Adverse renal effects of check-point inhibitors (ICI) in cancer patients: Recommendations of the Onco-nephrology Working Group of the Spanish Society of Nephrology.

The most widely used approach in the immunotherapy treatment of cancer is the administration of monoclonal antibodies directed against regulatory molecules of immune control that inhibit the activation of T cells, the so-called check point inhibitors (ICI). ICI nephrotoxicity epidemiology and pathology; its diagnosis with or without kidney biopsy; the type and duration of treatment; the possibility of rechallenging after kidney damage; and its indication in patients with cancer and renal transplantation are certainly controversial. In the absence of definitive studies, this document is intended to specify some recommendations agreed by the group of Onconephrology experts of the Spanish Society of Nephrology in those areas related to ICI nephrotoxicity, in order to help decision-making in daily clinical practice in Onconephrology consultations.

Efectos renales adversos por inhibidores del check-point (ICP) en pacientes con cáncer. Recomendaciones del grupo de Onconefrología de la Sociedad Española de Nefrología (SEN) / Adverse renal effects of check-point inhibitors (ICI) in cancer patients: Recommendations of the Onco-nephrology Working Group of the Spanish Society of Nephrology

El enfoque más utilizado en el tratamiento inmunoterápico del cáncer es la administración de anticuerpos monoclonales dirigidos contra moléculas reguladoras del control inmunitario que inhiben la activación de las células T, los llamados inhibidores del check-point (ICP). La epidemiología y patología de la nefrotoxicidad por los ICP, su diagnóstico con o sin biopsia renal, el tipo y la duración del tratamiento, la posibilidad de retratar después del daño renal, y su indicación en pacientes con cáncer y trasplante renal son ciertamente controvertidas. En ausencia de estudios definitivos, este documento está destinado a concretar unas recomendaciones consensuadas por el grupo de expertos de Onconefrología de la SEN en aquellas áreas relacionadas con la nefrotoxicidad por los ICP, con la finalidad de ayudar en la toma de decisiones en la práctica clínica diaria de las consultas de Onconefrología. (AU)

The most widely used approach in the immunotherapy treatment of cancer is the administration of monoclonal antibodies directed against regulatory molecules of immune control that inhibit the activation of T cells, the so-called check point inhibitors (ICI). ICI nephrotoxicity epidemiology and pathology; its diagnosis with or without kidney biopsy; the type and duration of treatment; the possibility of rechallenging after kidney damage; and its indication in patients with cancer and renal transplantation are certainly controversial. In the absence of definitive studies, this document is intended to specify some recommendations agreed by the group of onconephrology experts of the Spanish Society of Nephrology in those areas related to ICI nephrotoxicity, in order to help decision-making in daily clinical practice in onconephrology consultations. (AU)

The European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) Registry Annual Report 2015: a summary.

BACKGROUND: This article summarizes the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) Registry's 2015 Annual Report. It describes the epidemiology of renal replacement therapy (RRT) for end-stage renal disease (ESRD) in 2015 within 36 countries. METHODS: In 2016 and 2017, the ERA-EDTA Registry received data on patients who were undergoing RRT for ESRD in 2015, from 52 national or regional renal registries. Thirty-two registries provided individual patient-level data and 20 provided aggregated-level data. The incidence, prevalence and survival probabilities of these patients were determined. RESULTS: In 2015, 81 373 individuals commenced RRT for ESRD, equating to an overall unadjusted incidence rate of 119 per million population (pmp). The incidence ranged by 10-fold, from 24 pmp in Ukraine to 232 pmp in the Czech Republic. Of the patients commencing RRT, almost two-thirds were men, over half were aged ≥65 years and a quarter had diabetes mellitus as their primary renal diagnosis. Treatment modality at the start of RRT was haemodialysis for 85% of the patients, peritoneal dialysis for 11% and a kidney transplant for 4%. By Day 91 of commencing RRT, 82% of patients were receiving haemodialysis, 13% peritoneal dialysis and 5% had a kidney transplant. On 31 December 2015, 546 783 individuals were receiving RRT for ESRD, corresponding to an unadjusted prevalence of 801 pmp. This ranged throughout Europe by more than 10-fold, from 178 pmp in Ukraine to 1824 pmp in Portugal. In 2015, 21 056 kidney transplantations were performed, equating to an overall unadjusted transplant rate of 31 pmp. This varied from 2 pmp in Ukraine to 94 pmp in the Spanish region of Cantabria. For patients commencing RRT during 2006-10, the 5-year unadjusted patient survival probabilities on all RRT modalities combined was 50.0% (95% confidence interval 49.9-50.1).

The European Renal Association - European Dialysis and Transplant Association Registry Annual Report 2014: a summary.

Background: This article summarizes the European Renal Association - European Dialysis and Transplant Association Registry's 2014 annual report. It describes the epidemiology of renal replacement therapy (RRT) for end-stage renal disease (ESRD) in 2014 within 35 countries. Methods: In 2016, the ERA-EDTA Registry received data on patients who in 2014 where undergoing RRT for ESRD, from 51 national or regional renal registries. Thirty-two registries provided individual patient level data and 19 provided aggregated patient level data. The incidence, prevalence and survival probabilities of these patients were determined. Results: In 2014, 70 953 individuals commenced RRT for ESRD, equating to an overall unadjusted incidence rate of 133 per million population (pmp). The incidence ranged by 10-fold; from 23 pmp in the Ukraine to 237 pmp in Portugal. Of the patients commencing RRT, almost two-thirds were men, over half were aged ≥65 years and a quarter had diabetes mellitus as their primary renal diagnosis. By day 91 of commencing RRT, 81% of patients were receiving haemodialysis. On 31 December 2014, 490 743 individuals were receiving RRT for ESRD, equating to an unadjusted prevalence of 924 pmp. This ranged throughout Europe by more than 10-fold, from 157 pmp in the Ukraine to 1794 pmp in Portugal. In 2014, 19 406 kidney transplantations were performed, equating to an overall unadjusted transplant rate of 36 pmp. Again this varied considerably throughout Europe. For patients commencing RRT during 2005-09, the 5-year-adjusted patient survival probabilities on all RRT modalities was 63.3% (95% confidence interval 63.0-63.6). The expected remaining lifetime of a 20- to 24-year-old patient with ESRD receiving dialysis or living with a kidney transplant was 21.9 and 44.0 years, respectively. This was substantially lower than the 61.8 years of expected remaining lifetime of a 20-year-old patient without ESRD.

Strategy to estimate risk progression of chronic kidney disease, cardiovascular risk, and referral to nephrology: the EPIRCE Study

Background: Although the prevalence of chronic kidney disease (CKD) is 10-14%, several prospective studies note a low rate of progression to end-stage renal disease (ESRD) in stages 3 and 4. A correct classification of risk of progression, based on demonstrated predictive factors, would allow better management of CKD. Recent studies have demonstrated the high predictive value of a classification that combines estimated (e) glomerular filtration rate (GFR) and urine albumin-creatinine ratio (ACR). We estimated the clinical risk of progression to ESRD and cardiovascular mortality predicted by the combined variable of eGFR and ACR in the Spanish general population. Materials and Methods: This study was a cross-sectional evaluation in the Epirce sample, representative of Spanish population older than 20 years. GFR was estimated using MDRD and CKD-EPI formulas; microalbuminuria was considered to be an ACR 20-200 mg/g (men) or 30-300 mg/g (women) and macroalbuminuria was indicated beyond these limits. Population-weighted prevalence of risk (..) (AU)

Antecedentes: Si bien la prevalencia de la enfermedad renal crónica (ERC) es del 10-14 %, diversos estudios prospectivos indican que en las fases 3 y 4 existe una tasa baja de progresión hacia enfermedad renal terminal (ERT). Una clasificación correcta del riesgo de progresión basada en factores predictivos demostrados permitiría un mejor manejo de la ERC. Estudios recientes han demostrado el elevado valor predictivo de la clasificación que combina el valor estimado (e) de la tasa de filtrado glomerular (FG) con la ratio albúmina-creatinina (RAC) en orina. Realizamos una estimación del riesgo clínico de una progresión hacia una ERT y de mortalidad cardiovascular existente en la población general española basando la predicción en el uso combinado de las variables tasa (e) de FG y RAC. Materiales y métodos: Evaluación cruzada en la muestra Epirce, que era representativa de la población española mayor de 20 años. Para la estimación del FG se emplearon las fórmulas MDRD y CKD-EPI; se consideraba la existencia de microalbuminuria cuando los valores de RAC oscilaban entre 20-200 mg/g (hombres) o entre 30-300 mg/g (mujeres) y de macroalbuminuria cuando los valores superaban dichos límites. Se realizó una estimación de la prevalencia ponderada poblacionalmente del riesgo de progresión de ERC hacia ERT. Resultados: Con MDRD, el 1,4 % de la población (..) (AU)

Strategy to estimate risk progression of chronic kidney disease, cardiovascular risk, and referral to nephrology: the EPIRCE Study.

BACKGROUND: Although the prevalence of chronic kidney disease (CKD) is 10­14%, several prospective studies note a low rate of progression to end-stage renal disease (ESRD) in stages 3 and 4. A correct classification of risk of progression, based on demonstrated predictive factors, would allow better management of CKD. Recent studies have demonstrated the high predictive value of a classification that combines estimated (e) glomerular filtration rate (GFR) and urine albumin­creatinine ratio (ACR). We estimated the clinical risk of progression to ESRD and cardiovascular mortality predicted by the combined variable of eGFR and ACR in the Spanish general population. MATERIALS AND METHODS: This study was a cross-sectional evaluation in the Epirce sample, representative of Spanish population older than 20 years. GFR was estimated using MDRD and CKD-EPI formulas; microalbuminuria was considered to be an ACR 20­200 mg/g (men) or 30­300 mg/g (women) and macroalbuminuria was indicated beyond these limits. Population-weighted prevalence of risk of progression of CKD to ESRD was estimated. RESULTS: With MDRD, 1.4% of the adult Spanish population was at moderate risk of progression to ESRD, 0.1% at high risk, and 12.3% at low risk. With CKD-EPI, the moderate risk ratio rose to 1.7% and low risk to 12.6%, but high risk remained stable. CONCLUSIONS: The addition of ACR to eGFR best classifies the population at risk for renal impairment relative to Kidney/Disease Outcomes Quality Initiative grades 3 and 4. Estimating GFR with CKD-EPI modifies the distribution of low and moderate risk.

Characteristics of bone mineral metabolism in patients with stage 3-5 chronic kidney disease not on dialysis: results of the OSERCE study.

OSERCE is a multi-centre and cross-sectional study with the aim of analysing the biochemical, clinical, and management characteristics of bone mineral metabolism alterations and the level of compliance with K/DOQI guideline recommendations in patients with chronic kidney disease (CKD) not on dialysis. The study included a total of 634 patients from 32 different Spanish nephrology units, all with CKD, estimated glomerular filtration rates <60 ml/min/1.73 m(2), and not on dialysis (K/DOQI stage: 33% stage 3, 46% stage 4, and 21% stage 5). In 409 of these patients, laboratory parameters were also measured in a centralised laboratory, including creatinine, calcium, phosphorous, intact parathyroid hormone (PTH), 25-OH-vitamin D, and 1,25-OH2-Vitamin D levels. The rates of non-compliance with the K/DOQI objectives for calcium, phosphorous, intact PTH, and calcium x phosphate product among these patients were 45%, 22%, 70%, and 4%, respectively. Of the 70% of patients with intact PTH levels outside of the target range established by the K/DOQI guidelines, 55.5% had values above the upper limit and 14.5% had values below the lower limit. Of the 45% of patients with calcium levels outside of the target range, 40% had values above the upper limit and 5% had values below the lower limit. Of the 22% of patients with phosphorous levels outside of the target range, 19% had values above the upper limit, and 3% had values below the lower limit. Finally, 4% of patients also had values for the calcium x phosphate product that were outside of the recommended range. Only 1.8% of patients complied with all four K/DOQI objectives. The values detected in centralised laboratory analyses were not significantly different from those measured in the laboratories at each institution. In addition, 81.5% of patients had a deficiency of calcidiol (25-OH-D3) (<30 ng/ml); of these, 35% had moderate-severe deficiency (<15 ng/ml) and 47% had mild deficiency (15-30 ng/ml). Calcitriol (1,25-OH2-D3) levels were deficient in 64.7% of patients. Whereas the calcidiol deficiency was not correlated with the CKD stage, calcitriol deficit were more pronounced at more advanced stages of CKD. The results of the OSERCE study confirm the difficulty in reaching the target values recommended by the K/DOQI guidelines in patients with CKD not on dialysis, in particular in the form of poor control of secondary hyperparathyroidism and vitamin D deficiency. With this in mind, we must review strategies for treating bone mineral metabolism alterations in these patients, and perhaps revise the target parameters set by current guidelines.

Double treatment with paricalcitol-associated calcifediol and cardiovascular risk biomarkers in haemodialysis.

BACKGROUND: The deficit of 25-hydroxyvitamin D (25OHD) associated with secondary hyperparathyroidism (SHPT) is a frequent finding in chronic kidney disease (CKD) patients on haemodialysis (HD). These events are associated with increased morbidity and mortality rates of cardiovascular (CV) origin. Adequate 25OHD serum levels as well as the use of selective vitamin D receptor activators (VDRA) have been shown to have beneficial and independent effects on bone mineral metabolism and cardiovascular risk. Currently, there is still controversy regarding the type of supplementation needed by CKD patients on HD. OBJECTIVE: The aim of our study was to evaluate whether there is a benefit of combination therapy with 25OHD, calcifediol and a VDRA, oral paricalcitol, on bone-mineral metabolism and inflammatory markers, compared to single treatment with each of these in a group of patients on HD. MATERIAL AND METHOD: We performed a prospective study of 6 months, involving 26 patients in our HD unit. We randomised patients into two groups: group 1 (G1) received oral paricalcitol treatment at doses of 1 mcg/day. Group 2 (G2) was treated with 1 ampoule calcifediol/wk (0.266 mg/wk=16 000U) orally. After 3 months of treatment, calcifediol and paricalcitol were added to the G1 and G2 respectively at the same doses, keeping these treatments together for 3 months to complete the 6 months of follow-up. Laboratory tests were performed at months 0, 3 and 6, measuring in all patients serum markers of 25OHD, calcium (Ca), phosphorus (P) and PTH. Bone turnover markers measured were: alkaline phosphatase (AP), aminoterminal propeptide of procollagen type 1 (Pinp1) and carboxyl-terminal telopeptide of type I collagen (CrossLaps), and inflammatory markers: IL-8. We also collected data on levels of insulin, glucose, haemoglobin, erythropoiesis-stimulating agents (ESAs) and rates of resistance to EPO and HOMA (homeostasis model assessment). RESULTS: We detected a deficit of 25-hydroxyvitamin D in all patients studied, with a mean of 13.67 ± 4.81 ng/ml. Supplementation with oral calcifediol significantly corrects this deficit without evidence of toxicity (35.36 ± 33.68 ng/ml in G1 at 6 months and 59.21 ± 26.50 ng/ml in G2 at 3 months). Paricalcitol treatment significantly reduces PTH levels in G1 at 3 months (P<.039). We also noted a decrease in bone marker Pinp1 with paricalcitol, pointing to a possible direct effect on bone cells (P<.001). Both treatment with paricalcitol and with calcifediol produced a significant decrease in levels of IL-8 (P<.001), a known inflammatory marker, drawing attention to a trend towards better response to erythropoiesis-stimulating agents (ESAs), possibly related to the decrease in inflammation. The HOMA index did not change significantly. CONCLUSION: Based on our results, we cannot conclude that the association of calcifediol and paricalcitol produces advantages over the effect of each drug separately. In addition, Paricalcitol by itself appears to have a direct effect on cellular bone remodelling.

Tratamiento doble con calcifediol asociado a paricalcitol y biomarcadores de riesgo cardiovascular en hemodiálisis / Double treatment with paricalcitol-associated calcifediol and cardiovascular risk biomarkers in haemodialysis

Introducción: El déficit de 25-hidroxivitamina D (25OHD) asociado a un hiperparatiroidismo secundario son hallazgos frecuentes en pacientes con enfermedad renal crónica (ERC) en hemodiálisis (HD). Estos hechos se asocian con un incremento de la morbimortalidad de origen cardiovascular (CV). Niveles séricos adecuados de 25OHD, así como el uso de activadores selectivos del receptor de vitamina D (AsRVD), han demostrado tener efectos beneficiosos sobre el metabolismo óseo-mineral y el riesgo CV de manera independiente. Actualmente aún existe controversia respecto al tipo de suplementación que precisan los pacientes con ERC en HD. Objetivo: El objetivo de nuestro estudio fue evaluar si existe beneficio alguno en el tratamiento combinado de 25OHD, calcifediol oral y AsRVD, paricalcitol oral sobre el metabolismo óseo-mineral y marcadores inflamatorios, respecto al tratamiento único con cada uno de ellos, en un grupo de pacientes de HD. Material y métodos: Realizamos un estudio prospectivo de 6 meses de duración sobre 26 pacientes de nuestra (..) (AU)

Background: The deficit of 25-hydroxyvitamin D (25OHD) associated with secondary hyperparathyroidism (SHPT) are frequent findings in patients with chronic kidney disease (CKD) on hemodialysis (HD). These events are associated with increased morbidity and mortality of cardiovascular (CV). 25OHD adequate serum levels as well as the use of selective activators of the vitamin D receptor (AsRVD) have been shown to have beneficial effects on bone metabolism and mineral and cardiovascular risk independently. Currently there is still controversy regarding the type of supplementation needed by patients with CKD on HD. Aims: The aim of our study was to evaluate whether there is benefit in combination therapy with 25OHD, calcifediol and a AsRVD, oral paricalcitol on bone-mineral metabolism and inflammatory markers, compared to single treatment with each of them in a group HD patients. Material and methods: A prospective study of 6 months, over 26 patients in our HD unit. We randomized patients into two groups: group 1 (G1) received oral paricalcitol treatment at doses of 1mcg/day. Group 2 (G2) was treated with 1 ampoule calcifediol/wk (0.266mg/wk=16.000U) orally. After 3 months of treatment, was added (..) (AU)

Epidemiological study of 7316 patients on haemodialysis treated in FME clinics in Spain, using data from the EuCliD® database: results from years 2009-2010.

Observational study of patients on hemodialysis (HD) in FMC® Spain clinics over the years 2009 and 2010. The data were collected from the EuClid® database, implemented in the clinics of FMC®, which complies with the following feature: record online, compulsory, conducted in patients incidents and that it covers the entire population on HD in these clinics. Its aim is to understand the characteristics of patients and treatment patterns, comparing them with other studies described in the literature and in order to improve their prognosis and quality of life. Include 2637 incidents patients and 4679 prevalent, which makes a total of 7316 patients. In prevalent patients: 24.4% were diabetic; 76.3% had cardio-vascular disease (CVD) and 13.4% cancer. Among the incidents, these percentages were: 33.5% diabetic; 80.6% had CVD and 12.6% cancer. The prevalent patients had such as vascular access: FAV 68.5%, prosthesis 5.6%, permanent catheter 23.7% and 2.3% temporary catheter. The average of the duration of the sessions of HD was 230 minutes. 23.2% of the prevalent patients were on on-line hemodiafiltration. These patients hospitalization rates were 0.46 hospitalizations per incident patient per year and 0.52 per prevalent patient per year. The annual gross mortality rate was 12%. The mortality of the patients in this study HD is smaller than these of the Spanish Registry of Dialysis and Transplant (GRER). The result of morbidity and mortality of the FMC clinics of Spain can, therefore, be as good compared with these of the GRER and other international series. That does not mean that there are not areas of improvement as the increase in the time of dialysis, the percentage of patients on on-line hemodiafiltration convective techniques and the percentage of FAV.

Effects of weight loss after biliopancreatic diversion on metabolism and cardiovascular profile.

BACKGROUND: Obesity is associated with increased prevalence of cardiovascular risk factors. Biliopancreatic diversion (BPD) for morbid obesity has been reported to produce anemia and malnutrition in short-term follow-up. The aim of our study was to analyze the effect of weight reduction on cardiovascular profile, renal function and nutritional status. METHODS: 35 morbidly obese patients underwent BPD. We analyzed the presence of cardiovascular risk factors, renal status, proteinuria and nutritional status before and 1 year after BPD. RESULTS: Excess weight loss was 67% at 1 year after BPD. All cardiovascular risk factors (hypertension, diabetes, hyperlipidemia) improved during follow-up. We could not find any relevant signs of malnutrition in the patients. Microalbuminuria decreased and proteinuria disappeared after weight loss. We observed less urinary calcium and citrate excretion, with an increase in oxaluria, but these changes did not increase the incidence of renal stones. CONCLUSIONS: BPD was followed by improved cardiovascular profile and a lower pro-inflammatory state. BPD did not produce significant malnutrition, anemia or renal stone disease.

Antibody-mediated pure red cell aplasia (PRCA): ensuring future progress by collecting data from a registry.

The recent emergence of antibody (Ab)-mediated pure red cell aplasia (PRCA) resulting from administration of certain erythropoiesis-stimulating agents (ESAs) has heightened awareness of the potential for this disorder in patients receiving ESAs for anaemia associated with chronic kidney disease (CKD). The Spanish Society of Nephrology sponsored an independent registry for analysis of patients who developed epoetin-induced, Ab-mediated PRCA in Spain. Twelve patients from 11 regional hospitals were included in the Spanish PRCA registry from November 2000 to December 2002 that met the criteria for Ab-mediated PRCA. Patients were reported using a standardized form specifically developed for PRCA, and serum samples were analysed in a central laboratory at Reina Sofia University Hospital in Cordoba, Spain. The characteristics of these patients, their serological and haematological results, and the outcomes of immunosuppressive therapies are presented. The Spanish PRCA registry serves as a model for establishing an independent global PRCA registry sponsored by the various nephrology societies in European Union countries, and elsewhere and coordinated by key investigators from the respective countries.

Creatinine reduction ratio on post-transplant day two as criterion in defining delayed graft function.

Delayed graft function (DGF) is a common complication after renal transplant, affecting its outcome. A common definition of DGF is the need for dialysis within the first week of transplantation, but this criterion has its drawbacks. We tried to validate an earlier and better defined parameter of DGF based on the creatinine reduction ratio on post-transplant day 2 (CRR2). We analyzed the clinical charts of 291 cadaver kidney recipients to compare the outcome of patients with immediate graft function (IGF), dialyzed patients (D-DGF) and nondialyzed CRR2-defined DGF patients (ND-DGF) and to identify risk factors for D-DGF and ND-DGF. Creatinine reduction ratio on post-transplant day 2 correlates significantly with renal function during the first year. Patients with IGF have significantly better renal function throughout the first year and better graft survival than patients with D-DGF and ND-DGF, while we found no differences either in renal function from days 30-365 or in graft survival between D-DGF and ND-DGF patients. Defining DGF by CRR2 allows an objective and quantitative diagnosis after transplantation and can help to improve post-transplant management. Creatinine reduction ratio on post-transplant day 2 correlates with renal function throughout the first year. The worse survival in the ND-DGF group is an important finding and a major advantage of the CRR2 criterion.

Once-weekly compared with three-times-weekly subcutaneous epoetin beta: results from a randomized, multicenter, therapeutic-equivalence study.

BACKGROUND: The ability to reduce the administration frequency of subcutaneous (SC) epoetin could provide benefits. This multicenter open-label study investigated the therapeutic equivalence of SC epoetin beta once-weekly and thrice-weekly administration regimens in maintaining anemia correction in stable hemodialysis (HD) patients. METHODS: One hundred seventy-three patients were randomly assigned to either once-weekly epoetin beta (n = 84) or their original thrice-weekly regimen (n = 89) for 24 weeks. All patients were administered intravenous iron supplementation, as required. RESULTS: The per-protocol analysis included 134 patients (69 patients, once-weekly group; 65 patients, thrice-weekly group). Mean hematocrits in both groups remained stable throughout the study. The difference in mean time-adjusted area under the curve for hematocrits between the once-weekly and thrice-weekly groups (-0.54 vol%) and 90% confidence intervals (-1.27 to 0.19) were within the prespecified equivalence range (-2 to +2 vol%). There was no significant change in epoetin beta dose during the study. The ratio of mean weekly epoetin beta doses in the once-weekly and thrice-weekly groups (1.11) and 90% confidence interval (0.99 to 1.23) also remained within the prespecified range (0.8 to 1.25). Intention-to-treat analysis results were similar to per-protocol analysis results. Both regimens were well tolerated. CONCLUSION: Once-weekly and thrice-weekly SC epoetin beta administrations are statistically equivalent in terms of maintaining both stable hematocrits and epoetin beta dose requirements in HD patients. These findings may improve compliance among patients.