Epidemiology of Fabry disease in patients in hemodialysis in the Madrid community.

This study screened for Fabry disease (FD) in patients in hemodialysis (HD) in the region of Madrid (CAM) with a cross-sectional design to evaluate HD-prevalent patients, followed by a three-year period prospective design to analyze HD-incident patients. INCLUSION CRITERIA: patients older than 18 years on HD in the CAM, excluding patients diagnosed with any other hereditary disease with renal involvement different from FD, that sign the Informed Consent (IC). EXCLUSION CRITERIA: underaged patients or not agreeing or not being capable of signing the IC. RESULTS: 3470 patients were included, 63% males and with an average age of 67.9±9.7 years. 2357 were HD-prevalent patients and 1113 HD-incident patients. For HD-prevalent patients, average time in HD was 45.2 months (SD 51.3), in HD-incident patients proteinuria was present in 28.4%. There were no statistical differences in plasmatic alpha-galactosidase A (α-GAL-A) activity or Lyso-GL-3 values when comparing HD-prevalent and HD-incident populations and neither between males and females. A genetic study was performed in 87 patients (2.5% of patients): 60 male patients with decreased enzymatic activity and 27 female patients either with a decreased GLA activity, increased Lyso-Gl3 levels or both. The genetic variants identified were: p.Asp313Tyr (4 patients), p.Arg220Gln (3 patients) and M290I (1 patient). None of the identified variants is pathogenic. CONCLUSIONS: 76% of HD Centers of the CAM participated in the study. This is the first publication to describe the prevalence of FD in the HD-population of a region of Spain as well as its average α-GAL-A-activity and plasmatic Lyso-Gl3 levels. It is also the first study that combines a cross-sectional design with a prospective follow-up design. This study has not identified any FD patient.

Consensus document on palliative care in cardiorenal patients.

There is an unmet need to create consensus documents on the management of cardiorenal patients since, due to the aging of the population and the rise of both pathologies, these patients are becoming more prevalent in daily clinical practice. Chronic kidney disease coexists in up to 40%-50% of patients with chronic heart failure cases. There have yet to be consensus documents on how to approach palliative care in cardiorenal patients. There are guidelines for patients with heart failure and chronic kidney disease separately, but they do not specifically address patients with concomitant heart failure and kidney disease. For this reason, our document includes experts from different specialties, who will not only address the justification of palliative care in cardiorenal patients but also how to identify this patient profile, the shared planning of their care, as well as knowledge of their trajectory and the palliative patient management both in the drugs that will help us control symptoms and in advanced measures. Dialysis and its different types will also be addressed, as palliative measures and when the decision to continue or not perform them could be considered. Finally, the psychosocial approach and adapted pharmacotherapy will be discussed.

Impact of the COVID pandemic on vascular access creation for haemodialysis in 16 Spanish haemodialysis centres.

Background: The coronavirus disease (COVID) pandemic has resulted in a major disruption in healthcare that has affected several medical and surgical specialties. European and American Vascular Societies have proposed deferring the creation of an elective vascular access (VA) [autologous or prosthetic arteriovenous fistula (AVF) or arteriovenous graft (AVG)] in incident patients on haemodialysis (HD) in the era of the COVID pandemic. The aim of this study is to examine the impact of the COVID pandemic on VA creation and the central venous catheter (CVC)-related hospitalizations and complications in HD patients dialyzed in 16 Spanish HD units of three different regions. Methods: We compared retrospectively two periods of time: the pre-COVID (1 January 2019-11 March 2020) and the COVID era (12 March 2020-30 June 2021) in all HD patients (prevalent and incident) dialyzed in our 16 HD centres. The variables analysed were type of VA (CVC, AVF and AVG) created, percentage of CVC in incident and prevalent HD patients, CVC-related hospitalizations and complications (infection, extrusion, disfunction, catheter removal) and percentage of CVC HD sessions that did not reach the goal of Kt (>45) as a marker of HD adequacy. Results: A total of 1791 VAs for HD were created and 905 patients started HD during the study period. Patients who underwent vascular access surgery during the COVID period compared with pre-COVID period were significantly younger, with a significant decrease in surgical activity to create AVFs and AVGs in older HD patients (>75 and >85 years of age). There was a significant increase in CVC placement (from 59.7% to 69.5%; P < 0.001) from the pre-COVID to the COVID period. During the COVID pandemic, a significantly higher number of patients started HD through a CVC (80.3% versus 69.1%; P < 0.001). The percentage of CVC in prevalent HD patients has not decreased in the 19 months since the start of the pandemic [414 CVC/1058 prevalent patients (39.4%)]. No significant changes were detected in CVC-related hospitalizations between the pre-COVID and COVID periods. In the COVID period, a significant increase in catheter replacement and the percentage of HD session that did not reach the HD dose objective (Kt > 45) was observed. Conclusions: COVID has presented a public health system crisis that has influenced VA for HD, with an increase in CVCs relative to AVFs. A decrease in HD sessions that did not reach the HD dose objective was observed in the COVID period compared with a pre-COVID period.

TWEAK Signaling Pathway Blockade Slows Cyst Growth and Disease Progression in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: In autosomal dominant polycystic kidney disease (ADPKD), cyst development and enlargement lead to ESKD. Macrophage recruitment and interstitial inflammation promote cyst growth. TWEAK is a TNF superfamily (TNFSF) cytokine that regulates inflammatory responses, cell proliferation, and cell death, and its receptor Fn14 (TNFRSF12a) is expressed in macrophage and nephron epithelia. METHODS: To evaluate the role of the TWEAK signaling pathway in cystic disease, we evaluated Fn14 expression in human and in an orthologous murine model of ADPKD. We also explored the cystic response to TWEAK signaling pathway activation and inhibition by peritoneal injection. RESULTS: Meta-analysis of published animal-model data of cystic disease reveals mRNA upregulation of several components of the TWEAK signaling pathway. We also observed that TWEAK and Fn14 were overexpressed in mouse ADPKD kidney cysts, and TWEAK was significantly high in urine and cystic fluid from patients with ADPKD. TWEAK administration induced cystogenesis and increased cystic growth, worsening the phenotype in a murine ADPKD model. Anti-TWEAK antibodies significantly slowed the progression of ADPKD, preserved renal function, and improved survival. Furthermore, the anti-TWEAK cystogenesis reduction is related to decreased cell proliferation-related MAPK signaling, decreased NF-κB pathway activation, a slight reduction of fibrosis and apoptosis, and an indirect decrease in macrophage recruitment. CONCLUSIONS: This study identifies the TWEAK signaling pathway as a new disease mechanism involved in cystogenesis and cystic growth and may lead to a new therapeutic approach in ADPKD.

Diferencias entre los métodos de determinación de 2ª y 3ª generación de la parathormona sérica sobre la mortalidad en el paciente en hemodiálisis / Differences between 2nd and 3rd generation seric parathormone determination methods on mortality in haemodialysis patients

La paratohormona tiene un papel fundamental en el control del metabolismo mineral. Además es considerada como una toxina urémica al originar daño cardiovascular e influir en la mortalidad cardiovascular del paciente en diálisis. Existen dos métodos de medición denominados de 2.ª generación o PTH intacta (PTHi) y de 3.ª generación o bioPTH (PTHbio). Objetivo: Evaluar las diferencias en la mortalidad del paciente en diálisis entre ambas formas de medición de PTH, así como el posible papel pronóstico de su cociente. Métodos: Se incluyeron 145 pacientes en hemodiálisis con un seguimiento de 2 años con determinación analítica basal y posteriormente de forma anual. Resultados: Veintiún pacientes fallecieron el primer año y 28 el segundo. No se encontró correlación entre PTHi, PTHbio y cociente PTHbio/PTHi con la mortalidad. Ambas PTH tienen una buena correlación entre ellas y correlacionan de manera similar con otras moléculas del metabolismo mineral. Los valores basales de PTH extremos son los de mayor mortalidad. En la supervivencia por tramos de PTHi (según guías y estudio COSMOS) se observa una curva en J. A mayor aumento de PTHi el cociente desciende, posiblemente al aumentar los fragmentos no 1-84. No existe una mayor aproximación pronóstica sobre mortalidad con PTHbio que con PTHi. No se observan diferencias en el valor predictivo del cociente sobre la mortalidad. Tampoco hubo diferencias en mortalidad cuando se analiza la progresión del cociente PTHbio/PTHi. Conclusiones: No encontramos ventajas en la utilización de PTHbio sobre la PTHi como marcador de mortalidad. Se deben reevaluar los límites de la PTHbio pues su relación con la PTHi no es constante. El no conocer esos límites condiciona su utilidad pronóstica (AU)

Parathormone plays a key role in controlling mineral metabolism. PTH is considered a uremic toxin causing cardiovascular damage and cardiovascular mortality in dialysis patients. There are two different assays to measure PTH called 2nd generation or intact PTH (iPTH) and 3rd generation or bioPTH (PTHbio). Objective: To evaluate the differences in mortality of dialysis patients between both assays to measure PTH, as well as the possible prognostic role of the PTHbio/iPTH ratio. Methods: 145 haemodialysis patients were included with 2-year monitoring including baseline laboratory test and annually thereafter. Results: 21 patients died in the first year and 28 in the second. No correlation was found between PTH, PTHbio and PTHbio/iPTH ratio with mortality. Both PTH have a perfect correlation between them and correlate similarly with other molecules of the mineral metabolism. The extreme baseline values of PTH are those of higher mortality. In survival by iPTH intervals (according to guidelines and COSMOS study), a J curve is observed. When iPTH increases, the ratio decreases, possibly when increasing fragments no. 1-84. There is no greater prognostic approximation on mortality with PTHbio than PTHi. There was also no difference in mortality when progression ratio PTHbio/PTHi was analysed. Conclusions: We didn’t find any advantages to using bioPTH vs. PTHi as a marker of mortality. BioPTH limits of normality must be reevaluated because its relationship with iPTH is not consistent. Not knowing these limits affects its prognostic value (AU)

Rapidly progressive glomerulonephritis associated to afebrile endocarditis and anti-proteinasa 3 anca / Glomerulonefritis rápidamente progresiva asociada a endocarditis afebril y anca anti-proteinasa 3

Absctrat Endocarditis associated with antiPR3 ANCA and acute kidney injure generates a challenge in its diagnosis and treatment. In order to make a review about that combination, we presented a patient with necrotizing glomerulonephritis produced by a Enterococcus faecalis's subacute endocarditis and antiPR3 ANCA positive. Differential diagnosis is made between an acute kidney failure produced by ANCA's vasculitis vs necrotizing glomerulonephritis by endocarditis. Frequently it is necessary to make a biopsy to get a diagnosis. Negative immunofluorescence will guide to vasculitis associated ANCA, while positive immune complexes will guide to poststreptococcal glomerulonephritis. Other challenge that generates the association of acute kidney disease, endocarditis and antiPR3 ANCA is the treatment. ANCA positive can prompt to start immunosuppressant treatments. However, in the context of endocarditis, it could be inadvisable and even dangerous to use it. For this reason, it is controversial the use of immunosuppressant in combination with antibiotics in the acute process, in contrast with the use of only antibiotics. In the current paper we collect the 19 reports in the literature about endocarditis associated with antiPR3 ANCA, the treatment and the renal evolution of each patient. We concluded, generally, a better improvement of kidney function in patients treated with only antibiotics than those patients treated with the combination of antibiotics and corticoids. However, there are so few reports that we can't consider significant the different between both treatment groups.

Resumen La endocarditis asociada a ANCA anti-PR3 e insuficiencia renal plantea un dilema tanto en su diagnóstico como tratamiento. Para abordar una revisión de dicho tema, se presenta el caso de un paciente con glomerulonefritis rápidamente progresiva secundaria a endocarditis subaguda por Enterococcus faecalis y positividad para ANCA anti-PR3. El diagnóstico diferencial principal se establecería entre una afectación renal de una vasculitis asociada a ANCA no diagnosticada previamente vs una glomerulonefritis postinfecciosa secundaria a la endocarditis. En muchos casos es necesario disponer de una biopsia renal que esclarezca el diagnóstico, ya que una inmunofluorescencia negativa orientará hacia una vasculitis, mientras que una positividad para inmunocomplejos iría a favor de una glomerulonefritis postestreptocócica. El tratamiento a seguir es otro reto que se plantea en la coexistencia de insuficiencia renal aguda, endocarditis y ANCA anti-PR3 positivo. La positividad de ANCAs induce a valorar iniciar tratamiento con inmunosupresores, no obstante, en el lecho de una endocarditis puede resultar desaconsejado e incluso poner en riesgo la vida del paciente someterlo a un estado de inmunosupresión. Es, por tanto, controvertido el uso de inmunosupresión en combinación con antibioterapia en el proceso agudo en contraposición al uso de antibioterapia exclusivamente. En el actual artículo se recogen los 19 casos publicados en la literatura de endocarditis asociados a ANCA anti-PR3, así como el tratamiento que se realizó en cada uno de los casos y la evolución en la función renal de cada paciente, concluyendo, en general, una mejor recuperación de la función renal en los pacientes tratados con antibioterapia en exclusiva que en aquellos tratados con la combinación antibiótico-corticoides. Sin embargo, dado el pequeño tamaño muestral, no se puede considerar significativa la diferencia entre ambos tratamientos.

Differences between 2nd and 3rd generation seric parathormone determination methods on mortality in haemodialysis patients. / Diferencias entre los métodos de determinación de 2.ª y 3.ª generación de la parathormona sérica sobre la mortalidad en el paciente en hemodiálisis.

Parathormone plays a key role in controlling mineral metabolism. PTH is considered a uremic toxin causing cardiovascular damage and cardiovascular mortality in dialysis patients. There are two different assays to measure PTH called 2nd generation or intact PTH (iPTH) and 3rd generation or bioPTH (PTHbio). OBJECTIVE: To evaluate the differences in mortality of dialysis patients between both assays to measure PTH, as well as the possible prognostic role of the PTHbio/iPTH ratio. METHODS: 145 haemodialysis patients were included with 2-year monitoring including baseline laboratory test and annually thereafter. RESULTS: 21 patients died in the first year and 28 in the second. No correlation was found between PTH, PTHbio and PTHbio/iPTH ratio with mortality. Both PTH have a perfect correlation between them and correlate similarly with other molecules of the mineral metabolism. The extreme baseline values of PTH are those of higher mortality. In survival by iPTH intervals (according to guidelines and COSMOS study), a J curve is observed. When iPTH increases, the ratio decreases, possibly when increasing fragments no. 1-84. There is no greater prognostic approximation on mortality with PTHbio than PTHi. There was also no difference in mortality when progression ratio PTHbio/PTHi was analysed. CONCLUSIONS: We didn't find any advantages to using bioPTH vs. PTHi as a marker of mortality. BioPTH limits of normality must be reevaluated because its relationship with iPTH is not consistent. Not knowing these limits affects its prognostic value.

A decrease in intact parathyroid hormone (iPTH) levels is associated with higher mortality in prevalent hemodialysis patients.

BACKGROUND: The mortality of dialysis patients is 10- to 100-fold higher than in the general population. Baseline serum PTH levels, and more recently, changes in serum PTH levels (ΔPTH) over time, have been associated to mortality in dialysis patients. METHODS: We explored the relationship between ΔPTH over 1 year with mortality over the next year in a prospective cohort of 115 prevalent hemodialysis patients from a single center that had median baseline iPTH levels within guideline recommendations. RESULTS: Median baseline iPTH levels were 205 (116.5, 400) pg/ml. ΔiPTH between baseline and 1 year was 85.2 ± 57.1 pg/ml. During the second year of follow-up, 27 patients died. ΔiPTH was significantly higher in patients who survived (+157.30 ± 25.82 pg/ml) than in those who died (+39.03 ± 60.95 pg/ml), while baseline iPTH values were not significantly different. The highest mortality (48%) was observed in patients with a decrease in ΔiPTH (ΔiPTH quartile 1, negative ΔiPTH) and the lowest (12%) mortality in quartile 3 ΔiPTH (ΔiPTH increase 101-300 pg/ml). In a logistic regression model, ΔiPTH was associated with mortality with an odds ratio (OR) of 0.998 (95% CI 0.996-0999, p = 0.038). In multivariable analysis, mortality risk was 73% and 88% lower for patients with ΔiPTH 0-100 pg/ml and 101-300 pg/ml, respectively, than for those with a decrease in ΔiPTH. In patients with a decrease in ΔiPTH, the OR for death was 4.131 (1.515-11.27)(p = 0.006). CONCLUSIONS: In prevalent hemodialysis patients with median baseline iPTH values within the guideline recommended range, a decrease in ΔiPTH was associated with higher mortality. Further studies are required to understand the mechanisms and therapeutic implications of this observation that challenges current clinical practice.

Use of sevelamer in chronic kidney disease: beyond phosphorus control.

Sevelamer is a non-calcium phosphate binder used in advanced chronic kidney disease (CKD) and in dialysis for hyperphosphataemia control. Several experimental, observational studies and clinical trials have shown that sevelamer has pleiotropic effects, beyond hyperphosphataemia control, including actions on inflammation, oxidative stress, lipid profile and atherogenesis, vascular calcification, endothelial dysfunction and the reduction of several uremic toxins. This is the biological basis for its global effect on cardiovascular morbidity and mortality in patients with chronic kidney disease. This review focuses on these pleiotropic actions of sevelamer and their impact on cardiovascular health, with the experience published after more than ten years of clinical expertise.

Combination use of medicines from two classes of renin-angiotensin system blocking agents: risk of hyperkalemia, hypotension, and impaired renal function.

European and United States regulatory agencies recently issued warnings against the use of dual renin-angiotensin system (RAS) blockade therapy through the combined use of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs) or aliskiren in any patient, based on absence of benefit for most patients and increased risk of hyperkalemia, hypotension, and renal failure. Special emphasis was made not to use these combinations in patients with diabetic nephropathy. The door was left open to therapy individualization, especially for patients with heart failure, when the combined use of an ARB and ACEI is considered absolutely essential, although renal function, electrolytes and blood pressure should be closely monitored. Mineralocorticoid receptor antagonists were not affected by this warning despite increased risk of hyperkalemia. We now critically review the risks associated with dual RAS blockade and answer the following questions: What safety issues are associated with dual RAS blockade? Can the safety record of dual RAS blockade be improved? Is it worth trying to improve the safety record of dual RAS blockade based on the potential benefits of the combination? Is dual RAS blockade dead? What is the role of mineralocorticoid antagonists in combination with other RAS blocking agents: RAAS blockade?

Timing of eculizumab therapy for C3 glomerulonephritis.

Eculizumab is an anti-C5 antibody that inhibits C5 cleavage and prevents the generation of the terminal complement complex C5b-9. Eculizumab is licensed to treat paroxysmal nocturnal haemoglobinuria or atypical haemolytic uraemic syndrome (aHUS). Clinical trials are ongoing for C3 glomerulopathy. Given the unfamiliarity of physicians with these rare diseases and the variability of clinical presentation, a delayed initiation of eculizumab therapy is common. Thus, the question arises as to what extent improvement of kidney function may be expected when patients have been dialysis dependent for weeks or months already when eculizumab is initiated. Furthermore, given the high cost and potential adverse effects of eculizumab, the question arises of when to stop therapy because of futility when patients with kidney-only manifestations remain dialysis dependent. In literature reports, eculizumab was stopped as early as after 3 weeks because the patient remained dialysis dependent. In this issue of CKJ, Inman et al. report on eculizumab-induced reversal of dialysis-dependent kidney failure from C3 glomerulonephritis, illustrating both the potential benefit of eculizumab for this complement-mediated disease and the need for lengthy therapy-dialysis independency was reached after 5 months of eculizumab. Indeed, there are reports of renal function recovery when eculizumab was initiated after 4 months on dialysis and of recovery of renal function 2.0-3.5 months after initiation of eculizumab in dialysis-dependent patients with C3 glomerulopathy or aHUS.

Designing drugs that combat kidney damage.

INTRODUCTION: Kidney disease remains one of the last worldwide frontiers in the field of non-communicable human disease. From 1990 to 2013, chronic kidney disease (CKD) was the top non-communicable cause of death with a greatest increase in global years of life lost while mortality of acute kidney injury (AKI) still hovers around 50%. This reflects the paucity (for CKD) or lack of (for AKI) therapeutic approaches beyond replacing renal function. Understanding what the barriers are and what potential pathways may facilitate the design of new drugs to combat kidney disease is a key public health priority. AREAS COVERED: The authors discuss the hurdles and opportunities for future drug development for kidney disease in light of experience accumulated with drugs that made it to clinical trials. EXPERT OPINION: Inflammation, cell death and fibrosis are key therapeutic targets to combat kidney damage. While the specific targeting of drugs to kidney cells would be desirable, the technology is only working at the preclinical stage and with mixed success. Nanomedicines hold promise in this respect. Most drugs undergoing clinical trials for kidney disease have been repurposed from other indications. Currently, the chemokine receptor inhibitor CCX140 holds promise for CKD and the p53 inhibitor QPI-1002 for AKI.

Uso del sevelamer en la enfermedad renal crónica. Más allá del control del fósforo / Using sevelamer in chronic kidney disease. Beyond phosphorus control

El sevelamer es un captor no cálcico de fósforo que se utiliza en la ERC avanzada y en diálisis para el control de la hiperfosforemia. Varios estudios experimentales, observacionales y ensayos clínicos han mostrado que el sevelamer tiene efectos pleiotrópicos, más allá del control de la hiperfosforemia, incluyendo acciones sobre la inflamación, el estrés oxidativo, el perfil lipídico y la aterogénesis, la calcificación vascular, la disfunción endotelial y la disminución de diversas toxinas urémicas, todo lo cual sería la base biológica de su efecto global sobre la morbilidad y la mortalidad cardiovascular en pacientes con enfermedad renal crónica. En esta revisión, se hace énfasis en estas acciones pleiotrópicas del sevelamer y su impacto en la salud cardiovascular, con la experiencia publicada después de más de 10 años de experiencia clínica (AU)

Sevelamer is a calcium-free phosphate binder used in advanced chronic kidney disease (CKD) and in dialysis to control hyperphosphatemia. Several experimental and observational studies and clinical trials have shown that sevelamer has pleiotropic effects that go beyond controlling hyperphosphatemia; these pleiotropic effects include acting on inflammation, oxidative stress, lipid profile and atherogenesis, vascular calcification, endothelial dysfunction and decreasing various uremic toxins. All of these represent the biological basis for the global effect of sevelamer on cardiovascular morbidity and mortality in patients with CKD. In this review, we emphasis these pleiotropic actions of sevelamer and their impact on cardiovascular health, with the experience published after more than 10 years of clinical experience (AU)

Correction of hypocalcemia allows optimal recruitment of FGF-23-dependent phosphaturic mechanisms in acute hyperphosphatemia post-phosphate enema.

Both parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) are phosphaturic hormones. These hormones should increase in response to phosphate excess. However, they also regulate serum calcium; PTH increases serum calcium concentration and FGF23 suppresses renal production of calcitriol, favoring hypocalcemia. We report the case of an 83-year-old woman with hyperphosphatemia and hypocalcemia resulting from phosphate-containing enemas. PTH and calcitriol increased in response to hypocalcemia, and FGF23 increased in response to hyperphosphatemia. Unexpectedly, peak FGF23 did not coincide with peak serum phosphate. Rather, peak FG23 was observed only after severe hypocalcemia was partially corrected with exogenous calcium administration, even though serum phosphate had been already decreasing for 32 h. Correction of severe hypocalcemia was thus associated with peak FGF23 values and with a precipitous decrease in PTH. Peak FGF23 was followed by an accelerated decrease in serum phosphate and significant phosphaturia. This clinical report is consistent with experimental data in rats showing a blunted FGF23 response to high phosphate in the presence of severe hypocalcemia. Thus, complementary experimental and clinical data suggest that partial correction of severe hypocalcemia is required for optimal FGF23-mediated phosphaturia, which takes place despite correction of PTH levels. We believe this the first human report suggesting blunting of the FGF23 response to high phosphate by severe hypocalcemia.