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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
SPECIAL ARTICLE  
Year : 2014  |  Volume : 25  |  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


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

Click here for correspondence address and email

Date of Web Publication7-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 2020 Oct 30];25:133-48. Available from: https://www.sjkdt.org/text.asp?2014/25/1/133/124536

   Introduction Top


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. [1] 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 [2],[3] and cardiovascular mortality. [4] 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. [5] CKD-MBD comprises a group of inter-related abnormalities of serum bio-chemistry [4] [calcium, phosphorus, parathyroid hormone (PTH), or vitamin D metabolism], [6] bone (bone turnover, mineralization, volume, linear growth or strength) [7] and the vasculature (arterial stiffness and calcification) [8] associated with CKD. [9]


   Chronic Kidney Disease: Mineral and Bone Disorders and Cardiovascular Disease Top


Poor bone health and progressive decrease in kidney function is known to increase vascular calcification and adverse cardiovascular out-comes. [9],[10] 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. [11],[12] 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. [13] 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. [14]


   Overview of the KDIGO Guidelines Top


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." [15] 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. [15] 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. [15] 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." [16]


   Epidemiological Data on End-Stage Renal Disease (ESRD) in the Middle East Countries Top


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. [17] 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. [17] 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. [17] 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. [18]


   Physician's Perception Toward CKD-MBD in the KSA Top


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. [19] 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.

Recommendation 1

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. [20],[21] 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. [22],[23]

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 [25] , and the parathyroid glands. [25] 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. [26]

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]. [27],[28] It also up-regulates the expression of the Cyp24 gene that encodes 4-hydroxylase, the enzyme that hydrolyzes and inactivates calcitriol [29] . Reduced serum calcitriol levels leads to decreased phosphate absorption from the gut [30] . 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. [25],[31] This enhances FGF-23 activity as a counter-regulatory hormone for vitamin D. [26] 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. [26] 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. [32] 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. [33] 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. [34] Serum vita­min D levels decrease long before serum phos­phate levels increase during CKD progression, possibly as a result of the high FGF-23 levels. [35] As CKD progresses, elevated FGF-23 levels can no longer increase urinary phos­phate excretion, ultimately resulting in in­creased levels of serum phosphate. [33] 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. [36],[37]

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. [38],[39]


Recommendation 2

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. [40],[41] 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 [42] . 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. [43],[44] 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. [45] 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. [46] 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. [47] Given the choice bet­ween the two methods for the assessment of BMD, consideration should be given to the use of qCT over DEXA. [48],[49]

Recommendation 3

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. [50] A recent study suggests that both these complications appear early in patients with CKD, but only vascular calcification worsens as the disease progresses. [51] 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, [52] of which pulse pressure measurement has gained considerable attention. [53],[54] 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. [55]

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.

Recommendation 4

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. [56] 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. [57] 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. [15] 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. [57] There is a paucity of evi­dence supporting a specific therapeutic choice among phosphate binders. [16] 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. [58] 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. [59] 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. [60]

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. [61] 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. [62]

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. [63]

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.

Recommendation 5

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. [64],[65]

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. [66] 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. [67]

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. [68] 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. [69] 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. [70]

The panel recommended the use of pari­calcitol as another alternative for the treatment of HPT in CKD patients.

Recommendation 6

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.

Recommendation 7

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, [71],[72] 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. [73] 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.[74]


   Acknowledgment Top


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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Correspondence Address:
Mona Al Rukhaimi
Dubai Medical College, P.O. Box 22331, Dubai
United Arab Emirates
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DOI: 10.4103/1319-2442.124536

PMID: 24434398

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