Chronic Kidney Disease - Mineral Bone Disease (CKD-MBD) in Adults Information at Expert Level. Dr. BC Storey MB ChB MRCP DTM&H

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1 Expert Level European Dialysis and Transplant Nurses Association/ European Renal Care Association Chronic Kidney Disease - Mineral Bone Disease (CKD-MBD) in Adults Information at Expert Level. Dr. BC Storey MB ChB MRCP DTM&H Learning outcomes 1. To understand the mechanisms of the homeostatic control of Calcium, Phosphate, Vitamin D and Parathyroid hormone (PTH) 2. To gain knowledge of the disparate consequences of CKD-MBD and understand the spectrum of disease states in CKD-MBD with the KDIGO turnover, mineralisation and volume or TMV system 3. To understand the therapeutic options for improving CKD-MBD parameters with drugs, diet, dialysis prescription and surgery with knowledge of international guidelines 4. To gain knowledge of the post-transplant considerations in CKD-MBD advancing renal failure the system struggles and the biochemical and clinical consequences of CKD-MBD ensue. The main hormones involved are activated vitamin D 3, PTH and fibroblast growth factor 23 (FGF-23). These are discussed in more detail in Figure 1. Vitamin D has various forms or vitamers and this can make the nomenclature confusing. There are two major forms, vitamin D 2 (ergocalciferol) and vitamin D 3 (cholecalciferol). Combined they are called calciferol. Dropping the numerical subscript refers to these two main forms. Figure 1 details the names. Figure 1: Different names and hydroxylation of Vitamin D Collective Term Vitamin D 2 Vitamin D 3 Vitamin D Ergocalciferol Cholecalciferol Calciferol Introduction Chronic kidney disease mineral bone disease (CKD-MBD) is a universal consequence of advanced kidney failure and emphasises the kidneys central role in the complex homeostatic process of calcium and phosphate. CKD-MBD is defined as a systemic disorder of mineral and bone metabolism due to CKD by either one or a combination of the following: 1 1. Abnormalities of calcium, phosphorous or vitamin D metabolism 2. Abnormalities in bone turnover, mineralisation, volume, linear growth or strength 3. Vascular or other soft tissue calcification Poor CKD-MBD control leads to vascular calcification, left ventricular hypertrophy and is an independent risk factor for all-cause mortality. LIVER (after 1 st Hydroxylation) LIVER (after 1st Hydroxylation) 25-hydroxyvitamin D 2 25-hydroxyvitamin D or 3 or 25(OH)D 25(OH)D 3 2 Ercalcidiol KIDNEY (after 2 nd Hydroxylation) 1,25 Di-hydroxyvitamin D 2 or 1,25(OH 2 )D 2 Ercalcitriol Calcidiol KIDNEY (after 2 nd Hydroxylation) 1,25 Di-hydroxyvitamin D 3 or 1,25(OH 2 )D 3 or Activated vitamin D 3 Calcitriol 25-Hydroxyvitamin D or 25(OH)D 1,25-Di-hydroxyvitamin D or 1,25(OH 2 )D Mechanisms of Homeostatic Processes The kidney, skeleton and parathyroid gland are the principle organs involved in calcium and phosphate homeostasis. The skeleton houses rich sources of calcium and phosphate. Activated vitamin D in conjunction with the parathyroid hormone (PTH) can mobilise these stores if required. Various feedback mechanisms try and maintain a physiological balance but with Serum 25(OH)D 3 is considered the best form of vitamin D to measure as it measures both nutritional and dietary intakes and has a long half-life of~3 weeks. It informs clinicians whether patients have vitamin D deficiency or not. The recognised classification is as follows: >75nmol/l = Replete nmol/l = Insufficiency <37.5nmol/l = Deficient Dr. BC Storey MB ChB MRCP DTM&H 1

2 Since Hollick et al 2 estimated that vitamin D insufficiency or deficiency affected 1 billion people worldwide, fervent work has been conducted on the disparate roles, outside bone metabolism, that vitamin D plays. This includes endocrine, immunological and endothelial functions 3,4,5,6. Increased knowledge gained from this basic science and epidemiological data, better informs the renal community of the merits of adequate vitamin D replacement. Activated vitamin D 3 (1,25-dihydroxyvitamin D 3 ) or calcitriol is predominantly formed from UV light. The skin after being exposed to UV light converts 7-dehydrocholesterol to previtamin D 3. This then undergoes rapid conversion and isomerisation to vitamin D 3 or cholecalciferol. Dietary precursors of vitamin D 2 and vitamin D 3 account for ~ 10% of the total intake with UV light dominating at 90%. After the skin and gastrointestinal vitamin D combine, they firstly go to the liver where a hydroxyl side group at position 25 (25-OH) is added. The kidney adds another hydroxyl group at position 1, with the enzyme 1ɑ-hydroxylase. 1ɑ-hydroxylase conversion is the rate limiting and final step before calcitriol or activated vitamin D 3 is produced. (See Figure 2). Calcitriol increases serum calcium levels by increasing calcium uptake from the gut, mobilising calcium from bone and increasing the reabsorption of calcium in the tubular structures of the kidney. Calcitriol works in conjunction with PTH to raise serum calcium levels. See Figure 3. Figure 2: Synthesis of Activated Vitamin D3 Sunlight 7-dehydrocholesterol converted to Calciferol (inactive vitamin D3) in the skin Around 90% LIVER Conversion to 25-Hydroxyvitamin D2 (ercalcidiol) and 25-hydroxyvitamin D3 (calcidiol) with the addition of hydroxyl side group at position 25 KIDNEY With the action of 1α-hydroxlyase 25(OH) Vit D converted to 1,25-dihydroxyvitamin D Diet Absorption of inactive Vitamin D2 (ergocacliferol) and Vitamin D3 (cholecalciferol) Around 10% In patients with CKD the ability of 1ɑ-hydroxylase to continue its addition of a side group is reduced. This is combined with the increasingly scarred kidneys becoming less able to excrete enough phosphate in the urine, causing the serum levels to climb. The metabolic milieu of uraemia impacts other parts of vitamin D production 7. The ability of the skin to convert 7-dehydrocholesterol to cholecalciferol is impaired. Urinary loss of vitamin D binding protein, (the protein that carries 25, vitamin D to the kidney) is compounded in heavily proteinuric states. Parathyroid Hormone Parathyroid hormone (PTH) is an 84 amino acid which is secreted from the chief cells of the parathyroid gland generally situated behind the thyroid gland in the neck. In response to low serum calcium, through its calcium sensing receptors, it increases the production and secretion rate of PTH. Secondary hyperparathyroidism (SPTH) is a common and early consequence of progressive CKD with guidelines suggesting that it should be tested and managed from an early as an egfr <60ml/min. 1 PTH enhances the release of calcium from the bone stores, feeds back to the kidney to reabsorb more calcium in its tubular structures and increases urinary phosphate loss. It also up regulates the actions of 1ɑ-hydroxylase to help increase calcium, via vitamin D, absorption from the intestine Fibroblast Growth Factor-23 Fibroblast growth factor 23 (FGF-23) is the main regulator of phosphate metabolism whose impact and influence in the overall homeostatic control of phosphate has only relatively recently been recognised. The majority of FGF-23 is derived from the bone. It has a co-factor, Klotho, which is expressed on the parathyroid glands and the distal tubules of the kidney. Even in the infancy stages of CKD significant increases of FGF-23 are observed. FGF-23 rise well before calcium and phosphate levels change 8. FGF-23 acts on the kidney to produce a net urinary phosphate excretion. This is achieved by down regulating the activity of 1ɑ-hydroxylase. This tends to aggravate SPTH. In CKD patients high FGF-23 levels has been associated with progressive renal disease 9 and altered skeletal mineralisation of bone 10. It is also another independent risk factor for mortality in CKD patients 11. The interaction of PTH, vitamin D and FGF-23 is summarised in Figure 3 Figure 3: Summary Actions of main regulators of the serum calcium/phosphate Activated Vitamin D (Calcitrol or analogue) 1. Central Integrator for calcium, phosphate and skeletal homeostasis 2. Works in conjunction with PTH to mobilise calcium from bones when hypocalcaemic 3. Reduces PTH level 4. Promotes intestinal calcium and phosphate absorption PTH 1. Mobilises calcium from bone stores in conjunction with Vitamin D 2. Increases calcium absorption in the kidney 3. Reduce phosphate reabsorption in kidney 4. Increases production of activated of Vitamin D FGF Main regulator of serum phosphate levels 2. Secreted by the bone in response to elevated calcitriol levels 3. Increases excretion and decreases reabsorption of phosphate in kidneys 4. High levels contribute to SHPT 2 Dr. BC Storey MB ChB MRCP DTM&H

3 Bone Components Mature osteoblasts secrete collagen and bone matrix proteins which fill the bone trabecular. They are bone formers. They mature from mesenchymal stem cells in the bone marrow under the control of a various transcription and growth factors. 12 Osteoclasts are bone absorbers. They originate from blood based, haematopoietic stem cells and are from different lineage from osteoblasts. Excessive bone resorption leads to osteoporosis. Bisphosphonates are the most common drug which inhibit osteoclasts and are most commonly used in preventing fractures but they are unfortunately contraindicated in patients with an egfr of <30ml/min. When osteoclasts are underactive and not resorbing enough bone then patients can develop osteopetrosis, from relatively unopposed osteoblastic activity. Consequences of CKD-MBD CKD-MBD is generally an asymptomatic condition with only the extremes of its disease spectrum causing frank symptoms. General aches and pains are common and rather nonspecific and typically occur in weight bearing areas. Patients CKD-MBD parameters are in constant flux and should not be seen as a static entity. The parathyroid gland, (generally 4 glands) is located behind the thyroid gland in the neck. It recognises hypocalcaemia via its calcium sensing receptors (CaSR) which promotes a complex process of PTH gene expression and synthesis inside the gland. PTH secretion rises in response to low serum calcium, high phosphate and ineffectual or low vitamin D levels. In CKD, patients who are by definition also partially uraemic the whole regulatory system is changed and the normal feedback loops are lost 14. The regulatory feedback loops are depicted below: Skeletal and Extra-skeletal Calcification Peri-articular deposition of calcium and phosphate gives rise to arthritic symptoms. Other extra-skeletal calcifications can occur in any organ or tissue but the deposition on heart valves and within the vasculature seem to be of particular significance 15,16. Deposition within the peripheral vasculature reduces the compliance of the arteries and speeds up atherosclerosis, aggravating the cardiovascular risk burden of people with CKD 17. Vitamin K s role in the calcification of the arterial media is now well established but its precise interplay with CKD-MBD remains unclear. 18 Figure 5 illustrates the extra-skeletal calcium deposition Hyperparathyroidism The classical biochemical consequence of CKD-MBD is SPTH, where there is low calcium, high phosphate and high PTH levels. This is typically managed by calcium containing phosphate binders and vitamin D replacement. The four glands of the parathyroid respond by growing in size (hypertrophy) with increasing density (hyperplasia) and producing more PTH. 13 Tertiary hyperparathyroidism (3 o hpth) occurs when the parathyroid gland loses the feedback mechanisms and moves into a state where despite normal or high normal calcium levels, which would ordinarily slow or stop the production, it continues to produce PTH unabated. This generally results in hypercalcaemia, hyperphosphatemia and a high alkaline phosphatase (ALP) reflecting the high bone turnover. As severe hyperparathyroidism ensues, bone deformities can develop and lead to fractures with impaired healing; impacting on patients level of function and mobility. Ostetitis fibrosa is characterised by both over active osteoclasts and osteoblasts and gives rise to sub periosteal erosion and variable degrees of peri-trabecular fibrosis. Figure 5: Florid Soft tissue calcification. Note the numerous calcified small and large vessels to the skin in this thigh. This predisposed to calciphylaxis. Note the hemiarthroplasty from a previous hip fracture. Figure: 4: The cycle of development of 2HPT which is often visible on plain X-rays. PTH secretion increases with gland hypertrophy and hyperplasia Hypocalcaemia Reduced Intestinal Calcium absorption Reduced sensitivity of parathyroid gland to hypocalcaemia aggravated by metabolic milieu of CKD Reduced synthesis of 1, 25 Vitamin D3 Hyperphosphataemia Dr. BC Storey MB ChB MRCP DTM&H 3

4 Calciphylaxis, otherwise known as calcific uraemic arteriolopathy (CUA) deserves a particular mention. When calcium deposits in smaller vessels it can cause critical ischaemia of the distal tissues, known as ischaemic vasculopathy. When this tissue is the skin, CUA can develop. Patients develop severe pain, from the ischaemic tissue which quickly forms an eschar. It is a devastating condition, with up to 50% with a one year mortality and significant morbidity. Treatment of established CUA is limited but is centred on reducing a positive calcium load and the total Calcium x Phosphate product. This is generally achieved by with non-calcium phosphate binders, cinacalcet and good quality low calcium haemodialysis. Sodium thiosulphate, a chelating agent is an option occasionally used as is hyperbarbic oxygen 19. There is an international registry whose aims is to retrospectively analyse the natural history of the condition, identify risk factors and clarify the best treatments. 20 TMV KDGIO Classification The international consortium, KDIGO has classified the various forms of CKD-MBD into the following categories on the definition of CKD-MBD. It emphasises abnormalities of bone Turnover, Mineralization and bone Volume and is known as the TMV classification. Turnover reflects the speed of bone remodelling and is characterised by high osteoclast and osteoblast activity. Histomorphometry is required for its proper assessment. Mineralisation reflects how well the bone and collagen becomes calcified as it remodels. Bone Volume reflects the amount of bone per unit volume. With this classification the typical clinical manifestations of CKD-MBD can more easily be appreciated. Patients can and do move between the following labels: Osteitis Fibrosa (OF) /Hyperparathyroid related bone disease This reflects high bone turnover with high bone volume and normal bone mineralisation. Mixed Uraemic Osteodystrophy (MUA) High bone turnover, abnormal mineralisation with high bone volume Osteomalacia (OM) This reflects low bone turnover with abnormal mineralisation Adynamic Bone Disease (ADM) 21 Low Turnover of bone with relatively preserved mineralisation but of low bone volume. The paucity of bone biopsies that are performed in CKD- MBD patients prevents clinicians using this hard end point to accurately type the bone disease of CKD patients. Initial evaluation of CKD-MBD should be with calcium, phosphate, ALP, PTH and bicarbonate levels alongside any imaging for soft tissue calcification. Fracture Risk People with CKD, particularly those receiving haemodialysis have a significantly increased risk of fractures as well as a higher morbidity and mortality associated with them. 22 Repeated studies have put the magnitude of a fracture at double those of age matched individuals with a prevalence of fractures in the dialysis population of around 50% in those older than 50 years old. 23 Therapeutic options: Management decisions for CKD-MBD should be overseen by multi-disciplinary teams including physicians, nurses, renal dietician, and renal pharmacists. The following should inform what changes need to be made: Historical & current biochemical results of calcium, phosphate, 25(OH) Vitamin D, ALP, PTH levels Other bloods as indicated (e.g. Aluminium, Bicarbonate) Current drug prescription and concordance Patient factors Dialysis prescription duration on dialysis and vintage Diet and nutritional status Past medical history History of cardiovascular morbidity and of prior fracture history Smoking, Osteoporosis risk factors Skeletal X-Rays and other imaging as indicated by the clinical scenario International Guidelines The KDIGO, an international consortia of experts, CKD- MBD s guidance 24 suggests the following: Phosphate control Dialysis patients: suggest lowering an elevated phosphate towards normal range Non dialysis CKD patients: maintain normal range Calcium All CKD patients, including dialysis patients: maintain normal range PTH Dialysis patients: maintain between 2-9 times the upper normal limit Non-dialysis CKD patients: range unknown but correct modifiable factors and treat with calctriol or vitamin D analogues. 4 Dr. BC Storey MB ChB MRCP DTM&H

5 Strategies: Diet Phosphate and calcium advice may have to be balanced against the patient s general nutritional state and other dietary goals. Low potassium, salt and/or fluid restriction may also take precedent in some circumstances. Diabetes mellitus, coeliac disease or cultural/religious diet restrictions may also be relevant to individuals. However phosphate reduction in the diet is the key component to achieving good phosphate control. Examples of low phosphate foods would include the minimisation of dairy products and avoidance of liver, kidney, pate and chocolate. Phosphate Binders There are various vitamin D analogues that are licensed in CKD-MBD. They replace vitamin D insufficiency and mimic the physiological role of active vitamin D. They suppress PTH with a consequential rise in calcium and phosphate. Alfacalcidol is most frequently prescribed and can be given IV during haemodialysis sessions or orally and observed by the dialysis nursing staff on dialysis to help with concordance. Paricalcitol was thought to be less calcaemic, and phosphataemic than vitamin D analogues but this was not borne out in a randomised control trial against alfacalcidol. 28 Animal models have shown a variety of reno-protective effects to vitamin D replacement, all of which appear attractive: suppression of the renin-angiotensin system 29, amelioration of chronic fibrosis and reducing proteinuria. 30 However replacing vitamin D to normal levels has not been shown to improve patient survival. KDIGO guidelines merely suggest checking for vitamin D when egfr <60ml/min levels but do not guide clinicians on the frequency of testing nor the rate of replacement. 1 Calcium salts These are cheap and are to be taken with meals to help with phosphate binding. They contain various strengths of calcium salts. Their toleration by patients is variable because of the size and taste of the tablets. They are generally used first line to correct hypocalcaemia and hyperphosphataemia. With this effect they can also suppress the SPTH. Beyond the compliance issues of the tablets, hypercalcaemia is the other limitation to its use. Calcium acetate and calcium carbonate are the most frequently used, with the former having better phosphate binding. Non-calcium containing Phosphate Binders Sevelamer /Renagel or Renvela Lanthanum/Fosrenol Aluminium/AluCaps Iron Based Phosphate binder In research only 25 Sevelamer and Lanthanum have the advantage of not causing hypercalcaemia associated with calcium salts. They offer effective phosphate control but at considerable extra financial costs than calcium salts. Older non-calcium phosphate binders such as aluminium have historically been put aside because of the aluminium accumulation and toxicity. However if aluminium levels are checked, they remain a good alternative for some patients to achieve control. Sevelamer seems to offer other benefits to the metabolic environment of CKD by reducing LDL cholesterol, C-reactive protein and uric acid levels. 26 The dangers of aluminium toxicity include encephalopathy and fractures from adynamic bone disease. 27 Vitamin D Sterols Calcimimetics Cinacalcet (Europe)/Mimpara (North America) or Sensipar This drug mimics the effects of calcium on tissues by binding to the calcium sensing receptor in various organs. They are used in patients with severe SHPT. Different regulators, in different countries have given guidance on its use as cost is a limiting factor. 31 It offers an alternative to parathyroid surgery. The EVOLVE study did not show a reduction cardiovascular end points despite good reductions in PTH. 32 Hypocalcaemia is its major drawback. Parathyroid Surgery For severe SHPT that is unresponsive to medical treatment, parathyroidectomy offers a solution. However it comes at the expense potentially of rendering the bones adynamic especially if the patient fails to take their vitamin D sterols postoperatively. 33 Various surgical techniques have been used but total parathyroidectomy is the most common. Post-Transplant Bone Health Renal transplantation undoubtedly can have a positive effect on a patient s bone health as once again a functioning kidney graft is able to activate vitamin D and clear excessive phosphate loads in the urine. Transplantation though brings some negative factors to bone health which are of relevance. 34 Corticosteroids are used pre-implantation, for acute cellular rejection episodes and as maintenance immunosuppression. All these uses compound the low turnover which hugely increases fracture risk. Avascular necrosis (AVN) is a serious consequence of high dose exposure to steroids. A study of transplanted patients hospitalised for fracture showed that renal transplant patients had an adjusted risk ratio of 4.59 and an increased mortality risk of 1.6. With the changing demographics of transplanted patients; grafts lasting longer and increasing numbers of transplants in the > 55 years old this problem is likely to increase. Olgard K et al 35 offers Dr. BC Storey MB ChB MRCP DTM&H 5

6 an excellent précis of the management issues in this field by detailing the multifactorial nature of this condition and emphasising the complicating factors of pre-transplant bone health and the chosen immunosuppressive regime which effects the skeletal axis. 35 Summarising Comments, Future Prospects The main thrust of management in CKD-MBD is to try and obtain and maintain neutral bone health. Good phosphate control combined with dietary advice and phosphate binders does work but requires patient motivation and ongoing clinical vigilance. Working in partnership with patients and discussing the importance of their CKD-MBD blood test results can aid concordance. People with CKD relate to other aspects of their CKD health such as understanding that if they do not keep to their fluid restriction that they will become breathless. The implication of not taking those big horrible tablets is less immediate and perhaps harder to comprehend. Despite the lack of robust prospective multi-centre randomised control trials on the merits of managing specific CKD-MBD parameters it stand to reason to try and mitigate the morbidity it undoubtedly holds. Health care professionals interested in this area of nephrology need to pool their knowledge and resources to help design good quality randomised controlled trials to update the current evidence base. Learning Follow Up 1. Be able to describe the physiological factors controlling calcium, phosphate and vitamin D in normal health and CKD. 2. Understand the significant morbidity that poor CKD-MBD parameters carries for patients from skeletal pathologies and the consequences of vascular and soft tissue calcium deposition. 3. What is the increased fracture risk for dialysis patients? 4. Understand the spectrum of CKD-MBD using the TMV classification. Know the normal ranges of calcium, phosphate and PTH relevant to your area of practice. 5. Outline the multidisciplinary nature of treating CKD-MBD and the main classes of medicines used. 6 Dr. BC Storey MB ChB MRCP DTM&H

7 References 1. KDIGO Clinical Practice Guidelines for the Diagnosis, Evaluation, Prevention and Treatment of Chronic Kidney Disease- Mineral Bone Disease (CKD-MBD).Kid Int;73(s113)si-s130(2009) 2. Hollick MF. Vitamin D Deficiency. NEJM ; 357: (2007) 3. Forman JP, Williams JS, Fisher ND. Plasma 25-hydroxyvitamin D and regulation f renin-angiotenisin system in humans. Hypertension; 55: (2010) 4. Gunta SS, Thadthani RI, Mak RH. The effect of vitamin D status on risk factors for cardiovascular disease. Nat Rev Neph;9: (2013) 5. Zhang Y, et al. Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J Immunol ;188: (2012) 6. Caprio M, Mammi C, Rosano GM. Vitamin D: a novel player in endothelial function and dysfunction. Arch Med Sci; 8:4-5-(2012) 7. Christakos S, Dare V et al. Vitamin D Metabolism. Endo Met Clin N Am ; 39(2): (2010) 8. Yilmaz MI, Sonmez A, Saglam M et al. FGF-23 and vascular dysfunction in patients with stage 3 and 4 chronic kidney disease. Kid Int; 78(7): (2010) 9. Fliser D, Kollerits B, Neyer U et al. Fibroblast growth factor 23 (FGF-23) predicts progression of chronic keindey disease: the Mild to Moderate Kidney Disease (MMKD) Study. J Am Soc Nephrol;18(9): (2007) 10. Palmer SC, Hayen A, Macaskill P et al. Serum levels of phosphorous, PTH and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and meta-analysis. JAMA;305(11): (2011) 11. Isakova T, Xie H, Yang W et al. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA;305(23): (2011) 12. Komori T. Regulation of osteoblast differentiation by transcription factors. J of Cell Biochem ;99: (2006) 13. Goto S, Komaba H, Fukagawa M. Pathophysiology of parathyroid hyperplasia in chronic kidney disease: preclinical and clinical basis for parathyroid intervention. Nephrol Dial Trans plus;1(suppl 3):iii2-iii8 14. Lewin E, Rodriguez M. Abnormal parathyroid gland function in CKD. The Spectrum of Mineral and Bone Disease Disorders in Chronic Kidney Disease 2nd Edition (2010) Chapter 6 pp London Gm, Guerin AP, Marchais SJ et al. Aterial Media calcification in end-stage renal disease: impact on all cause and cardiovascular mortality. Nephrol Dial Trans;18: Amann K. Medial calcification and intima calcification are distinct entities in chronic kidney disease. Clin J Am Soc Nephrol;3: (2008) 17. Davies MR, Hruska KA. Pathophysiological mechanisms of vascular calcification in end-stage renal disease. Kid Int;60: Krueger T, Westenfeld, Ketteler M et al. Vitamin K deficiency in CKD patients: a modifiable risk factor for vascular calcification? Kid Int;76:18-22 (2009) 19. Basile C, Montanaro A, masi M et al. Hyperbarbic oxygen therapy for calcific uremic arteriopathy: a case series. J Nephro (2002); 15: Brandenburg VM, Floege J. Adynamic bone disease bone and beyond. Nephro Dial Trans Plus 3: (2008) 22. MittalHenkle A, Gillen DL, Stehman-Breen CO. Increased risk of mortality associated with hip fractures in the dialysis population. Am J Kid Dis;44: Alem AM, Sherrard DJ, Gillen DL et al. Increased risk of hip fracture among patients with end-stage renal disease. Kid Int;58: (2000) 24. KDIGO Clinical Practice Guidelines for the Diagnosis, Evaluation, Prevention and Treatment of Chronic Kidney Disease- Mineral Bone Disease (CKD-MBD).Kid Int;73(s113)si-s130(2009) 25. Geisser P, Philipp E. PA21: a novel phosphate binder for the treatment of hyperphosphatemia in chronic kidney disease. Clin Nephrol;74(1):4-11(2010) 26. Evenepoel P, Selgas R, Caputo F et al. Efficacy and safety of sevelamer hydrochloride and calcium acetate in patients on peritoneal dialysis. Nephrol Dial Trans; 24: (2009) 27. Platts MM, Goode, GC, Hislopp JS. Composition of the domestic water supply and the incidence of fractures and encephalopathy in patients on home dialysis. BMJ 2: (1997) 28. Hansen D, Rasmussen K, Danielsen H et al. No difference between alfacalcidol and paricalcitol in the treatment of secondary hyperparathyroidism in hemodialysis patients: a randomised crossover trial. Kid Int;80: (2011) 29. Li YC, Qiao G, Uskokovic et al. Vitamin D: a negative endocrine regualrot of the renin-angiotensin system and blood pressure. J Steroid Biochem Mol Biol;89-90: (2004) Dr. BC Storey MB ChB MRCP DTM&H 7

8 30. Scwarz U, Amann K, Orth SR et al. Effect of 1,25 (OH)2 Vitamin D3 on glomerulosclerosis in subtotally nephrectomised rats. Kid Int;53: (1998) 31. Cinacalcet for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy. NICE Guidelines Jan EVOLVE Trial Investigators, Chertow GM, Block GA et al. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis N Engl J Med;367(26): (2012) 33. Ogata H, Mizobuchi M, Koiwa F et al. Clinical significance of parathyroid intervention on CKD-MBD management. Nephrol Dial Trans plus;1(s3):iii9-iii Sprague SM, Belozeroff V, Danese MD et al. Abnormal bone and mineral metabolism in kidney transplant patients A Review. Am J Nephrol;28; (2008) 35. Olgard K, Salusky IB, Silver J. The Spectrum of Mineral and Bone Disorders in Chronic Kidney Disease. Oxford Clinical Nephrology Series 2nd Edition (2010) Chapter 29 pp Dr. BC Storey MB ChB MRCP DTM&H