ESAs: future developments Alternative methods of ESA administration: aerosol, mucosal, tran sder- mal, and oral are currently drawing much attention. New ESAs \200 EPO fusion proteins: Contain additional C-terminal peptides to i half-life. \200 EPO-EPO: two EPO molecules jo ined via a polypeptide bridge. \200 GM-CSF-EPO: provides two haematopoietic growth factor s at once. \200 Fc-EPO: incorporates the Fc region of human IgG to promote cellular recycling and i half-life. CTNO 528 is an EPO-mimetic antibody fusion protein, with no structural similarity to EPO but erythropoietic effects. Synthetic erythropoiesis protein (SEP): 51kDa protein-polymer construct that activates the EPO-R. Long half-life. Peptide-based ESAs: Unrelated in sequence to EPO but able to bind the EPO-R and induce intracellular signaling. Peginesatide (formerly hematide) is a pegylated dimeric peptide ESA currently in phase III clinical trials. It has been successfully used to treat patients with PRCA ( b p. 225). Manufactured by a relatively simple process, less immunogenic, and stable at room temperature. Administered IV/SC x 1/month. \200 Currently awaiting FDA approval. Non-peptide ESAs: Offer potential for oral administration. \200 Prolyl hydroxylase inhibitors (HIF stabiliz ers). Prevent the hydroxylation and inactivation of HIF A ( b p. 218). \200 Problem: many other genes are regulated by prolyl hydroxylation. \200 HIF stabilizer FG-4592 currently in cl inical trials. GATA inhibition: GATA are a family of transcription factors. GATA-2 is a negative regulator of EPO gene expr ession, so its inhibition is of interest. Haemopoietic cell phosphatase (HCP) inhibitors: HCP is a tyrosine phosphatase that dephosphorylates JAK-2 and functions as a negative regul ator of intracellular EPO signaling. Gene therapy: Various delivery systems, such as adenovirus transfection, are under investigation. EPO could be released into the circulation at any site and by any cell type. Regulation of expression is likely to be the greatest obstacle to this approach. CHAPTER 3 Chronic kidney disease (CKD) 222 Prescribing ESAs When to start? Consider an ESA when Hb <11g/dL (local protocols may vary). X There is uncertainty as to the optimum time to commence ESA therapy. Does a numerical Hb threshold decide the best time, or would an earlier start prevent CV complications? ESAs h ave previously been thought of as safe and effective \200\224 but recent evidence suggests you can have too much of a good thing ( b p. 226). UK Renal Association guidelines 6 recom - mend that treatment should be reserved for patients who are likely to bene \201 t from i mproved quality of life or physical function and to avoid transfusions. They remain relativ ely underprescribed in CKD (only 1/3 of patients starting dialysis are receiving an ESA). E conomic considerations will inevitably apply. Preparation for ESA therapy \200 2 Have other causes of anemia been considered ( b p. 217 ), especially iron de \201 ciency? Is the patient likely to respond? Cytokine release associated with infection (or chronic in \202 ammation) impairs ESA response. Identify and treat these \201 rst. i CRP usually predicts poor response. Is BP controlled? ESAs tend to i BP. Severe i BP was not uncommon in the early days of ESA use (mechanism: vasoconstriction and enhanced adrenergic responsiv eness) but has d in incidence with the re \201 nement of treatment algorithms (which gener ally aim for a slower rise in Hb). Investigations \200 FBC with red cell indices. \200 Determine iron status: Serum ferritin; recommended range 200 \200\223 500 micrograms/L. \200 Serum iron and tot al iron-binding capacity (TIBC). \200 Transferrin saturation (TSAT); recommended range 20 \200\223 40%. \200 % hypochromic RBCs (% HRBC); recommended target <6%. CRP. \200 Serum B12 and folate. \200 Consider fecal occult blood testing. \200 2 Meas urement of EPO levels is expensive, misleading, and unnecessary. Choice of ESA There is no evidence to distinguish between ESAs on the basis of clinical ef \201 cacy. Choice will depend on local protocols, availability, and patient/ physician pre ference. Route of administration \200 Either SC or IV (IV often used in haemodialysis patients \200\224 given at the end of a dialysis treatment to reduce dialyser absorption). This can also assist compliance. PRESCRIBING ESAs 223 Pre-dialysis CKD and peritoneal dialysis patients can be taught to self-administer an ESA at home, using a range of user-friendly devices. There is a dose adjustment between SC and IV administration for some ESAs ( b p. 220), but there is much interpatient variability. \200 Rare reports of pure red cell aplasia (PRCA) in patients treated with SC epoetin A have been resolved. Starting ESAs \200 2 Ensure iron-replete; iron stores may rapidly deplete once an ESA is commenced so will require monitoring. See Table 3.7 ( b p. 220) for typical starting doses. \200 The initial dose can be i if t here is clinical urgency and/or ESA resistance is likely. \200 Measure Hb and BP 2 \200\223 4-weekly at \201 rst (and afte r a dose change). \200 If deterioration in BP, intensify antihypertensive medications (it is rarely necessary to withhold ESA). Aim for i Hb of 1 \200\223 2g/dL/month until target achieved. \200 i dose monthly ( 7 25 % increments) if slow Hb rise. \200 d dose by 25 \200\223 50% if Hb rises >2g/dL in a mo nth. \200 Changing dose intervals can be a convenient way of dose increases/ reductions \200\224 avoiding the need to dispense a substitute dose and waste existing supplies. Once in \200\230 steady state \200\231 , monitor Hb 1 \200\223 2-monthly in pre-dialysis patients and monthly in dialysis patients. An intercurrent illness may reduce Hb. There is no consensus on the best approach, but consider temporary i dose. ESA resistance or hyporesponsiveness \200 True ESA resistance is variously de \201 ned a s: Failure to reach target Hb, or \200 The need to administer above a threshold ESA dose (e. g. \211 300IU/kg/wk of epoetin A or B ) or 1.5 micrograms/kg/wk of darbepoetin A to maintain target Hb. Relative resistance is common. \200 Run through, and proactively exclude, the alternative causes of CKD-associated anemia (see b p. 217). 2 Always exclude iron de \201 ciency. \200 If iron stores prove refractory to iron admin istration, check for fecal occult blood, and consider further GI investigation. Assess compliance. \200 Check reticulocyte count in non-responders. High: suggests an appropriate marrow response (i.e. there is probably bleeding or compromised RBC survival). Low: RBC production problem (e.g. in \202 ammation) or poor compliance. If haemolysis suspected, check LDH, haptoglobins, direct Coombs \200\231 test. CHAPTER 3 Chronic kidney disease (CKD) 224 ESAs: additional bene \201 ts Non-hematological effects of ESAs \200 Enhanced quality of life scores. \200 Improved exercise capacity. \200 Reduced fatigue. \200 Improved ca rdiac functional status. \200 Regression of LVH and improved LV architecture. \200 d sy mptomatic angina. \200 Improved survival in ESA-treated patients after starting dialysis. \200 d hospitalization. \200 Improved cognitive function. \200 Improved sexual funct ion. \200 Improved sleep quality. \200 Partial normalization of cortisol and carbohydra te metabolism. \200 Avoidance of transfusion. \200 Improved immune responses. \200 X Slowed progresson of CKD (con \202 icting evidence: suggested mechanisms include d oxidati ve stress, d tubular hypoxia, i angiogenesis, and d apoptosis). X Cytoprotection ( b p. 219). X Adjuncts to ESA therapy In addition to iron, there has been interest in several other age nts as possible adjuncts to ESA therapy. \200 Ascorbic acid: Increases iron release from ferritin and the reticuloendothelial system. Enhances iron utilization during Hb synthesis. \200 Needs to be given IV as orally ineffe ctive. \200 s oxalosis is a safety concern. \200 Insuf \201 cient evidence for routine use. L-carnitine: Required for long chain fatty acid transportation into mitochondria. \200 Membrane-stabil izing effect l i RBC survival (+ i formation of bone marrow erythroid colonies). IV administration may i Hb and d ESA requirement. \200 Inadequate and unconvincing body o f evidence. Androgens: Patchy evidence to support nandrolone (given IM). \200 Side effects, including acne, viri lization, and abnormal LFTs, make it an unattractive option. ESAs: ADDITIONAL BENEFITS 225 Pure red cell aplasia (PRCA): a detective story \200 Presents as an abrupt decline in Hb, with normal platelets, normal WCC, and reticulocyte count <1%. Bone marrow examination reveals absent erythroid precursors. \200 Anti-EPO antibodies can be measured. \200 There has always been a low background incidence of PRCA due to viral infections (parvovirus), lymphoma, and certain drugs. \200 Acquired PRCA was \201 rst reported in the late 1990s, with 7 250 patients worldwide developing anti-EPO antibodies. These antibodies cross-react with endogenous EPO, rendering patients profoundly anemic and transfusion-dependent. Almost all these cases occurred in dialysis patients on SC (but not IV) epoetin A (a handfu l of cases have been described with other ESAs). Extensive (and expensive) investigation suggested that polysorbate (in the drug vehicle) wa s able to react with compounds leaching from uncoated rubber stoppers in pre \201 lled syr inges. This had an adjuvant effect, promoting the molecules \200\231 immunogenicity (which is already higher by the SC route). Switching to a different ESA proved unhelpful because the antibody cross-reacted. Immunosuppression was tried, with variable success. \200 Peginesatide (formerly hematide) ( b p. 221) differs in structure and does not cross-react with the antibody. It has been s uccessfully used as treatment. PRCA led many countries to abandon epoetin A by the SC route. However, following a change t o the manufacturing process, its use remains widespread. CHAPTER 3 Chronic kidney disease (CKD) 226 ESAs: target hemoglobin X Although ESAs can be bene \201 cial for patients with CKD-relate d anae- mia, they are not without intrinsic risks. Despite observational data sug- gesting an association between lower Hb and poorer outcomes, recent randomized trials have demonstr ated overall worse outcomes and higher risk of death with ESA treatment, particularly with higher Hb targets. In \202 uential clinical trials CHOIR \200 Correction of Hemoglobin and Outcomes in Rena l Insuf \201 ciency study. \200 USA; published 2007. \200 Hypothesis: using epoetin A to achieve an Hb of 13.5g/dL, compared to Hb 11.3g/dL, would d CV complications and death. Randomized, open label design; 1,432 patients, CKD 3 \200\223 4 (non-dialysis); initial Hb targets 10.5 \200\223 11.0g/dL and 13.0 \200\223 13.5g/dL, but a protocol amen dment changed the targets to absolute values (Hb 11.3g/dL vs 13.5g/dL). p outcome: time to all-cause mortality or MI, CVA, heart failure (HF). \200 Stopped early ; mean 16 months \200\231 follow-up. \200 Finding: 34% increase in the risk of primary c omposite outcome in higher target group (mainly HF). Little difference in quality of life. \200 Problems: high dropout rate, differences in two groups at baseline, higher target not actually achieved \200\224 despite huge ESA doses. CREATE \200 Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin study. European; published 2007. \200 Hypothesis: early vs late anemia correction with epoetin A will d mortality and CV morbidity in CKD 3 \200\223 4. Randomized, open label design; 603 patients, CKD 3 \200\223 4 (non-dialysis); Hb targets 10.5 \200\223 11.5g/dL and 13.0 \200\223 15.0g/dL. p outcome: time to CV event. \200 24 months \200\231 follow-up. \200 Finding: trend to higher event rate in higher target group (not statistically signi \201 cant). Quality of life better in higher target group. Problems: low CV event rate (6%). Although both studies had faults, the trends toward poorer outcomes led the US Food and Dru g Administration to signi \201 cantly escalate the label warnings for ESA drugs, strongly cautioning against higher targets. TREAT \200 Trial to Reduce Cardiovascular Events with Aranesp Therapy study. \200 World wide (24 countries); published 2009. \200 Hypothesis: treatment with darbepoietin A would d risk of death, major CV events, and renal events in patients with T2DM and CKD. \200 Randomized, placebo -controlled, double-blind; 4,038 patients, CKD 3 \200\223 4 (non-dialysis) with T2DM. ESAs: TARGET hemoglobin 227 2,012 patients assigned to ESA, with Hb target 7 13g/dL (median achieved 12.5g/dL), and 2,026 patients to placebo, with rescue ESA if Hb <9g/dL (median Hb 10.6g/dL). p outcome: composite of death or a CV event and of death or end-stage renal disease ( 2 the death and CV event rate in the trial overall was an incredi ble 31% \200\224 re \202 ecting the huge CV disease burden in this population). \200 29 months \200\231 follow-up. \200 Finding: no d in the risk of either death or CV event w ith ESA, but this group did have an i risk of stroke. Modest bene \201 ts ( d fatigue, d t ransfusion). Authors suggested ESA might be best avoided in T2DM. Problems: differences in baseline group characteristics; may not be applicable to non-diabetic population. Adverse outcomes: putative mechanisms The mechanism for the apparent outcomes associated wi th higher Hb targets is unclear, but it is likely that a number of interdependent factors a re operative. \200 Effect of i Hb ( i blood volume, i blood viscosity, endothelial damage ). \200 i BP. \200 i platelet aggregation. \200 Direct ESA toxicity (particularly wit h large and rapidly escalating doses). \200 Interaction with patient \200\231 s comorbid ity (particularly if poor ESA response and higher doses, e.g. in \202 ammation, CV disease ). The future Further large, well-designed clinical studies are needed to clarify the safety a nd ef \201 cacy of ESAs. Ideally, target Hb would be individualized, with a risk-bene \201 t assessment based on a patient \200\231 s speci \201 c level of function, life- sty le, and comorbidity. Current targets (see Table 3.8) (cid:2) For now, ESA treatment to Hb targets above 11 \200 \223 12g/dL, particularly in those with signi \201 cant CV morbidity, should be avoided. S ome would go further and suggest that, given current evidence, the use of ESAs should no lo nger be habitual in pre-dialysis patients, especially in relatively asymp- tomatic patients with mild to moderate anemia (Hb 7 9 \200\223 11g/dL), and that large ESA doses should ce rtainly be avoided in this situation. Table 3.8 Guidelines for target indices in CKD-associated anemia Hb target (g/dL) Iron indices KDOQI 11.0 \200\223 12.0 (avoid >13.0) Ferritin >200 micrograms/L (HD) or >100 (non-HD) TSAT >20% UK Renal Association 11.0 \200\223 12.0 Ferritin 200 \200\223 500 micrograms/L (HD) or >100 \200\223 500 micrograms/L (non-HD) TS AT >20% or % HRBC <6% CHAPTER 3 Chronic kidney disease (CKD) 228 Iron: metabolism and markers Key facts \200 Iron is an essential component of haem, so ad equate amounts are obligatory for RBC synthesis. Iron de \201 ciency is found in 7 40% of patients with advanced CKD and virtually all dialysis patients. For optimal RBC production, CKD patients require different targets for iron markers than non-CKD individuals ( b p. 230). \200 ESA treatment leads to almost universal iron de \201 ciency. \200 Iron absorption from the gut is lower in CKD patien ts. Consequently, oral iron is usually ineffective ( b p. 229). Many CKD patients and virtually all dialysis patients require parenteral iron therapy. Iron therapy alone may treat anemia in pre-dialysis CKD patients. Causes of iron de \201 ciency in CKD Absolute iron de \201 ciency \200 Occurs when body iron stores are genuinely low. \200 Characterized by a low serum ferritin. \200 Reduce d intake: Poor appetite. \200 Dietary restrictions. Increased iron loss: GI bleeding (often subclinical). \200 Multiple blood tests. \200 Haemodialysis (may los e up to 2g of iron per year through blood left in the dialyser circuit; 10 \200\223 20 x l osses in general population). Functional iron de \201 ciency \200 Despite adequate storage iron, it is not made availa ble at a rate that satis \201 es demand. This is common when the ESA-driven \200\230 supraphysiological \200\231 rate of erythropo iesis has outpaced the delivery of iron by transferrin. \200 Characterized by a normal or raised ferritin and low TSAT (<20%). Reticuloendothelial ( \200\230 in \202 ammatory \200\231 ) block \200 Occurs with infe ction or in \202 ammation (the \200\230 anemia of chronic disease \200\231 ). \200 Iro n is trapped in the reticuloendothelial system and is not released to transferrin for Hb synthesis. Characterized by i CRP, i ferritin, d TSAT (but current markers are unable to distinguish from functional iron de \201 ciency). Markers of iron status Several markers of iron status are available. Unfortunately, they la ck sensi- tivity and speci \201 city to predict the response to iron therapy in the contex t of CKD. It is generally recommended that ferritin and at least one addi- tional test are used. \200 Ferritin: Cellular storage protein and marker of storage iron. \200 An acute phase protein, raised in in \202 ammation and liver disease. IRON: METABOLISM AND MARKERS 229 TSAT: Transferrin is a serum protein involved in iron delivery. \200 TSAT = (serum iron / TIBC) x 100. \200 A measure of available iron. Percentage hypochromic red blood cells (% HRBC): \200 Measure of the iron incorporated in to RBCs. Reticulocyte Hb count (CHr): Measure of the iron incorporated into immature RBCs. Others: serum transferrin receptor and erythrocyte zinc protoporphyrin levels are mainly research tools at present. Hepcidin This recently described, hepatically synthesized peptide has emerged as a key regu lator of iron homeostasis. \200 Inhibits both GI iron absorption and iron release from th e liver and reticuloendothelial system. Hepcidin exerts its actions through binding to ferroportin, a cellular iron ef \202 ux channel. Binding l internalization and degradation. Animal models: Hepcidin knockout l severe iron overload. \200 Hepcidin overexpression l severe iron de \201 ciency anemia. \200 Human haemochromatosis results from either de \201 ciency or fa iled regulation of hepcidin. Plays a key role in the anemia of CKD, ESA resistance, and the anemia of chronic disease. Synthesis is induced by iron loading and in \202 ammation, and suppressed by erythropoiesi s, iron de \201 ciency, and hypoxia. \200 Iron loading/in \202 ammation l i hepcidin l d GI iron absorption + d hepatic and reticuloendothelial iron release l d plasma iron levels. Erythropoiesis/iron de \201 ciency/hypoxia l d hepcidin l i GI iron absorption + i hepatic and reticuloendothelial iron release l i plasma iron levels. Hepcidin is eliminated by the kidney, so CKD indirectly causes reduced GI iron absorption and iron store availability. Hepcidin levels rise as CKD progresses (highest in dialysis patients). Levels also increase in infection and in \202 ammation. Hepcidin could prove to be a useful marker of iron status: Functional iron de \201 ciency l low hepcidin. \200 Reticuloendothelial blockade l high hepcidin. \200 Levels i with iron loading so may help avoid iron overload. \200 Low hep cidin levels may identify those patients likely to respond to oral iron. The future: hepcidin antagonists could stimulate iron absorption and mobilization, blocking the inhibitory effect of CKD or in \202 ammation on red cell production ( l d parenteral iron administration and d ESA requirement). CHAPTER 3 Chronic kidney disease (CKD) 230 Iron: therapy and targets 2 Prescribing an ESA to an iron-de \201 cient patient is a waste of time and money. Targets \200 Ferritin: >200 micrograms/L (haemodialysis). \200 >100 micrograms/L (non-haemodialysis). \200 Gen erally, aim 200 \200\223 500 micrograms/L. (cid:2) Avoid >800 micrograms/L, i.e. targets well above the normal physiological range. TSAT: >20% (unless ferritin >800 micrograms/L). \200 Generally, aim 20 \200\223 40%. % HRBC: <6% (unless ferritin >800 micrograms/L). \200 Reticulocyte Hb content (CHr): >29p g/cell. Monitoring Measure iron stores 1 \200\223 3-monthly, depending on the clinical situation a nd response to treatment (and no earlier than 1 week after IV iron administration). Oral iron therapy \200 Generally little bene \201 t, particularly in higher CKD stages. \200 Ferrous sulfate 200mg tablets contain just 65mg of elemental iron. \200 GI side ef fects, including nausea, dyspepsia, and constipation, are considerable. Has to be taken as part from mealtimes and phosphate binders \200\224 so challenging for patients already on complex tablet regimens. Compliance is often poor. \200 Some guidelines (e.g. UK Renal Association) suggest \201 rst-line in CKD, but this is rarely the case in practice. Consider a trial in pre-dialysis patients, with iron stores checked after 4 \200\223 6 weeks of treatment. Intramuscular iron (cid:2) Avoid: very painful; causes skin discoloration; CKD bleeding ten dency l haematomas. Intravenous iron \200 Safe and effective. \200 Increases ferritin and TSAT. Decreases E SA requirement. \200 Concerns about iron overload ( l oxidative stress, infection risk, and CV damage) not as strong as previously (provided appropriate monitoring in place). Defer administration if active infection, as potential risk of compromised neutrophil function. Current preparations contain elemental iron enclosed in a carbohydrate shell. IRON: THERAPY AND TARGETS 231 The elemental iron is released to transferrin and then to the reticuloendothelial system for storage. The more stable the preparation, the larger the permissible dose. \200 In haemodialysis p atients, it is practical to give regular low doses of iron, e.g. 100mg weekly. This is obviously less convenient in pre-dialysis or peritoneal di alysis patients. 2 Adverse reactions \200 Free iron reaction: d BP, nausea, vomiting, dizziness, sweating, myalgia, back pain, arthralgia, pruritus. Often less problematic with slower administration. Usually self-limiting, but consider treatment with hydrocortisone and/or antihistamines. 3 Anaphylaxis: risk low, but staff should be appropriately trained and adequate resuscitation facilities immediately available. Preparations of intravenous iron Iron III hydroxide sucrose complex (iron sucrose/saccharat e) \200 Venofer . \200 Low incidence of adverse reactions. Anaphylaxis very rare (0. 05%). \200 Test dose unnecessary. \200 Widely used, particularly in Europe. \200 IV i nfusion or slow IV injection (20mg/min), often diluted in 100mL saline. Typical dosing pre-dialysis or peritoneal dialysis: 200mg every 1 \200\223 3 months (200mg weekly for three doses, if clinical urgency). \200 Haemodialy sis: initially 100mg for ten dialysis sessions. Continue weekly if ferritin <500 micrograms/L. Sodium ferric gluconate \200 Ferrlecit . \200 Anaphylaxis rare. Test dose unnecessar y. \200 Widely used. \200 More iron may be released directly to storage and not to tran sferrin. \200 Usually administered as 62.5 \200\223 125mg IV over 10min on haemodialysis . \200 Diluted for slower administration in pre-dialysis and peritoneal dialysis patients. Iron dextran \200 Higher risk of reactions and anaphylaxis (0.6%), the latter due to the formation of anti-dextran antibodies. Popularity declining in view of this. \200 (cid:2) A test dose is mandatory. \200 Total dose of iron infusions of low MW iron (III) hydroxide dextran complex (Cosmofer ) (e.g. 20mg/kg over 4 \200\223 6h) have been used for more rapid iron repletion and to avoid mul tiple infusions. Newer preparations \200 Include ferric carboxymaltose (Ferinject ) and ferumoxytol (Feraheme ). Both facilitate the delivery of higher doses of iron in a single administra tion. CHAPTER 3 Chronic kidney disease (CKD) 232 CKD mineral and bone disorder (CKD-MBD) De \201 nitions (see Table 3.9) \200 CKD mineral and bone disorder (CKD-MBD) is a relatively new term that describes the mineral, skeletal, and related CV consequences of CKD (particularly CV calci \201 cation). This expanded focus has been driven by observational studies suggesting that CKD-MBD (and its treatment) may impact on CV morbidity and mortality. Vascular disease is common and progresses rapidly in CKD, particularly at stage 5 \200\224 usually occlusive lesions due to atheromatous plaques. Th e full spectrum of arterial disease in CKD is broader, however, including vessel wall calci \201 cation with resulting impaired vascular function. Renal bone disease (osteodystrophy) is reserved to describe the bone pathologies associated with CKD. Osteodystrophy is a heterogeneous disorder that ultimately leads to diminished b one strength. CKD-MBD is invariably present beyond CKD 3, and its management represents a signi \201 cant clinical challenge. There is no single therapeutic intervention that \201 ts all \200\224 instead, a package of management, customized to the individual patient, is necessary. Several important international practice guidelines have been formulated to help inform the optimal treatment of CKD-MBD ( b p. 244). Table 3.9 KDIGO a classi \201 cation of CKD-MBD and renal osteodystrophy De \201 nition of CKD-MBD A systemic disorder of mineral and bone metabolism due to CKD, manifested by either one or a combination of the following: \200 Abnormalities of calcium, phosphorus, PTH, or vitami n D metabolism. \200 Abnormalities of bone turnover, mineralization, volume, linear growt h, or strength. Vascular or other soft tissue calci \201 cation. De \201 nition of renal osteodystrophy \200 Renal osteodystrophy is an alteration of bone morphology in patients with CKD. \200 It is one measure of the skeletal component of the systemic disorder that is quanti \201 able by histomorphometry of bone biopsy material. a KDIGO, Kidney Disease: Improving Global Outcomes. KDIGO clinical practice guidelines for the diagnosis, evaluation, prevention and treatment of chronic kidney disease-mineral and b one disorder (CKD-MBD) (2009). Kidney Int , 76 (Suppl 113), 1 \200\223 132. Classi \201 cation (See Fig. 3.4) CKD MINERAL AND BONE DISORDER (CKD-MBD) 233 y t i l a u q l a c g o o d o h t e M i d e h s i l l y a r - X y g r e n e - l a u d , L O Q b a t s e - l l ; d n u o s a r t l u e v i t a t i t n a u q . 2 3 1 \200\223 1 e w t n e s e r p e r , 3 1 1 S , 6 7 , A X D s w o r r a d ; e s a e s i d r a l u c s a v o d r a c l a n o i t a n r e t n , S U ) q ( i l o S . t s e r e t n ; I T C e v i t a t i t n a u q y e n d K m o r f i i i f o n o i t s e u q a o t d n o p s e r r o c d n a , D V C d e c u d o r p e R , . T C ) q ( y t n a t r e c i ; T C e c i l s i t l u m r e t a e r g h t i . D B M D K C w d e h s i l , T C S M f o t n e m t a e r t d n a s p h s n o i t a l e r i b a t s e e b o t d e e n t a h t ; s s e n k c h t . p u o r G g n h s i l i t n e s e r p e r l a d e m , n o i t n e v e r p i i l a m s w o r r A b u P e r u t a N m o r f n o i s s i i t n s n o i t a c o s s a , n o i t a u l a v e i , T M i . m g d a r a p g n g r e m e n a I ; T C m a e b n o r t c e e i t n e s e r p e r , s i s o n g a d e h t i i m r e p h t i s w o r r a d e h s a D l r o , T C B E f : D B M D K C O G D K m o r F w , ) 9 0 0 2 ( I ; y r t e m o i t p r o s b a . s n o i t a c o s s a , h c a o r p p A 4 3 . . i e f i l . g i F f o CHAPTER 3 Chronic kidney disease (CKD) 234 CKD-MBD: bone disease Osteodystrophy is a function of bone turnover, mineralization, and vo l- ume. Strictly speaking, bone biopsy (usually from the iliac bone) with his- tological an d histomorphometric assessment is required for diagnosis and classi \201 cation. In practi ce, biopsies are very rarely performed (invasive, with considerable expertise needed to int erpret), and surrogate markers of bone turnover are 6 (over) relied on (see Table 3.10). Se e Fig. 3.5 for the spectrum of renal bone disease. Secondary hyperparathyroidism (SHPT) i PTH causes i bone resorption and formation ( \200 \230 high turnover \200\231 disease). Haphazardly organ- ized, weakened bone results (clas sically, osteitis \201 brosa cystica). Adynamic bone disease Paucity of cells with d bone resorption and formation ( \200\230 low turnover \200\231 disease). Pathophysiology rema ins poorly understood, but incidence has i rapidly over the last two decades. Mixed uraemic osteodystrophy This is also relatively common, as is evolution from one form to another. Osteomalacia This refers to a defect in mineralization. Uncommon as an isolated \201 ndin g and not helpful as a clinical description in this situation. Generally related to a de \201 ciency of 1,25(OH) 2 D, but aluminum intoxication and uraemic acidosis are also import ant risk factors. Osteoporosis Usually de \201 ned in terms of bone mineral density (BMD) so has little diag nos- tic meaning in the context of osteodystrophy where low BMD can coexist with low or hig h turnover disease. DEXA (dual-energy X-ray absorptiom- etry) scanning does not predict fra cture risk in advanced CKD so is of lim- ited clinical utility in this setting (stages 4 \200\223 5D). Stage 3 CKD encompasses large numbers of patients, many with age-related decl ines in GFR, who will exhibit a mixed bag of skeletal pathologies (including mild SHPT, ost eopo- rosis, and vitamin D de \201 ciency). Extrapolating general management from the non- CKD population is 6 dif \201 cult (and not evidence-based), and the role of anti-resorptiv e agents, such as bisphosphonates, is uncertain. One approach is to gather a dataset of Ca 2+ , PO 4 , PTH, serum 25(OH) 2 D, and BMD. Any abnormalities of mineral metabolism can be addressed as described over the next few pages. If none exists, then low BMD can be treated as for non-CKD patients. Stages 1 \200\223 2 CKD should be treated as per the non-CKD pop ulation. Factors contributing to adynamic bone disease Low PTH. \200 Aluminum accumulation. \200 Acidosis. \200 CAPD. Overtreatment with vitamin D. \200 i calcium intake. \200 Diabetes mellitus. \200 Age . CKD-MBD: BONE DISEASE 235 Calcium containing binders, vitamin D, ?calcimimetics \200\230Low turnover \200\231 \200\230High turnover \200\231 PTH <100pg/mL 150 \200\223300pg/mL >450pg/mL Adynamic bone Normal bone turnover Mild SHPT Osteitis fibrosa Osteomalacia Fig. 3.5 The spectrum of renal bone disease. Table 3.10 Features of \200\230 high \200\231 and \200\230 low turnover \200\231 renal bone disease High turnover Hyperparathyroid bone disease i osteoblast and osteoclast activity Fibrosis Low turnover Adynamic bone disease d osteoblast and osteoclast activity Thin osteoid seams Osteomalacia d osteoblast and osteoclast activity Widened osteoid seams Aluminum deposition Bone biopsy \201 ndings PTH High Low or normal Usually low or normal Alkaline phosphatase Raised Normal Normal Often i Normal or i Calcium Variable i i Normal or i 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.