|Year : 2014 | Volume
| Issue : 1 | Page : 133-148
|Adaptation and Implementation of the "Kidney Disease: Improving Global Outcomes (KDIGO)" Guidelines for Evaluation and Management of Mineral and Bone Disorders in Chronic Kidney Disease for Practice in the Middle East Countries
Mona Al Rukhaimi1, Ali Al Sahow2, Yousef Boobes3, David Goldsmith4, Jose Khabouth5, Tarek El Baz6, Hisham Mahmoud7, Mohammad Reza Ganji8, Faissal A. M. Shaheen9
1 Dubai Medical College, Dubai, United Arab Emirates
2 Nephrology Unit, Jahra Hospital, Kuwait
3 Nephrology Division, Tawam Hospital, Al Ain, United Arab Emirates
4 Renal Unit, Guy's and St. Thomas' NHS Foundation Hospital, London, United Kingdom
5 Lebanese University, Beirut, Division of Nephrology, Lebanon
6 AlAzhar University, Cairo, Egypt
7 Medical Affairs, SANOFI Middle East, Dubai, United Arab Emirates
8 University of Tehran, Tehran, Iran
9 Saudi Center for Organ Transplantation, Riyadh, Kingdom of Saudi Arabia
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|Date of Web Publication||7-Jan-2014|
| Abstract|| |
This review presents the views of an expert group of nephrologists from the Middle East along with an international expert on adaptation and implementation of the 2009 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for evaluation and management of mineral and bone disorders in chronic kidney disease (CKD-MBD) for practice in the Middle East countries. The members of the panel examined the KDIGO guidelines and formulated recommendations that can be implemented practically for the management of CKD-MBD in the Middle East. There was a broad agreement on most of the recommendations made by the KDIGO work-group. However, the panelists commented on specific areas and amplified certain concepts that might help the nephrologists in the Middle East. The final document was reviewed by all participants as well as by members of the Middle East task force implementation group for KDIGO guidelines. Their comments were incorporated. The guideline statements are presented along with detailed rationale and relevant discussion as well as limitations of the evidence. The panel recognized the need to upgrade the suggestion of KDIGO related to lateral abdominal radiograph and echocardiogram in patients with CKD stages 3-5D into a stronger recommendation. The panel underlined the risk of hyper-phosphatemia to CKD-MBD and the importance of prompt initiation or modification of therapy according to rising trends in parathyroid hormone level. They recommended the use of non-calcium-based phosphate binders as the first-line therapy in CKD patients with signs of vascular calcification. The panel agreed that all aspects of the KDIGO recommendations concerning bone biopsy, evaluation and treatment of bone disease after kidney transplantation should be implemented as such.
|How to cite this article:|
Al Rukhaimi M, Al Sahow A, Boobes Y, Goldsmith D, Khabouth J, El Baz T, Mahmoud H, Ganji MR, Shaheen FA. Adaptation and Implementation of the "Kidney Disease: Improving Global Outcomes (KDIGO)" Guidelines for Evaluation and Management of Mineral and Bone Disorders in Chronic Kidney Disease for Practice in the Middle East Countries. Saudi J Kidney Dis Transpl 2014;25:133-48
|How to cite this URL:|
Al Rukhaimi M, Al Sahow A, Boobes Y, Goldsmith D, Khabouth J, El Baz T, Mahmoud H, Ganji MR, Shaheen FA. Adaptation and Implementation of the "Kidney Disease: Improving Global Outcomes (KDIGO)" Guidelines for Evaluation and Management of Mineral and Bone Disorders in Chronic Kidney Disease for Practice in the Middle East Countries. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2021 Jun 18];25:133-48. Available from: https://www.sjkdt.org/text.asp?2014/25/1/133/124536
| Introduction|| |
Chronic kidney disease (CKD) is a leading cause of morbidity and mortality worldwide, affecting 5-10% of the world population with an ever-increasing prevalence. It is characterized by features that include progressive loss of kidney function, cardiovascular disease (CVD) and premature death.  Disturbances in mineral and bone metabolism (MBM) are well-known complications of CKD that can have a significant impact on morbidity; these complications are often manifested with increased vascular calcification, which is a major risk factor of CVD , and cardiovascular mortality.  The abnormalities in MBM were traditionally included under the heading "renal osteodystrophy." However, the Kidney Disease: Improving Global Outcomes (KDIGO) organization coined the term "chronic kidney disease mineral and bone disorders" (CKD-MBD) covering a wide spectrum of clinical syndromes that manifest as a systemic disorder of MBM due to CKD.  CKD-MBD comprises a group of inter-related abnormalities of serum bio-chemistry  [calcium, phosphorus, parathyroid hormone (PTH), or vitamin D metabolism],  bone (bone turnover, mineralization, volume, linear growth or strength)  and the vasculature (arterial stiffness and calcification)  associated with CKD. 
| Chronic Kidney Disease: Mineral and Bone Disorders and Cardiovascular Disease|| |
Poor bone health and progressive decrease in kidney function is known to increase vascular calcification and adverse cardiovascular out-comes. , Thus, a considerable proportion of CKD-MBD patients, even in the early stages of CKD, are at high risk of developing cardiovascular mortality associated with vascular calcification. , Recently, it has been elucidated that hyper-phosphatemia, which is an inevitable consequence of the gradual decline in renal phosphate excretion, is central to the development of CKD-MBD and its early and late clinical consequences including vascular calcification.  In addition, a new marker, fibroblast growth factor-23 (FGF-23), a bone-derived phosphaturic hormone, has been identified as an inducer of vascular calcification and development of CVD in CKD. 
| Overview of the KDIGO Guidelines|| |
The KDIGO was established in 2003 with a mission to "improve the care and outcomes of kidney disease patients worldwide through promoting coordination, collaboration, and integration of initiatives to develop and implement clinical practice guidelines."  The KDIGO has published clinical practice guidelines based on clinical trial evidence for the diagnosis, evaluation, prevention and treatment of CKD-MBD in 2009. The guidelines were designed to assist the practitioner caring for adults and children with CKD stages 3-5, on chronic dialysis therapy or with a kidney transplant.  The guidelines were aimed at maintaining calcium, phosphate, PTH and vitamin D homeostasis and preventing alterations in bone morphology specific to CKD, while minimizing vascular and soft tissue calcification. The guidelines also emphasized the need to individualize clinical management and base treatment decisions on trends in the patient's test results rather than single laboratory values.  However, due to lack of clinical evidence for clinical targets and practices, the KDIGO guidelines were more generalized, leaving room for the provider and the patient to make judgments and decisions based on the case in question, justifying one of the principles of KDIGO: "think global, act local." 
| Epidemiological Data on End-Stage Renal Disease (ESRD) in the Middle East Countries|| |
End-stage renal disease (ESRD) represents the final stage of CKD with irreversible loss of kidney function requiring renal replacement therapy (dialysis and kidney transplantation) for survival.  Few studies have been conducted on the incidence, prevalence and mortality rate of ESRD in the Middle Eastern countries. The available evidence shows an increasing burden of ESRD, which is consistent with the reported epidemiological data worldwide.  A recent systematic review showed that the leading cause of ESRD in the member countries of the Gulf Cooperative Council was diabetic nephropathy (17%), followed by glomerulonephritis (13%) and hypertensive nephropathy (8%). Hypertension (78%) and infectious diseases like those caused by hepatitis C virus (48%) were the most prevalent comorbid conditions among ESRD patients. The study also showed that approximately 37% and 19% of all reported deaths with known causes among ESRD patients were related to CVD and sepsis, respectively.  Nevertheless, it is important to recognize that most of the studies included in the aforementioned systemic review date back to the early '90s. Figures from the 2011 annual report of the Saudi Center of Organ Transplantation show that diabetic nephropathy accounts for 37.3% and hypertension accounts for 36.1% of ESRD in the Kingdom of Saudi Arabia (KSA). Moreover, findings from another study highlighted that the incidence of ESRD is increasing substantially in the Middle Eastern countries, and that diabetes was the leading cause of ESRD. 
| Physician's Perception Toward CKD-MBD in the KSA|| |
A recent survey by Souqiyyeh et al, which was aimed to determine physicians' perception toward the assessment and management of CKD-MBD patients in Saudi Arabia, showed that physicians were well aware of the morbidity and mortality caused by CKD-MBD. The survey indicated that although the physicians were aware of the current treatment strategies, including vitamin D and phosphate binder therapies, and their indications for management of CKD-MBD, there was inadequate awareness on current prevalence, mechanism and success in managing different aspects of CKD-MBD.  The study suggested that there was inadequate assessment of the results of interventions for CKD, and emphasized the need for more local studies on this subject.
In view of the current status of CKD-MBD in the Middle Eastern countries, a committee of experienced nephrologists from countries across the Middle East was constituted. This committee met thrice between 2011 and 2013 and discussed the adaptability and implementation of the KDIGO guidelines for evaluation and management of CKD-MBD in clinical practice.
This review presents the deliberations of the group along with an international expert who facilitated the discussion and contributed to the development of this document. The members of the panel examined the KDIGO recommendations and formulated recommendations based on their clinical experience and expertise. It is expected that these recommendations will help define practically implementable best practices based on current disease concepts among physicians, available research evidence and economic and logistic constraints prevalent in the region.
There was broad agreement on most of the recommendations made by the KDIGO workgroup. However, the authors commented on specific areas and amplified certain concepts where it was felt that further guidance might help the nephrologists in the Middle East in their appropriate implementation. Recent evidence published between 2009 and 2013 that calls for an analytical re-evaluation of the recommendations provided by the KDIGO workgroup was considered and appropriately incorporated in this manuscript. The final document was sent for review to all participants as well as to members of the Middle Eastern Task Force Implementation Group for KDIGO guidelines, and their comments were incorporated. The key aspects of the final commentary are presented hereafter. In the following section, the recommendation of KDIGO is presented in italicized text and is followed by the expert panel's interpretation and suggestions.
Diagnosis of CKD-MBD: Biochemical abnormalities
- We recommend monitoring serum levels of calcium, phosphorus, PTH and alkaline phosphatase activity beginning in CKD stage 3 (1C). In children, we suggest such monitoring beginning in CKD stage 2 (2D).
- In patients with CKD stages 3-5D, it is reasonable to base the frequency of monitoring serum calcium, phosphorus and PTH on the presence and magnitude of abnormalities and the rate of progression of CKD (not graded). Reasonable monitoring intervals would be: In CKD stage 3: For serum calcium and phosphorus, every six to 12 months; and for PTH, based on baseline level and CKD progression. In CKD stage 4: For serum calcium and phosphorus, every three to six months; and for PTH, every six to 12 months. In CKD stage 5, including 5D: For serum calcium and phosphorus, every one to three months; and for PTH, every three to six months.
- In CKD stages 4-5D: For alkaline phosphatase activity, every 12 months, or more frequently in the presence of elevated PTH. In CKD patients receiving treatment for CKD MBD, or in whom biochemical abnormalities are identified, it is reasonable to increase the frequency of measurements to monitor for trends and treatment efficacy and side-effects (not graded).
- In patients with CKD stages 3-5D, we suggest that 25 (OH)D (calcidiol) levels might be measured and repeated testing determined by baseline values and therapeutic interventions (2C). We suggest that vitamin D deficiency and insufficiency be corrected using treatment strategies recommended for the general population (2C).
- In patients with CKD stages 3-5D, we recommend that therapeutic decisions be based on trends rather than on a single laboratory value, taking into account all available CKD MBD assessments (1C).
- In patients with CKD stages 3-5D, we suggest that individual values of serum calcium and phosphorus, evaluated together, be used to guide clinical practice rather than the mathematical construct of calcium-phosphorus product (Ca x P) (2D).
- In reports of laboratory tests for patients with CKD stages 3-5D, we recommend that clinical laboratories inform clinicians of the actual assay method in use and report any change in methods, sample source (plasma or serum) and handling specifications to facilitate the appropriate interpretation of biochemistry data (IB).
The panel endorsed the above recommendations with a slight modification. Furthermore, the panel discussed and summarized recent data on the role of FGF-23 and KLOTHO as follows:
FGF-23 is a hormone produced by bone osteocytes and osteoblasts. It reduces the expression of sodium-dependent phosphate co-transporters 2a and 2c (NPT2a and NPT2c) in the proximal renal tubules, thereby diminishing phosphate reabsorption and increasing urinary phosphate excretion. , FGF-23 binds to and activates fibroblast growth factor receptor 1 (FGFR 1), which is functional only if co-expressed with the KLOTHO trans-membrane protein, as the KLOTHO-FGF receptor complex. ,
The KLOTHO gene, named after a Greek goddess who spins the thread of life, is a putative aging suppressor gene that encodes the single-pass trans-membrane protein, KLOTHO, expressed predominantly in the kidneys  , and the parathyroid glands.  It should be noted that KLOTHO is expressed much more abundantly in distal convoluted tubules than in proximal tubules, whereas both phosphate reabsorption and vitamin D synthesis take place in the proximal tubules. 
A possible explanation for this discrepancy is that FGF-23 may act first on the distal convoluted tubules and then generate a secondary signal that instructs the proximal tubules to reduce phosphate reabsorption and vitamin D synthesis. FGF-23 also reduces calcitriol (1,25-OH 2 D 3 ) levels by downregulating the expression of the Cyp27b1 gene, which encodes 1α -hydroxylase, the enzyme that synthesizes the active form of vitamin D (l,25-OH 2 D 3 ) from its inactive precursor [25(OH)D3]. , It also up-regulates the expression of the Cyp24 gene that encodes 4-hydroxylase, the enzyme that hydrolyzes and inactivates calcitriol  . Reduced serum calcitriol levels leads to decreased phosphate absorption from the gut  . The parathyroid gland expresses an adequate amount of KLOTHO protein endogenously, indicating that the parathyroid is a target organ of FGF-23, which reduces PTH expression and release. , This enhances FGF-23 activity as a counter-regulatory hormone for vitamin D.  FGF-23 also increases calcium-sensing receptor (CaSR) and vitamin D receptor (VDR) expression on the parathyroid gland. However, CKD patients have secondary hyperparathyroidism (HPT) associated with high serum FGF-23 levels. The possible explanation is that low serum vitamin D levels in CKD may reduce KLOTHO expression not only in the kidney but also in the parathyroid glands, and make these organs resistant to FGF-23.  In CKD, the decline in number of functional nephrons and the decline in KLOTHO expression in these nephrons leads to a progressive rise in the FGF-23 levels as it acts on a resistant kidney. KLOTHO expression declines progressively in CKD. Its decline precedes both FGF-23 increase and hyperphosphatemia.  Plasma FGF-23 levels increase in an attempt to increase phosphate excretion per nephron to maintain normo-phosphatemia in most patients until the glomerular filtration rate falls below 20 mL/min.  The increase in the FGF-23 level occurs earlier and to a greater extent than that observed for serum phosphate, and also precedes the increase in PTH level.  Serum vitamin D levels decrease long before serum phosphate levels increase during CKD progression, possibly as a result of the high FGF-23 levels.  As CKD progresses, elevated FGF-23 levels can no longer increase urinary phosphate excretion, ultimately resulting in increased levels of serum phosphate.  Excess of biologically active FGF-23 ceases to be protective and may lead to pathological off-target effects such as the rapid progression toward end-stage kidney disease (ESKD) and the independent association with left ventricular hypertrophy (LVH) and aortic calcification. Proactive interventions to control serum phosphate may help prevent CKD-related increase in FGF-23 levels. ,
Based on the findings described, the panel decided to include the measurement of FGF-23 in early stages of CKD in countries that can afford to perform the test and endorse the following reasonable monitoring intervals:
- CKD stage 3: Serum calcium and phosphorous every three months; PTH, FGF-23 based on baseline level and CKD progression.
- CKD stage 4: Serum calcium, phosphorous and FGF-23 every three months; PTH once in 12 months unless clinical indications for more frequent estimation occur.
- CKD stages 5-5D: Serum calcium and phosphorous every month; PTH and FGF-23 every three months.
- CKD stages 4-5D: Total alkaline phosphatase every three to six months in stage 4 and every three months in stage 5.
- In those receiving treatment for CKD-MBD or with identified biochemical abnormalities, it is reasonable to increase the frequency of measurements to monitor for trends, treatment efficacy and side-effects. Monitoring of trend rather than affecting abrupt treatment changes based on single values was emphasized, unless the values were clearly abnormal and correlated with the overall clinical picture.
- With respect to vitamin D and its broad pleotropic effect, in addition to its well-known effect on bone and parathyroid gland, the consensus was that a baseline value of 25(OH)D 3 should be obtained and repeated once in 12 months in all stages of CKD or, more frequently, according to the baseline levels.
- The group underlines the importance of the impact of the methodological issues on PTH assays. Proper collection, storage and transport conditions must be ensured. Samples need to be collected properly (in pre-chilled tubes) and transported on ice (especially important during summer months). However, PTH should be measured at diagnosis to establish baseline values.
- As a bone-specific alkaline phosphatase assay is not commercially available, total alkaline phosphatase can be used to guide therapy for high-turnover bone disease. It is also cost-effective.
- Corrected serum calcium levels should be taken into consideration rather than the actual laboratory values. However, use of ionized calcium levels may be necessary in patients with CKD and low total C0 2 and/or plasma albumin levels, as measurement of total calcium may be erroneous in up to 30% of such cases. ,
Diagnosis ofCKD-MBD: Bone
- In patients with CKD stages 3-5D, it is reasonable to perform a bone biopsy in various settings including, but not limited to, unexplained fractures, persistent bone pain, unexplained hypercalcemia, unexplained hypophosphatemia, possible aluminum toxicity and prior to therapy with bisphosphonates in patients with CKD MBD (not graded).
- In patients with CKD stages 3-5D with evidence of CKD MBD, we suggest that bone mineral density (BMD) testing not be performed routinely because BMD does not predict fracture risk as it does in the general population, and BMD does not predict the type of renal osteodystrophy (2B).
- In patients with CKD stages 3-5D, we suggest that measurements of serum PTH or bone-specific alkaline phosphatase can be used to evaluate bone disease because markedly high or low values predict underlying bone turnover (2B).
- In patients with CKD stages 3-5D, we suggest not to routinely measure bone-derived turnover markers of collagen synthesis (such as procollagen type IC-terminal propeptide) and breakdown (such as type I collagen cross-linked telopeptide, cross-laps, pyridinoline or deoxypyridinoline) (2C).
- We recommend that infants with CKD stages 2-5D should have their length measured at least quarterly, while children with CKD stages 2-5D should be assessed for linear growth at least annually (IB).
Currently, the most reliable diagnostic tool as well as the test that helps in the classification of renal osteodystrophy is based on bone biopsies and evaluation of mineralized bone sections after double tetracycline labeling. , A clear understanding of the pathophysiology and course of bone disease, histological findings relative to clinical symptoms of pain and fracture and the effectiveness of treatment is only possible through bone biopsies  . They are strongly indicated when there are inconsistencies in the levels of biochemical markers (e.g., high PTH but low alkaline phosphatase), unexplained bone pain or unexplained fractures. , Although there is no clinical evidence of the efficacy of therapeutic strategies derived from bone biopsy information, data from currently used non-invasive tests (e.g., PTH levels) provide an ambiguous picture of bone turnover and mineralization states, consequently exposing a considerable number of patients to the risk of inappropriate therapeutic choices.  Nonetheless, the paucity of trained nephrologists capable of performing bone biopsy and the difficulties encountered in understanding histologic results in a practical clinical context have hindered the use of bone biopsies, even in developed countries.
Accordingly, the panel agreed with the KDIGO recommendations for bone biopsies and underlined the importance of a special level of expertise in order to interpret the bone biopsies.
Bone density measurements, which predict non-traumatic bone fractures, are of value for diagnosing patients with osteoporosis. They are of less value in patients with CKD-MBD and, thus, not recommended to be performed on a routine basis. Dual-energy X-ray absorptiometry (DEXA) scanning, although widely performed, has significant limitations and values have not been shown to correlate with risk of fracture. Moreover, it is routinely employed without adequate justification, even by non-nephrologists.  Newer imaging techniques such as quantitative computed tomography (qCT), which provides volumetric assessments of bone density and is able to discriminate bone micro-architecture, is an effective tool in assessment of bone strength, being more specific and accurate than DEXA. However, compared with qCT, DEXA is less expensive and is associated with lower absorbed doses of radiation.  Given the choice between the two methods for the assessment of BMD, consideration should be given to the use of qCT over DEXA. ,
Diagnosis of CKD-MBD: Vascular calcification
- In patients with CKD stages 3-5D, we suggest that a lateral abdominal radiograph can be used to detect the presence or absence of vascular calcification and an echocardiogram can be used to detect the presence or absence of valvular calcification as reasonable alternatives to computed tomography-based imaging (2C).
- We suggest that patients with CKD stages 3-5D with known vascular/valvular calcification be considered at highest cardiovascular risk (2A). It is reasonable to use this information to guide the management of CKD-MBD (not graded).
Increased vascular stiffness and vascular calcification are important predictors of cardiovascular mortality in patients with CKD-MBD.  A recent study suggests that both these complications appear early in patients with CKD, but only vascular calcification worsens as the disease progresses.  Given that a large number of the patients with CKD have diabetes and the risk of adverse cardiovascular outcome is high in this group, there is a need for early detection of vascular calcification to ensure early treatment and prevention. In recent years, a number of non-invasive imaging techniques have been developed to quantify vascular calcification,  of which pulse pressure measurement has gained considerable attention. , Vascular calcification leads to increased vascular stiffness that can be identified clinically by a widening of the pulse pressure peak, left ventricular hypertrophy, impaired coronary perfusion and myocardial ischemia.
Early identification of patients who are at risk of coronary artery disease is possible through pulse pressure measurement, as it can identify subclinical coronary artery calcification, which can be prevented through early therapeutic intervention. Adverse clinical outcomes associated with alterations in vessel wall might also be inferred from the results of the high pulse pressure technique. 
The panel agreed that in most places in the Middle East, lateral abdominal radiograph and echocardiogram could be obtained easily and pulse pressure is checked routinely during clinic visits. Accordingly, the panel recommended that all patients with CKD stages 3-5D should be assessed by plain X-ray of the abdomen and echocardiography once every year, while pulse pressure can be recorded on each visit for early detection of stiffness and calcification and, hence, modification of therapy.
Treatment of CKD-MBD targeted at lowering high serum phosphorus and maintaining serum calcium
- In patients with CKD stages 3-5, we suggest maintaining serum phosphorus in the normal range (2C). In patients with CKD stage 5D, we suggest lowering elevated phosphorus levels toward the normal range (2C).
- In patients with CKD stages 3-5D, we suggest maintaining serum calcium in the normal range (2D).
- In patients with CKD stage 5D, we suggest using a dialysate calcium concentration between 1.25 and 1.50 mmol/L (2.5 and 3.0mEq/L)(2D).
- In patients with CKD stages 3-5 (2D) and 5D (2B), we suggest using phosphate-binding agents in the treatment of hyperphosphatemia. It is reasonable that the choice of phosphate binder takes into account CKD stage, presence of other components of CKD MBD concomitant therapies and side-effect profile (not graded).
- In patients with CKD stages 3-5D and hyperphosphatemia, we recommend restricting the dose of calcium-based phosphate binders and/or the dose of calcitriol or vitamin D analog in the presence of persistent or recurrent hypercalcemia (IB).
- In patients with CKD stages 3-5D and hyperphosphatemia, we suggest restricting the dose of calcium-based phosphate binders in the presence of arterial calcification (2C) and/or adynamic bone disease (2C) and/or if serum PTH levels are persistently low (2C).
- In patients with CKD stages 3-5D, we recommend avoiding the long-term use of aluminum-containing phosphate binders and, in patients with CKD stage 5D, avoiding dialysate aluminum contamination to prevent aluminum intoxication (1C).
- In patients with CKD stages 3-5D, we suggest limiting dietary phosphate intake in the treatment of hyperphosphatemia alone or in combination with other treatments (2D).
- In patients with CKD stage 5D, we suggest increasing dialytic phosphate removal in the treatment of persistent hyperphosphatemia (2C).
The panel underlined the risk of hyperphosphatemia as a key contributor to CKD-MBD. Endocrine alterations in response to increased serum phosphorus, individually and collectively, contribute to bone disease, vascular calcification and CVD.  The fact that hyperphosphatemia is a predictor of mortality in patients with CKD stage 5 receiving dialysis, and is attested by data from large epidemiological studies, early phosphate control is warranted in both early- and late-stage CKD to mitigate adverse clinical outcomes.  Evidence from the KSA-DOPPS pilot study indicates the presence of high mean serum phosphorus levels among -40% of patients on hemodialysis in Saudi Arabia. The data clearly showed poorer control of hyperphosphatemia in Saudi Arabia compared with European countries despite a higher percentage of patients being prescribed phosphate binders. In view of these data and other similar unpublished data from the Gulf countries, the group felt that certain issues related to better management strategies for hyperphosphatemia in Middle Eastern countries need to be emphasized.
The KDIGO suggests using phosphate binders for the treatment of hyperphosphatemia in patients with CKD.  For nephrologists, however, the central challenge is the choice of an optimal phosphate binder, especially in relation to addressing the cardiovascular risk in dialysis patients.  There is a paucity of evidence supporting a specific therapeutic choice among phosphate binders.  Evidence regarding the superiority of non-calcium-based binders over calcium-based-binders in controlling hyper-phosphatemia is scarce. However, there is growing evidence indicating the advantage of non-calcium-based binders, e.g., Sevelamer versus calcium-based binders, in regression of vascular calcification.  Other potential benefits of Sevelamer include positive effects on bone turnover, lipid metabolism, hyper-uricemia, inflammation and fetuin-A metabolism, apart from preventing calcium load.  Sevelamer was also shown to significantly reduce glycated hemoglobin and increase anti-oxidant markers, independently of phosphorus, in patients with diabetes and early kidney disease, indicating beneficial effects in the management of diabetic CKD. 
Recently, results from the INDEPENDENT study have suggested that Sevelamer, compared with a calcium-containing phosphate binder, improved survival in a cohort of incident hemodialysis patients.  Additionally, a meta-analysis of 11 randomized trials (4622 patients) showed that CKD patients assigned to non-calcium-based binders had a 22% reduction in all-cause mortality compared with those assigned to calcium-based phosphate binders. 
The panel therefore recommended the use of non-calcium-based phosphate binders as a first-line therapy in all patients with evidence of vascular calcification.
Vascular calcification is also one of the recently revealed side-effects of vitamin K-antagonist (VKA). Matrix Gla protein (MGP) is a vitamin K-dependent protein involved in the inhibition of calcification. VKA treatment inhibits the carboxylation of MGP thus inhibiting its function and thereby accelerating vascular calcification. 
The KDIGO did not report on the role of VKA in accelerating vascular calcification. The panel, after reviewing the recent data, recommended that all patients with CKD stage 3 and above should avoid VKA therapy as much as possible.
New compounds such as factor Xa inhibitors (e.g., rivaroxaban, apixaban) and factor Ha inhibitors (e.g., dabigatran) may provide an alternative to VKA. However, further studies are needed to verify the safety of these new drugs, especially in patients on dialysis, as they are cleared predominantly via the kidney.
Treatment of abnormal PTH levels in CKD-MBD
- In patients with CKD stages 3-5 not on dialysis, the optimal PTH level is not known. However, we suggest that patients with levels of intact PTH (iPTH) above the upper normal limit of the assay are first evaluated for hyperphosphatemia, hypocalcemia and vitamin D deficiency (2C). It is reasonable to correct these abnormalities with any or all of the following: Reducing dietary phosphate intake and administering phosphate binders, calcium supplements and/or native vitamin D (not graded).
- In patients with CKD stages 3-5 not on dialysis, in whom serum PTH is progressively rising and remains persistently above the upper limit of normal for the assay despite correction of modifiable factors, we suggest treatment with calcitriol or vitamin D analogs (2C).
- In patients with CKD stage 5D, we suggest maintaining iPTH levels in the range of approximately two to nine times the upper normal limit for the assay (2C). We suggest that marked changes in PTH levels in either direction within this range prompt an initiation or change in therapy to avoid progression to levels outside of this range (2C).
- In patients with CKD stage 5D and elevated or rising PTH, we suggest calcitriol or vitamin D analogs or calcimimetics or a combination of calcimimetics and calcitriol or vitamin D analogs to be used to lower PTH (2B).
- It is reasonable that the initial drug selection for the treatment of elevated PTH be based on serum calcium and phosphorus levels and other aspects of CKD MBD (not graded).
- It is reasonable that calcium- or non-calcium-based phosphate binder dosage be adjusted so that treatments to control PTH do not compromise levels of phosphorus and calcium (not graded).
- We recommend that in patients with hypercalcemia, calcitriol or another vitamin D, sterol be reduced or stopped (IB). We suggest that in patients with hyperphosphatemia, calcitriol or another vitamin D, sterol be reduced or stopped (2D).
- We suggest that in patients with hypocalcemia, calcimimetics be reduced or stopped depending on severity, concomitant medications and clinical signs and symptoms (2D).
- We suggest that if the intact PTH levels fall below two times the upper limit of normal for the assay, calcitriol, vitamin D analogs and/or calcimimetics be reduced or stopped (2C).
- In patients with CKD stages 3-5D with severe HPT who fail to respond to medical/pharmacological therapy, we suggest parathyroidectomy (2B).
The panel recognized that the iPTH range suggested by the KDIGO (maintaining iPTH levels in the range of approximately two to nine times the upper limit of normal for the assay) for patients with CKD stage 5D is too wide. Therefore, the panel underlined the importance of prompt initiation or modification of therapy according to rising trends in iPTH level, with the aim of keeping iPTH at its lowest level within the given range. Furthermore, the panel recommended that vitamin D deficiency/insufficiency be corrected by natural vitamin D supplementation and, if a high iPTH trend continues, the panel recommended supplementation with vitamin D analogues.
The panel also recommended the use of cinacalcet, a calcimimetic drug, which was shown to effectively reduce the serum PTH levels and allowed favorable management of the serum calcium and phosphorus levels in patients receiving hemodialysis or peritoneal dialysis. ,
A recent study evaluated the efficacy of cinacalcet on the achievement of targets in the treatment of HPT in hemodialysis patients in Saudi Arabia; cinacalcet twice weekly was shown to be safe and effective in suppressing high PTH levels, favoring it to be a suitable regimen for patients in Middle Eastern countries.  However, the EVOLVE randomized trial comparing the effects of cinacalcet and placebo on mortality and cardiovascular events among hemodialysis patients with moderate to severe hyperparathyroidism failed to show significant survival benefits for cinacalcet. 
On the other hand, selective vitamin D receptor activators (VDRA) are thought to interact with VDR at different affinities depending on the cell type, resulting in different levels of VDR activation and up-regulation. A selective VDRA may have a greater effect on VDR in the parathyroid than those in the intestine and bone, resulting in suppression of the parathyroids with minimal impact on serum calcium. Paricalcitol, as a selective VDR activator, has been reclassified by the World Health Organization (WHO) as an anti-parathyroid agent instead of being a vitamin D analogue.  Paricalcitol has been proven to be effective in reducing PTH levels, leading to regression of albuminuria when added to renin-angiotensin-aldosterone system (RAAS) inhibitors in type-2 diabetic nephropathy.  Similarly, treatment with paricalcitol in patients with CKD was shown to reduce left atrial volume index and attenuated the rise in levels of brain natriuretic peptide. 
The panel recommended the use of paricalcitol as another alternative for the treatment of HPT in CKD patients.
Treatment of bone with bisphosphonates, other osteoporosis medications and growth hormone
- In patients with CKD stages 1-2 with osteoporosis and/or high risk of fracture, as identified by World Health Organization criteria, we recommend management as for the general population (1A).
- In patients with CKD stage 3 with PTH in the normal range and osteoporosis and/or high risk of fracture, as identified by the World Health Organization criteria, we suggest treatment as for the general population (2B).
- In patients with CKD stage 3 with biochemical abnormalities of CKD MBD and low BMD and/or fragility fractures, we suggest that treatment choices take into account the magnitude and reversibility of the biochemical abnormalities and the progression of CKD, with consideration of a bone biopsy (2D).
- In patients with CKD stages 4-5D having biochemical abnormalities of CKD MBD, and low BMD and/or fragility fractures, we suggest additional investigation with bone biopsy prior to therapy with anti-resorptive agents (2C).
- In children and adolescents with CKD stages 2-5D and related height deficits, we recommend treatment with recombinant human growth hormone when additional growth is desired, after first addressing malnutrition and biochemical abnormalities ofCKD-MBD (1A).
The panel agreed that all the aspects of the KDIGO recommendations concerning treatment of bone with bisphosphonates, other osteoporosis medications and growth hormone can be accepted as such.
Evaluation and treatment of kidney transplant bone disease
- In patients in the immediate post-kidney-transplant period, we recommend measuring serum calcium and phosphorus at least weekly, until stable (IB).
- In patients after the immediate post-kidney transplant period, it is reasonable to base the frequency of monitoring serum calcium, phosphorus and PTH on the presence and magnitude of abnormalities and the rate of progression of CKD (not graded).
- Reasonable monitoring intervals would be:
- In CKD stages 1-3T, for serum cal cium and phosphorus, every six to 12 months; and for PTH, once, with sub sequent intervals depending on base line level and CKD progression.
- In CKD stage 4T, for serum calcium and phosphorus, every three to six months; and for PTH, every six to 12 months.
- In CKD stage 5T, for serum calcium and phosphorus, every one to three months; and for PTH, every three to six months.
- In CKD stages 3-5T, measurement of alkaline phosphatase annually, or more frequently in the presence of elevated PTH.
- In CKD patients receiving treatment for CKD MBD, or in whom biochemical abnormalities are identified, it is reasonable to increase the frequency of measurements to monitor for efficacy and side-effects (not graded).
It is reasonable to manage these abnormalities as for patients with CKD stages 3-5 (not graded).
- In patients with CKD stages 1-5T, we suggest that 25(OH)D (calcidiol) levels might be measured and repeated testing determined by baseline values and interventions (2C).
- In patients with CKD stages 1-5T, we suggest that vitamin D deficiency and insufficiency be corrected using treatment strategies recommended for the general population (2C).
- In patients with an estimated glomerular filtration rate greater than approximately 30 mL/min/1.73 m 2 , we suggest measuring BMD in the first 3 months after kidney transplant if they receive corticosteroids or have risk factors for osteoporosis as in the general population (2D).
- In patients in the first 12 months after kidney transplant with an estimated glomerular filtration rate greater than approximately 30 mL/min/1.73 m 2 and low BMD, we suggest that treatment with vitamin D, calcitriol, alfacalcidol or bisphosphonates be considered (2D).
- We suggest that treatment choices be influenced by the presence of CKD MBD, as indicated by abnormal levels of calcium, phosphorus, PTH, alkaline phosphatases and 25(OH)D (2C).
- It is reasonable to consider a bone biopsy to guide treatment, specifically before the use of bisphosphonates, due to the high incidence of adynamic bone disease (not graded). There are insufficient data to guide treatment after the first 12 months.
- In patients with CKD stages 4-5T, we suggest that BMD testing not be performed routinely because BMD does not predict fracture risk as it does in the general population and BMD does not predict the type of kidney transplant bone disease (2B).
- In patients with CKD stages 4-5T with known low BMD, we suggest management as for patients with CKD stages 4-5 not on dialysis, (2C).
The panel agreed that all the aspects of the KDIGO recommendations concerning evaluation and treatment of kidney transplant bone disease should be implemented, and suggests adding FGF-23 measurement as recommended for patients with CKD. The panel emphasized that persistent hyperparathyroidism with or without hypercalcemia may be observed in approximately 17-50% of patients at one year after kidney transplantation, and that involution of the parathyroid gland post-transplant may take from few months (if mild) up to several years to reach completion. The panel also emphasized that surgery may be required for refractory cases. Osteopenia and osteonecrosis, the two major osseous complications of renal transplantation, , are believed to be caused by multiple factors including persistent uremia-induced abnormalities in calcium homeostasis and acquired defects in mineral metabolism induced by immunosuppressive medications.  Therefore, the panel recommended measures to prevent and treat post-transplant bone disease, including minimizing the use of glucocorticoids, providing supplemental calcium, treating vitamin D deficiency and encouraging weight-bearing exercise. Use of anti-resorptive agents such as bisphospho-nates should also be considered as recommended by the KDIGO.
| Acknowledgment|| |
Guideline recommendations included in this article were originally published in the Kidney International journal and have been reproduced with permission from the KDIGO.
The manuscript was reviewed by the KDIGO Implementation Task Force-Middle East comprising of the following members: Dr. Essam Khedr (Egypt), Dr. Hassan AlEied (KSA), Dr. Reem Asad (Kuwait), Dr. Sadik AlLawati (Sultanate of Oman), Dr. Antoine Barbari (Lebanon), Dr. Mohammed Ghnaimat, Dr. Riyad Said (Jordan), Dr. Sumaya Gharib (Bahrain), Dr. Bassem Saeed (Syria) and Dr. Abdulkarim AlShaibani (Yemen).
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Mona Al Rukhaimi
Dubai Medical College, P.O. Box 22331, Dubai
United Arab Emirates
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