INTRODUCTION



After publication of the European guidelines,1 the American National Kidney Foundation published its own clinical practice guidelines (K/DOQITM or Kidney Disease Outcome Quality Initiative) for bone metabolism and disease in chronic kidney disease (CKD) in 2003, which became the worldwide reference used for many years.1 Although they were always disputed because of the high degree of «expert opinion» contained in their recommendations, it is clear that they are not only a worldwide reference but also very popular, well-known and extensively followed in the management of dialysis patients.3-5. However, the condition previously known as «renal osteodystrophy»6 and now generically called chronic kidney disease-mineral and bone disorder7-9 starts long before the need for dialysis,10 and early control of biochemical parameters is also recommended in CKD stages 3-5 predialysis.2 The aim of this

study was to analyze adherence to the K/DOQITM guidelines for bone and mineral metabolism disorders in patients with CKD stages 3-5 predialysis in a survey of Spanish nephrologists participating in the OSERCE study, three years after publication of the K/DOQITM guidelines.



PATIENTS AND METHODS



OSERCE is the Spanish acronym for «Epidemiological Study of Bone Disease in Chronic Kidney Disease in Spain». It is was a cross-sectional multicenter study, whose aim was to analyze the clinical and biochemical characteristics

and the therapeutic management of mineral and bone disorders in CKD (CKD-MBD) in adult patients > 18 years of age with an estimated glomerular filtration rate (GFR) < 60 ml/min/1.73 m2 not yet included in dialysis (CKD stages

3, 4 and 5). The patients included were from the outpatient clinics of different nephrology department in Spain and

gave their informed consent to participate in the study. The primary aims of the OSERCE study were to analyze the

percentage of patients with intact parathyroid hormone (iPTH) levels outside the values recommended by the

K/DOQITM guidelines,11,12 and to determine the percentage of patients in whom PTH was measured routinely. Each investigator completed a questionnaire before starting the study. The results of this questionnaire are reported in the present paper.



Questionnaire

The study included a questionnaire completed by each investigator/center on their clinical practice in CKD-MBM requesting both the frequency of measurements of bone metabolism parameters (calcium, phosphorus, intact PTH and calcidiol) and the target ranges considered as treatment goals in this population in the different stages of CKD. Practices related to the measurement of plasma bicarbonate and the performance of imaging tests to assess the presence of calcifications were also analyzed. The study was carried out from April to May 2006 and completed in 32 centers.



We considered «inadequate» responses as those outside the ranges recommended in the K/DOQITM clinical practice guidelines for CKD patients not on dialysis and shown in table I. Hypercalcemia was defined as corrected calcium values exceeding 10.2 mg/dl in accordance with the guidelines.2



The results are expressed as the mean (mean percentage) and 95% confidence intervals (CI) (95% CI, lower limitupper limit).



RESULTS

The questionnaires were answered by the 32 investigators participating in the OSERCE study, all of whom were nephrologists treating patients with CKD not on dialysis. The polled nephrologists were 16 women and 16 men with a mean age of 44.6 ± 9.1 years, median age of 44 years (range: 27-60) (95% CI: 41-48), and a mean of 17 ± 6 years working in nephrology (95% CI: 14-21).



Frequency of measurement of recommended biochemical parameters

Table II shows the frequency of measurement of the most important biochemical parameters and their comparison with the follow-up recommended by the K/DOQITM guidelines.2 As much as 87.5% of polled nephrologists stated that they did not systematically measure calcidiol plasma levels despite of these recommendations. Among polled nephrologists, 50% never performed this measurement (95% CI, 33-66), 37.5% performed it sometimes (95% CI, 22-54) and only five investigators (12.5%) always performed it (95% CI, 5-29).



Treatment goals for iPTH, calcium, phosphorus and calcium-phosphorus product

Tables III, IV, V and VI show the percentage reported as the treatment goal for plasma levels of intact PTH, phosphorus, calcium and calcium x phosphorus product, respectively. Table 3 shows that treatment goals for intact PTH were adequately reported for patients in stage 3 by only 41% of polled nephrologists (95% CI, 24-57). They were adequately reported by 36% (95% CI, 21-54) in stage 4 and by 78% (95% CI, 59-89) in stage 5.



Table IV shows that treatment goals for plasma phosphorus were adequately reported only in 50% of patients in stage 3 (95% CI, 33-67) and 50% in stage 4 (95% CI, 33-67), and in 53% of patients in stage 5 (95% CI, 36-69). The most frequent discrepancy was to consider adequate phosphorus levels between 3.5 and 5.5 mg/dl in stages 3 and 4, which are usually recommended in stage 5 in dialysis patients. Table V shows that treatment goals for calcium were inadequately reported by only 30-35% of polled nephrologists, but goals between 9.5 and 10.2 mg/dl were still considered adequate in 31% of the responses (95% CI, 17-49). Hypercalcemia was defined as corrected calcium levels greater than 9.5, 10.2 and 10.5 mg/dl by 10% (95% CI, 4-26), 52% (95% CI, 35-68) and 38% (95% CI, 23-56) of nephrologists, respectively. Table V shows that at least 90% of polled nephrologists was knowledgeable of the recommended values for the Ca x P product (< 55 mg/dl) in the different stages of CKD.



Other aspects of the questionnaire

We finally note that 93% of polled nephrologists stated that they did not regularly measure bicarbonate levels (95% CI, 78-98). A target level of 22-25 mEq/l was considered adequate by 76% (95% CI, 58-87), 17% (95% CI, 8-34) accepted a certain degree of acidosis (18-21 mEq/l) and the rest considered adequate levels between 26-28 mEq/l. In addition, 72% of nephrologists (95% CI, 54-85) performed imaging tests to evaluate the presence of calcifications (mainly plain chest or abdominal X-rays or echocardiograms in approximately 50% of cases), while bone densitometry was performed in 39% of cases (95% CI, 24-57).



DISCUSSION



Although the European guidelines were published previously, 1 the American National Kidney Foundation published

shortly afterwards its own K/DOQITM clinical practice guidelines for bone metabolism and disease in CKD.2 It was

also in these same K/DOQITM guidelines that the current concept of CKD was first defined, and which has been recently adopted with minor changes by the KDIGO (Kidney Disease Improving Global Outcomes) international initiative.13,14 It is clear that the K/DOQITM guidelines have become the worldwide reference used in most countries and studies, and they were a common standard of definitions and treatment goals for many years.  Although the guidelines for bone metabolism and disease were always disputed because of the high degree of «expert opinion» contained in their recommendations,2 it is clear that they have been a unifying element that has permitted all nephrologists to use the same language and to compare uniformly the results of different studies, and thus they have been very popular, well-known and extensively followed in the management of dialysis patients.3-5



Recently, and coinciding with the growing importance of early diagnosis of CKD and cardiovascular risk factors associated with CKD in clinical practice,13-19 several articles have demonstrated the association between mortality and serum levels of different biochemical parameters related to mineral metabolism.20-22 So much so that the KDIGO international guidelines have introduced a new broader concept (CKD-MBD, or Chronic Kidney Disease-Mineral and Bone Disorder) which emphasizes the importance of control of bone and mineral disorders associated with CKD beyond mere control of bone disease to achieve a systemic dimension,7 but only a draft version for discussion showing their guidelines in this area has been published. It is for this reason that the K/DOQITM guidelines are still the worldwide reference, especially in dialysis patients, at least until forthcoming publication of the next version of the KDIGO guidelines.



However, CKD-MBD starts long before the need for dialysis, 10,23,24 so the K/DOQITM guidelines also included target recommendations for predialysis CKD patients.2 In this study, it can be clearly seen that the degree of knowledge of predialysis guidelines is very poor among the Spanish nephrologists working in the outpatient clinics of the different centers participating in the OSERCE study.



First, it is notable that the different biochemical parameters were measured less frequently than recommended by current guidelines except in patients with CKD stage 3 and measurement of intact PTH in patients with CKD stage 5. Intact PTH was measured more frequently in patients in stage 3 (PTH was measured yearly in about 30% of patients and two or more times a year in up to 70%) and in stage 5, where PTH was measured in 83% of patients with equal or greater frequency than recommended (33% of patients even had monthly measurement of intact PTH). This frequency was even higher for calcium and phosphorus in patients in stage 3, where more than 90% of patients had measurements in periods of less than 6 months. Obviously, it is well known that stage 3 encompasses a heterogeneous group of patients with kidney function ranging from the upper limit of the definition of CKD (60 ml/min/1.73 m2) to glomerular filtration rates of 30 ml/min/1.73 m2. Some have thus considered it appropriate to divide stage 3 in stage 3A (< 60-45 ml/min/1.73 m2) and 3B (< 45-30 ml/min/1.73 m2) to make this population more homogeneous for follow-up, referral to the specialist or even different therapeutic management.17,25 It is then likely that this frequency of measurement will better match the real needs of these patients than the lax recommendation of the K/DOQITM guidelines. In contrast, calcium and phosphorus levels were measured less frequently than recommended by current guidelines in CKD stages 4 and 5, probably better reflecting not only the different care realities, but also, especially in stage 5, the lack of division of stage 5 between patients on dialysis

(current stage 5D where monthly measurement of patients is logistically feasible) and those who glomerular filtration rate is < 15 ml/min/1.73 m2, but who are not yet in a dialysis program.



It is also notable that 87% of nephrologists did not measure systematically calcidiol levels in their predialysis patients despite the fact that measurement of calcidiol has been recommended since the implementation of the K/DOQITM guidelines, at least for management of hyperparathyroidism in patients with CKD stages 3 and 4.2 This fact has particular relevance if we consider that CKD patients frequently have vitamin D deficiency or insufficiency, sometimes severe,11,23,24 even in our setting,11,24 and that vitamin D is attributed multiple pleiotropic effects and effects on survival that go beyond bone metabolism.26,27 In addition, different vitamin D receptor activators can have different effects on survival.28 In Spain, the easy availability of cholecalciferol or ergocalciferol in the

required doses, as well as the lack of comparative analyses between active forms and native vitamin D has no doubt influenced this observation. Only recently has an article appeared on an observation study analyzing the relationship between differences in early survival in dialysis patients and plasma vitamin D levels in patients treated or not with active forms of vitamin D.29



Of note regarding the K/DOQITM guidelines was the extensive knowledge of treatment goals for PTH in stage 5, where 78% of polled nephrologists had target PTH values between 150-300 pg/ml considered with a grade of evidence in the K/DOQITM guidelines,2 although currently questioned.8,30 In stages 3 and 4, only approximately 40% (36-41%) of nephrologists had the treatment goal for PTH recommended in the guidelines. This observation is important in that different studies have determined the difficulty in complying with K/DOQITM guidelines and the need for new drugs to achieve treatment goals both in patients on dialysis4,31,32 and in predialysis,12,24,33,34,35

but our results provide the new information that not only is there a lack of approved and effective therapeutic agents in predialysis, but also a high degree of unawareness or disbelief of current recommendations. In fact, it can be seen in the analysis of the responses that the most frequent bias was to consider normal in stages 3 and 4 values that are more widely known and which are recommended in the K/DOQITM guidelines for patients in stage 5 on dialysis (for example, phosphorus levels of 3.5-5.5 mg/dl). Strictly inadequate plasma calcium levels were reported by less than 4% of nephrologists. However , there was still nearly 30% of nephrologists whose treatment goal was calcium levels between 9.5-10.2 mg/dl (the limit between desirable calcium and the definition of  hypercalcemia is poorly defined in the K/DOQITM guidelines). Similarly, 38% of polled nephrologists considered hypercalcemia as values > 10.5 mg/dl, whereas only 10% defined hypercalcemia as values > 9.5 mg/dl, thus still reflecting the treatment trends maintained until not long ago.6,36 This finding has recently been documented in the distribution of the results of the DOPPS (Dialysis Outcomes and Practice Patterns Study), where it can be seen that Spain, Germany and Sweden were the only countries in which plasma calcium did not decrease significantly in dialysis patients during its different phases (covering from 1996 to the present).37 Curiously, 90% of nephrologists were knowledgeable of Ca x P recommended values, despite the fact that it is probably the least precise parameter

in control of mineral metabolism, especially in predialysis. 12



It is notable the high percentage of follow-up reported for bicarbonate levels in patients with CKD. Although the bicarbonate levels recommended by the guidelines are clearly defined as greater than or equal to 22 mEq/L, 17% of polled nephrologists accept a slight degree of acidosis. In view of current knowledge, it is likely that the degree of control of acidosis will require revision in the near future.38,39 Finally, it is worth mentioning that a large percentage of nephrologists (72%) uses imaging tests to search for vascular calcification in the diagnosis of CKD-MBD,7 generally tests of low complexity. However, although bone densitometry is not recommended in patients with CKD,7 it is still used by 39% of nephrologists participating in this study.



Our study has several limitations, all related to the relatively small number of nephrologists who completed the questionnaire and the validity that can be given to the results of a questionnaire. To add a measurement of precision, the percentages are accompanied by their respective 95% confidence intervals. Nevertheless, the participants were professionals dedicated especially to CKD not on dialysis or predialysis units. In any case, the results obtained could have shown an even lower degree of knowledge of the K/DOQITM guidelines if nephrologists dedicated to other areas of nephrology had been surveyed. The surveys were conducted in nephrologists from all areas of the Spanish territory, and although random sampling was not performed for selection of participants because the number of CKD or predialysis units is not significantly higher than that included, the data might be representative of the CKD population in Spain. Nevertheless, and with the consequent limitations, the information obtained is of great importance for knowing clinical practices in CKD-MBD.



In summary, these results demonstrate that there is a great degree of unawareness of K/DOQITM predialysis guidelines. Thus, their poor implementation is probably not only due to the lower availability of approved therapeutic agents, but also to unawareness or disbelief of current recommendations. It would be desirable that the recently published new guidelines of the Spanish Society of Nephrology8 or forthcoming international guidelines include not only well-defined information on predialysis patients but also educational efforts on the need for early diagnosis and treatment of CKD-MBD.