Achievement of 2009 and 2017 Kidney Disease: Improving Global Outcomes mineral and bone targets and survival in a French cohort of chronic kidney disease Stages 4 and 5 non-dialysis patients

Achievement of 2009 and 2017 Kidney Disease: Improving Global Outcomes mineral and bone targets... Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/710/4938506 by Ed 'DeepDyve' Gillespie user on 17 October 2018 Clinical Kidney Journal, 2018, vol. 11, no. 5, 710–719 doi: 10.1093/ckj/sfy015 Advance Access Publication Date: 15 March 2018 Original Article ORIGI N AL A R TICLE Achievement of 2009 and 2017 Kidney Disease: Improving Global Outcomes mineral and bone targets and survival in a French cohort of chronic kidney disease Stages 4 and 5 non-dialysis patients 1 2 3 4 Denis Fouque , Hubert Roth , Bernadette Darne ´ , Jean-Louis Bouchet , 5 6 7 8 Eric Daugas , Tilman B. Dru ¨ eke , Thierry Hannedouche , Guillaume Jean and Ge ´ rard M. London , for the French Calcium and Phosphate Observatory 1 2 Department of Nephrology, CH Lyon Sud, Univ Lyon, Lyon, France, Department of Nephrology, Centre de Recherche en Nutrition Humaine Rho ˆ ne-Alpes, Po ˆ le Recherche CHU-Grenoble, Inserm U1055-Bioe ´ nerge ´ tique, 3 4 Universite ´ J. Fourier, Grenoble, France, Monitoring Force Group, Maisons-Laffitte, France, Centre de Traitement des Maladies Re ´ nales Saint-Augustin, Bordeaux, France, HU-Paris Nord site Bichat, Paris, France, 6 7 Inserm U1018, CESP, Universite ´ Paris-Saclay, Universite ´ Paris-Sud, UVSQ, Villejuif, France, Service de Ne ´ phrologie, Ho ˆ pitaux Universitaires de Strasbourg & Faculte´de Me ´ decine, Strasbourg, France, NephoCare, Tassin-Charcot, Sainte-Foy-le ` s-Lyon, France and Ho ˆ pital Manhes, Fleury-Me ´ rogis, France Correspondence and offprint requests to: Denis Fouque; E-mail: denis.fouque@univ-lyon1.fr; Twitter handle: @denisfouque1 ABSTRACT Background. The aim of the third French Phosphorus and Calcium Observatory (Photo-Graphe 3) was to assess the achievement of international Kidney Disease: Improving Global Outcomes (KDIGO) recommendations on optimal serum phosphate, calcium and parathyroid hormone (PTH) levels and possible associations with mortality in patients with chronic kidney disease (CKD). Methods. This was a prospective, observational study conducted with nephrologists in France who were selected using a clustering approach. Adult patients with non-dialysis Stage 4 or 5 CKD and no kidney graft history were eligible. Data about clinical events, serum biochemistry and treatment were collected every 6 months for 2.5 years and 12 months thereafter. The Kaplan–Meier method was used for survival analysis and Cox proportional hazards model for identification of factors associated with survival. Results. Overall, 566 CKD Stage 4 patients (men, 56%) and 153 CKD Stage 5 patients (men, 62%) were included. In Stage 4, only 14–15% patients achieved the three main 2009 KDIGO targets during the first 2 years and 22% at 2.5 years. In Stage 5 patients, the proportion remained<6% throughout. The percentages of patients achieving the three main 2017 KDIGO targets were slightly higher at each time point. Overall, 14% of Stage 4 and 10% of Stage 5 patients died in the observation period. Only age and haemoglobin level were significantly associated with risk of all-cause mortality. Received: 31.10.2017. Editorial decision: 23.1.2018 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 710 Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/710/4938506 by Ed 'DeepDyve' Gillespie user on 17 October 2018 Achievement of 2009 and 2017 KDIGO CKD mineral and bone guidelines | 711 Conclusions. Few CKD patients achieved KDIGO mineral targets. Increased mortality risk was linked to older age and lower haemoglobin level, but not to serum calcium, phosphate or PTH targets. Keywords: calcium, chronic kidney disease, KDIGO, phosphate, survival study undertaken by nephrologists in France. The primary objec- INTRODUCTION tive of the study was to estimate the percentage of CKD patients Advanced chronic kidney disease (CKD) is a powerful risk factor achieving 2009 KDIGO recommendations for the three main, rou- for all-cause and cardiovascular (CV) mortality [1]. A systematic tinely measured parameters of calcium and phosphate metabo- review of 35 studies, published in 2009, showed that a signifi- lism [serum phosphate, serum calcium and serum intact PTH cant part of the excessive risk of mortality (CV and all-cause (iPTH)] over a 3.5-year follow-up period (once every 6 months for mortality) and of CV events was associated with the mineral 2.5 years and then 12 months thereafter). Nephrologists working in and bone disorder of CKD (CKD–MBD) [2]. This issue was mainly public, private and community centres were invited to participate. studied and reported in dialysis patients [2, 3]. A total of 70 active nephrologists included 736 subjects out of the The Kidney Disease Outcomes Quality Initiative (KDOQI) guide- theoretical sample size of 1328 non-dialysis patients. The theoreti- lines in the USA for CKD–MBD were published in 2003 [4]. The cal sample size was calculated to obtain a 2.5% precision of a 95% KDOQI guidelines focused and recommended to maintain serum confidence interval of the prevalence of patients achieving 2009 phosphate, calcium and parathyroid hormone (PTH) within nar- KDIGO recommendations. Nephrologists were selected using a row ranges, although adherence to the recommended target clustering approach, where clusters (nephrologists) were randomly ranges has proved challenging [5–8]. Six years later, the interna- drawn, in respect of geographical distribution and type of practice. tional Kidney Disease: Improving Global Outcomes (KDIGO) guide- The study was proposed to nephrologists in chronological order in line for CKD–MBD became available, with serum phosphate, the drawn list, until the number of required clusters was reached. calcium and PTH targets different from those of the KDOQI guide- Patients were selected within each cluster in chronological order. lines [3]. However, the evidence supporting these guidelines has All adult patients referred for the first time to the nephrolo- been challenged subsequently as it was mainly based on retro- gist and with Stage 4 or 5 CKD who were not yet receiving dialy- spective observational studies [9, 10]. Of particular concern is the sis therapy, and had no kidney graft history, were eligible. fact that for non-dialysis-dependent CKD Stages 3–5, even obser- vational evidence has remained scarce. The 2009 KDIGO clinical practice guideline on the manage- Data collection ment of CKD–MBD was updated in 2017 and is intended to assist Clinical events, serum biochemistry data and information on the the practitioner caring for adults and children with CKD Stages treatment of CKD patients were collected at the above fixed time 3–5, on long-term dialysis therapy, or with a kidney transplant points. The following data were retrieved: laboratory parameters [3, 11]. This guideline has been endorsed in Europe since 2010 [serum levels of C-reactive protein, phosphate, calcium, iPTH, [12]. However, effective management of CKD–MBD includes a alkaline phosphatase both total and bone-specific enzymes], 25- substantial effort on the part of patients to be adherent with diet- hydroxyvitamin D [25(OH)D], albumin, low-density lipoprotein ary restrictions, thrice daily doses of oral phosphate binders, and, cholesterol, ferritin, transferrin saturation, blood haemoglobin for many patients, regular use of several other oral medications (Hb) concentration, glycated Hb level, demographics, blood pres- [13, 14]. Following the release of the 2009 KDIGO guideline, sev- sure, CV and valvular calcifications, current treatments eral studies have estimated the percentage of patients achieving {medications to control serum phosphate, vitamin D [oral or 2009 KDIGO targets for CKD–MBD [15]. A recent report based on a intravenous (IV) route], erythropoiesis stimulating agent (ESA), IV large international sample of chronic haemodialysis patients iron, hypolipidaemic drug, antihypertensive, oral anticoagulant showed that the treatment approaches for secondary hyperpara- and anticonvulsive}, history of parathyroidectomy, hospital- thyroidism had changed between 1996 and 2011 and that serum izations, bone fracture and CV events. Patient status (on dialysis, PTH levels had increased in most countries [15]. To the best of dead, lost to follow-up, moved to another centre and kidney our knowledge, no information is available on the proportion of transplantation) was also recorded during follow-up. All labora- patients who reach KDIGO target ranges in CKD Stages 3–5 before tory evaluations were performed locally. the initiation of renal replacement therapy [16, 17]. R Patients were prospectively enrolled between October 2010 The main objective of the observational Photo-Graphe 3study and October 2012. Data were collected every 6 months between in France was to estimate the percentage of CKD Stages 4–5 and October 2010 and April 2013 and then lastly in April 2014. 5D patients (patients with CKD requiring dialysis) who achieved Therefore, seven data collections were available for some the target ranges suggested by the 2009 KDIGO guideline. A secon- patients included in October 2010, whereas patients included in dary objective was to investigate the relationship between the October 2012 had a maximum of three data collections. control of mineral metabolism and patient outcomes. We report Data were entered in an electronic case report system here the results of the study in non-dialysis CKD Stages 4–5 TM (Photo-Graph software developed by Genzyme S.A.S. then patients regarding the 2009 and 2017 KDIGO guidelines. Sanofi France). Data collected in each region were anonymized at each patient level and then centralized by regional coordina- tors. After regional data collection was completed, 19 regional MATERIALS AND METHODS electronic files were transferred after centre anonymization to the national coordinating centre for data processing. Thus, data Population collection was performed with respect to patient’s anonymity at V R The French Phosphorus and Calcium Observatory (Photo-Graphe the regional and national levels. Inconsistencies were checked 3) is a prospective, multicentre, epidemiological observational after consolidation of national data. The national coordinator Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/710/4938506 by Ed 'DeepDyve' Gillespie user on 17 October 2018 712 | D. Fouque et al. might ask for data correction or deletion. As data were handled (56%) CKD Stage 4 patients and 95 (62%) CKD Stage 5 patients. in an anonymous way, data source verification was not Patient characteristics at inclusion are shown in Table 1. After planned. This study was conducted according to French inclusion and whatever the time point, serum 25(OH)D was regulatory rules and good clinical practices. available in few patients and was not included in further analyses. Statistical analysis Achievement of KDIGO targets Statistical analyses were performed using SAS/STAT 14.1 (SAS The evolution of serum calcium and serum phosphate over Institute Inc., Cary, NC, USA). Statistical analysis is at the patient level. Patients who discontinued the study after the baseline visit time is displayed in Figure 1. The percentage of patients achiev- ing the three main 2009 KDIGO targets remained between 14% were excluded from all survival analyses. Patients who started dial- ysis therapy or were transplanted or lost to follow-up were and 15% during the first 2 years and slightly increased there- after, reaching a maximum of 22% at 2.5 years in CKD Stage 4 included in analyses to the point of study discontinuation. Statistical analyses were independently performed in each popula- patients, and remained <6% throughout the study in CKD Stage 5 patients. Slightly more patients fulfilled the three mains 2017 tion (CKD Stage 4 and CKD Stage 5) except survival analysis. Standard descriptive statistics were used for demographic, KDIGO targets whatever the time (Table 2). In Stage 4, the percentage of patients achieving 2009 KDIGO biological and clinical data, to determine mean and standard deviation for normally distributed data, and median and 25th targets for serum phosphate decreased over time (P¼ 0.0001), while no significant trend was observed over time either for cal- and 75th percentile values for non-normally distributed data. No replacement of missing data was performed and, therefore, cium (P¼ 0.90), PTH (P¼ 0.36) or the three parameters combined (P¼ 0.12). In Stage 5, no significant trend was reported over time the number of patients with documented laboratory data may change according to the time point. for serum phosphate (P¼ 0.80), calcium (P¼ 0.47), PTH (P¼ 0.77) or the three parameters combined (P¼ 0.66). The percentage of patients achieving the three KDIGO targets, according to the 2009 and 2017 guideline, respectively, was esti- As expected, at each data collection and in both CKD stages, 2009 KDIGO targets were not fulfilled most often because serum mated at inclusion and at each following determination (abnor- mal PTH value was defined as an iPTH value above the upper calcium and phosphate levels were below and above KDIGO tar- gets, respectively (Table 3). normal limit of the assay kit). The evolution of the percentage of patients achieving the main three KDIGO targets was evaluated Using the 2017 KDIGO guideline, abnormal PTH level corre- sponded mainly to two consecutive iPTH above the upper nor- using a generalized estimating equation (GEE) model on available data with a binomial distribution and a logit function. As the mal limit of the assay kit (Table 4). Whatever the time, >50% of the patients have an abnormal iPTH value. Moreover, >30% of study was performed at the time of the 2009 KDIGO guideline, this analysis was restricted to the 2009 KDIGO targets. the Stage 4 patients and >50% of the patients with abnormal iPTH have concomitant hyperphosphataemia and/or hypocal- Furthermore, for serum phosphate and calcium levels and, at each data collection, patients were classified into three groups caemia whatever the time (Table 4). CKD–MBD-directed therapies at each data collection time according to normal laboratory ranges: patients below, within and above normal ranges. Normal ranges were 2.15–2.55 and 0.9– point are displayed in Table 5. The number of patients receiving various treatments decreased over time for most drugs: any 1.4 mmol/L for serum calcium and phosphate, respectively. In addition, for the analysis of the comparison with the 2017 vitamin D sterol, any phosphate binder and any calcium salt; in contrast, cinacalcet slightly rose. However, for some time peri- KDIGO guidelines and starting from the 6-month time point, abnormal PTH was defined as two consecutive values above the ods, the effective of patients is very low, precluding any reason- able interpretation. upper normal limit of the laboratory kit or >5% increase in the second consecutive PTH determination compared with the pre- vious one, whatever the interval between two time points. Survival analysis Modifiable factors were hyperphosphataemia and hypocalcae- mia at the time of the second PTH determination. Median duration of follow-up was 23 (6; 36) months in CKD The survival curves were plotted using the Kaplan–Meier Stage 4 patients and 8 (3; 18) months in CKD Stage 5 patients. method and the differences in survival were determined using a Over the study period, 34 (6%) patients with CKD Stage 4 and 41 log-rank test. A Cox proportional hazards model was used to iden- (27%) with CKD Stage 5 started dialysis, and 16 (3%) patients tify the factors measured at baseline and significantly associated with CKD Stage 4 patients and 7 (5%) patients with CKD Stage 5 with survival using a backward selection method. The backward underwent kidney transplantation. Overall, 81 (14%) patients selection was started with all variables significant at the 0.20 thresh- with CKD Stage 4 and 15 (10%) patients with CKD Stage 5 died old level in univariate analysis and after the proportional hazards during the observation period. In addition, 126 (22%) patients assumption has been checked. The significance level for removing with CKD Stage 4 and 31 (20%) patients with CKD Stage 5 were an explanatory variable from the model was set at 0.10, with com- lost to follow-up at the end of the study. The 157 patients lost to parison between two adjacent models using Akaike’s information follow-up were significantly older (median age 77 versus 73 criterion. Interactions between two variables were tested on the years, P< 0.001) and less often patients with diabetes (10% ver- final model. All tested factors were recorded at inclusion. sus 35%, P< 0.0001) than the other patients. No statistically sig- nificant differences in gender and glomerular filtration rate were observed between patients lost to follow-up and the RESULTS others. No statistically significant difference in survival was Patient population observed between the two CKD stages (P¼ 0.10) (Figure 2). Overall, 566 CKD Stage 4 patients and 153 CKD Stage 5 patients Age, history of CV disease, Hb and albumin levels, treatment were included. More than half of the patients were males: 316 with an ESA, IV iron and classes of serum phosphate and Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/710/4938506 by Ed 'DeepDyve' Gillespie user on 17 October 2018 Achievement of 2009 and 2017 KDIGO CKD mineral and bone guidelines | 713 Table 1. Characteristics of the patients at inclusion CKD Stage 4 (n¼ 566) CKD Stage 5 (n¼ 153) Variables nn Male 316 (55.8) 95 (62.1) Age (years) 566 74 (63; 81) 153 73 (59; 81) Body mass index (kg/m ) 355 26.5 (23.9; 30.1) 106 27.3 (23.2; 30.8) Systolic blood pressure (mmHg) 447 142 (130; 156) 133 140 (134; 158) Diastolic blood pressure (mmHg) 447 80 (70; 85) 133 80 (70; 86) 2 a Estimated GFR (mL/min/1.73 m ) 566 22.4 (18.9; 25.8) 153 12.1 (10.5; 13.7) Serum albumin (g/L) 455 38 (35; 41) 128 38 (35; 41) Hb (g/dL) 506 12.1 (1.4) 142 11.4 (1.2) Serum 25(OH)D (ng/mL) 457 61.0 (32.5; 90.0) 121 60.0 (39.0; 95.0) Smoker 566 153 Former 105 (18.6) 34 (22.2) Current 36 (6.4) 20 (13.1) Associated risk factors and disease 566 153 Arterial hypertension 362 (64.0) 111 (72.6) Diabetes mellitus 168 (29.7) 45 (29.4) History of CV disease 234 (41.3) 57 (37.3) Any CKD–MBD-directed therapy 566 153 Active vitamin D 64 (11.3) 26 (17.0) Native vitamin D 282 (49.8) 83 (54.3) Calcium-free phosphate binder 17 (3.0) 23 (15.0) Calcium-based phosphate binder 123 (21.7) 43 (28.1) Any calcium salt 135 (23.9) 61 (39.9) Cinacalcet 2 (0.4) 5 (3.3) Other drug treatments 566 153 ESA 129 (22.8) 64 (41.8) IV iron 24 (4.2) 9 (5.9) Antihypertensive drug 472 (83.4) 130 (85.0) Continuous data are presented as mean6 standard deviation or median (25%; 75%); categorical data are presented as n (%) patients. GFR¼ glomerular filtration rate calculated using the modification of the diet in renal disease formula. calcium at inclusion were associated with survival in univariate In particular, the proportion of patients who achieved the indi- analysis (Table 6). In multivariable analysis, only two of those vidual 2009 KDIGO target, after 2 years and 3.5 years, for serum parameters were selected by the backward selection method: PTH was 25% and 10% in Stage 4 CKD and Stage 5 CKD, older age and lower blood Hb level were associated with an respectively. Note that the 2009 KDIGO guideline suggested not increased risk of overall mortality over the study period (Table 6). to routinely prescribe vitamin D supplements or vitamin D ana- logues, in the absence of suspected or documented deficiency, for the control of elevated PTH concentrations in people with CKD not on dialysis [20]. This could explain the high percentage DISCUSSION of patients receiving no vitamin D supplement at inclusion in This is the first study showing that it is quite difficult to achieve the present study. KDIGO CKD–MBD targets in patients with Stages 4 and 5 CKD. The proportion of patients achieving the individual 2009 Patients with CKD are stratified using five stages based on glo- KDIGO target for serum phosphate decreased significantly from merular filtration rate [3, 18], and taking into account the degree 74% at inclusion to 61% after 3.5 years in CKD Stage 4 and was of albuminuria as well [18]. TheCKD stagingsystemis usefulin mainly related to the increase in the percentage of patients many regards, including the prediction of the associated comor- with serum phosphate above the target range. This fact, not bidities [18]. A review of data from 19 general-population studies unexpected since the CKD progression leads to a further impair- from 13 European countries showed considerable differences in ment in renal phosphate excretion, might have been limited both CKD Stages 1–5 and CKD Stages 3–5 prevalence across through a more intensive control, including phosphate binders European study populations. The adjusted CKD Stages 1–5 preva- prescription. No significant trend over time was observed for lence varied between 3.31% in Norway and 17.3% in Northeast that parameter in CKD Stage 5 patients. As to serum calcium, no Germany. The adjusted CKD Stages 3–5 prevalence varied significant trend was observed over time in the proportion of between 1.0% in Central Italy and 5.9% in Northeast Germany CKD patients who achieved the individual 2009 KDIGO target. [19]. In this context, the Photo-Graphe 3 is one of the most However >80% of the patients, both in CKD Stage 4 and Stage 5, recent and largest European prospective studies, specifically achieved the 2009 KDIGO calcium targets after 2 years of follow- aimed at assessing disturbances of phosphate, calcium and PTH up. With regards to serum PTH, <30% of patients in CKD Stage 4 metabolism. and <20% of patients in CKD Stage 5 achieved the 2009 KDIGO The present analysis confirms that adherence to the recom- targets at each time point. mended target ranges for serum PTH, phosphate and calcium Even if the 2017 KDIGO guideline had been used the conclu- remains challenging despite several therapeutic advances. sions regarding achievement of KDIGO objectives would have Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/710/4938506 by Ed 'DeepDyve' Gillespie user on 17 October 2018 714 | D. Fouque et al. FIGURE 1: Serum phosphate and calcium levels over time. Horizontal lines correspond to lower and upper limit levels of normal. O indicate stage 4 CKD; þ indicate stage 5 CKD. likely been the same. Clearly, more studies are needed in order these data may suggest some improvement in care at these pre- to understand the reason why so many CKD patients failed to dialysis stages. achieve the KDIGO targets and to find out how guideline com- The longitudinal analysis of CKD–MBD-directed therapy pliance can be improved, or to realize that the guideline may reported a decrease in most prescribed drugs (Table 5). This is not be appropriate for very advanced stages of CKD. interesting to note because at the same time, the control for Information obtained on 25(OH)D seems of interest. At inclu- serum calcium, PTH and phosphorus could have been sion, nearly 80% of CKD patients were assessed for serum con- improved. It is important to point out this fact since these data centration. However, the mean serum 25(OH)D was 60 ng/mL have been obtained through a well-designed prospective longi- whatever the stage, quite below the 75 ng/mL minimal value, tudinal study, which further suggests that in the real life, results indicating that >60% of patients were vitamin D deficient. This might have been even poorer. is to be paralleled to the number of patients receiving a vitamin As expected, more Stage 5 patients started dialysis than D supplement (50% at Stage 4 and 54% at Stage 5). Altogether, Stage 4 patients and underwent kidney transplantation over the Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/710/4938506 by Ed 'DeepDyve' Gillespie user on 17 October 2018 Achievement of 2009 and 2017 KDIGO CKD mineral and bone guidelines | 715 Table 2. Percentage of patients achieving the three main KDIGO targets of calcium and phosphate metabolism Data collection Inclusion 6 months 1 year 1.5 year 2 years 2.5 years 3.5 years CKD Stage 4 n patients with documented data 469 327 286 246 194 136 127 Patients achieving the three 2009 KDIGO targets (%) 67 (14.3) 50 (15.3) 41 (14.3) 36 (14.6) 28 (14.4) 30 (22.1) 23 (18.1) Patients achieving the three 2017 KDIGO targets (%) 84 (17.9) 59 (18.0) 53 (18.5) 42 (17.1) 31 (16.0) 33 (24.3) 26 (20.5) CKD Stage 5 n patients with documented data 139 83 57 35 21 14 9 Patients achieving the three 2009 KDIGO targets (%) 2 (1.4) 1 (1.2) 3 (5.3) 2 (5.7) 0 0 0 Patients achieving the three 2017 KDIGO targets (%) 5 (3.6) 3 (3.6) 5 (8.8) 2 (5.7) 0 0 0 n (%) patients with available data. Starting from the third determination, the time between two determinations is 6 months or 1 year depending on time of patient inclusion in the study. Achievement defined as serial assessment and the three parameters less than the upper normal limit, for serum iPTH upper normal limit of the assay kit. Table 3. Numbers (proportion) of patients within normal range for calcium and phosphate metabolism at each data collection time point Data collection Inclusion 6 months 1 year 1.5 year 2 years 2.5 years 3.5 years CKD Stage 4 Serum phosphate (mmol/L) Value unavailable 21 165 197 192 190 142 185 Hypo 0.9 (%) 31 (5.7) 27 (6.7) 25 (8.0) 15 (5.4) 14 (6.3) 6 (3.9) 9 (6.2) Normal (%) 404 (74.1) 280 (69.8) 218 (70.1) 180 (65.0) 148 (66.4) 103 (67.8) 89 (60.9) Hyper >1.4 (%) 110 (20.2) 94 (23.5) 68 (21.9) 82 (29.6) 61 (27.3) 43 (28.3) 48 (32.9) Serum total calcium (mmol/L) Value unavailable 19 162 194 193 187 141 185 Hypo 2.15 (%) 69 (12.6) 54 (13.4) 37 (11.8) 37 (13.4) 27 (11.9) 22 (14.4) 17 (11.6) Normal (%) 455 (83.2) 334 (82.7) 259 (82.5) 221 (80.1) 185 (81.9) 127 (83.0) 125 (85.6) Hyper >2.55 (%) 23 (4.2) 16 (3.9) 18 (5.7) 18 (6.5) 14 (6.2) 4 (2.6) 4 (2.7) Serum iPTH Value unavailable 90 233 220 221 216 156 201 upper normal limit of the assay kit (%) 108 (22.7) 80 (24.0) 69 (24.0) 60 (24.2) 45 (22.8) 41 (29.7) 33 (25.4) CKD Stage 5 Serum phosphate (mmol/L) Value unavailable 2 56 67 84 83 67 78 Hypo 0.9 (%) 4 (2.6) 2 (2.1) 2 (3.3) 0 (0.0) 1 (4.3) 0 (0.0) 0 (0.0) Normal (%) 54 (35.8) 42 (43.3) 22 (36.1) 16 (40.0) 8 (34.8) 8 (50.0) 4 (40.0) Hyper >1.4 (%) 93 (61.6) 53 (54.6) 37 (60.6) 24 (60.0) 14 (60.9) 8 (50.0) 6 (60.0) Serum total calcium (mmol/L) Value unavailable 2 56 67 84 83 68 78 Hypo 2.15 (%) 44 (29.1) 24 (24.7) 18 (29.5) 10 (25.0) 7 (30.4) 3 (20.0) 2 (20.0) Normal (%) 102 (67.6) 65 (67.0) 42 (68.9) 30 (75.0) 16 (69.6) 12 (80.0) 8 (80.0) Hyper >2.55 (%) 5 (3.3) 8 (8.3) 1 (1.6) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Serum iPTH Value unavailable 14 70 70 88 85 69 79 upper normal limit of the assay kit (%) 15 (10.8) 9 (10.8) 9 (15.5) 5 (13.9) 2 (9.5) 1 (7.1) 1 (11.1) n (%) patients with documented data. study period (27% versus 6% and 5% versus 3%, respectively). than people of comparable age in the general population, with Overall, 81 (14%) patients with CKD Stage 4 and 15 (10%) patients 25% among them dying before reaching end-stage kidney dis- with CKD Stage 5 died within 3.5 years. In the 20th century, CKD ease [24]. replaced infection and malnutrition as leading causes of mor- The present study has several limitations. First, centres that tality in the general population [21]. Individuals with CKD have participated on a voluntary basis were likely to be more inter- an increased risk of all-cause mortality, mainly from CV disease ested in correcting CKD–MBD in their patients than those who [2, 22]. Somewhat surprisingly, the 1- and 2-year survival rates did not join the study group. On the other hand, the high num- (68% and 47%) among CKD Stage 5 patients aged >75 years and ber of unavailable CKD–MBD laboratory parameters suggests not undergoing dialysis were found to be lower than survival that even in that population, compliance to the guidelines for rates of patients receiving dialysis therapy (84% and 76%), sug- the management of those patients is low. Secondly, the per- gesting a selection bias in patients referred to maintenance dial- centage of patients lost to follow-up over 3.5 years was 22% in ysis [23]. However, even early CKD patients have poorer survival patients with CKD Stage 4 and 20% in patients with CKD Stage 5. Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/710/4938506 by Ed 'DeepDyve' Gillespie user on 17 October 2018 716 | D. Fouque et al. Table 4. Numbers (proportion) of patients with abnormal iPTH levels (KDIGO 2017) at each follow-up Data collection 6 months 1 year 1.5 year 2 years 2.5 years 3.5 years CKD Stage 4 n evaluable patients 333 288 248 197 138 130 Above the upper normal limit of the laboratory kit (%) 208 (62.5) 156 (54.2) 150 (60.5) 124 (62.9) 71 (51.5) 75 (57.7) >5% increase (%) 44 (13.2) 53 (18.4) 33 (13.3) 24 (12.2) 33 (23.9) 25 (19.2) Not abnormal (%) 81 (24.3) 79 (27.4) 65 (26.2) 49 (24.9) 34 (24.6) 30 (23.1) Modifiable factors Hyperphosphataemia (%) 47 (18.7) 40 (19.1) 38 (20.8) 30 (20.3) 20 (19.6) 29 (29.3) Hypocalcaemia (%) 23 (9.2) 16 (7.7) 10 (5.5) 8 (5.4) 7 (6.9) 7 (7.1) Both (%) 11 (4.4) 8 (3.8) 17 (9.3) 8 (5.4) 8 (7.8) 5 (5.1) CKD Stage 5 n evaluable patients 83 58 36 21 14 9 Above the upper normal limit of the laboratory kit (%) 68 (81.9) 40 (69.0) 25 (69.4) 16 (76.2) 9 (64.3) 6 (66.7) >5% increase (%) 5 (6.0) 3 (5.2) 4 (11.1) 1 (4.8) 3 (21.4) 0 Not abnormal (%) 10 (12.1) 15 (25.8) 7 (19.4) 4 (19.0) 2 (14.3) 3 (33.3) Modifiable factors Hyperphosphataemia (%) 26 (35.6) 17 (39.5) 11 (39.3) 5 (29.4) 3 (25.0) 3 (50.0) Hypocalcaemia (%) 3 (4.1) 2 (4.7) 3 (10.1) 1 (5.9) 0 1 (16.7) Both (%) 16 (21.9) 13 (30.2) 6 (21.4) 6 (35.3) 3 (25.0) 1 (16.7) n (%) patients; abnormal iPTH: two consecutive determinations above the upper normal limit of the assay kit or >5% increase in the second consecutive PTH determi- nation compared with the previous one. On the subgroup of patients with abnormal iPTH. Hyperphosphataemia or hypocalcaemia at the time of the second PTH determination. Table 5. CKD–MBD-directed therapy at each data collection time point Data collection Inclusion 6 months 1 year 1.5 year 2 years 2.5 years 3.5 years Stage 4 Number of patients 566 566 508 469 413 294 331 Any vitamin D sterol (%) 313 (55.3) 245 (43.3) 202 (39.8) 189 (40.3) 153 (37.1) 106 (36.1) 103 (31.1) Any phosphate binder (%) 152 (26.9) 118 (20.9) 90 (17.7) 83 (17.7) 72 (17.4) 48 (16.3) 53 (16.0) Any calcium salt (%) 135 (23.9) 107 (18.9) 80 (15.8) 71 (15.1) 64 (15.5) 38 (12.9) 42 (12.7) Cinacalcet (%) 2 (0.4) 3 (0.5) 3 (0.6) 6 (1.3) 5 (1.2) 5 (1.7) 8 (2.4) Stage 5 Number of patients 153 153 128 124 106 83 88 Any vitamin D sterol (%) 97 (63.4) 61 (39.9) 45 (35.2) 32 (25.8) 17 (16.0) 12 (14.5) 6 (6.8) Any phosphate binder (%) 84 (54.9) 53 (34.6) 38 (29.7) 26 (21.0) 13 (12.3) 10 (12.1) 8 (9.1) Any calcium salt (%) 61 (39.9) 40 (26.1) 26 (20.3) 17 (13.7) 8 (7.6) 6 (7.2) 6 (6.8) Cinacalcet (%) 5 (3.3) 3 (2.0) 4 (3.1) 2 (1.6) 2 (1.9) 1 (1.2) 1 (1.1) n (%) patients receiving the corresponding therapy at each data collection time point. FIGURE 2: Survival of patients with CKD Stages 4 and 5. Product-limit survival estimates with number of subjects at risk in in each CKD stage. Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/710/4938506 by Ed 'DeepDyve' Gillespie user on 17 October 2018 Achievement of 2009 and 2017 KDIGO CKD mineral and bone guidelines | 717 Table 6. Univariate and multivariate Cox proportional analysis with overall mortality Univariate analysis Multivariate analysis Number of Hazard Variable observations used ratio 95% CI P-value Hazard ratio 95% CI P-value Female sex 719 0.74 0.49–1.10 0.13 4 4 Age (years) 719 1.08 1.06–1.10 <10 1.09 1.06–1.11 <10 History of CV disease: yes 719 2.24 1.49–3.35 <10 2 2 Hb (g/dL) 648 0.82 0.71–0.95 <10 0.78 0.67–0.92 <10 Serum albumin (reference 39.5 g/L) Serum albumin 33 583 2.49 1.35–4.59 <10 Serum albumin (33.1–36.9) 583 1.63 0.84–3.16 0.15 Serum albumin (37.0–39.4) 583 1.42 0.75–2.69 0.28 Diabetes mellitus: yes 719 1.27 0.86–1.89 0.23 Serum phosphate, 2009 KDIGO classes 696 0.10 Phosphate (mmol/L)  0.9 0.51 0.16–1.63 0.26 Phosphate (mmol/L) > 1.4 1.43 0.94–2.18 0.09 Serum total calcium, 2009 KDIGO classes 698 0.03 Calcium (mmol/L)  2.15 1.85 1.16–2.96 0.01 Calcium (mmol/L) > 2.55 0.88 0.28–2.78 0.83 Serum iPTH: achieved 2009 KDIGO target 615 0.89 0.54–1.48 0.66 ( upper normal limit of the assay kit) ESA: yes 719 1.97 1.34–2.91 <10 IV iron: yes 719 2.10 1.06–4.16 0.03 Hypertension: yes 719 1.31 0.80–2.14 0.28 All variables are variables measured at inclusion. CI, confidence interval. Backward selection was started with all variables significant at the 0.20 threshold level in univariate analysis. The significance level for removing an explanatory varia- ble from the model was set at 0.10, with comparison between two adjacent models using Akaike’s information criterion. Interactions between two variables were tested on the final model. Such relatively high rates may have biased our interpretation of CONFLICT OF INTEREST STATEMENT the results; loss to follow-up of10% would have been desir- Sanofi did not interfere with the statistical analysis. D.F. able. Patients lost to follow-up were significantly older than served as national coordinator and received honoraria from those who remained in the study. Missing information on them Sanofi for travel and lectures. H.R. reports personal fees was probably mainly due to deaths unknown to the treating from Sanofi during the conduct of the study and grants from physician. Because of the small number of deaths, the power of Genzyme outside the submitted work. E.D. declares having the survival analysis was low, but the survival curves are in served as consultant for Amgen, Sanofi, Shire and Astra favour of no real difference in all-cause mortality risk between CKD Stage 4 and CKD Stage 5 patients. Zeneca, and having received speaker honoraria from Amgen In conclusion, the present study shows that only few and Sanofi, and having received travel grants from Sanofi, patients eventually achieved the 2009 KDIGO targets. In the Roche, Shire and Alexion. T.B.D. declares having served as present study older age and lower blood Hb levels, but abnormal consultant for Amgen, F. Hoffman-La Roche, FMC, Sanofi- serum calcium, phosphate or PTH, were not associated with an Genzyme and Vifor, and having received speaker honoraria increased risk of all-cause mortality. from Amgen, Kyowa Hakko Kirin and Sanofi-Genzyme. B.D., With the inherent limitation of its small size and the possi- T.H., G.M.L., G.J. and J.-L.B declared no competing interests. bility that some patients have been lost to follow-up because of death, this study does not support that the achievement of KDIGO CKD–MBD targets is associated with better survival in LIST OF COORDINATORS patients with CKD Stage 4 or 5. B. Dallaporta, B. Vendrely, C. Delcroix, D. Joly, E. Daugas, E. Laruelle,G.Choukroun,G. Jean, H. LerayMoragues, L. Azzouz,M. ACKNOWLEDGEMENTS Essig, M. Hammadi, M. Kessler,M.Touam,P.Bories, P. Brunet,P. Henri, P. Zaoui, R. Azar, S. Delbes, T. Hannedouche, V. Esnault. The authors are thankful to the many staff, coordinators and physicians whose work was essential for the comple- tion of this study. LIST OF PHYSICIANS A. Abbassi, M. Abtahi, C. Achard Hottelart, H. Adda, G. Al FUNDING Chahin,B.AlJalaby, I. Al Moubarak,M.AlRifai,M.Aladib, Sanofi France, the sponsor of this observational study, N. Albeiriss, S. Albitar, J. Aldigier, F. Alenabi, A. Amaouche, C. secured the funding required throughout study implemen- Araujo, U. Assogba, L. Azeroual, D. Babici, B. Ball, S. Bally, E. tation and managed the development of the protocol, the Barga, F. Basse, N. Bassilios, J. Batho, C. Baudeau, M. electronic case report form, the regulatory submissions and Bauwens, D. Bazin, B. Ben Taarit, S. Benarbia, J. Bendini, F. logistics. Berge, P. Bernadet, J. Bertheleme, F. Besson, S. Billion, A. Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/710/4938506 by Ed 'DeepDyve' Gillespie user on 17 October 2018 718 | D. Fouque et al. chronic kidney disease. Nephrol Dial Transplant 2009; 24: Blanpain, C. Bonniol, C. Boriceanu, J. Bosc, B. Bouali, K. 1506–1523 Boubenider, L. Boudier, J. Bouet, M. Bouiller, M. Boukelmoune, 3. Kidney Disease: Improving Global Outcomes (KDIGO) CKD- Z. Boukhalfa, R. Boula, H. Boulanger, J. Bourdenx, F, Bourdon, MBD Work Group. KDIGO clinical practice guideline for the F. 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Hadj Abdelkader, A. Hafi, P. Halin, P. Hallonet, 9. Akbari A, Clase CM, Acott P et al. Canadian Society of N. Hamdini, M. Hanoy, S. Helou, P. Hiernaux, D. Hristea, M. Nephrology commentary on the KDIGO clinical practice guideline for CKD evaluation and management. Am J Kidney Isnard, D. Jacq, M. Jamali, D. Jaubert, C. Jolimoy, A. Jolivot, A. Dis 2015; 65: 177–205 Karame, S. Kaysi, A. Keller, E. Kernaonet, R. Khayat, Z. 10. Alseiari M, Meyer KB, Wong JB. Evidence underlying KDIGO Koochaki Pour, N. Kossari, F. Kriaa, C. Lamotte, B. Lamy (Kidney Disease: Improving Global Outcomes) guideline recom- Cavalerie, P. Lan Yue Wah, I. Landru, A. Laradi, N. Larroumet, mendations: a systematic review. Am J Kidney Dis 2016; 67: R. Latif, F. Lavainne, O. Lavelle, B. Legallicier, N. Legros, M. 417–422 Leteif, H. Lokmane, A. Lyon, M. Maaz, S. Mailliez, H. Maiza, G. 11. Kidney Disease: Improving Global Outcomes (KDIGO) CKD- Majdalani, E. Maksour, E. Marcu, M. Marraoui, S. Martin, V. 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A compa- tion, prevention, and treatment of chronic kidney disease- rative survival study of patients over 75 years with chronic kid- mineral and bone disorder (CKD-MBD). Kidney Int 2009; 76 ney disease stage 5. Nephrol Dial Transplant. 2007; 22: 1955–1962 (Suppl 113): S3–S8 24. Daly C. Is early chronic kidney disease an important risk fac- 21. Omran AR. The epidemiologic transition: a theory of the epi- tor for cardiovascular disease? A background paper prepared demiology of population change. 1971. Milbank Q 2005; 83: for the UK Consensus Conference on early chronic kidney 731–757 disease. Nephrol Dial Transplant 2007; 22 (Suppl 9): ix19–ix25 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press

Achievement of 2009 and 2017 Kidney Disease: Improving Global Outcomes mineral and bone targets and survival in a French cohort of chronic kidney disease Stages 4 and 5 non-dialysis patients

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Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/710/4938506 by Ed 'DeepDyve' Gillespie user on 17 October 2018 Clinical Kidney Journal, 2018, vol. 11, no. 5, 710–719 doi: 10.1093/ckj/sfy015 Advance Access Publication Date: 15 March 2018 Original Article ORIGI N AL A R TICLE Achievement of 2009 and 2017 Kidney Disease: Improving Global Outcomes mineral and bone targets and survival in a French cohort of chronic kidney disease Stages 4 and 5 non-dialysis patients 1 2 3 4 Denis Fouque , Hubert Roth , Bernadette Darne ´ , Jean-Louis Bouchet , 5 6 7 8 Eric Daugas , Tilman B. Dru ¨ eke , Thierry Hannedouche , Guillaume Jean and Ge ´ rard M. London , for the French Calcium and Phosphate Observatory 1 2 Department of Nephrology, CH Lyon Sud, Univ Lyon, Lyon, France, Department of Nephrology, Centre de Recherche en Nutrition Humaine Rho ˆ ne-Alpes, Po ˆ le Recherche CHU-Grenoble, Inserm U1055-Bioe ´ nerge ´ tique, 3 4 Universite ´ J. Fourier, Grenoble, France, Monitoring Force Group, Maisons-Laffitte, France, Centre de Traitement des Maladies Re ´ nales Saint-Augustin, Bordeaux, France, HU-Paris Nord site Bichat, Paris, France, 6 7 Inserm U1018, CESP, Universite ´ Paris-Saclay, Universite ´ Paris-Sud, UVSQ, Villejuif, France, Service de Ne ´ phrologie, Ho ˆ pitaux Universitaires de Strasbourg & Faculte´de Me ´ decine, Strasbourg, France, NephoCare, Tassin-Charcot, Sainte-Foy-le ` s-Lyon, France and Ho ˆ pital Manhes, Fleury-Me ´ rogis, France Correspondence and offprint requests to: Denis Fouque; E-mail: denis.fouque@univ-lyon1.fr; Twitter handle: @denisfouque1 ABSTRACT Background. The aim of the third French Phosphorus and Calcium Observatory (Photo-Graphe 3) was to assess the achievement of international Kidney Disease: Improving Global Outcomes (KDIGO) recommendations on optimal serum phosphate, calcium and parathyroid hormone (PTH) levels and possible associations with mortality in patients with chronic kidney disease (CKD). Methods. This was a prospective, observational study conducted with nephrologists in France who were selected using a clustering approach. Adult patients with non-dialysis Stage 4 or 5 CKD and no kidney graft history were eligible. Data about clinical events, serum biochemistry and treatment were collected every 6 months for 2.5 years and 12 months thereafter. The Kaplan–Meier method was used for survival analysis and Cox proportional hazards model for identification of factors associated with survival. Results. Overall, 566 CKD Stage 4 patients (men, 56%) and 153 CKD Stage 5 patients (men, 62%) were included. In Stage 4, only 14–15% patients achieved the three main 2009 KDIGO targets during the first 2 years and 22% at 2.5 years. In Stage 5 patients, the proportion remained<6% throughout. The percentages of patients achieving the three main 2017 KDIGO targets were slightly higher at each time point. Overall, 14% of Stage 4 and 10% of Stage 5 patients died in the observation period. Only age and haemoglobin level were significantly associated with risk of all-cause mortality. Received: 31.10.2017. Editorial decision: 23.1.2018 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 710 Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/710/4938506 by Ed 'DeepDyve' Gillespie user on 17 October 2018 Achievement of 2009 and 2017 KDIGO CKD mineral and bone guidelines | 711 Conclusions. Few CKD patients achieved KDIGO mineral targets. Increased mortality risk was linked to older age and lower haemoglobin level, but not to serum calcium, phosphate or PTH targets. Keywords: calcium, chronic kidney disease, KDIGO, phosphate, survival study undertaken by nephrologists in France. The primary objec- INTRODUCTION tive of the study was to estimate the percentage of CKD patients Advanced chronic kidney disease (CKD) is a powerful risk factor achieving 2009 KDIGO recommendations for the three main, rou- for all-cause and cardiovascular (CV) mortality [1]. A systematic tinely measured parameters of calcium and phosphate metabo- review of 35 studies, published in 2009, showed that a signifi- lism [serum phosphate, serum calcium and serum intact PTH cant part of the excessive risk of mortality (CV and all-cause (iPTH)] over a 3.5-year follow-up period (once every 6 months for mortality) and of CV events was associated with the mineral 2.5 years and then 12 months thereafter). Nephrologists working in and bone disorder of CKD (CKD–MBD) [2]. This issue was mainly public, private and community centres were invited to participate. studied and reported in dialysis patients [2, 3]. A total of 70 active nephrologists included 736 subjects out of the The Kidney Disease Outcomes Quality Initiative (KDOQI) guide- theoretical sample size of 1328 non-dialysis patients. The theoreti- lines in the USA for CKD–MBD were published in 2003 [4]. The cal sample size was calculated to obtain a 2.5% precision of a 95% KDOQI guidelines focused and recommended to maintain serum confidence interval of the prevalence of patients achieving 2009 phosphate, calcium and parathyroid hormone (PTH) within nar- KDIGO recommendations. Nephrologists were selected using a row ranges, although adherence to the recommended target clustering approach, where clusters (nephrologists) were randomly ranges has proved challenging [5–8]. Six years later, the interna- drawn, in respect of geographical distribution and type of practice. tional Kidney Disease: Improving Global Outcomes (KDIGO) guide- The study was proposed to nephrologists in chronological order in line for CKD–MBD became available, with serum phosphate, the drawn list, until the number of required clusters was reached. calcium and PTH targets different from those of the KDOQI guide- Patients were selected within each cluster in chronological order. lines [3]. However, the evidence supporting these guidelines has All adult patients referred for the first time to the nephrolo- been challenged subsequently as it was mainly based on retro- gist and with Stage 4 or 5 CKD who were not yet receiving dialy- spective observational studies [9, 10]. Of particular concern is the sis therapy, and had no kidney graft history, were eligible. fact that for non-dialysis-dependent CKD Stages 3–5, even obser- vational evidence has remained scarce. The 2009 KDIGO clinical practice guideline on the manage- Data collection ment of CKD–MBD was updated in 2017 and is intended to assist Clinical events, serum biochemistry data and information on the the practitioner caring for adults and children with CKD Stages treatment of CKD patients were collected at the above fixed time 3–5, on long-term dialysis therapy, or with a kidney transplant points. The following data were retrieved: laboratory parameters [3, 11]. This guideline has been endorsed in Europe since 2010 [serum levels of C-reactive protein, phosphate, calcium, iPTH, [12]. However, effective management of CKD–MBD includes a alkaline phosphatase both total and bone-specific enzymes], 25- substantial effort on the part of patients to be adherent with diet- hydroxyvitamin D [25(OH)D], albumin, low-density lipoprotein ary restrictions, thrice daily doses of oral phosphate binders, and, cholesterol, ferritin, transferrin saturation, blood haemoglobin for many patients, regular use of several other oral medications (Hb) concentration, glycated Hb level, demographics, blood pres- [13, 14]. Following the release of the 2009 KDIGO guideline, sev- sure, CV and valvular calcifications, current treatments eral studies have estimated the percentage of patients achieving {medications to control serum phosphate, vitamin D [oral or 2009 KDIGO targets for CKD–MBD [15]. A recent report based on a intravenous (IV) route], erythropoiesis stimulating agent (ESA), IV large international sample of chronic haemodialysis patients iron, hypolipidaemic drug, antihypertensive, oral anticoagulant showed that the treatment approaches for secondary hyperpara- and anticonvulsive}, history of parathyroidectomy, hospital- thyroidism had changed between 1996 and 2011 and that serum izations, bone fracture and CV events. Patient status (on dialysis, PTH levels had increased in most countries [15]. To the best of dead, lost to follow-up, moved to another centre and kidney our knowledge, no information is available on the proportion of transplantation) was also recorded during follow-up. All labora- patients who reach KDIGO target ranges in CKD Stages 3–5 before tory evaluations were performed locally. the initiation of renal replacement therapy [16, 17]. R Patients were prospectively enrolled between October 2010 The main objective of the observational Photo-Graphe 3study and October 2012. Data were collected every 6 months between in France was to estimate the percentage of CKD Stages 4–5 and October 2010 and April 2013 and then lastly in April 2014. 5D patients (patients with CKD requiring dialysis) who achieved Therefore, seven data collections were available for some the target ranges suggested by the 2009 KDIGO guideline. A secon- patients included in October 2010, whereas patients included in dary objective was to investigate the relationship between the October 2012 had a maximum of three data collections. control of mineral metabolism and patient outcomes. We report Data were entered in an electronic case report system here the results of the study in non-dialysis CKD Stages 4–5 TM (Photo-Graph software developed by Genzyme S.A.S. then patients regarding the 2009 and 2017 KDIGO guidelines. Sanofi France). Data collected in each region were anonymized at each patient level and then centralized by regional coordina- tors. After regional data collection was completed, 19 regional MATERIALS AND METHODS electronic files were transferred after centre anonymization to the national coordinating centre for data processing. Thus, data Population collection was performed with respect to patient’s anonymity at V R The French Phosphorus and Calcium Observatory (Photo-Graphe the regional and national levels. Inconsistencies were checked 3) is a prospective, multicentre, epidemiological observational after consolidation of national data. The national coordinator Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/710/4938506 by Ed 'DeepDyve' Gillespie user on 17 October 2018 712 | D. Fouque et al. might ask for data correction or deletion. As data were handled (56%) CKD Stage 4 patients and 95 (62%) CKD Stage 5 patients. in an anonymous way, data source verification was not Patient characteristics at inclusion are shown in Table 1. After planned. This study was conducted according to French inclusion and whatever the time point, serum 25(OH)D was regulatory rules and good clinical practices. available in few patients and was not included in further analyses. Statistical analysis Achievement of KDIGO targets Statistical analyses were performed using SAS/STAT 14.1 (SAS The evolution of serum calcium and serum phosphate over Institute Inc., Cary, NC, USA). Statistical analysis is at the patient level. Patients who discontinued the study after the baseline visit time is displayed in Figure 1. The percentage of patients achiev- ing the three main 2009 KDIGO targets remained between 14% were excluded from all survival analyses. Patients who started dial- ysis therapy or were transplanted or lost to follow-up were and 15% during the first 2 years and slightly increased there- after, reaching a maximum of 22% at 2.5 years in CKD Stage 4 included in analyses to the point of study discontinuation. Statistical analyses were independently performed in each popula- patients, and remained <6% throughout the study in CKD Stage 5 patients. Slightly more patients fulfilled the three mains 2017 tion (CKD Stage 4 and CKD Stage 5) except survival analysis. Standard descriptive statistics were used for demographic, KDIGO targets whatever the time (Table 2). In Stage 4, the percentage of patients achieving 2009 KDIGO biological and clinical data, to determine mean and standard deviation for normally distributed data, and median and 25th targets for serum phosphate decreased over time (P¼ 0.0001), while no significant trend was observed over time either for cal- and 75th percentile values for non-normally distributed data. No replacement of missing data was performed and, therefore, cium (P¼ 0.90), PTH (P¼ 0.36) or the three parameters combined (P¼ 0.12). In Stage 5, no significant trend was reported over time the number of patients with documented laboratory data may change according to the time point. for serum phosphate (P¼ 0.80), calcium (P¼ 0.47), PTH (P¼ 0.77) or the three parameters combined (P¼ 0.66). The percentage of patients achieving the three KDIGO targets, according to the 2009 and 2017 guideline, respectively, was esti- As expected, at each data collection and in both CKD stages, 2009 KDIGO targets were not fulfilled most often because serum mated at inclusion and at each following determination (abnor- mal PTH value was defined as an iPTH value above the upper calcium and phosphate levels were below and above KDIGO tar- gets, respectively (Table 3). normal limit of the assay kit). The evolution of the percentage of patients achieving the main three KDIGO targets was evaluated Using the 2017 KDIGO guideline, abnormal PTH level corre- sponded mainly to two consecutive iPTH above the upper nor- using a generalized estimating equation (GEE) model on available data with a binomial distribution and a logit function. As the mal limit of the assay kit (Table 4). Whatever the time, >50% of the patients have an abnormal iPTH value. Moreover, >30% of study was performed at the time of the 2009 KDIGO guideline, this analysis was restricted to the 2009 KDIGO targets. the Stage 4 patients and >50% of the patients with abnormal iPTH have concomitant hyperphosphataemia and/or hypocal- Furthermore, for serum phosphate and calcium levels and, at each data collection, patients were classified into three groups caemia whatever the time (Table 4). CKD–MBD-directed therapies at each data collection time according to normal laboratory ranges: patients below, within and above normal ranges. Normal ranges were 2.15–2.55 and 0.9– point are displayed in Table 5. The number of patients receiving various treatments decreased over time for most drugs: any 1.4 mmol/L for serum calcium and phosphate, respectively. In addition, for the analysis of the comparison with the 2017 vitamin D sterol, any phosphate binder and any calcium salt; in contrast, cinacalcet slightly rose. However, for some time peri- KDIGO guidelines and starting from the 6-month time point, abnormal PTH was defined as two consecutive values above the ods, the effective of patients is very low, precluding any reason- able interpretation. upper normal limit of the laboratory kit or >5% increase in the second consecutive PTH determination compared with the pre- vious one, whatever the interval between two time points. Survival analysis Modifiable factors were hyperphosphataemia and hypocalcae- mia at the time of the second PTH determination. Median duration of follow-up was 23 (6; 36) months in CKD The survival curves were plotted using the Kaplan–Meier Stage 4 patients and 8 (3; 18) months in CKD Stage 5 patients. method and the differences in survival were determined using a Over the study period, 34 (6%) patients with CKD Stage 4 and 41 log-rank test. A Cox proportional hazards model was used to iden- (27%) with CKD Stage 5 started dialysis, and 16 (3%) patients tify the factors measured at baseline and significantly associated with CKD Stage 4 patients and 7 (5%) patients with CKD Stage 5 with survival using a backward selection method. The backward underwent kidney transplantation. Overall, 81 (14%) patients selection was started with all variables significant at the 0.20 thresh- with CKD Stage 4 and 15 (10%) patients with CKD Stage 5 died old level in univariate analysis and after the proportional hazards during the observation period. In addition, 126 (22%) patients assumption has been checked. The significance level for removing with CKD Stage 4 and 31 (20%) patients with CKD Stage 5 were an explanatory variable from the model was set at 0.10, with com- lost to follow-up at the end of the study. The 157 patients lost to parison between two adjacent models using Akaike’s information follow-up were significantly older (median age 77 versus 73 criterion. Interactions between two variables were tested on the years, P< 0.001) and less often patients with diabetes (10% ver- final model. All tested factors were recorded at inclusion. sus 35%, P< 0.0001) than the other patients. No statistically sig- nificant differences in gender and glomerular filtration rate were observed between patients lost to follow-up and the RESULTS others. No statistically significant difference in survival was Patient population observed between the two CKD stages (P¼ 0.10) (Figure 2). Overall, 566 CKD Stage 4 patients and 153 CKD Stage 5 patients Age, history of CV disease, Hb and albumin levels, treatment were included. More than half of the patients were males: 316 with an ESA, IV iron and classes of serum phosphate and Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/710/4938506 by Ed 'DeepDyve' Gillespie user on 17 October 2018 Achievement of 2009 and 2017 KDIGO CKD mineral and bone guidelines | 713 Table 1. Characteristics of the patients at inclusion CKD Stage 4 (n¼ 566) CKD Stage 5 (n¼ 153) Variables nn Male 316 (55.8) 95 (62.1) Age (years) 566 74 (63; 81) 153 73 (59; 81) Body mass index (kg/m ) 355 26.5 (23.9; 30.1) 106 27.3 (23.2; 30.8) Systolic blood pressure (mmHg) 447 142 (130; 156) 133 140 (134; 158) Diastolic blood pressure (mmHg) 447 80 (70; 85) 133 80 (70; 86) 2 a Estimated GFR (mL/min/1.73 m ) 566 22.4 (18.9; 25.8) 153 12.1 (10.5; 13.7) Serum albumin (g/L) 455 38 (35; 41) 128 38 (35; 41) Hb (g/dL) 506 12.1 (1.4) 142 11.4 (1.2) Serum 25(OH)D (ng/mL) 457 61.0 (32.5; 90.0) 121 60.0 (39.0; 95.0) Smoker 566 153 Former 105 (18.6) 34 (22.2) Current 36 (6.4) 20 (13.1) Associated risk factors and disease 566 153 Arterial hypertension 362 (64.0) 111 (72.6) Diabetes mellitus 168 (29.7) 45 (29.4) History of CV disease 234 (41.3) 57 (37.3) Any CKD–MBD-directed therapy 566 153 Active vitamin D 64 (11.3) 26 (17.0) Native vitamin D 282 (49.8) 83 (54.3) Calcium-free phosphate binder 17 (3.0) 23 (15.0) Calcium-based phosphate binder 123 (21.7) 43 (28.1) Any calcium salt 135 (23.9) 61 (39.9) Cinacalcet 2 (0.4) 5 (3.3) Other drug treatments 566 153 ESA 129 (22.8) 64 (41.8) IV iron 24 (4.2) 9 (5.9) Antihypertensive drug 472 (83.4) 130 (85.0) Continuous data are presented as mean6 standard deviation or median (25%; 75%); categorical data are presented as n (%) patients. GFR¼ glomerular filtration rate calculated using the modification of the diet in renal disease formula. calcium at inclusion were associated with survival in univariate In particular, the proportion of patients who achieved the indi- analysis (Table 6). In multivariable analysis, only two of those vidual 2009 KDIGO target, after 2 years and 3.5 years, for serum parameters were selected by the backward selection method: PTH was 25% and 10% in Stage 4 CKD and Stage 5 CKD, older age and lower blood Hb level were associated with an respectively. Note that the 2009 KDIGO guideline suggested not increased risk of overall mortality over the study period (Table 6). to routinely prescribe vitamin D supplements or vitamin D ana- logues, in the absence of suspected or documented deficiency, for the control of elevated PTH concentrations in people with CKD not on dialysis [20]. This could explain the high percentage DISCUSSION of patients receiving no vitamin D supplement at inclusion in This is the first study showing that it is quite difficult to achieve the present study. KDIGO CKD–MBD targets in patients with Stages 4 and 5 CKD. The proportion of patients achieving the individual 2009 Patients with CKD are stratified using five stages based on glo- KDIGO target for serum phosphate decreased significantly from merular filtration rate [3, 18], and taking into account the degree 74% at inclusion to 61% after 3.5 years in CKD Stage 4 and was of albuminuria as well [18]. TheCKD stagingsystemis usefulin mainly related to the increase in the percentage of patients many regards, including the prediction of the associated comor- with serum phosphate above the target range. This fact, not bidities [18]. A review of data from 19 general-population studies unexpected since the CKD progression leads to a further impair- from 13 European countries showed considerable differences in ment in renal phosphate excretion, might have been limited both CKD Stages 1–5 and CKD Stages 3–5 prevalence across through a more intensive control, including phosphate binders European study populations. The adjusted CKD Stages 1–5 preva- prescription. No significant trend over time was observed for lence varied between 3.31% in Norway and 17.3% in Northeast that parameter in CKD Stage 5 patients. As to serum calcium, no Germany. The adjusted CKD Stages 3–5 prevalence varied significant trend was observed over time in the proportion of between 1.0% in Central Italy and 5.9% in Northeast Germany CKD patients who achieved the individual 2009 KDIGO target. [19]. In this context, the Photo-Graphe 3 is one of the most However >80% of the patients, both in CKD Stage 4 and Stage 5, recent and largest European prospective studies, specifically achieved the 2009 KDIGO calcium targets after 2 years of follow- aimed at assessing disturbances of phosphate, calcium and PTH up. With regards to serum PTH, <30% of patients in CKD Stage 4 metabolism. and <20% of patients in CKD Stage 5 achieved the 2009 KDIGO The present analysis confirms that adherence to the recom- targets at each time point. mended target ranges for serum PTH, phosphate and calcium Even if the 2017 KDIGO guideline had been used the conclu- remains challenging despite several therapeutic advances. sions regarding achievement of KDIGO objectives would have Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/710/4938506 by Ed 'DeepDyve' Gillespie user on 17 October 2018 714 | D. Fouque et al. FIGURE 1: Serum phosphate and calcium levels over time. Horizontal lines correspond to lower and upper limit levels of normal. O indicate stage 4 CKD; þ indicate stage 5 CKD. likely been the same. Clearly, more studies are needed in order these data may suggest some improvement in care at these pre- to understand the reason why so many CKD patients failed to dialysis stages. achieve the KDIGO targets and to find out how guideline com- The longitudinal analysis of CKD–MBD-directed therapy pliance can be improved, or to realize that the guideline may reported a decrease in most prescribed drugs (Table 5). This is not be appropriate for very advanced stages of CKD. interesting to note because at the same time, the control for Information obtained on 25(OH)D seems of interest. At inclu- serum calcium, PTH and phosphorus could have been sion, nearly 80% of CKD patients were assessed for serum con- improved. It is important to point out this fact since these data centration. However, the mean serum 25(OH)D was 60 ng/mL have been obtained through a well-designed prospective longi- whatever the stage, quite below the 75 ng/mL minimal value, tudinal study, which further suggests that in the real life, results indicating that >60% of patients were vitamin D deficient. This might have been even poorer. is to be paralleled to the number of patients receiving a vitamin As expected, more Stage 5 patients started dialysis than D supplement (50% at Stage 4 and 54% at Stage 5). Altogether, Stage 4 patients and underwent kidney transplantation over the Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/710/4938506 by Ed 'DeepDyve' Gillespie user on 17 October 2018 Achievement of 2009 and 2017 KDIGO CKD mineral and bone guidelines | 715 Table 2. Percentage of patients achieving the three main KDIGO targets of calcium and phosphate metabolism Data collection Inclusion 6 months 1 year 1.5 year 2 years 2.5 years 3.5 years CKD Stage 4 n patients with documented data 469 327 286 246 194 136 127 Patients achieving the three 2009 KDIGO targets (%) 67 (14.3) 50 (15.3) 41 (14.3) 36 (14.6) 28 (14.4) 30 (22.1) 23 (18.1) Patients achieving the three 2017 KDIGO targets (%) 84 (17.9) 59 (18.0) 53 (18.5) 42 (17.1) 31 (16.0) 33 (24.3) 26 (20.5) CKD Stage 5 n patients with documented data 139 83 57 35 21 14 9 Patients achieving the three 2009 KDIGO targets (%) 2 (1.4) 1 (1.2) 3 (5.3) 2 (5.7) 0 0 0 Patients achieving the three 2017 KDIGO targets (%) 5 (3.6) 3 (3.6) 5 (8.8) 2 (5.7) 0 0 0 n (%) patients with available data. Starting from the third determination, the time between two determinations is 6 months or 1 year depending on time of patient inclusion in the study. Achievement defined as serial assessment and the three parameters less than the upper normal limit, for serum iPTH upper normal limit of the assay kit. Table 3. Numbers (proportion) of patients within normal range for calcium and phosphate metabolism at each data collection time point Data collection Inclusion 6 months 1 year 1.5 year 2 years 2.5 years 3.5 years CKD Stage 4 Serum phosphate (mmol/L) Value unavailable 21 165 197 192 190 142 185 Hypo 0.9 (%) 31 (5.7) 27 (6.7) 25 (8.0) 15 (5.4) 14 (6.3) 6 (3.9) 9 (6.2) Normal (%) 404 (74.1) 280 (69.8) 218 (70.1) 180 (65.0) 148 (66.4) 103 (67.8) 89 (60.9) Hyper >1.4 (%) 110 (20.2) 94 (23.5) 68 (21.9) 82 (29.6) 61 (27.3) 43 (28.3) 48 (32.9) Serum total calcium (mmol/L) Value unavailable 19 162 194 193 187 141 185 Hypo 2.15 (%) 69 (12.6) 54 (13.4) 37 (11.8) 37 (13.4) 27 (11.9) 22 (14.4) 17 (11.6) Normal (%) 455 (83.2) 334 (82.7) 259 (82.5) 221 (80.1) 185 (81.9) 127 (83.0) 125 (85.6) Hyper >2.55 (%) 23 (4.2) 16 (3.9) 18 (5.7) 18 (6.5) 14 (6.2) 4 (2.6) 4 (2.7) Serum iPTH Value unavailable 90 233 220 221 216 156 201 upper normal limit of the assay kit (%) 108 (22.7) 80 (24.0) 69 (24.0) 60 (24.2) 45 (22.8) 41 (29.7) 33 (25.4) CKD Stage 5 Serum phosphate (mmol/L) Value unavailable 2 56 67 84 83 67 78 Hypo 0.9 (%) 4 (2.6) 2 (2.1) 2 (3.3) 0 (0.0) 1 (4.3) 0 (0.0) 0 (0.0) Normal (%) 54 (35.8) 42 (43.3) 22 (36.1) 16 (40.0) 8 (34.8) 8 (50.0) 4 (40.0) Hyper >1.4 (%) 93 (61.6) 53 (54.6) 37 (60.6) 24 (60.0) 14 (60.9) 8 (50.0) 6 (60.0) Serum total calcium (mmol/L) Value unavailable 2 56 67 84 83 68 78 Hypo 2.15 (%) 44 (29.1) 24 (24.7) 18 (29.5) 10 (25.0) 7 (30.4) 3 (20.0) 2 (20.0) Normal (%) 102 (67.6) 65 (67.0) 42 (68.9) 30 (75.0) 16 (69.6) 12 (80.0) 8 (80.0) Hyper >2.55 (%) 5 (3.3) 8 (8.3) 1 (1.6) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Serum iPTH Value unavailable 14 70 70 88 85 69 79 upper normal limit of the assay kit (%) 15 (10.8) 9 (10.8) 9 (15.5) 5 (13.9) 2 (9.5) 1 (7.1) 1 (11.1) n (%) patients with documented data. study period (27% versus 6% and 5% versus 3%, respectively). than people of comparable age in the general population, with Overall, 81 (14%) patients with CKD Stage 4 and 15 (10%) patients 25% among them dying before reaching end-stage kidney dis- with CKD Stage 5 died within 3.5 years. In the 20th century, CKD ease [24]. replaced infection and malnutrition as leading causes of mor- The present study has several limitations. First, centres that tality in the general population [21]. Individuals with CKD have participated on a voluntary basis were likely to be more inter- an increased risk of all-cause mortality, mainly from CV disease ested in correcting CKD–MBD in their patients than those who [2, 22]. Somewhat surprisingly, the 1- and 2-year survival rates did not join the study group. On the other hand, the high num- (68% and 47%) among CKD Stage 5 patients aged >75 years and ber of unavailable CKD–MBD laboratory parameters suggests not undergoing dialysis were found to be lower than survival that even in that population, compliance to the guidelines for rates of patients receiving dialysis therapy (84% and 76%), sug- the management of those patients is low. Secondly, the per- gesting a selection bias in patients referred to maintenance dial- centage of patients lost to follow-up over 3.5 years was 22% in ysis [23]. However, even early CKD patients have poorer survival patients with CKD Stage 4 and 20% in patients with CKD Stage 5. Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/710/4938506 by Ed 'DeepDyve' Gillespie user on 17 October 2018 716 | D. Fouque et al. Table 4. Numbers (proportion) of patients with abnormal iPTH levels (KDIGO 2017) at each follow-up Data collection 6 months 1 year 1.5 year 2 years 2.5 years 3.5 years CKD Stage 4 n evaluable patients 333 288 248 197 138 130 Above the upper normal limit of the laboratory kit (%) 208 (62.5) 156 (54.2) 150 (60.5) 124 (62.9) 71 (51.5) 75 (57.7) >5% increase (%) 44 (13.2) 53 (18.4) 33 (13.3) 24 (12.2) 33 (23.9) 25 (19.2) Not abnormal (%) 81 (24.3) 79 (27.4) 65 (26.2) 49 (24.9) 34 (24.6) 30 (23.1) Modifiable factors Hyperphosphataemia (%) 47 (18.7) 40 (19.1) 38 (20.8) 30 (20.3) 20 (19.6) 29 (29.3) Hypocalcaemia (%) 23 (9.2) 16 (7.7) 10 (5.5) 8 (5.4) 7 (6.9) 7 (7.1) Both (%) 11 (4.4) 8 (3.8) 17 (9.3) 8 (5.4) 8 (7.8) 5 (5.1) CKD Stage 5 n evaluable patients 83 58 36 21 14 9 Above the upper normal limit of the laboratory kit (%) 68 (81.9) 40 (69.0) 25 (69.4) 16 (76.2) 9 (64.3) 6 (66.7) >5% increase (%) 5 (6.0) 3 (5.2) 4 (11.1) 1 (4.8) 3 (21.4) 0 Not abnormal (%) 10 (12.1) 15 (25.8) 7 (19.4) 4 (19.0) 2 (14.3) 3 (33.3) Modifiable factors Hyperphosphataemia (%) 26 (35.6) 17 (39.5) 11 (39.3) 5 (29.4) 3 (25.0) 3 (50.0) Hypocalcaemia (%) 3 (4.1) 2 (4.7) 3 (10.1) 1 (5.9) 0 1 (16.7) Both (%) 16 (21.9) 13 (30.2) 6 (21.4) 6 (35.3) 3 (25.0) 1 (16.7) n (%) patients; abnormal iPTH: two consecutive determinations above the upper normal limit of the assay kit or >5% increase in the second consecutive PTH determi- nation compared with the previous one. On the subgroup of patients with abnormal iPTH. Hyperphosphataemia or hypocalcaemia at the time of the second PTH determination. Table 5. CKD–MBD-directed therapy at each data collection time point Data collection Inclusion 6 months 1 year 1.5 year 2 years 2.5 years 3.5 years Stage 4 Number of patients 566 566 508 469 413 294 331 Any vitamin D sterol (%) 313 (55.3) 245 (43.3) 202 (39.8) 189 (40.3) 153 (37.1) 106 (36.1) 103 (31.1) Any phosphate binder (%) 152 (26.9) 118 (20.9) 90 (17.7) 83 (17.7) 72 (17.4) 48 (16.3) 53 (16.0) Any calcium salt (%) 135 (23.9) 107 (18.9) 80 (15.8) 71 (15.1) 64 (15.5) 38 (12.9) 42 (12.7) Cinacalcet (%) 2 (0.4) 3 (0.5) 3 (0.6) 6 (1.3) 5 (1.2) 5 (1.7) 8 (2.4) Stage 5 Number of patients 153 153 128 124 106 83 88 Any vitamin D sterol (%) 97 (63.4) 61 (39.9) 45 (35.2) 32 (25.8) 17 (16.0) 12 (14.5) 6 (6.8) Any phosphate binder (%) 84 (54.9) 53 (34.6) 38 (29.7) 26 (21.0) 13 (12.3) 10 (12.1) 8 (9.1) Any calcium salt (%) 61 (39.9) 40 (26.1) 26 (20.3) 17 (13.7) 8 (7.6) 6 (7.2) 6 (6.8) Cinacalcet (%) 5 (3.3) 3 (2.0) 4 (3.1) 2 (1.6) 2 (1.9) 1 (1.2) 1 (1.1) n (%) patients receiving the corresponding therapy at each data collection time point. FIGURE 2: Survival of patients with CKD Stages 4 and 5. Product-limit survival estimates with number of subjects at risk in in each CKD stage. Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/710/4938506 by Ed 'DeepDyve' Gillespie user on 17 October 2018 Achievement of 2009 and 2017 KDIGO CKD mineral and bone guidelines | 717 Table 6. Univariate and multivariate Cox proportional analysis with overall mortality Univariate analysis Multivariate analysis Number of Hazard Variable observations used ratio 95% CI P-value Hazard ratio 95% CI P-value Female sex 719 0.74 0.49–1.10 0.13 4 4 Age (years) 719 1.08 1.06–1.10 <10 1.09 1.06–1.11 <10 History of CV disease: yes 719 2.24 1.49–3.35 <10 2 2 Hb (g/dL) 648 0.82 0.71–0.95 <10 0.78 0.67–0.92 <10 Serum albumin (reference 39.5 g/L) Serum albumin 33 583 2.49 1.35–4.59 <10 Serum albumin (33.1–36.9) 583 1.63 0.84–3.16 0.15 Serum albumin (37.0–39.4) 583 1.42 0.75–2.69 0.28 Diabetes mellitus: yes 719 1.27 0.86–1.89 0.23 Serum phosphate, 2009 KDIGO classes 696 0.10 Phosphate (mmol/L)  0.9 0.51 0.16–1.63 0.26 Phosphate (mmol/L) > 1.4 1.43 0.94–2.18 0.09 Serum total calcium, 2009 KDIGO classes 698 0.03 Calcium (mmol/L)  2.15 1.85 1.16–2.96 0.01 Calcium (mmol/L) > 2.55 0.88 0.28–2.78 0.83 Serum iPTH: achieved 2009 KDIGO target 615 0.89 0.54–1.48 0.66 ( upper normal limit of the assay kit) ESA: yes 719 1.97 1.34–2.91 <10 IV iron: yes 719 2.10 1.06–4.16 0.03 Hypertension: yes 719 1.31 0.80–2.14 0.28 All variables are variables measured at inclusion. CI, confidence interval. Backward selection was started with all variables significant at the 0.20 threshold level in univariate analysis. The significance level for removing an explanatory varia- ble from the model was set at 0.10, with comparison between two adjacent models using Akaike’s information criterion. Interactions between two variables were tested on the final model. Such relatively high rates may have biased our interpretation of CONFLICT OF INTEREST STATEMENT the results; loss to follow-up of10% would have been desir- Sanofi did not interfere with the statistical analysis. D.F. able. Patients lost to follow-up were significantly older than served as national coordinator and received honoraria from those who remained in the study. Missing information on them Sanofi for travel and lectures. H.R. reports personal fees was probably mainly due to deaths unknown to the treating from Sanofi during the conduct of the study and grants from physician. Because of the small number of deaths, the power of Genzyme outside the submitted work. E.D. declares having the survival analysis was low, but the survival curves are in served as consultant for Amgen, Sanofi, Shire and Astra favour of no real difference in all-cause mortality risk between CKD Stage 4 and CKD Stage 5 patients. Zeneca, and having received speaker honoraria from Amgen In conclusion, the present study shows that only few and Sanofi, and having received travel grants from Sanofi, patients eventually achieved the 2009 KDIGO targets. In the Roche, Shire and Alexion. T.B.D. declares having served as present study older age and lower blood Hb levels, but abnormal consultant for Amgen, F. Hoffman-La Roche, FMC, Sanofi- serum calcium, phosphate or PTH, were not associated with an Genzyme and Vifor, and having received speaker honoraria increased risk of all-cause mortality. from Amgen, Kyowa Hakko Kirin and Sanofi-Genzyme. B.D., With the inherent limitation of its small size and the possi- T.H., G.M.L., G.J. and J.-L.B declared no competing interests. bility that some patients have been lost to follow-up because of death, this study does not support that the achievement of KDIGO CKD–MBD targets is associated with better survival in LIST OF COORDINATORS patients with CKD Stage 4 or 5. B. Dallaporta, B. Vendrely, C. Delcroix, D. Joly, E. Daugas, E. Laruelle,G.Choukroun,G. Jean, H. LerayMoragues, L. Azzouz,M. ACKNOWLEDGEMENTS Essig, M. Hammadi, M. Kessler,M.Touam,P.Bories, P. Brunet,P. Henri, P. Zaoui, R. Azar, S. Delbes, T. Hannedouche, V. Esnault. The authors are thankful to the many staff, coordinators and physicians whose work was essential for the comple- tion of this study. LIST OF PHYSICIANS A. Abbassi, M. Abtahi, C. Achard Hottelart, H. Adda, G. Al FUNDING Chahin,B.AlJalaby, I. Al Moubarak,M.AlRifai,M.Aladib, Sanofi France, the sponsor of this observational study, N. Albeiriss, S. Albitar, J. Aldigier, F. Alenabi, A. Amaouche, C. secured the funding required throughout study implemen- Araujo, U. Assogba, L. Azeroual, D. Babici, B. Ball, S. Bally, E. tation and managed the development of the protocol, the Barga, F. Basse, N. Bassilios, J. Batho, C. Baudeau, M. electronic case report form, the regulatory submissions and Bauwens, D. Bazin, B. Ben Taarit, S. Benarbia, J. Bendini, F. logistics. Berge, P. Bernadet, J. Bertheleme, F. Besson, S. Billion, A. Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/710/4938506 by Ed 'DeepDyve' Gillespie user on 17 October 2018 718 | D. Fouque et al. chronic kidney disease. Nephrol Dial Transplant 2009; 24: Blanpain, C. Bonniol, C. Boriceanu, J. Bosc, B. Bouali, K. 1506–1523 Boubenider, L. Boudier, J. Bouet, M. Bouiller, M. Boukelmoune, 3. Kidney Disease: Improving Global Outcomes (KDIGO) CKD- Z. Boukhalfa, R. Boula, H. Boulanger, J. Bourdenx, F, Bourdon, MBD Work Group. KDIGO clinical practice guideline for the F. 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Clinical Kidney JournalOxford University Press

Published: Mar 15, 2018

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