Clinical Practice Guideline for the Management of Chronic Kidney Disease‐Mineral and Bone Disorder

The kidney plays an important role in the mineral metabolism 1; in addition to being a target organ for various hormones involved in calcium and phosphorus metabolism, the kidney is the main organ that activates vitamin D 2. Thus, it is quite understandable that kidney dysfunction can result in derangement of mineral metabolism. Ever since the first report of severe osteitis fibrosa cystica with parathyroid hyperplasia 3, this disorder was considered to be a skeletal/bone disease and was named “renal osteodystrophy”. The clinical management of renal osteodystrophy, therefore, primarily aimed to maintain parathyroid hormone (PTH) levels appropriate for normal bone metabolism 4. In the last decade, it has become widely accepted that deranged mineral metabolism in patients with chronic kidney disease (CKD) results not only in bone disease, but a higher risk of cardiovascular disease and reduced survival, through the development of vascular calcification. This lead to the proposal of a new concept, “CKD-Mineral and Bone Disorder (CKD-MBD)” 5. CKD-MBD is a systemic condition that manifests as abnormalities in PTH, calcium, phosphorus and vitamin D; bone abnormalities and extraskeletal calcification 5. As a systemic disease, management of these abnormalities should ultimately aim to reduce the risk of cardiovascular events, bone fracture and survival 5. The Japanese Society for Dialysis Therapy (JSDT) clinical practice guidelines for the management of secondary hyperparathyroidism in chronic dialysis patients was originally published in Japanese in 2006, then in English in 2008 6. This guideline put emphasis on improving patient survival and it was one of the first guidelines in this therapy area, preceding the Kidney Disease: Improving Global Outcomes (KDIGO) guideline 7. In this original guideline, we set target ranges for serum phosphorus, calcium, phosphorus, and PTH levels based on survival data of Japanese dialysis patients, and we set an order of priorities for clinical management: management of serum phosphorus levels, management of serum calcium levels, and then control of parathyroid function. In addition, considering that Japanese dialysis patients tend to have a longer dialysis duration than American and European patients, we proposed that parathyroid intervention is to be done at an earlier stage in this population 6. During the last 5 years, this first guideline has considerably contributed to a better understanding and control of secondary hyperparathyroidism in CKD patients by physicians, other medical professionals and by patients themselves 8. However, since its publication, several new therapeutic modalities have become available for Japanese patients, which added more evidence to this area. Thus, we revised the guideline to include several new policies, and the new guideline was published in Japanese in 2012 9. This article contains the new guideline text, and footnotes translated into English. We hope this guideline will be useful for daily practice and will lead to better quality of life and survival in CKD patients. AIn evaluating the results of a laboratory examination, we recommend that information concerning the timing of blood sampling and drug administration, drug adherence, and the measurement method is ascertained (1C). CInitially use the ALP concentration, as a marker of bone metabolism, which is usually measured monthly in regular dialysis practice. Even in this revised guideline, the basic policy of the previous version has been retained; that is, the results of blood examinations measured routinely in regular dialysis practice are utilized, and specific examinations are only performed in accordance with specific situations. The measurements of bone metabolism markers are also limited in daily clinical practice. Because serum ALP levels can substitute for bone ALP levels in patients without hepatobiliary complications and serum ALP is usually measured monthly, it is considered to be reasonable to use serum ALP levels as a first-line test. However, as in previous versions, Payne's equation was adopted in the present guideline for three reasons. First, this equation has been accepted widely in many fields, including dialysis medical care, for several decades in Japan. Second, this equation is simple because it does not need to multiply 0.8. Third, there are not significant differences in the serum corrected calcium levels calculated by each of the two equations 13. It should be noted that correction by serum albumin is important to avoid overlooking hypercalcemia modified by hypoalbuminemia. Laboratory test results can be affected by various factors. For example, serum calcium levels change according to timing of blood sampling (because of the circadian rhythm and the effects of hemodialysis such as water removal), and medical treatments can affect blood calcium levels. In particular, because serum calcium and PTH levels decrease from 4 to 8 h after cinacalcet hydrochloride administration 14, 15, it is important to ascertain the timing of blood sampling and drug administration, and drug adherence. For PTH measurement, intact PTH assays are mainly used, as recommended in the previous guideline (see Chapter 3). There are several commercially available kits that measure intact PTH with second-generation assays, but measurement variability between kits can occur depending on whether the samples are serum or plasma as well as the measurement bias by the kit 16, 17. Thus, the modality of assay, including sample collection, is a significant concern, and we recommend taking this information into account when evaluating intact PTH levels. In addition, adequate dialysis, appropriate protein intake based on the nutrition status, and appropriate phosphorus binder administration should also be confirmed, as these factors are essential for the evaluation and management of serum phosphorus and calcium levels. We recommend that evaluation of a patient's condition and determination of therapeutic plans should be based on the trends of several measurements, not by a single result of a laboratory test. In evaluating parathyroid function using PTH levels, progression to secondary hyperparathyroidism can be predicted when PTH levels remain at a high level or increase continuously, even within the normal range. Additionally, mortality may increase and complications such as cardiovascular calcification will develop if serum phosphorus and calcium levels persist around the upper limit of the target range 18, 19. In such a case, we suggest that treatment plans are changed, even if the test results are within the normal range. With regard to the timing of blood sampling for patients who have a typical thrice weekly dialysis prescription; serum phosphorus and calcium levels are higher at the beginning of the week, being affected by food intake and removal by dialysis sessions 20. In particular, serum phosphorus levels are significantly higher when measured 3 days after dialysis than those measured midweek 20. Because it is the convention in Japan that blood sampling is done at the beginning of the week; in other words, from the first dialysis session in each week, it is reasonable to use the blood sampling results obtained at this moment for the evaluation of CKD-MBD. The frequency of measuring serum phosphorus and calcium levels is described as monthly in the 2003 KDOQI guideline, and every 1–3 months in the 2009 KDIGO guidelines. It is reasonable for the frequency to be set for the purpose of monitoring the efficacy of treatment and/or adverse events, caused by deviation from the target ranges, although there is currently no clinical evidence that the frequency of measurement is associated with patient mortality. However, if the measurement interval is extended, there may be a risk of inadequate monitoring. In particular, serum phosphorus and calcium levels will vary with a meal; thus, we consider that statements that suggest making treatment adjustments, based on a single laboratory measurement value that is measured only once a month, are not acceptable. We consider that it is reasonable to measure serum phosphorus and calcium levels at least 1–2 times a month, considering clinical practice in Japan. However, more frequent measurements of serum phosphorus and calcium are suggested under circumstances when these levels deviate, or are likely to deviate, markedly from target ranges, when initiating therapy, changing the dose and/or discontinuing treatment with intravenous VDRA and/or cinacalcet hydrochloride; or when patients undergo parathyroid interventions, such as PTx or selective percutaneous ethanol injection therapy (PEIT). The recommended measurement frequency of PTH levels is once every 3 months in this guideline. Although the frequency in the KDIGO guideline is set at every 3–6 months, which is longer than in this guideline, the long-term control of PTH levels and monitoring of parathyroid function over time are essential in Japan where there are many dialysis patients with a long dialysis vintage. Thus, we suggest that intact PTH be usually measured once every 3 months, but be measured monthly until the values stabilize if the PTH values deviate from the target range, there is a change in therapy or the patient is taking active therapy (intravenous VDRA, cinacalcet hydrochloride, or parathyroid interventions) as treatment for secondary hyperparathyroidism. AWhen serum phosphorus levels are high, we suggest to ensure that the dialysis dose is adequate and instruct the patient to reduce intake of dietary phosphorus (2D). If malnutrition is thought to be the cause of hypophosphatemia, we suggest to try to improve patient's nutritional status (2C). BDecreasing the dose of or discontinuation of calcium carbonate (CaCO3) is suggested if the patient is likely to develop hypercalcemia, when significant vascular calcification is seen, if adynamic bone disease is suspected, or if a low PTH level persists (2C). CWhen hypercalcemia or hypocalcemia is prolonged, we suggest to consider changing the calcium concentration of dialysate (2D). DWhen cinacalcet hydrochloride is to be started, we suggest that the corrected serum calcium concentration is ≥9.0 mg/dL (2D). Control of phosphorus and calcium during treatment. Nine example clinical scenarios (1–9) show how serum phosphorus and corrected serum calcium levels can be used to guide the selection of a therapeutic modality. ↑ = start or increase of treatment and ↓ = reduction or suspension of treatment where serum parathyroid hormone (PTH) is high* and low**. CaCO3, calcium carbonate; Cinacalcet, cinalcalcet hydrochloride; NCPB, non-calcium-containing phosphorus binder (calcium-free phosphorus binder); VDRA, vitamin D receptor activators. Guidance notes Classifying the serum levels of phosphorus and calcium. Classify the serum levels of phosphorus and calcium using the following 9 patterns to select the appropriate treatment: 1. Serum phosphorus levels ≥target range. Irrespective of the serum calcium levels; a sufficient dialysis dose should be ensured, and dietary advice should be given to limit the intake of phosphorus. Then select the appropriate treatment for hyperphosphatemia based on the serum calcium levels. High serum calcium levels (1)† Confirm that CaCO3 is being taken orally during meals or immediately afterward. Dose reduction or discontinuation of CaCO3 and/or VDRA administration (switch to or increase the dose of a calcium-free phosphorus binder, such as sevelamer hydrochloride or lanthium carbonate). When serum PTH levels are high, consider starting/increasing the dose of cinacalcet hydrochloride. Serum calcium within the target range (2) Confirm that CaCO3 is being taken orally during meals or immediately afterward. Commence treatment with or increase the dose of a calcium-free phosphorus binder and/or CaCO3 administration. Reduce the dose of or discontinue VDRA. When serum PTH level is high, consider starting/increasing the dose of cinacalcet hydrochloride. Low serum calcium (3)† Confirm whether oral CaCO3 is actually being taken. Commence treatment with or increase the dose of CaCO3 and/or a calcium-free phosphorus binder. When serum PTH level is low, reduce the dose or discontinue cinacalcet hydrochloride. In addition, ensure that a serum phosphorus binder is administered. 2. Serum phosphorus is within the target range High serum calcium (4)† Dose reduction or discontinue CaCO3 (switch to a calcium-free phosphorus binder). Reduce the dose or discontinue VDRA. When the serum PTH level is high, commence treatment with or increase the dose of cinacalcet hydrochloride. Serum calcium within the target range (5) Continue the current treatment and optimize the PTH level. Low serum calcium (6)† Commence treatment with or increase the dose of CaCO3 (administration between meals). Commence treatment with or increase the dose of VDRA. When serum PTH level is low, consider reducing the dose or discontinuing cinacalcet hydrochloride. 3. Serum phosphorus ≤target range Confirm whether food intake is sufficient and whether the nutritional state is poor, irrespective of the serum calcium level. If malnutrition exists, correct this. High serum calcium (7)† Reduce the dose or discontinue CaCO3/calcium-free phosphorus binder. Reduce the dose or discontinue VDRA. Serum calcium level within the target range (8) Reduce the dose or discontinue CaCO3/calcium-free phosphorus binder. Commence or increase the dose of VDRA. Low serum calcium (9)† Reducing the dose or discontinue calcium-free phosphorus binder. Commence treatment with or increase the dose of CaCO3 given between meals, or commence treatment with/increase the dose of VDRA. When the serum PTH level is low, reduce the dose or discontinue cinacalcet hydrochloride. †If hypercalcemia or hypocalcemia persists even after the above treatment, identify the cause and consider adjusting the calcium concentration of dialysis fluid. Differentiation between vitamin D receptor activators (VDRA) and cinacalcet hydrochloride when parathyroid hormone (PTH )levels are high. When cinacalcet hydrochloride is to be started, we suggest that the corrected serum calcium concentration is ≥9.0 mg/dL (2D). One of the main characteristics of CKD-MBD, according to the 2003 KDOQI guideline, is that abnormal calcium/phosphorus metabolism in renal patients is not just associated with bone disease. CKD-MBD is also related to clinically significant vascular calcification and an increased risk of mortality 4. In the present JSDT guidelines, the serum phosphorus and calcium target ranges are based on patient prognosis, and recommendations are made regarding the treatment and doses to use for maintaining serum phosphorus/calcium concentrations at appropriate levels. A number of reports have been published concerning the validation of target ranges for serum phosphorus and calcium concentrations 18, 21-30. These studies, mainly from the Western world have largely used mortality as a primary endpoint. In this 2012 JSDT guideline, we define target serum phosphorus/calcium ranges according to the results of an analysis of data from the JSDT patient registry, where patients were treated in accordance with the previous JSDT guideline 6, 31. Following publication of the previous 2008 guideline 6, awareness about CKD-MBD has increased in Japan, and new drugs, such as cinacalcet hydrochloride and lanthanum carbonate, have been listed in Japan's National Health Insurance formulary. Accordingly, data from 128 125 dialysis patients, who could be monitored from the end of 2006 to the end of 2009, were analyzed 32. In addition to analysis of the previous baseline model (B) (with a 3-year life expectancy), time-dependent (TD) and time average (TA) models were used to set target levels for serum phosphorus/calcium and PTH, using mortality as an endpoint. Based on this analysis, we have set a target range for serum phosphorus of 3.5–6.0 mg/dL. The dialysis serum phosphorus range was set at 3.5–5.5 mg/dL in the KDOQI guideline, while the new 2009 CKD-MBD KDIGO guidelines 7 recommended that the serum phosphorus level should be lowered if higher than the reference level. We derived the target level by stratifying serum phosphorus levels in our dataset, and this analysis produced a J-shaped curve: mortality being increased with both hyperphosphatemia and hypophosphatemia. When P < 0.01 was used to indicate statistical significance, the recommended target level range was 3.6–5.0 mg/dL for model B, 4.1–6.0 mg/dL for model TD, and 4.1–5.5 mg/dL for model TA. When a hazard ratio (HR) of >1.2 was considered statistically significant, the recommended range was 3.1–6.0 mg/dL for model B, 3.6–6.5 mg/dL for model TD, and 4.1–6.0 mg/dL for model TA. Model TD characteristically reflects a relatively short-term prognosis, whereas model TA reflects a relatively long-term prognosis. Regardless of the differences between models, the results were generally similar, and, therefore, we continue to recommend that the serum phosphorus target range should be between 3.5–6.0 mg/dL, in accordance with the previous guidelines 6. We recommend that the target range for serum calcium should be between 8.4–10.0 mg/dL. The KDOQI guideline states that serum calcium levels should be from 8.4–9.5 mg/dL, while KDIGO states that the target should be within the normal range. Serum calcium levels were validated in the same way as phosphorus levels; when the significance level was set at P < 0.01, the recommended range was determined to be ≤9.0 mg/dL for model B, ≤9.0 mg/dL for model TD, and 8.6–9.5 mg/dL for model TA. When a HR of >1.2 was considered statistically significant, the recommended range was ≤10.0 mg/dL for model B, ≤9.0 mg/dL for model TD, and 8.1–10.0 mg/dL for model TA. Unlike with serum phosphorus concentrations, the risk of mortality increased in a linear pattern for both models B and TD. There is still scope for discussion concerning the elimination of the lower limit, and based on the J-shaped curve from modeled TA results and the reference level for healthy people, we consider that 8.4–10.0 mg/dL should be used as the target level, in accordance with the previous guidelines 6. Nevertheless, this statistical validation using data from the JSDT patient database indicate that serum calcium concentrations in patients on dialysis should be maintained at the lowest possible. This guideline clearly recommends that control of serum phosphorus should have the highest priority, followed by that of calcium, and then that of PTH. Previous reports showed that appropriate control of serum phosphorus and calcium levels resulted in a better prognosis than control of PTH alone 26, 33, 34. However, it was not clear whether serum phosphorus or calcium levels should have a higher priority. We projected the 3-year prognosis for different combinations of serum phosphorus, calcium, and PTH that reached the target levels specified in the earlier guidelines 6, and found that a good prognosis would be obtained using the following parameters: [attainment of target for serum phosphorus, calcium, and PTH] > [serum phosphorus and calcium] > [serum phosphorus only] > [calcium only] > [PTH only] > [target not attained for any for the three variables]. Therefore, based on these observations, we recommend that the target priorities should be: serum phosphorus, then calcium, and then PTH. We also suggest that the serum levels of serum phosphorus and corrected calcium should be controlled first, and then the VDRA or cinacalcet hydrochloride doses should be adjusted to keep serum PTH levels within the target range. From the previous guidelines, the 9-section chart (Fig. 1) has been adopted as a treatment tool for keeping serum levels of serum phosphorus and calcium optimal. In each of the nine categories shown in Figure 1, the method for adjusting the dose to keep serum phosphorus/calcium levels in the target range is provided. To validate the recommendations published in the previous guideline, we used the same JSDT patient registry dataset to project the 3-year prognosis for patients in each of the nine categories. The results showed that the risk of mortality decreased in the group with normal serum calcium/phosphorus levels and in the group with normal serum phosphorus plus low calcium levels. These findings indicate that the prognosis improves when both serum phosphorus and calcium are kept within the target range. When we examined the relationship between the frequency of attaining target serum phosphorus/calcium levels and prognosis from 2006 to the end of 2008, we found that the more frequently the target level is attained, the lower is the mortality risk. This suggests that constant maintenance of serum phosphorus/calcium levels within the target ranges leads to improvement in life expectancy. Based on these findings, we recommend prompt treatment change when the serum phosphorus or corrected calcium levels are constantly high. In accordance with Figure 1, and as discussed earlier in Chapter 1, when serum phosphorus levels are high we suggest that a sufficient dialysis dose is ensured and that patients are instructed regarding dietary phosphorus restriction. Also, it is important to assess a patient's nutritional state, including the amount of food eaten, when serum phosphorus levels are low. However, caution is advised with regard to excessive phosphorus restriction. As the intake of phosphorus strongly correlates with the amount of protein intake, excessive phosphorus restriction may induce malnutrition and exacerbate the mortality risk. In this regard, it is important to reduce the consumption of significant amounts of phosphorus-rich food, including dairy products, small fish, as well as products with phosphorus-containing additives/preservatives, such as processed food, instant food, confectionary, and pre-packaged convenience store lunches. Once these precautions are taken, we suggest that pharmacologic therapy should be started to control the mineral parameters in the following order of priority: serum phosphorus, calcium, and PTH. In cases with high serum phosphorus levels, the start/increase of a phosphorus binder should be considered, and VDRA should be reduced/suspended depending upon the patient. When a phosphorus binder is prescribed, patient be it is important to in that are more when taken at specific as shown in and 3. For according to sevelamer hydrochloride should be taken a and CaCO3 and lanthanum carbonate should be taken immediately after a As the efficacy of CaCO3 is by of a may the efficacy carbonate, a should be and if an the it should be and If the serum phosphorus level is low, of phosphorus binder should be considered, and starting/increasing VDRA should be considered in to cause hypercalcemia with is by of a adverse than other not calcium to progression of vascular calcification effects including and not calcium and other evidence for long-term administration be taken at the same time each is taking into account that the PTH level is lowest at 4 to 8 h after administration and that the calcium level is lowest at 8 to h after administration the drug when the calcium level is mg/dL When serum calcium levels are high, dose of VDRA and/or CaCO3 are When a high measured PTH level is or the dose of cinacalcet hydrochloride should be If hypercalcemia the for the of including low should be and a change in the calcium concentration in the dialysate should be When the serum calcium level is low, treatment the dose of VDRA and/or CaCO3 should be and if cinacalcet hydrochloride is being the dose may need to be of CaCO3 between meals is also because it the serum calcium level The addition of cinacalcet hydrochloride to this 9-section chart is a change from the previous guideline. Although cinacalcet hydrochloride is mainly used to PTH, it is in the cases in which the PTH level is high because cinacalcet hydrochloride serum phosphorus/calcium levels and PTH control and serum phosphorus/calcium control are In other words, cinacalcet hydrochloride as a method to control the serum calcium or phosphorus level is for patients with high serum PTH levels. Nevertheless, there are several precautions to be taken when cinacalcet hydrochloride. First, when the drug is to be it is reasonable for the corrected calcium level to be maintained ≥9.0 mg/dL in order to avoid excessive Second, any should into account that the PTH level is lowest 4 to 8 h after cinacalcet administration, and the calcium level is lowest 8 to h after cinacalcet administration 14, Figure how to the use of VDRA and cinacalcet hydrochloride for secondary hyperparathyroidism on the 9-section When the PTH level is high and serum phosphorus or calcium is normal to high, administration of cinacalcet is to be considered, and administration of VDRA is to be when serum phosphorus or calcium is normal to low. kidney should be considered not only as a tool for serum phosphorus/calcium but also from a prognosis A number of of dialysis patients indicate that VDRA is associated with lower mortality from of serum levels a low level of D a hormone of active vitamin is a significant mortality risk even in healthy dialysis patients hemodialysis have and the active of vitamin D VDRA may be long as the serum phosphorus/calcium levels not show a significant As shown in and VDRA may be used of PTH levels. hydrochloride is to progression of vascular calcification and improve prognosis because it can lower serum levels in the of the result of showed that the risk for vascular was reduced in cinacalcet hydrochloride a that cinacalcet hydrochloride was associated with a low risk for mortality the Therapy to a controlled is The primary is the time to of such as mortality or cardiovascular As for on serum phosphorus an of patients started on hemodialysis showed that the risk of mortality was lower in patients treated with phosphorus than in those not treated with phosphorus In accordance with the previous guidelines, it is reasonable to consider the appropriate upper limit for CaCO3 administration to be around 3 which for the of excessive calcium to the number of reports on phosphorus as there are more that sevelamer hydrochloride progression of vascular calcification therefore, we suggest to the dose of CaCO3 in patients. of CaCO3 may be considered when hypercalcemia is likely to when there is vascular bone disease is suspected, or when the blood PTH level is constantly low. In addition, to a calcium-free phosphorus binder is reports on lanthanum carbonate are available with regard to prognosis and vascular calcification and therefore, long-term results and data need to be each phosphorus binder has different there is no regarding which phosphorus binder is for improving prognosis It is not which calcium concentration in dialysate should be or KDIGO states that a calcium level between and is reasonable 7. We suggest to the dialysate calcium level as a method for the serum calcium level should be done in patients who have hypercalcemia or With a dialysate the serum calcium concentration can be kept at a relatively low level, making administration of VDRA and/or CaCO3 relatively although the PTH level is likely to increase and blood during dialysis may become using