Normal or i Phosphate DFO test a Normal Normal Often elevated a DFO test, desferrioxamine test: a non-invasive means of detecting aluminum overload. Poss ible indications for bone biopsy include: unexplained fractures, unexplained hypercalcaemia . unexplained bone pain, suspected aluminum toxicity, X before treatment with bisphosphonat es. CHAPTER 3 Chronic kidney disease (CKD) 236 CKD-MBD: physiology If renal function is intact, concentrations of PO 4 and Ca 2+ are maint ained through interaction between PTH, 1,25(OH) 2 D (calcitriol), \201 broblast growth fa ctor-23 (FGF-23), and their principal targets: bone, kidney, the GI tract, and parathyroid glands. Parathyroid hormone PTH secretion (and parathyroid gland proliferation) are stimulated by d Ca 2+ , d 1,25(OH) 2 D, and i PO 4 . PTH acts on three fronts: (i) mobiliz- ing skeletal c alcium; (ii) d urinary Ca 2+ + i urinary PO 4 excretion; (iii) i renal production of 1,25(O H) 2 D (in turn l i intestinal Ca 2+ and PO 4 absorption). Vitamin D Inactive vitamin D sterols, e.g. colecalciferol (from dietary sources and UV conv ersion in the skin), are metabolized in the liver to 25(OH)D (calcidiol) and converted to 1 ,25(OH) 2 D (principally) by the renal 1 A -hydroxylase enzyme. 1,25(OH) 2 D exerts many im portant biological effects via its intra- cellular receptor (VDR) (see Fig. 3.6). FGF-23 Produced in bone by osteocytes and osteoblasts. FGF-23 levels i as GFR d , potently suppressing 1 A -hydroxylase and 6 1,25(OH) 2 D produc- tion. It also i urinary PO 4 excret ion. FGF-23 excess underlies autoso- mal dominant hypophosphataemic rickets, X-linked hypop hosphataemia, and tumor-induced osteomalacia (all characterized by PO 4 wasting, d 1,25(OH) 2 D, and skeletal abnormalities). 2 Emerging as a very powerful biomarker for mortality. Klotho A putative ageing suppressor gene, encoding a transmembrane pro- tein that forms a c omplex with the FGF receptor to i FGF-23 af \201 nity. Expressed principally in the kidney , brain, and parathyroid gland, it is a mandatory cofactor for the actions of FGF-23 within mineral homeostasis. d Klotho expression is one of the earliest biomarkers for CKD (preced ing i PO 4 and i FGF-23) and continues to decline as GFR falls. Bone biology Bone is not st atic; it continuously adapts to mechanical and metabolic requirements by a remodeling proce ss centered around the coupling of osteoblastic formation and osteoclastic resorption. Mult iple systemic hor- mones (including PTH and 1,25(OH) 2 D) and local growth factors (e.g. th e RANK/OPG system) in \202 uence this process. Bone is the most important body reservoir o f Ca 2+ and PO 4 . See Fig. 3.7 for the pathogenesis of SHPT. CKD-MBD: PHYSIOLOGY 237 The effect of CKD \200 Loss of functioning renal mass l : \200 Phosphate accumulation. \200 d 1,25(OH) 2 D ( l d serum Ca 2+ ). \200 d Klotho expression l i FGF-23 ( l d 1,25 (OH) 2 D). \200 \200\230 Nutritional \200\231 vitamin D insuf \201 ciency is also comm on in CKD ( b p. 250). Secondary hyperparathyroidism: d Ca 2+ + d 1,25(OH) 2 D + i PO 4 l i PTH synthesis and release. \200 Prolonged stimulati on of parathyroid tissue l clonal proliferation of parathyroid cells (with areas of nodular hyperplasia). These clones express less Ca 2+ -sensing receptor (CaR) and VDR. \200 Refractoriness to t reatment is inevitable (termed tertiary or autonomous hyperparathyroidism). In addition, there is relative \200\230 skeletal resistance \200\231 to the effects of PTH (mechanisms unclear). Abnormal bone turnover results. \200 i PTH also has non-skeletal effects, including LVH, cardiac \201 brosis, extraskeletal calci \201 cation, peripheral neuropathy, impotence. 25 (OH)D \200\223 + PO4 & FGF-23 The kidney PTH \200\223 1,25(OH)2D Parathyroid gland Cellular Kidney Gut Bone iCa2+ + PO4 absorption iCa2+ PO4 absorption Proliferation Differentiation Apoptosis iosteoclast activity dPTH secretion Fig. 3.6 Overview of vitamin D metabolism. CHAPTER 3 Chronic kidney disease (CKD) 238 dVDR dCaR iPTH iPTH Parathyroid glands Skeletal resistance dCa2+ Systemic toxicity (e.g. cardiovascular) Bone disease d1,25(OH)2D iPO4 iFGF-23 d25(OH)2D Unknown factors dGFR Fig. 3.7 The pathogenesis of SHPT. CKD-MBD: PHYSIOLOGY 239 CHAPTER 3 Chronic kidney disease (CKD) 240 CKD-MBD: clinical features Secondary hyperparathyroidism (SHPT) \200 Usually asymptomatic . Clinical sequelae occur late (with signi \201 cant biochemical and histological disease), including: \200 Bone pain, arthralgia, and muscle weakness (esp. proximal). \200 Pruritus (cutaneous calcium phosphate deposition). \200 Bony deformity (e.g. resorption of terminal phalanges). i fracture risk (hip fracture risk 7 5 x in dialysis patients). Fracture risk is equivalent to a non-dialysis patient 10 \200\223 20 years older. 2 Mortality following a fracture ri ses by 7 2.5 x . Marrow \201 brosis contributes to anemia and poor ESA response. Adynamic bone disorder \200 Usually asymptomatic and probably no i fracture risk X . \200 Adynamic bone buffers calcium poorly; i Ca 2+ is common, particularly if oral calcium intake is signi \201 cant. i risk of soft tissue and vascular calci \201 cation. \200 i risk of osteopenia post-tra nsplantation ( (cid:2) steroids). \200 Aluminum-related low turnover bone disease is ofte n painful, with an i risk of spontaneous fracture. Cardiovascular risk \200 2 Poor control of serum PO 4 , serum Ca 2+ , calcium phosphate product (CaxP), and PTH are all associated with i CV morbidity and mortality. i CaxP is associated with soft tissue and cardiac calci \201 cation. Diagnosis No one marker is perfect, so a clinical dataset is used (see Table 3.11). Biochemical \200 Check Ca 2+ , PO 4 , and PTH, as in Table 3.11. More often if treatment changes made. PTH: the ability of serum PTH to predict high and low turnover disease is actually quite poor though improves at extremes of PTH (<2 x upper limit of norm al for PTH: low turnover; >9 x upper limit of normal: high turnover). Calcium: d in untreated SHPT (though rises with vitamin D analog and calcium-based phosphat e binder treatment); often i in ABD. Phosphate: raised (early). \200 Alkaline phosphatase: i in SHPT and a useful, if underuti lized, component of the clinical dataset. It is a marker of bone formation (others, e.g. osteocalc in, are also elevated though not routinely measured). Radiology The availability of PTH measurements means X-rays are rarely necessary. CKD-MBD: CLINICAL FEATURES 241 SHPT: subperiosteal bone resorption (distal and middle phalanges of hands and feet), osteosclerosis ( l \200\230 rugger jersey spine \200\231 on lateral \201 lms), solitary cysts ( \200\231 brown tumors \200\231 ), particularly in jaw, pelvis , or ribs. ABD: often normal (osteopenia dif \201 cult to detect on standard X-rays). \200 DEXA doe s not predict fracture risk in advanced CKD although may in stages 1 \200\223 3 ( b p. 234 ). Quantitative CT of the spine may prove to have a role in predicting high and low turnove r disease. Table 3.11 KDIGO recommendations for frequency of biochemical testing in CKD CKD stage Calcium Phosphorus PTH Alkaline phosphatase Calcidiol (25(OH)D) a BaselineX 3 Every 6 \200\223 12 months Every 6 \200\223 12 months Baseline Baseline 4 Every 3 \200\223 6 months Every 3 \200\223 6 months Every 6 \200\223 12 months Every 6 \200\223 12 months Baseline 5 and 5D Every 1 \200\223 3 months Every 1 \200\223 3 months Every 3 \200\223 6 months Every 3 \200\223 6 months Baseline X Other guidelines, including those produced by NICE in the UK, do not advocate routine tes ting of serum PTH in CKD stage 3. a Calcitriol (1,25(OH) 2 D) is not routinely measured, as it is present in only tiny amounts in serum, and the assay is technically dif \201 cult a nd expensive. PTH assays \200 PTH (1-84) is the active hormone synthesized by the parathyroid glands and released into the circulation. PTH (1-84) exerts its biological effects via the type 1 PTH receptor (PTHR1). PTH fragments are also present in the circulation. These include a large C-terminal fragment called PTH (7-84). Routinely used \200\230 \201 rst-generation \200\231 immunometric assays or \200\230 i ntact \200\231 PTH assays detect both PTH (1-84) and PTH (7-84). PTH (1-84) has a circulatory half-life of <5min. PTH (7-84) undergoes renal clearance, and its half-life is appreciably longer. \200 PTH (7-84) appea rs to exert an inhibitory in \202 uence on osteoclastic bone resorption (probably via a di stinct C-PTH receptor). This opposes the action of PTH (1-84) and may be a contributory fac tor to the apparent skeletal resistance to PTH seen in CKD. \200\230 Second-generation \200\231 immunometric assays, more speci \201 c for PTH (1-84 ), are available and are likely to attract increasing attention as their clinicopathologica l validation progresses. At present, however, international CKD-MBD guidelines have not sup ported their routine use. There may prove to be a role for combining the different assays, e.g. a PTH (1-84)/PTH (7-8 4) ratio <1 has been correlated with adynamic bone. CHAPTER 3 Chronic kidney disease (CKD) 242 CKD-MBD: vascular calci \201 cation Background \200 Vascular calci \201 cation may pred ict, or even contribute to, the i CV morbidity and mortality associated with CKD. Prevalence in CKD far exceeds the general population (>80% of dialysis patients). Progression is also much more rapid. Appears intimately linked to the aberrant mineral and bone metabolism of CKD (as well as to its treatment X ). May explain the association between i P O 4 , i CaxP and i PTH, and adverse CV outcomes in observational studies. The \201 nding of vascular calci \201 cation is, in itself, associated with signi \201 cant i CV risk. Types Two types of arterial calci \201 cation (often co-localized): \200 Intimal \200 \224 within atherosclerotic plaques. Associated with stenotic lesions and CV events, such as MI and stroke. The calcium content of plaques from CKD patie nts is greater than age-matched controls. \200 Medial \200\224 within the intima media; classically, M nckeberg \200\231 s calcinosis. This causes vascular stiffness ( l eleva ted pulse pressure l LVH l LV dysfunction). In addition, cardiac valvular, and other soft tissue, calci \201 cation is a frequent \201 nding in advanced CKD. Calci \201 cation also makes vascular interventions , such as CABG or angioplasty, more challenging. Should we screen? The role of screening is unclear at present, as screening criteria are no t ful \201 lled: (i) best therapy is uncertain and (ii) unknown if CV outcomes can be modi \201 ed. Possible methods, however: \200 Electron beam (EBCT) or multislice (MSCT) CT s canning (esp. coronary arteries and aorta) most sensitive and speci \201 c. Generate a calci \201 catio n score for prospective monitoring. Problems: expensive, cannot distinguish intimal and med ial calci \201 cation. Plain X-ray (usually lateral AXR) can document \200\230 pipe stem \200\231 calci \201 cation, with reasonable sensitivity; quanti \201 cation more dif \201 cult (r ecommended by KDIGO). Vascular ultrasound, e.g. carotid intimal medial thickness. \200 Pulse wave velocity yiel ds functional information. \200 Echocardiography identi \201 es valvular calci \201 cat ion. Relationship with osteodystrophy \200 Most commonly associated with ABD where the skeleto n fails to buffer Ca 2+ and PO 4 , leaving them \200\230 available for use \200\231 in calci \201 c ation. In SHPT, the release of Ca 2+ and PO 4 during bone resorption may also favor calci \201 cation. X Both calcium-containing phosphate binders and active vitamin D can create a +ve calcium b alance, with a risk of ABD and i CaxP. There is evidence linking calcium intake to arterial calci \201 cation. This has provoked an extremely robust, ongoing debate within CKD-MBD: VASCULAR CALCIFICATION 243 nephrology about the future role of these treatments (both previously cornerstones of thera py) (see b pp. 246 \200\223251). Prevention and treatment \200 Follow best practice guidelines for CKD-MBD, as outlined on b p. 244. \200 Some evidence that sevelamer HCl, a non-calcium-containing binder, may slow progression of coronary and aortic calci \201 cation. Calcimimetics may help control PTH without i CaxP or large doses of vitamin D. A potential future role is currently under study ( b p. 252). Daily or long-hours dialysis with superior PO 4 control (negating the need for binders) may help, as might transplantation. Biology of vascular calci \201 cation in CKD A new paradigm that departs from the traditio nal view of i CaxP passively promoting calci \201 cation has recently emerged, revealing a n extremely com- plex \200\224 and closely regulated \200\224 process. The evidence trail is as follows: \200 Although calci \201 cation appears to correlate, in part, with calc ium intake, it was frequently encountered prior to the widespread use of calcium-based phosphat e binders. A poorly understood association between arterial calci \201 cation and bone disease has lo ng been recognized in the context of osteoporosis where mineral metabolism is less overtly disturbed. \200 The calcium deposited in vessels is in the form of hydroxyapatite crystals \200\224 the same as in the skeleton. Spontaneous vascular calci \201 cation occurs in rodents carrying speci \201 c gene deletions (e.g. apolipoprotein-E, fetuin-A, and OPG). Certain hitherto \200\230 bone-speci \201 c \200\231 regulatory transcription factors (particularly Cbfa1) and proteins (e.g. osteocalcin, osteonectin, and alkaline phosphatase) have been demonstrated in calci \201 ed vessels. Several stimuli (including i PO 4 and uraemic serum) are able to promote the differentiation of vascular smooth muscle cells to an osteoblastic phenotype (v ia the upregulation of the Na-dependent cotransporter Pit-1). Such cells then form matrix v esicles and initiate the process of matrix deposition and mineralization. Regulation of calci \201 cation is achieved through a balance of promoters (e.g. BMP-2, RA NKL) and inhibitors (e.g. matrix GIa protein, itself inhibited by warfarin, osteopontin, fe tuin-A, PTHrP, OPG). In addition, i PTH, i BP, abnormal glucose metabolism, dyslipidaemia (particularly d HDL), in \202 ammation ( i CRP, i IL-6, i TNF- A , d fetuin- A), oxidative stress, and natural inhibitor de \201 ciencies are all likely to play a role . Further complexity is suggested by the discovery of cross-talk between osteoblasts and adipocytes (via leptin and other hormones) and 6 bone remodeling an d energy metabolism. This may have particular relevance in diabetes where low bone turnover is common. This integration of bone and vascular biology may yield novel treatments; for example, BMP-7 has been shown to be ef \201 cacious in animal models of va scular calci \201 cation and bone disease. OPG and fetuin-A are also potential future ther apies. CHAPTER 3 Chronic kidney disease (CKD) 244 CKD-MBD: treatment Goals \200 Keep serum Ca 2+ and PO 4 within the normal range. \200 K eep bone turnover and strength as near normal as possible. \200 Keep serum PTH appropriat e to these objectives. \200 Prevent the development of parathyroid hyperplasia. The standard treatment package comprises: Measures to d serum PO 4 : \200 Dietary PO 4 restriction. \200 Oral phosphate binders ( prevent absorption). \200 Removal through adequate dialysis. Measures to suppress PTH synthesis and secretion: Calcitriol or vitamin D analogs (e.g. alfacalcidol, paricalcitol). \200 Calcimimetic agen ts. Measures to normalize serum Ca 2+ : Appropriate calcium intake supplementation (including calcium-containing binders). Appropriate vitamin D treatment. \200 Appropriate dialysate concentration. Therapeutic targets An area of healthy debate within nephrology. NKF KDOQI (2003) (see Table 3.12) \200 Guidelines developed by NKF KDOQI re \202 ected t he growing concern that CKD-MBD and its treatment might be associated with a potentially modi \201 ab le increase in CV risk. Principally opinion-based, they advocated much more rigorous targets for Ca 2+ , PO 4 , and PTH than previously suggested (see Table 3.12). These targets: Proved extremely challenging from the clinician \200\231 s perspective. Multiple studies, as well as national registry data, showed that current practice fell well short of achievin g them. Table 3.12 NKF KDOQI treatment guidelines a CKD stage GFR (mL/min) PTH (pg/mL) Calcium (mmol/L) Phosphorus (mmol/L) 3 30 \200\223 59 35 \200\223 70 Normal 0.87 \200\223 1.48 70 \200\223 110 b Normal 0.87 \200\223 1.48 4 15 \200\223 29 150 \200\223 300 b 5 and 5D <15 or dialysis 2.1 \200\223 2.37 1.13 \200\223 1.78 a National Kidney Foundation (2003). K-DOQI clinical practice guidelines for bone metabolis m and disease in chronic kidney disease. Am J Kid Dis , 42 , S1, 51 \200\223 201 (M http:/ /www.kidney.org/ professionals/kdoqi ). b A PTH target above the upper limit of normal re \202 ects observational data that suggest normal bone turnover is most likely to be achieve d in uraemic bone when PTH is modestly elevated. Reprinted from Americal Journal of Kidney Diseases , 42 , S3, 51 \200\223 201, Garabed Eknoyan, Adeera Levin, Nathan W. Levin. Bone metabolism & disease in chronic kidney disease, 1 \200\223 12. Copyright (2003), with perm ission from Elsevier. CKD-MBD: TREATMENT 245 Outcome data showing a signi \201 cant impact on mortality through attaining them have, thus far, not been upcoming. Provided a framework for the pharmaceutical industry to introduce novel and (sometimes) expensive treatments as well as for healthcare purchasers to set reim bursement targets. KDIGO (2009) (see Table 3.13) \200 The more recent KDIGO clinical practice guidelines pre sent a comprehensive and systematic review of available evidence in this area and hope to harmoniz e international guidelines. While not universally accepted, they have generally superseded the NKF KDOQI guidelines. \200 The principal differences are: \200 Much less prescriptive. \200 Less emphasis on attaining narrow Ca 2+ , PO 4 , and PTH targets, e.g. the target for PTH in pre-dialysis CKD is effectively removed beyond treatment of a pr ogressively rising value. The guidelines generally recommend decision-making based on trends, rather than single values. The guidelines suggest there is no evidence to underpin a more stringent PTH target, so focus on avoidance of risk at extremes of PTH, i.e. at <2 x or >9 x normal in dialysis patients. A \200\230 multiplication \200\231 range of 2 \200\223 9 x normal is given, as opposed t o an absolute range in pg/mL or pmol/L, because absolute PTH levels can vary signi \201 ca ntly between assays. The guidelines read more as a summary of evidence, punctuated by pointers and advice, rather than dogmatic targets. Criticisms: the new broader PTH targets risk \200\230 letting the genie out of the bottle \200\231 , with progressive hyperparathyroidism that could subsequently prove unstoppable. Additionally, some were expecting (and prefer) more prescriptive guidance. Table 3.13 KDIGO treatment guidelines a CKD stage PTH (pg/mL) Calcium (mmol/L) Phosphorus (mmol/L) No numerical target a 3 Normal range Normal range No numerical target a Normal range Normal range 4 No numerical target a 2 \200\223 9 x upper limit of normal range Normal range Normal range 5 5D Normal range Lowered toward normal range a It is suggested that if the PTH is progressively rising and remains persistently above th e upper limit of normal, it warrants treatment but not to a speci \201 c numerical target because the optimal PTH level in this situation is unknown. From Kidney Int , 2009, 76 , Su ppl. 113, 1 \200\223 132. (cid:2) Very few statements in either guideline are based on high-quality evidence \200 \224 in fact, the only two recommendations graded 1A within the KDIGO report are in areas w ithin pediatric practice. This serves to high- light the pressing need for RCTs to inform f uture guidelines in this area. CHAPTER 3 Chronic kidney disease (CKD) 246 CKD-MBD: hyperphosphataemia Control of phosphate PO 4 control is the weak link in the thera peutic approach to CKD-MBD. Dietary restriction \200 Phosphate is contained in almost all foods (esp. meat, milk, eggs, cheese, yogurt, bran cereals, cola, chocolate drinks, beer, baked beans, dried peas (e.g. c hick peas), nuts, and many convenience foods). It is dif \201 cult to balance dietary phosphate restriction against adequate protein inta ke (recommended levels of daily dietary protein provide 30 \200\223 40mmol of phosphate). Patients are advised to reduce unnecessary PO 4 intake (e.g. cola), so they can maintain an adequate protein intake (e.g. meat, eggs). Phosphate binders See Table 3.14. \200 Taken with meals to bind phosphate in the gut. The amount taken is proportional to size of meal (and, ideally, to its PO 4 content) as well as to serum PO 4 ( usually 1 \200\223 3 tablets/meal). Potency is modest, and some patients require large doses. GI side effects are frequent. 2 T he most effective binder is one that the patient will take: demanding regimens + unpalatabl e tablets = poor compliance (>50% dialysis patients do not take their binders regularly). Should not be taken at the same time as iron supplements. \200 Aluminum hydroxide is the most effective binder, but potential aluminum toxicity (skeletal and neurological) restricts its use (<4 weeks). Calcium-containing phosphate binders (CCPBs) have been the mainstay: \200 Not only bind PO 4 , but help correct d Ca 2+ (and 6 suppress PTH). \200 Patients receiving CCPBs are often in +ve calcium balance, so they have been implicated as contributors to vascular calci \201 cation (and adverse CV outcome). This can probably be avoided by limiting CCPB dose (and lowering dialysate calcium, e.g. to 1.25mmol/L). CCPBs should be restricted to 1,500mg elemental calcium/day, particularly if low turnover disease likely (PTH <2 x upper limit of normal). Avoid if hypercalcaemia. \200 Non-calcium-based binders are preferred in patients with se vere vascular and/or soft tissue calci \201 cations. Non-calcium, non-aluminum-containing binders, e.g. sevelamer hydrochloride (Renagel ) or carbonate (Renvela ) and lanthanum carbonate (Fosrenol ), allow calcium and aluminum to be avoided. \200 They are much more expensive than calc ium- or aluminum-based binders. Equally as effective as CCPBs. \200 Sevelamer is associated with slower progression of co ronary calci \201 cation and possibly with improved survival. Sevelamer lowers LDL cholesterol and may provide additional CV risk reduction. CKD-MBD: HYPERPHOSPHATAEMIA 247 Magnesium-calcium combination binders, e.g. calcium acetate + magnesium carbonate (Osvaren ), reduce calcium burden and appear cost-effective (SE: GI, including diarrheoa). The recent KDIGO guidelines suggest current available evidence does not favor a speci \201 c phosphate binder. Choice of agent in a particular patient should 6 be based on serum bio chemistry, presence of vascular calci \201 cation, and bone histology (if available). A lo cal policy will usually be in place. One strategy is to use a combination of binding agents to reduce PO 4 , avoid excessive cal cium administration, and ameliorate the cost of newer binders. Adequate dialysis \200 Dietary intake of PO 4 exceeds daily removal by dialysis. \200 A signi \201 cant amount of PO 4 is in the intracellular compartment, so signi \201 cant rebound occurs post-HD treatment. CAPD is more ef \201 cient at PO 4 remo val than HD. Poor PO 4 control may be an indication for more frequent dialysis. \200 Daily dialysis re gimens can control PO 4 , with no binder requirement (supplementation is often necessary!). Aluminum toxicity History. In the 1970 \200\223 80s, clusters of dialysis units reported p atients with aluminum toxicity. Investigation identi \201 ed a high geographic con- centra tion in dialysate water as the cause, and improved puri \201 cation techniques eliminated this route of exposure. Aluminum-containing phosphate binders were left as the main source. Presentation. Aluminum toxicity ( l d PTH secretion, d mineralization, and d osteoblastic a ctivity) previously accounted for the majority of low turnover bone pathology. This was oft en painful, with an i risk of frac- ture. Also: ESA-resistant anemia, encephalopathy, and n eurotoxicity. Current practice. Aluminum-containing phosphate binders should gen- erally be avoided (use for a limited period, e.g. <4 weeks, a possible exception). If extended use is necessary, a luminum levels should be monitored. Serum aluminum should be <20 micrograms/L (0.7 mol/L ) in dialysis patients. Levels >60 micrograms/L (2.2 mol/L) suggest alu- minium overload . Sequential levels may detect the development of overload in at-risk patients. However, se rum aluminum is not a reli- able indicator of overall body content, and a desferrioxamine ( DFO) stimulation test may be required ( l rise in aluminum level after IV DFO). Symptomatic patients may bene \201 t from regular DFO chela- tion treatment. Interestingly, recent da ta suggest that long-term use of aluminum-based binders in dialysis patients is not associa ted with toxic- ity as measured by desferrioxamine (DFO) stimulation test, so perhaps their clinical use is about to go full circle. CHAPTER 3 Chronic kidney disease (CKD) 248 Table 3.14 Phosphate binders Binder Advantages Disadvantages Examples Calcium carbonate: Titralac (168mg calcium) Calcichew (500mg calcium) Calcium 500 (500mg calcium) Adcal (600mg calcium) Calcium acetate: Phosex (250mg calcium) Calcium load may predispose to vascular and soft tissue calci \201 cation Hypercalcaemia Calcium- based binders Inexpensive Help to correct low Ca 2+ and suppress PTH Calcium acetate has a smaller calciu m load per equivalent phosphate-binding dose (though i Ca 2+ is common) Osvaren Calcium acetate 435mg + magnesium carbonate 235mg Inexpensive Lower calcium load per equivalent phosphate-binding dose Less i Ca 2+ Inexpensi ve Very effective Calcium acetate + magnesium carbonate Need for magnesium monitoring Alu-cap (Al(OH) 3 475mg) Aluminum hydroxide suspension Aluminum- based Risk of aluminum toxicity Need to monitor levels Short-term use only Expensive GI intoleran ce Large doses needed (average 8 tablets/day) Causes a reduction in serum bicarbonate Sevelamer hydrochloride (Renagel ), 1 \200\223 3 800mg tablets with each meal Sevelamer HCl Non-absorbed, does not accumulate Avoids calcium May slow progression of coronary and aorti c calci \201 cation Other bene \201 cial effects: d LDL, d urate, d in \202 ammation Sim ilar to sevelamer HCl Better GI tolerance Avoids d bicarbonate Avoids calcium and aluminum Minimally absorbed Lower tablet burden (500mg, 750mg, and 1,000mg available) Expensive Large doses needed Sevelamer carbonate (Renvela ), 1 \200\223 3 800mg tablets or one 2,400mg powder sachet with each meal Sevelamer carbonate Lanthanum carbonate (Fosrenol ), 500 \200\223 1,500mg with meals Expensive Long-term outcome and safety data currently lacking Lanthanum carbonate CKD-MBD: HYPERPHOSPHATAEMIA 249 Renal bone disease management summary SHPT \200 Check Ca 2+ and PO 4 , PTH, and 25(OH)D, according to Table 3.11 ( b p. 241) (more often if treatment changes made). If serum 25(OH)D <30ng/mL (<75nmol/L), consider replacement ( b p. 250). Aim to reduce serum PO 4 to the normal range through a combination of diet, phosphate binders, and adequate dialysis ( b p. 246). Once PO 4 controlled, add alfacalcidol or calcitriol, titrating the dose to achieve a local ly agreed target PTH, according to CKD stage ( b p. 244). Aim to keep serum Ca 2+ in the normal range (If i Ca 2+ , switch to non-calcium-containing binder; review dialysate Ca 2+ ; reduce/stop vitamin D, as necessary). Uncontrolled SHPT: review diet; review compliance (especially before prescribing multiple expensive therapies); intensify phosphate binder and vitamin D therapy, as serum Ca 2+ allows. Consider paricalcitol ( b p. 251) and cinacalcet ( b p. 252) if high calcium limits vitamin D treatment. Parathyroidectomy: reserve for those cases refractory to medical management ( b p. 254). ABD \200 Aim to increase PTH-driven bone turnover: Reduce or stop calcium-containing binders and vitamin D analogs (aim for serum Ca 2+ in the normal range). Lowering dialysate calcium concentration (e.g. 1.0mmol/L for both HD and CAPD) may help d Ca 2+ and i PTH. Exclude signi \201 cant aluminum deposition, if applicable ( b p. 247). \200 Exogenous P TH (pulsatile administration) and calcimimetics may prove to have an anabolic role in ABD ( circadian PTH release is anabolic for bone, whereas sustained PTH release is catabolic). CHAPTER 3 Chronic kidney disease (CKD) 250 CKD-MBD: vitamin D treatment There are two vitamin D treatment strategies in CKD \200\224 which are not mutually exclusive. \200 The conventional rationale is to suppress PTH and control SHPT. Failure of the kidney to produce 1,25(OH) 2 D is a key part of the pathogenesis of SHPT, so it is logical that 1,25(OH) 2 D replacement should form part of ma nagement. Vitamin D requires 1 A -hydroxylation in the kidney for activation. In renal failure, this can be pharmacologically bypassed by using the 1 A -hydroxylated ana logs calcitriol or alfacalcidol (1 A -calcidol). \200 Newer vitamin D analogs, (e.g. pari calcitol or doxercalciferol) provide alternatives. There is evidence (retrospective studies) that mortality d in dialysis patients taking vitamin D, compared with those who do not. \200 A newer justi \201 catio n for vitamin D treatment is correction of vitamin D \200\230 substrate \200\231 de \201 ciency, using non-activated vitamin D products (co lecalciferol, ergocalciferol). \200 Largely based on theoretical bene \201 ts (see Box 3 .3) and assumes independent bene \201 ts for non-activated vitamin D via local conversion of 25(OH)D l 1,2 5(OH) 2 D (autocrine effects) in a wide range of target tissues. See also b p. 208. Treatment: control of SHPT \200 2 Control serum phosphate \201 rst . \200 Start with a low dose (0.25 micrograms/day alfacalcidol PO), and increase, as necessary, over several weeks (rarely, >0.5 \200\223 1.0 micrograms/day). See b p. 244 for treatment targets; local policies may differ. \200 Pulsed oral and IV th erapy (usually 0.5 \200\223 2.0 micrograms x 3/week) are an alternative to daily regimens and appear equally ef \201 cacious. Giving therapy, either IV or oral, during a dialysis t reatment can aid compliance. Monitoring Monitor serum Ca 2+ , PO 4 , and PTH (monthly initi ally). Avoid i Ca 2+ and PTH oversuppression. Side effects and toxicity i Ca 2+ and i CaxP ( i GI absorption and i mobilization from bone) frequently complicate treatment. More than just a therapeutic inconvenience, this has implications for bone turnover ( l ABD), soft ti ssue/vascular calci \201 cation, and CV morbidity/mortality ( b p. 242). Treatment: \200\230 nutritional \200\231 vitamin D de \201 ciency \200 Low serum 25(OH )D (calcidiol) levels are very common in patients with CKD (<15ng/mL in 7 20% if GFR <30mL/min). Probable cause: comorbidity l sedentary indoor lifestyle l insuf \201 cient sunlight expos ure l d available vitamin D substrate (rather than poor dietary intake or a renal abnormali ty). KDIGO guidelines recommend screening in CKD stages 3 \200\223 5. \200 Serum 25(OH)D <30n g/mL (<75nmol/L) represents insuf \201 ciency, but there is no real consensus on what de \201 nes \200\230 adequate \200\231 levels. Usually treated with colecalciferol in formulations with calcium, e.g. calcium 600mg with D 3 400 units (one tablet bd). An alternative is CKD-MBD: VITAMIN D TREATMENT 251 colecalciferol D3 as 20,000 unit capsules: two capsules once daily for 7 days, then mainten ance 2 x 20,000 unit capsules x 1/month. However, there is no current consensus on repletio n strategies. These doses may actually have limited effects on vitamin D stores. The bene \201 ts are not clear, but treatment appears very safe (with little risk of i Ca 2+ , i CaxP, or PTH oversuppression, though modest reduction in PTH may be seen). Box 3.3 Vitamin D: beyond mineral metabolism \200 Vitamin D-dependent genes are in \202 uenced through an intracellular vitamin D receptor (VDR). In addition to its \200\230 classical \200\231 role in mineral metabolism, vitamin D is n ow known to exert various non-classical effects on cell function, including differentiation , proliferation, and apoptosis. This occurs across a variety of cell types (including leucocytes, cardiac myocytes, skeleta l muscle cells, and pancreatic islets). \200 Vitamin D is involved in immune and in \202 ammatory responses, the RAS, and development of myocardial hypertrophy. It has been implicated (on epidemiological and biological evidence) in the pathogenesis of several disorders, including psoriasis, various cancers, diabetes mellitus, and i BP. 25(OH)D (calcidiol) is the major circulating form of vitamin D and is measured in routine l ab testing. Circulating 1,25(OH) 2 D (calcitriol) levels are 1,000-fold lower and much more dif \201 cult to estimate. \200 25(OH)D may have bene \201 ts independent of renal con version and is a better indicator of overall vitamin D status than 1,25(OH) 2 D. Newer vitamin D analogs \200 Much attention has been given to the development of vitamin D analogs that suppress PTH, with less propensity to hypercalcaemia. \200 Various mechanism s are proposed for this selective action, including less GI Ca 2+ absorption. They are members of a group of compounds known as vitamin D receptor agonists (VDRAs) or \200\230 active vitamin D compounds \200\231 . \200 Many have shown potential in the exp erimental setting, and a few are available for clinical use (e.g. paricalcitol, 22-oxacalci trol, and doxercalciferol). Widely used outside the UK, especially the USA and Japan. \200 They potently suppress PTH , but i Ca 2+ and i CaxP do still occur. \200 Advantages over calcitriol and alfacalcidol remain unproven, though there may be marginal bene \201 ts. X A large retrospective cohort study suggested a possible survival advantage for patients treated with paricalcitol. A therapeutic trial may be warranted in patients prone to i Ca 2+ . \200 Paricalcitol is given IV on dialysis (initially, dose is baseline PTH in pg/mL divided by 80). An oral form ulation is also available. Doxercalciferol (not available in the UK) can be given IV or ora l. Further randomized prospective studies are awaited. CHAPTER 3 Chronic kidney disease (CKD) 252 CKD-MBD: calcimimetics The calcium-sensing receptor (CaR) First cloned in 1993, the CaR is constitutively expressed across multiple cell types and credited with roles in many aspects of cell function. Its main purpose is the control of extracellular Ca 2+ concentration and regulation of steady state PTH secretion. Calcimimetic agents \200 Small molecules that bind to the parathyroid CaR and mimic the e ffect of i extracellular Ca 2+ : \200 Type I: include Ca 2+ itself and other cationic compounds . Directly activate the CaR. Type II: not strictly agonists but allosteric modulators that i CaR sensitivity to ambient Ca 2+ . Cinacalcet is currently the only calcimimetic available for clinical use. Calcimimetics d PTH, with a simultanous d in serum Ca 2+ . \200 Parallel reductions in PO 4 and CaxP are also seen. In this respect, they differ importantly from other available tr eatments (see Table 3.15). Side effects: dose-dependent upper GI intolerance, modest d Ca 2+ frequent (though rarely problematic). Despite the ubiquitous distribution of the CaR, CNS, cardiac, and other side effects not evident. Evidence for clinical ef \201 cacy using biochemical endpoints is unequivocal and has been shown to facilitate improved compliance with international Ca 2+ , PO 4 , and PTH targets. d risk of parathyroidectomy, fracture, and cardiovascular hospitalization in short-term studies. There is evidence that cinacalcet may improve CV calci \201 cation (large vessels and card iac valves). However, its impact on important CV outcomes remains unknown; in the EVOLVE st udy, it did not reduce risk of death or major CV events in dialysis patients with moderate to severe secondary hyperparathyroidism. But: \200 Expensive. Uptake in many countries likely to be limited (a NICE guideline in the UK effectively restricts their use to refractory i PTH where parathyroidec tomy is contraindicated). Role More data are needed to decide where need is greatest. \200 From the biochemical sta ndpoint, therapy (vitamin D or calcimimetic) can be chosen, according to the clinical pheno type of the patient (see Table 3.16). \200 The \200\230 vitamin D phenotype \200\231 : the SHPT patient in whom serum Ca 2+ , PO 4 , and CaxP product are all low normal or subnor mal. Vitamin D therapy is usually effective in bringing biochemical parameters to target. R isk of i Ca 2+ or i PO 4 is relatively low. The \200\230 calcimimetic phenotype \200\231 : potentially more dif \201 cult to treat. Here, SHPT is accompanied by a high normal or frankly elevated Ca 2+ , often with i PO 4 an d CaxP product. Treatment with vitamin D will d PTH but aggravate i Ca 2+ and i PO 4 . CKD-MBD: CALCIMIMETICS 253 Vitamin D and calcimimetics work well together. Their modes of action at the level of the parathyroid are different, and effects on PTH suppression appear additive. Calcimimetics may d serum Ca 2+ , \200\230 making room \200\231 for the use of vitamin D analogs. Dosing: cinacalcet (Mimpara UK, Sensipar USA) Oral; initially, 30mg od, increased inc rementally (60mg, 90mg, 120mg, 180mg), as necessary, to maintain target PTH. Check Ca 2+ 2 weeks after starting treatment and after any dose change. Hypocalcaemia may require dose re duction. Ca 2+ usually checked monthly for \201 rst 6 months and PTH 2 \200\223 3-monthl y. Table 3.15 Relative actions of current treatments on calcium, phosphorus, CaxP, and PTH con centrations Calcium-based binder Calcium-free binder Vitamin D sterols Calcimimetics d d d n or i d d d d d d d d PTH i i i d Calcium d d i d Phosphate d or i d i d CaxP Table 3.16 The two clinical phenotypes of CKD-MBD frequently encountered (designated by app ropriate treatment) Calcium Phosphorus CaxP \200\230 Vitamin D phenotype \200\231 Low normal or low In target In target \200\230 Calcimimetic phenotype \200\231 High normal or high Above target High CHAPTER 3 Chronic kidney disease (CKD) 254 CKD-MBD: parathyroidectomy 2 An elevated PTH alone is not an indication for parathyroidecto my. Indications \200 Tertiary or autonomous hyperparathyroidism: failure of hyperplasic, over active glands to suppress adequately in response to optimal medical therapy. Manifests clinically as i PTH (usually >500pg/mL), with persistent i Ca 2+ . \200 PO 4 an d alkaline phosphatase are usually raised. \200 If calcium is low or normal, i PTH indica tes SHPT, and further medical treatment is necessary.