating and managing kidney diseases.

Introducción: PROGRESER es un estudio multicéntrico, prospectivo, observacional, con tres años de seguimiento, de una cohorte de pacientes con enfermedad renal crónica (ERC)-3 KDOQI, incluidos en servicios de Nefrología del Sistema Nacional de Salud en 14 comunidades autónomas de España. El objetivo primario fue analizar los factores de riesgo asociados con la progresión de la ERC, para identificar posibles diferencias entre pacientes con y sin diabetes mellitus (DM). El objetivo secundario fue investigar si los factores asociados con hospitalizaciones y mortalidad. Material y métodos: Se incluyeron 462 pacientes (342 hombres y 120 mujeres, con una edad media de 66,5 ± 11,5 añ os), reclutados en 25 centros. Se recogieron datos epidemiológicos, clínicos y analíticos cada seis meses, registrados en cuaderno electrónico. Se recogieron y congelaron muestras biológicas para biobanco basales y a 18 y 36 meses.Resultados: El filtrado glomerular estimado (FGe), calculado inicialmente mediante la ecuación Modification of Diet in Renal Disease (MDRD) y después recalculado mediante CKD-EPI fue de 43,9 ± 7,9 mL/min/1,73 m2 en el momento basal y de 29,9 ± 6,8 mL/min/1,73 m2 a los tres añ os de seguimiento. Dos tercios de los pacientes (66,2%) presentaron progresión del daño renal según criterio del estudio (descenso mayor del 15% del FGe sobre el valor basal). Un 38,7% presentaron una reducción del FGe ≥ 30%; un 20,3% tuvieron una reducción del FGe≥ 40%; un 10,4% tuvieron una reducción ≥ 50% y un 6,9%, una reducción ≥ 57%. De los 199 diabéticos, 134 (67,3%) presentaron progresión. De los 263 no diabéticos, 172 (65,3%) presentaron progresión (p = 0,456). El 27,3% de pacientes presentaban microalbuminuria y el 22,5%, proteinuria. El estudio mostró que la progresión de un estadio a otros más avanzados no fue superior en los pacientes con DM respecto a los no diabéticos. El análisis multivariante reveló que la presencia de hipertensión arterial (HTA) se aproximó a la significación estadística (p = 0,07) asociado a la progresión en los pacientes sin DM, y que en los pacientes con DM unos niveles basales de calcio más bajos y de PTH-i más elevados sobre el valor basal tuvieron significación estadística como factores de progresión de la ERC. Conclusión: Nuestro estudio no ha revelado nuevos factores de progresión de daño renal con relación a los factores clásicos ya conocidos. No hemos encontrado diferencias significativas en cuanto a la progresión en pacientes con y sin DM. La progresión del daño renal en pacientes con ERC-3 KDOQI debe interpretarse en un contexto multifactorial. Se precisa la búsqueda de nuevos biomarcadores, diferentes de los tradicionales, para establecer nuevas estrategias terapéuticas para prevenir la progresión de la ERC.

Bone strength is determined not only by bone quantity [bone mineral density (BMD)] but also by bone quality, including matrix composition, collagen fiber arrangement, microarchitecture, geometry, mineralization, and bone turnover, among others. These aspects influence elasticity, the load-bearing and repair capacity of bone, and microcrack propagation and are thus key to fractures and their avoidance. In chronic kidney disease (CKD)-associated osteoporosis, factors traditionally associated with a lower bone mass (advanced age or hypogonadism) often coexist with non-traditional factors specific to CKD (uremic toxins or renal osteodystrophy, among others), which will have an impact on bone quality. The gold standard for measuring BMD is dual-energy X-ray absorptiometry, which is widely accepted in the general population and is also capable of predicting fracture risk in CKD. Nevertheless, a significant number of fractures occur in the absence of densitometric World Health Organization (WHO) criteria for osteoporosis, suggesting that methods that also evaluate bone quality need to be considered in order to achieve a comprehensive assessment of fracture risk. The techniques for measuring bone quality are limited by their high cost or invasive nature, which has prevented their implementation in clinical practice. A bone biopsy, high-resolution peripheral quantitative computed tomography, and impact microindentation are some of the methods established to assess bone quality. Herein, we review the current evidence in the literature with the aim of exploring the factors that affect both bone quality and bone quantity in CKD and describing available techniques to assess them.

Background: Chronic kidney disease (CKD) is a common complication of a non-kidney solid organ transplant (NKSOT). Identifying predisposing factors is crucial for an early approach and correct referral to nephrology. Methods: This is a single-center retrospective observational study of a cohort of CKD patients under follow-up in the Nephrology Department between 2010 to 2020. Statistical analysis was performed between all the risk factors and four dependent variables: end-stage renal disease (ESKD); increased serum creatinine ≥50%; renal replacement therapy (RRT); and death in the pre-transplant, peri-transplant, and post-transplant periods. Results: 74 patients were studied (7 heart transplants, 34 liver transplants, and 33 lung transplants). Patients who were not followed-up by a nephrologist in the pre-transplant (p < 0.027) or peri-transplant (p < 0.046) periods and those who had the longest time until an outpatient clinic follow-up (HR 1.032) were associated with a higher risk of creatinine increase ≥50%. Receiving a lung transplant conferred a higher risk than a liver or heart transplant for developing a creatinine increase ≥50% and ESKD. Peri-transplant mechanical ventilation, peri-transplant and post-transplant anticalcineurin overdose, nephrotoxicity, and the number of hospital admissions were significantly associated with a creatinine increase ≥50% and developing ESKD. Conclusions: Early and close follow-up by a nephrologist was associated with a decrease in the worsening of renal function.

Diabetic kidney disease (DKD) is the leading cause of chronic and end-stage kidney disease worldwide. Its pathogenic mechanism is complex, and it can affect the entire structures of the kidneys such as the glomerulus, tubules and interstitium. Currently, the urinary albumin excretion rate and the estimated glomerular filtration rate are widely accepted as diagnostic criteria. However, some studies have reported a different or non-classical clinical course of DKD, with some patients showing declined kidney function with normal levels of albuminuria, known as the 'non-albuminuric DKD' phenotype. The pathogenesis of this phenotype remains unclear, but some clinical and pathological features have been postulated. This review explores the evidence regarding this topic.

Introduction: Secondary hyperparathyroidism (SHP) is frequent in patients with chronic kidney disease (CKD), particularly in those in dialysis. To treat this complication, the current options available include phosphorus restriction, phosphate binders, the inhibition of parathyroid hormone (PTH) synthesis and secretion by the supplementation of vitamin D or VDR activators, or the use of calcimimetics. Beyond the control of PTH, the effects of the treatment of SHP on other biomarkers of risk may represent an additional benefit for this population. In this study, we explore the benefits of current SHP treatment options, mainly paricalcitol and/or etelcalcetide in the inflammatory state of hemodialysis (HD) patients. Results: the study finally included 142 maintenance HD patients (5 patients were excluded) followed for 6 months (dialysis vintage 26 ± 30 months, mean age 70 years old, 73% women, 81% Spanish white, 47% diabetic). In this case, 52 patients were on regular treatment with paricalcitol for SHP and 25 patients were eligible to initiate etelcalcetide. The baseline serum levels of Ca, P, PTH, Ferritin, albumin, C-reactive protein (CRP), and other variables were measured. We found serum PTH levels showed an improvement after the treatment with etelcalcetide again paricalcitol and no treatment (p < 0.04). Of note, serum levels of CRP were significantly lower in a small group of patients (n = 11) receiving paricalcitol + etelcalcetide compared to paricalcitol or etelcalcetide alone. The proportion of patients with CRP within target ranges (≤1.0 mg/dL) increased significantly after combined treatment (p < 0.001). Conclusions: etelcalcetide proved to safely reduce the PTH levels without significant adverse events and the possibility of a synergic anti-inflammatory effect with the simultaneous use of Paricalcitol in HD patients.

Background: Sodium glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists (MRAs) reduce the urinary albumin-to-creatinine ratio (UACR) and confer kidney and cardiovascular protection in patients with CKD. We assessed efficacy and safety of the SGLT2 inhibitor dapagliflozin and MRA eplerenone alone and in combination in patients with CKD. Methods: We conducted a randomized open-label crossover trial in patients with urinary albumin excretion ≥100 mg/24 hr, eGFR 30-90 ml/min per 1.73 m2, who had been receiving maximum tolerated stable doses of an ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB). Patients were assigned to 4-week treatment periods with dapagliflozin 10 mg/day, eplerenone 50 mg/day, or their combination in random order, separated by 4-week washout periods. Primary outcome was the correlation in UACR changes between treatments. Secondary outcome was the percent change in 24-hour UACR from baseline. Results: Of 57 patients screened, 46 were randomly assigned (mean eGFR, 58.1 ml/min per 1.73 m2; median UACR, 401 mg/g) to the three groups. Mean percentage change from baseline in UACR after 4 weeks of treatment with dapagliflozin, eplerenone, and dapagliflozin-eplerenone was -19.6% (95% confidence interval [CI], -34.3 to -1.5), -33.7% (95% CI, -46.1 to -18.5), and -53% (95% CI, -61.7 to -42.4; P<0.001 versus dapagliflozin; P=0.01 versus eplerenone). UACR change during dapagliflozin or eplerenone treatment did not correlate with UACR change during dapagliflozin-eplerenone (r=-0.13; P=0.47; r=-0.08; P=0.66, respectively). Hyperkalemia was more frequently reported with eplerenone (n=8; 17.4%) compared with dapagliflozin (n=0; 0%) or dapagliflozin-eplerenone (n=2; 4.3%; P between-groups=0.003). Conclusions: Albuminuria changes in response to dapagliflozin and eplerenone did not correlate, supporting systematic rotation of these therapies to optimize treatment. Combining dapagliflozin with eplerenone resulted in a robust additive UACR-lowering effect. A larger trial in this population is required to confirm long-term efficacy and safety of combined SGLT2 inhibitor and MRA treatment.