Diagnóstico y tratamiento de la enfermedad de Fabry

El texto en español se encuentra disponibe en http://doi.org/10.1016/j.medcli.2016.09.047This work was supported by FIS PI13/00047, PI15/00298, CP14/00133, FEDER funds ISCIII-RETIC REDinREN RD12/0021 and RD16/0009, Sociedad Española de Nefrología, Programa Intensificacion Actividad Investigadora (ISCIII/Agencia LainEntralgo/CM) to AO, Miguel Servet MS14/00133 to MDS

Unravelling drug-induced hypertension: Molecular mechanisms of aldosterone-independent mineralocorticoid receptor activation by posaconazole

Drug-induced hypertension offers the opportunity to further understand pathways involved in the regulation of blood pressure. Posaconazole is an antifungal agent known to induce hypertension and hypokalaemia. In recent months, a flurry of reports has unravelled the metabolic processes involved. In this issue of CKJ, Barton K, Davis TK, Marshall B et al. Posaconazole-induced hypertension and hypokalemia due to inhibition of the 11β-hydroxylase enzyme. Clin Kidney J 2018; 11: 691-693 present convincing evidence of 11β-hydroxylase inhibition resulting in a biochemical syndrome resembling genetic congenital adrenal hyperplasia and characterized by high 11-deoxycorticosterone and 11-deoxycortisol levels as well as androgen levels. This adds to prior evidence supporting inhibition of 11β-hydroxysteroid dehydrogenase 2, the enzyme that inactivates cortisol in aldosterone-sensitive tissues such as the kidneys, yielding a syndrome resembling genetic apparent mineralocorticoid excess or licorice toxicity, characterized by a high cortisol/cortisone ratioThe authors were supported by FIS PI16/02057, PI18/01366, ISCIII-RETIC REDinREN RD016/0009 Fondos FEDER, Sociedad Española de Nefrología, Comunidad de Madrid B2017/BMD-3686 CIFRA2-CM, Miguel Servet MS14/00133 to M.D.S.-N

Sarcopenia in CKD: A roadmap from basic pathogenetic mechanisms to clinical trials

Sarcopenia and frailty are recognized as key risk factors for adverse outcomes in patients on renal replacement therapy or with non-dialysis chronic kidney disease (CKD). However, there is still debate about their pathogenesis and, thus, about the best therapeutic approaches, as well as the impact on outcomes of current approaches based on different exercise programmes. In the past two issues of Clinical Kidney Journal, several manuscripts address the issue of sarcopenia in CKD from the point of view of pathogenesis and new therapeutic approaches, monitoring of results, implementation of exercise programmes and specific potential benefits of exercise programmes in dialysis and non-dialysis CKD patients, as assessed by clinical trial

Chronodisruption: A poorly recognized feature of CKD

Multiple physiological variables change over time in a predictable and repetitive manner, guided by molecular clocks that respond to external and internal clues and are coordinated by a central clock. The kidney is the site of one of the most active peripheral clocks. Biological rhythms, of which the best known are circadian rhythms, are required for normal physiology of the kidneys and other organs. Chronodisruption refers to the chronic disruption of circadian rhythms leading to disease. While there is evidence that circadian rhythms may be altered in kidney disease and that altered circadian rhythms may accelerate chronic kidney disease (CKD) progression, there is no comprehensive review on chronodisruption and chronodisruptors in CKD and its manifestations. Indeed, the term chronodisruption has been rarely applied to CKD despite chronodisruptors being potential therapeutic targets in CKD patients. We now discuss evidence for chronodisruption in CKD and the impact of chronodisruption on CKD manifestations, identify potential chronodisruptors, some of them uremic toxins, and their therapeutic implications, and discuss current unanswered questions on this topicThis work was funded by FIS CP14/00133, PI16/02057, PI18/01366, PI19/00588, PI19/00815, DTS18/00032, ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071, National Institute of Health (2R01AI063331), ISCIII-RETIC REDinREN RD016/0009 Fondos FEDER, FRIAT, Sociedad Española de Nefrología, Comunidad de Madrid B2017/BMD-3686 CIFRA2-CM, Miguel Servet MS14/00133 to MDSN and ABS. IIS-Fundacion Jimenez Diaz Biobank, part of the Spanish Biobanks Platform (PT17/0015/0006). The APC was funded by PI19/0081

Gender, albuminuria and chronic kidney disease progression in treated diabetic kidney disease

Background: Women are reported to have a lower incidence of renal replacement therapy, despite a higher prevalence of chronic kidney disease (CKD). Aim: To analyze diabetic kidney disease (DKD) progression in men and women. Methods: Prospective cohort: n = 261, 35% women, new consecutive nephrology DKD referrals. Results: Women smoked less and better complied with the dietary phosphate and sodium restrictions. Despite a less frequent nephrology referral, women had lower baseline albuminuria. Over a 30 + - 10-month follow-up, albuminuria decreased in women and the estimated glomerular filtration rate (eGFR) loss was slower than in men. However, the percentage of rapid progressors was similar in both sexes. The best multivariate model predicting rapid progression in men (area under curve (AUC) = 0.92) and women differed. Albuminuria and fractional excretion of phosphate (FEphosphate) were part of the men multivariable model, but not of women. The AUC for the prediction of rapid progression by albuminuria was higher in men than in women, and the albuminuria cut-off points also differed. In women, there was a higher percentage of rapid progressors who had baseline physiological albuminuria. Conclusions: Female DKD differs from male DKD: albuminuria was milder and better responsive to therapy, the loss of eGFR was slower and the predictors of rapid progression differed from men: albuminuria was a better predictor in men than in women. Lifestyle factors may contribute to the differencesThis work and the APC was funded by FIS grant numbers CP14/00133, PI16/02057, PI18/01366, PI19/00588, PI19/00815, DTS18/00032, ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071, National Institute of Health (2R01AI063331), ISCIII-RETIC REDinREN RD016/0009 Fondos FEDER, FRIAT, Sociedad Española de Nefrología, Comunidad de Madrid B2017/BMD-3686 CIFRA2-CM, Miguel Servet MS14/00133 to M.D.S.-N. and A.B.S. and Cátedra Mundipharma UAM. IIS-Fundacion Jimenez Diaz Biobank, part of the Spanish Biobanks Platform (PT17/0015/0006)

TWEAK/Fn14 and non-canonical NF-kappaB signaling in kidney disease

The incidence of acute kidney injury (AKI) and chronic kidney disease (CKD) is increasing. However, there is no effective therapy for AKI and current approaches only slow down, but do not prevent progression of CKD. TWEAK is a TNF superfamily cytokine. A solid base of preclinical data suggests a role of therapies targeting the TWEAK or its receptor Fn14 in AKI and CKD. In particular TWEAK/Fn14 targeting may preserve renal function and decrease cell death, inflammation, proteinuria, and fibrosis in mouse animal models. Furthermore there is clinical evidence for a role of TWEAK in human kidney injury including increased tissue and/or urinary levels of TWEAK and parenchymal renal cell expression of the receptor Fn14. In this regard, clinical trials of TWEAK targeting are ongoing in lupus nephritis. Nuclear factor-kappa B (NF-κB) activation plays a key role in TWEAK-elicited inflammatory responses. Activation of the non-canonical NF-κB pathway is a critical difference between TWEAK and TNF. TWEAK activation of the non-canonical NF-κB pathways promotes inflammatory responses in tubular cells. However, there is an incomplete understanding of the role of non-canonical NF-κB activation in kidney disease and on its contribution to TWEAK actions in vivo.Grant support: ISCII and FEDER funds FIS PS09/00447, ISCIII-RETIC REDinREN/RD06/0016, RD12/0021, Comunidad de Madrid/CIFRA/S2010/BMD-2378. Salary support: FIS to MDSN, Programa Intensificación Actividad Investigadora (ISCIII/Agencia Laín-Entralgo/CM) to AO, FPU (Ministerio de Educación, Cultura y Deporte) to JP, Fundacion Conchita Rabago to LCT

Tacrolimus prevents TWEAK-induced PLA2R expression in cultured human podocytes

Primary membranous nephropathy is usually caused by antibodies against the podocyte antigen membrane M-type phospholipase A2 receptor (PLA2R). The treatment of membranous nephropathy is not fully satisfactory. The calcineurin inhibitor tacrolimus is used to treat membranous nephropathy, but recurrence upon drug withdrawal is common. TNF superfamily members are key mediators of kidney injury. We have now identified key TNF receptor superfamily members in podocytes and explored the regulation of PLA2R expression and the impact of tacrolimus. Data mining of single cell transcriptomics and glomerular transcriptomics data identified TNFRSF12a/Fn14 as the highest expressed TNF receptor superfamily gene in human membranous nephropathy, and this was confirmed by immunohistochemistry that also identified NFκB activation in membranous nephropathy podocytes. Additionally, glomerular transcriptomics identified PLA2R1 expression as being increased in membranous nephropathy in the parenteral administration of the Fn14 ligand TWEAK increased podocyte PLA2R expression in mice. Furthermore, in cultured human podocytes, TWEAK increased the expression of PLA2R as well as the expression of other genes recently identified by GWAS as linked to membranous nephropathy: NFKB1 and IRF4. Interestingly, IRF4 encodes the FK506-binding protein 52 (FKBP52), a protein associated with tacrolimus. Tacrolimus prevented the increased expression of PLA2R, NFKB1 and IRF4 induced by TWEAK in cultured podocytes. In conclusion, TWEAK upregulates the expression of PLA2R and of other genes linked to membranous nephropathy in podocytes, and this is prevented by tacrolimus. An impact of tacrolimus on the expression of PLA2R and other genes in podocytes may underlie its efficacy in treating the disease as well as the frequent recurrence of nephrotic syndrome upon tacrolimus withdrawalThis research was funded by Instituto de Salud Carlos III FIS PI15/00298, PI16/02057, PI18/01366, PI19/00588, PI19/00815, DTS18/00032, ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071), ISCIII-RETIC REDinREN RD016/0009 Fondos FEDER, Sociedad Española de Nefrología, EUTOX, Comunidad de Madrid B2017/BMD-3686 CIFRA2-CM, Fundacion Renal Iñigo Alvarez de Toledo (FRIAT) and Grant Fondecyt (Conicyt Chile) 1160465

MAP3K kinases and kidney injury

Mitogen-activated protein kinases (MAP kinases) are functionally connected kinases that regulate key cellular process involved in kidney disease such as all survival, death, differentiation and proliferation. The typical MAP kinase module is composed by a cascade of three kinases: a MAP kinase kinase kinase (MAP3K) that phosphorylates and activates a MAP kinase kinase (MAP2K) which phosphorylates a MAP kinase (MAPK). While the role of MAPKs such as ERK, p38 and JNK has been well characterized in experimental kidney injury, much less is known about the apical kinases in the cascade, the MAP3Ks. There are 24 characterized MAP3K (MAP3K1 to MAP3K21 plus RAF1, BRAF and ARAF). We now review current knowledge on the involvement of MAP3K in non-malignant kidney disease and the therapeutic tools available. There is in vivo interventional evidence clearly supporting a role for MAP3K5 (ASK1) and MAP3K14 (NIK) in the pathogenesis of experimental kidney disease. Indeed, the ASK1 inhibitor Selonsertib has undergone clinical trials for diabetic kidney disease. Additionally, although MAP3K7 (MEKK7, TAK1) is required for kidney development, acutely targeting MAP3K7 protected from acute and chronic kidney injury; and targeting MAP3K8 (TPL2/Cot) protected from acute kidney injury. By contrast MAP3K15 (ASK3) may protect from hypertension and BRAF inhibitors in clinical use may induced acute kidney injury and nephrotic syndrome. Given their role as upstream regulators of intracellular signaling, MAP3K are potential therapeutic targets in kidney injury, as demonstrated for some of them. However, the role of most MAP3K in kidney disease remains unexploredLas proteínas quinasas activadas por mitógenos (MAP quinasas) son quinasas conectadas funcionalmente que regulan procesos celulares clave involucrados en la enfermedad renal como la supervivencia, la muerte, la diferenciación y la proliferación. El típico módulo MAP quinasa está compuesto por una cascada de 3 quinasas: una MAP quinasa quinasa quinasa (MAP3K) que fosforila y activa una MAP quinasa quinasa (MAP2K) que, a su vez, fosforila una MAP quinasa (MAPK). Si bien el papel de las MAPK como ERK, p38 y JNK se ha caracterizado bien en las lesiones renales experimentales, se sabe mucho menos acerca de las quinasas apicales en la cascada, las MAP3K. Hay 24 MAP3K (MAP3K1 a MAP3K21, más RAF1, BRAF y ARAF). En este trabajo revisamos el conocimiento actual sobre la participación de MAP3K en la enfermedad renal no maligna y las herramientas terapéuticas disponibles. Existe evidencia intervencionista experimental in vivo que respalda claramente el papel de MAP3K5 (ASK1) y MAP3K14 (NIK) en la patogenia de la enfermedad renal experimental. De hecho, el inhibidor de ASK1, selonsertib, ha sido estudiado en ensayos clínicos en la enfermedad renal diabética. Además, aunque la MAP3K7 (MEKK7, TAK1) es necesaria para el desarrollo renal, la inhibición de MAP3K7 en el adulto protegió de la lesión renal aguda y crónica experimental; e inhibir MAP3K8 (TPL2/Cot) protegió de la lesión renal aguda. Por el contrario, MAP3K15 (ASK3) puede proteger de la hipertensión y los inhibidores de BRAF, en uso clínico, pueden inducir lesión renal aguda y síndrome nefrótico. Dado su papel como reguladores de los primeros pasos de la señalización intracelular, las MAP3K son posibles dianas terapéuticas en la lesión renal, como se ha demostrado para algunas de ellos. Sin embargo, el papel de la mayoría de las MAP3K en la enfermedad renal no ha sido exploradoGrant support: Instituto de Salud Carlos III (ISCIII) and FEDER– Fonds Européen de Développement Économique et Régional (FEDER) funds EUTOX, CP14/00133, PI15/00298, PI16/01900,PI16/02057, PI18/01366, Sociedad Española de Nefrologia, Fun-dación Renal Iñigo Alvarez de Toledo (FRIAT), ISCIII Red de Investigacion Renal (REDinREN) RD016/009, Salary support: ISCIII Miguel Servet to MDSN, Universidad Autónoma deMadrid to LC

Association Among Polyphenol Intake, Uric Acid, and Hyperuricemia: A CrossSectional Analysis in a Population at High Cardiovascular Risk

Dietary polyphenol intake has been associated with a decreased risk of hyperuricemia, but most of this knowledge comes from preclinical studies. The aim of the present study was to assess the association of the intake of different classes of polyphenols with serum uric acid and hyperuricemia. This cross- sectional analysis involved baseline data of 6332 participants. Food polyphenol con- tent was estimated by a validated semiquantitative food frequency questionnaire and from the Phenol-Explorer database. Multivariable-adjusted linear regression models with serum uric acid (milligrams per deciliter) as the outcome and polyphenol intake (quintiles) as the main independent variable were fitted. Cox regression models with constant follow-up time (t=1) were performed to estimate the prevalence ratios (PRs) of hyperuricemia (≥7 mg/dL in men and ≥6 mg/dL in women). An inverse association between the intake of the phenolic acid class (β coefficient, −0.17 mg/dL for quintile 5 versus quintile 1 [95% CI, −0.27 to −0.06]) and hydroxycinnamic acids (β coefficient, −0.19 [95% CI, −0.3 to −0.09]), alkylmethoxyphenols (β coefficient, −0.2 [95% CI, −0.31 to −0.1]), and methoxyphenols (β coefficient, −0.24 [95% CI, −0.34 to −0.13]) subclasses with serum uric acid levels and hyperuricemia (PR, 0.82 [95% CI, 0.71– 0.95]; PR, 0.82 [95% CI, 0.71– 0.95]; PR, 0.80 [95% CI, 0.70– 0.92]; and PR, 0.79 [95% CI, 0.69– 0.91]; respectively) was found. The intake of hydroxybenzoic acids was directly and significantly as- sociated with mean serum uric acid levels (β coefficient, 0.14 for quintile 5 versus quintile 1 [95% CI, 0.02– 0.26]) but not with hyperuricemia