HIF-alpha HRE Epo gene Fig. 11.8.1 Oxygen sensing and regulation of the erythropoietin gene. Table 11.8.1 Causes of anemia in CKD Erythropoietin de \201 ciency Decreased red cell survival \200 Chronic uremic hemolysis \200 Gastric antral vascular ectasia or other GI loss \200 Hemodialysis Decreased bone marrow response \200 Absolute iron de \201 ciency \200 Functional iron de \201 ciency \200 \200\230Uremic inhibit ors \200\231 \200 Aluminum toxicity Relating to underlying disease \200 Myeloma \200 SLE \200 Amyloid \200 Sickle cell Relating to treatment \200 Immunosuppressant therap y \200 Idiosyncratic reactions Concurrent unrelated disease \200 Pernicious anemia \200 Hemoglobinopathies \200 Celiac disease \200 Hypothyroidism M. HALL 428 In practice, patients are usually started on a dose of ESA that corresponds as closely as p ossible to one of the avail- able pre \201 lled syringes. Higher initial doses may be appr opriate in severe anemia (hemoglobin <8.0 g/dL). Darbepoetin-A has two additional glycosyla tion chains and eight additional sialic acid residues making it more resistant to metabolic degradation. One microgram of darbepoetin-A is approximately bioequivalent to 200 U of epo etin-A, -B and -D. Mircera (methoxy-polyethylene glycol \200\223epoetin-B) is a continuou s erythropoietin receptor activator which has a longer biological half-life allowing monthl y dosing. Newer ESAs in development include: \200 \200 \200 Serum iron measurement is effectively obsolete as the amounts present are minute and quanti ties are markedly labile. Serum ferritin offers an estimation of reticuloendothelial iron, the predominant source of stored iron. Ferritin may be elevated in infection, in \202 amma tion, malignancy or liver disease, independent of iron stores. A low ferritin is diag- nost ic of iron de \201 ciency Transferrin acts as a binding protein to transportation iron to bone marrow. The percentage of transferrin saturated with iron (TSAT) reveals the balance b etween iron supply and demand. The percentage of red cells which are hypochromic is more se nsitive at con \201 rming iron de \201 ciency but is less available. Reticulocyte hemoglo bin concentration is a more accu- rate assessor of functional iron status but, again, this is not widely available. Oral supplemental iron is rarely adequate to maintain erythropoies is in CKD. Tolerability is limited by gastroin- testinal side-effects. Interaction with pho sphate binders in the gut limits iron bioavailability. IV iron preparations are more effect ive in increasing meas- urements of iron store availability and attaining hemo- globin targ et. Newer preparations have a low incidence of side-effects. biosimilars/generic ESAs (e.g. epoetin-G); erythropoietin-mimetic peptides (hematide); oral agents which inhibit hydroxylation of HIF-A. Clinical bene \201 ts of ESAs include: \200 increased exercise tolerance; \200 decreas ed angina episodes; \200 decreased left ventricular hypertrophy; \200 improved quality of life; \200 improved cognitive function. Inadequate correction of anemia limits these bene \201 ts. Conversely, correction of anemi a to \200\230normal values \200\231 may lead to increased cardiovascular morbidity. ESA resistance An inadequate response to ESA may be caused by: \200 \200 \200 \200 \200 \200 \200 Treatment guidelines There is slight variation between the various national and internation al guidelines for the management of renal ane- mia and these are summarized in Table 11.8.4 . Assessment of response to treatment by hemoglobin concentration measurement is recommende d every 2 weeks until target hemoglobin is reached with a stable ESA dose. Hemoglobin conce ntration should not rise by >2 g/dL/ month. When hemoglobin is stable, hemoglobin concentra tion should be checked every 1 \200\2232 months and ESA dose adjusted accordingly (Fig. 11. 8.3). absolute or relative iron de \201 ciency; in \202 ammation; underdialysis; hyperparathyro idism; malignancy; other hematinic de \201 ciencies; aluminum toxicity. Acute illness in patients with advanced CKD frequently precipitates anemia. Increasing ESA dose is rarely effective and blood transfusion may be required. Side-effects of ESA therapy ESA therapy may be associated with: \200 \200 \200 \200 \200 hypertension; vascular access thrombosis; encephalopathy; in \202 uenza-like symptoms; hyp erkalemia. Iron Erythropoiesis requires 30 \200\22340 mg of iron per day. In the steady state this is available from red cell destruction. During the correction phase of anemia supplemental iro n is required. Insuf \201 cient availability of iron is the most common cause of an inadeq uate response to ESA therapy. Absolute iron de \201 ciency occurs when iron loss, usually as a result of blood loss, exceeds the erythropoietic requirement. Functional iron de \201 ciency is a result of inadequate mobili- zation of iron from stores to bone marrow. Target values for iron stores are higher in CKD than those regarded as normal in the non-CKD popu lation (Table 11.8.4). Measurement of iron stores is challenging (Fig. 11.8.4). Iron staini ng of bone marrow is widely quoted as the \200\230gold standard \200\231 but is invasive. Iatrogenic polycythemia should be avoided. Pure red cell aplasia is a rare complication of ESA therapy characterized by: \200 \200 antibodies against EPO; absent erythropoiesis on bone marrow examination and very low retic ulocyte count; ESA resistance; transfusion-dependent anemia. \200 Immunosuppressive regimes using corticosteroids and cyclophosphamide, ciclosporin and ritux imab have led to the disappearance of anti-EPO antibodies in some patients. Reintroduction of ESA therapy may be successful in those without measurable antibody titers following trea tment. CHAPTER 11.8 Hematological disorders in chronic kidney disease 429 Table 11.8.3 Recommended dosing for ESA therapy ESA Epoetin-A Initiation Maintenance 50 U/kg 3 times per week 1 \200\2233 times/week Epoetin-B 20 U/kg 3 times per week 1 \200\2233 times/week 50 U/kg 3 times per week (IV) 2 times per week (SC) 1 \200\2233 times/week Epoetin- Darbepoetin 450 ng/kg Once per week Weekly or fortnightly (or monthly if predialysis) Mircera Monthly 0.6 g/kg Once per 2 weeks 10000 1000 Serum erythropoietin (mU/ml) 100 10 4 5 6 7 8 10 Hemoglobin (g/dl) 9 11 12 13 14 15 16 Fig. 11.8.2 Relationship between serum erythropoietin levels and hemoglobin in patients wit h normal renal function. Table 11.8.4 Guidelines for target indices in managing renal anemia Hb 11.0 \200\22312.0 g/dLa European Best Practice Guidelines (2004) Ferritin >100 ng/ml TSAT >20% or hypochromic red cells <10% or CHr >29 pg/cell NICE (2006) Hb 10.5 \200\22312.5 g/dL Ferritin 200 \200\223500 ng/mL TSAT >20% or hypochromic red cells <6% Renal Association (2007) Hb 10.5 \200\22312.5 g/dL Ferritin 200 \200\223500 ng/mL (HD) or 100 \200\223500 ng/mL (non-HD) TSAT >20% or hypochro mic red cells <6% NKF-K/DOQI (2007) Hb 11.0 \200\22312.0 g/dL Ferritin >200 ng/mL (HD) or >100 ng/mL (non-HD) TSAT >20% or CHr >29 pg/cell a Target Hb up to 14.0 g/dL for patients with chronic obstructive pulmonary disease. Hb, hemoglobin; TSAT, transferrin saturation; CHr, reticulocyte hemoglobin concentration; H D, hemodialysis. M. HALL 430 Measure Hb Hb <11g/dl Hb 11-12g/dl Hb 12-15g/dl Hb >15g/dl Increase ESA by 25%-50% unless Hb rising by >1g/dl/month Decrease ESA by 25%-50% unless Hb falling by >1g/dl/month No change unless Hb rising by >1g/dl/month Decrease ESA by 50%-100% and repeat Hb in 2 weeks Fig. 11.8.3 Adjusting ESA dosage. Oral intake Total body iron: 4 to 5 g Small bowel absorption Red cells Hemoglobin (65%) Plasma Transferrin (0.1%) Tissue Free iron Ferritin (30%) Heme compounds (0.9%) Myoglobin (4%) Fig. 11.8.4 Iron utilization. CHAPTER 11.8 Hematological disorders in chronic kidney disease 431 ESA therapy and tumor progression The use of ESAs in treating anemia associated with malig- nancy has shown an increase in the rate of tumor progres- sion in some patients. Increased rates of malignancy in patients with CKD treated with ESAs have not been identi \201 ed. Platelet function improves after: \200 \200 \200 correction of anemia; adequate renal replacement therapy; desmopressin. Desmopressin promotes the release of preformed von Willebrand factor and can improve platel et function for up to 4 h. Treatment is with 0.2 \200\2230.3 g/kg of desmopressin IV prio r to renal biopsy or surgery. Other therapies Patients with profound symptomatic anemia or ESA resist- ance may bene \201 t from blood transfusion. Repeated trans- fusions can be complicated by: \200 \200 \200 Leukocyte abnormalities Functional defects of humoral and cellular immunity are common with uremia. Phagocytic activity of circulating neutrophils is decreased and rates of lymphocyt e matura- tion and activation are reduced. Adequacy of dialysis does not correlate with rec overy of leukocyte function. Vaccination in patients with advanced renal insuf \201 ciency is often unsuccessful. Lymphoid and myeloid suppression may also be associated with underl ying disease and its treatment, including: \200 \200 \200 \200 \200 iron overload; transmission of bloodborne infections; HLA sensitization. Androgens stimulate endogenous EPO production and can decrease ESA requirements and blood t ransfusions. They have limited ef \201 cacy, however, and treatment can be com- plicated b y hepatobiliary disease, virilization and muscle damage. Polycythemia Excess erythrocyte production is uncommon in patients with failing renal funct ion. Increased EPO secretion may be associated with: \200 autosomal dominant polycystic k idney disease; \200 hydronephrosis; \200 renal cell carcinoma; \200 simple renal cyst s. SLE; rheumatoid arthritis; myeloma; human immunode \201 ciency virus; hepatitis C. Further reading Dr eke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006; 355; 2071 \200\22320 84. The etiology is unclear, although local tissue hypoxia sec- ondary to structural changes ha s been implicated. Mannucci PM, Remuzzi G, Pusineri F, et al. Deamino-8-D-arginine vasopressin shortens the bl eeding time in uraemia. N Engl J Med 1983; 308: 8 \200\22312. Post-transplant polycythemia Up to a \201 fth of patients develop polycythemia following renal transplantation. This can be secondary to increased bone marrow sensitiv- ity, or to recovery of the hypoxic response of \201 broblasts in the native kidney leading to excess EPO synthesis. Treatment with ACEIs is effective at reducing the poly- cythemic response. Venesection is recommended if the hematocrit remains >50%. Ratcliffe PJ. Understanding hypoxia signaling in cells \200\223 a new thera- peutic opportunity? Clin Med 2006; 6: 573 \200\223578. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidn ey disease. N Engl J Med 2006; 355; 2085 \200\2232098. Internet resources Renal Association Clinical Practice Guidelines: http://www.renal.org/pages/pages/clinical- affairs/guidelines.php National Kidney Federatio n Dialysis Outcomes Quality Initiative (NKF-KDOQI): Platelet dysfunction Impaired platelet function in renal impairment is character- ized by: \200 http://www.kidney.org/professionals/kdoqi/ European Best Practice Guidelines: impaired von Willebrand factor-dependent platelet aggregation; impaired endothelial adhesio n; reduced thrombopoiesis and decreased mean platelet half-life. http://www.ndt-educational.org/guidelines.asp National Institute for Clinical Excellence: \200 http://www.nice.org.uk/ Thrombocytopenia is uncommon but may be associated with hepatitis C infection or following heparin exposure in hemodialysis. By contrast, platelet dysfunction is common in patients w ith CKD and manifests as bruising, purpura and epistaxis. Platelet function is further impa ired by aspirin, dipyrida- mole or heparin. Platelet count and coagulation cascade studies do not reveal abnormal platelet function. See also Coagulation disorders in CKD, p. 444 Immune function in CKD, p. 440 Medical manage ment of dialysis patients, p. 528 A. HUTCHISON 432 Skeletal disorders in chronic kidney disease In CKD, de \201 ciency of 1A-hydroxylase results in calcitriol de \201 ciency. If not rep laced this results in: \200 \200 \200 Introduction Renal bone disease (osteodystrophy) has its origins early in the course of CKD , so that by the time GFR has fallen to 50% of normal (CKD 3), 50% of patients have abnorm al bone histology. This approaches 100% in patients by the time of starting dialysis (CKD 5 ). Disordered skeletal metabolism is associated with an increased risk of cardio- vascular disease. reduced dietary calcium uptake; hypocalcemia and PTH stimulation; failure to directly suppr ess parathyroid cells. Vitamin D also has immunoregulatory functions and may be involved in immune surveillance fo r tumor cells. Parathyroid hormone and calcium PTH is a single-chain protein of 84 amino acids, synthesize d in the parathyroid chief cell. Increased secretion increases both number and activity of osteoclasts and osteoblasts. PTH secretion is: \200 Bone as a tissue The skeleton is continually remodeled in health, with a bal- ance between synthesis, mineralization and resorption. Bone is formed from parallel bundles of collagen, calci \201 ed by \201 xation of hydroxyapatite crystals. There are three main cell type s in bone: \200 \200 controlled by the concentration of ionized calcium, so hypocalcemia stimulates, and hyperca lcemia suppresses, PTH levels; stimulated by hyperphosphatemia; suppressed by oral or IV vi tamin D, via receptors on par- athyroid cell nuclei, and by severe hypomagnesemia. osteoblasts (build new bone) at bone surfaces; osteoclasts (cut into and resorb bone) relea sing calcium and phosphate; osteocytes buried within calci \201 ed bone, connected to one another by micro \201 laments within canaliculi. \200 PTH is incompletely metabolized in CKD 4/5 so that PTH fragments accumulate and may give fa lse readings with cer- tain PTH assays. Mild elevations of PTH are evident even at a GFR of 60 mL/min. Classi \201 cation of skeletal lesions Little is known about skeletal lesions in CKD 3 and 4, but most patients have abnormal histology in CKD 5. There are three main diagnostic gro ups: High turnover lesions Associated with high PTH, hyperactive bone cells and excess bone reso rption. Phosphate Hyperphosphatemia is associated with vascular and cardiac calci \201 cation and mortality. Increased serum phosphate levels: \200 Low turnover lesions Associated with normal or low PTH and little or no bone cell activity (adynamic bone). suppress 1A-hydroxylase activity and therefore vitamin D production; directly stimulate PTH production; stimulate mineralization of vascular tissue in vitro. Mixed lesions Features of high and low turnover, and no correlation with PTH levels. In add ition, elderly patients, or those exposed to steroids, may have superimposed osteoporosis. Osteomalacia due to aluminum deposition or vitamin D de \201 ciency is now rare except in certain ethnic groups. \200 Magnesium Levels tend to be elevated in CKD, but overall importance unclear. Low magnesium levels are uncommon in CKD, but: \200 \200 moderate hypomagnesemia stimulates PTH production; severe hypomagnesemia inhibits PTH produ ction. Pathogenesis Control of bone metabolism is incompletely understood, even in health, and the refore many aspects of renal bone disease remain controversial. It is multifactorial, and d ependent on complex interactions between: \200 \200 \200 \200 \200 Acid \200\223base balance Acidosis tends to stimulate PTH production and osteoclast activit y. Treatment with sodium bicarbonate can reduce PTH levels by up to 20%. Clinical features History Important factors to consider include: \200 \200 \200 \200 \200 \200 vitamin D metabolism; PTH & calcium; phosphate; magnesium; acid \200\223base balance. gender; menopausal status; duration of renal impairment; chronic back pain; previous fractu res with minimal trauma; drug history (steroids, ciclosporin, thyroid hormone, anticonvulsa nts, heparin); alcohol intake. For simplicity each will be considered individually: Vitamin D de \201 ciency Vitamin D3 (calciferol) circulates in the blood bound to vitamin D-binding protein, and is metabolized in the liver by vitamin-D-25-hydroxylase to form 25-( OH) vitamin D. In the kidney 25-(OH) vitamin D is further metabolized by 1A-hydroxylase to form 1,25-(OH)2 vitamin D3 (calcitriol), the biologically active form of vitamin D. CHAPTER 11.9 Skeletal disorders in chronic kidney disease 433 It is relatively invasive, and requires two doses of tetracy- cline at 14 days and 4 days b efore the biopsy, which appear in the bone as discrete bands on \202 uorescent microscopy , enabling measurement of bone growth rates. It can be helpful, but few laboratories have t he expertise to process and analyze biopsies so it is only routinely used within research p rojects. Symptoms and signs Low turnover lesions are usually asymptomatic, but osteo- malacia and ad vanced high turnover lesions with very high PTH cause nonspeci \201 c symptoms such as pro ximal muscle weakness and fatigue. High PTH also causes: \200 \200 \200 depression; limb and abdominal aches and pains; tendon ruptures. Treatment By controlling serum values of various ions and molecules, mineral metabolism can be in \202 uenced. Many guidelines exist but almost all are based on opinion. Signi \201 cant differences exist between UK and US practice. Table 11.9.1 summarizes UK Renal Associ ation guidelines. In CKD 5, management is dif \201 cult unless dialysis adequacy is approp riate and basic dietary advice is being followed. Currently only 10% of dialysis patients achieve all targets simultaneously. Once adequate dialysis and dietary management are in pl ace almost all patients require pharmacological interven- tion too. If phosphate remains ve ry high with adequate doses of phosphate binder, severe high turnover bone lesions should b e considered as a possible cause, not dietary intake. Table 11.9.2 summarizes the assessmen t and treatment of the patient with CKD 5 and suspected disorder of bone and mineral metabo lism. Available agents include: Unless the patient has severe hyperparathyroidism it is unlikely that there will be signs o n examination, but estab- lished osteoporosis may be evident, particularly in elderly femal es. Investigations Few CKD patients undergo formal skeletal assessment despite being high risk for a variety of skeletal problems including osteoporosis. Parathyroid hormone Measurement of circulating PTH is the most useful method of assessing b one turnover rate. Measurement of PTH every 3 months is usual in dialysis patients. Measure ment of PTH should also be considered in earlier stages of CKD (CKD 4 and possibly CKD 3) a lthough opinion varies about the required frequency and utility of this. There is no indica tion to measure PTH in CKD 1 or 2 in the absence of a suspected disorder of bone and minera l metabolism. Older assay methods detect PTH fragments as well as whole PTH molecules, but values still appear to re \202 ect bone turnover. Values between 0 and 2 \227 upper limit of normal (ULN) sug- gest a low turnover lesion. Values >8 \227 ULN suggest a high turnover lesion. Values between 2 and 8 \227 ULN on a single measurement are unhelpful; the trend m ay help to guide treatment. Oral sodium bicarbonate Usually not required in PD patients, but may be required to maintai n serum bicarbonate within the normal range in HD patients and CKD 4/5. Oral phosphate binders These must be in the stomach with food to bind phosphate and reduce serum levels. As many patients only eat two main meals per day, twice daily dosing is commo n, divided 2/3 and 1/3 in proportion to meal size. All binders cause GI side-effects in up to 20% of patients. Calcium, phosphate and alkaline phosphatase In high turnover bone lesions, serum calcium an d phos- phate may be elevated because of release from the skele- ton by overactive osteocla sts, rather than dietary intake. In low turnover adynamic lesions, hypercalcemia is com- mo n because excess calcium cannot be incorporated into bone by inactive osteoblasts. Alkaline phosphatase is produced by intestine, liver and bone, so does not correlate well with bone turnover. The bone-speci \201 c isoenzyme gives a better correlation but is not used in r outine practice. Aluminum hydroxide Effective but signi \201 cant toxicity limits usefulness. Requires 3-mo nthly serum aluminum monitoring. Avoid if possible. Inexpensive. Calcium carbonate/acetate Effective binders but increasing (unproven) concern exists about calcium loading contributing to cardiovascular mortality. Avoid if there is hypercalcemia. Inexpensive. Radiology, bone density and isotope studies Skeletal surveys are not regularly used to moni tor osteod- ystrophy, except when myeloma is suspected. Plain radiographs will only detect advanced osteodystro- phy, but will reveal vascular calci \201 cation. DEXA measurement of bone density at the start of dialysis is useful if locally available, so that sequential s tudies enable meaningful monitoring of change. Sevelamer hydrochloride \200 \200 Large doses and pill burden may be required. Expensive. Lanthanum carbonate \200 \200 Bone biopsy Transiliac bone biopsy is the only way to accurately diag- nose the type and se verity of osteodystrophy. Effective with reduced pill burden. Expensive. A. HUTCHISON 434 Table 11.9.1. UK Renal Association targets for calcium, phosphate, PTH and calcium phosphat e product in CKD Serum calcium CKD 1 \200\2234 Should be maintained within the local laboratory \200\231s normal range. Hypercalcemia will accelerate loss of renal function. CKD 5 Should be maintained within the local laboratory \200\231s normal range (albumin-corrected, measured before a \200\230short gap \200\231 dialysis session in HD patients). Ideally ke ep <2.5 mmol/L. Higher values are associated with vascular calci \201 cation and (in retrospective studies only) increased mortality. Serum phosphate CKD 1 \200\2234 Should be maintained between 0.9 and 1.5 mmol/L: dietary restriction initially. CKD 5 Should be maintained between 1.1 and 1.8 mmol/L (measured before a \200\230short gap \200 \231 dialysis session in HD patients). Ideally keep <1.4 mmol/L. Higher values are strongly associated with vascular calci \201 cation and (in retrospectiv e studies only) increased mortality. Values <1.0 mmol/L suggest poor nutrition and should p rompt dietetic review. Phosphate clearance can be improved by intensifying the dialysis regimen. Slow prolonged dialysis (>8h at night) or daily dialysis increases phosphate removal. However, these options may be feasible only for patients on home dialysis. Should be maintained <4.8 mmol2/L2 (with comment now in brackets underneath) (If the calciu m and phosphate are within the desired ranges, then the product will be also, and calculati ng the product is probably unnecessary. \200\223 authors opinion) Calcium \227 phosphate product Parathyroid hormone UK target ranges for CKD, and post transplant, as follows: CKD 1 \200\2233 CKD 4 Within the normal range. Between the ULN and 2 \227 ULN. Between 2 and 4 \227 ULN. CKD 5 ULN, upper limit of normal. Pulse therapy probably has a less hypercalcemic effect and achieves higher serum calcitriol levels. Vitamin D analogs Vitamin D therapy is used to reduce PTH levels. A signi \201 cant side-e ffect is increased intestinal absorption of calcium and phosphate which may aggravate skele tal problems. Care must be taken not to oversuppress PTH and push the skeletal lesion towar ds adynamic bone. Although newer expensive vitamin D analogs (e.g. pari- calcitol) are said to have advantages over calcitriol or alfa- calcidol, this remains to be proven. No prospe ctive outcome studies have shown bene \201 t. Bisphosphonates These can be used for osteoporosis if GFR >30 mL/min. Bone biopsy recommend ed before use. If GFR <30 mL/min, risks need to weighed against bene \201 ts, but remember that major fractures can be fatal. Parathyroidectomy and calcimimetics Surgical parathyroidectomy is indicated for treatment o f symptomatic uncontrollable, tertiary hyperparathyroidism. Features include: \200 \200 \200 \200 CKD 3 \200\2234 Current UK recommendation is that if the PTH is above target range, 25-(OH) vitamin D levels should be meas- ured and replacement therapy started if <75 nmol/L. Many laboratories are unable to provide the 25-(OH) vitamin D assay so the recommendation is var iably applied. NICE is currently reviewing guidelines for the investigation and management of patients with CKD (available 2008). bone pain, anemia, malaise; PTH >10 \227 ULN and rising; calcium and phosphate uncontrolled ; calci \201 c uremic arteriolopathy (calciphylaxis). Surgery can be subtotal, total, or total with some tissue reimplanted in a limb. Perioperat ive risk is greater in people with CKD, and there is the risk that any remaining parathyroi d tissue may become hyperplastic and require repeat surgery. CKD 5 Calcitriol or alfacalcidol therapy suppresses PTH in dialysis patients, and can be us ed in two ways. If serum calcium <2.3 mmol/L: \200 Cinacalcet Cinacalcet is a calcimimetic which increases the sensitivity of calcium-sensing receptors to extracellular calcium ions, inhibiting the release of PTH. The starting dose i s 30 mg daily, titrated every 2 \200\2234 weeks to maximum of 180 mg daily, to achieve the target level of intact PTH. give daily oral dosages (250 \200\223500 ng) to raise calcium towards 2.5 mmol/L If serum calcium >2.3 mmol/L: \200 try twice weekly \200\230pulse therapy \200\231 (1.0 \200\2232.0 g) either orally or IV and monitor effect on calcium and PTH. CHAPTER 11.9 Skeletal disorders in chronic kidney disease 435 It is usually associated with severe hyperphosphatemia in CKD 5. Occasionally it may be mis taken for osteosarcoma. It will regress if phosphate and calcium can be tightly con- trolle d to <1.4 and <2.5 mmol/L respectively. Table 11.9.2. Management of mineral metabolism in CKD stage 5 History Review skeletal history: gender, age, fractures Review previous drug history, especially steroid use if previously received renal transplan t Check for symptoms of skeletal disease, including non-speci \201 c aches/pains and depre ssion Calci \201 c uremic arteriolopathy This is a rare complication that can occur in people wi th CKD 5, usually with severe hyperparathryoidism. It causes painful, purple/red cutaneous nodules (singular or numerous). It progresses rapidly to ulceration, necrosis and sepsis of the skin and subcutaneous tissues. Skin biopsy may make ulceration worse. Mortality is hig h at 50%, but it may respond to tight phosphate control and parathyroidectomy or cinacalce t treatment. Examination Vertebral collapse: \200\230Dowager \200\231s hump \200\231 Proximal muscle we akness Initial radiology Plain radiographs of hands and pelvis Look for vascular calci \201 catio n Consider DEXA bone density measurement Biochemistry targets Serum calcium within normal range, ideally <2.5 mmol/L Serum phosphate 1.1 \200\2231.8 mmol/L Serum PTH 2 \200\2234 \227 ULN General interventions Arrange approp riate dietary modi \201 cation Ensure dialysis adequacy is optimal Check dialyzate calcium concentration is appropriate Future prospects There is a pressing need for randomized prospective out- come studies in C KD to examine cost:bene \201 t ratios of newer expensive pharmacological agents, as well a s bene- \201 ts of phosphate and PTH control (currently unproven). Measurement of vascula r calci \201 cation (with latest genera- tion CT scanners or possibly plain X-ray) may ide ntify patients who should avoid calcium-containing phosphate binders. New oral noncalcium p hosphate binders are in develop- ment including magnesium iron hydroxycarbonate and fer- ri c citrate (both effective in phase II studies). Prevention of intestinal phosphate absorpti on may be pos- sible in the future by blockade of the ileal sodium-depend- ent phosphate co transporter. Pharmacological interventions Oral sodium bicarbonate to correct venous serum bicarbonate O ral phosphate binder taken with main meals If PTH >4 \227 ULN give alfacalcidol: \200 0.25 g daily if serum calcium <2.3 mmol/L \200 2.0 g twice weekly if serum calcium >2.3 mmol/L Monitoring Monthly biochemistry if on hemodialysis 1 \200\2233-monthly biochemistry if on P D PTH check every 3 months, and look at trend Further reading Favus MJ (ed.). Primer on the metabolic bone diseases and disorders of mine ral metabolism, 6th edn. American Society for Bone and Mineral Research; 2006. Education Educate patient regarding signi \201 cance of biochemistry results Review adhere nce to diet, dialysis, drugs Review latest results with patient Bushinsky D (ed). Renal osteodystrophy. Philadelphia: Lippincott \200\223 Raven Press; 1998. Internet resources UK Renal Association Mineral Bone Disease Guidelines: NICE guidelines (UK) on its use are: Not recommended for the routine treatment of secondary hyperparathyroidism in patients with ESRD on mainte- nance dialysis therapy. Recommended f or the treatment of refractory secondary hyperparathyroidism in patients with ESRD (includi ng those with calciphylaxis) only in those: \200 http://www.renal.org/guidelines/module2.html The National Kidney Federation Dialysis Outcom es Quality Initiative Bone and Mineral Metabolism Guidelines: http://www.kidney.org/professionals/kdoqi/ guidelines_bone/index.htm European Best Practice Guidelines: with \200\230very uncontrolled \200\231 plasma levels of PTH (>85 pmol/ L (800 pg/mL)) and refractory to standard therapy, and a normal or high adjusted serum calcium level, http://www.ndt-educational.org/guidelines.asp National Institute for Health and Clinical Ex cellence (NICE): and \200 in whom surgical parathyroidectomy is contraindicated, in that the risks of surgery are con sidered to outweigh the bene \201 ts http://www.nice.org.uk See also Medical management of dialysis patients, p. 528 Cardiovascular risk factors in CKD , p. 412 Treatment should be continued only if a reduction in PTH of \211 30% is seen within 4 mont hs. Tumoral calci \201 cation This is often periarticular, and occasionally associated with ac ute periarticular in \202 ammation. R. BAINES 436 b2-Microglobulin amyloidosis in chronic kidney disease B2-Microglobulin amyloidosis (AB2M) is a systemic disor- der characteristically observed in individuals with chronic uremia. Th e hallmark of the disease is the abnormal tissue deposi- tion of amyloid \201 brils of wh ich the primary constituent is B2-microglobulin (B2M). The underlying process is unaffected by mode of dialysis and potentially AB2M can be detected in predialysis patients. AB2M car ries with it a signi \201 cant morbidity and mortality to patients with ESRD although chan ges in practice are aiming to reduce its burden. Understanding the early pathological chang es is crucial and makes this a fertile research \201 eld. An interaction between advanced glycation end-products (AGE) and B2M has been reported resu lting in activation of the receptor for AGE (RAGE) and a variety of intracel- lular signali ng processes. This occurs prior to the histologi- cal detection of AB2M. If pathophysiologi cally relevant processes are active before clinical disease becomes apparent, new therapies may be able to interrupt the long term effects of AB2M. Epidemiology This is markedly dependent upon the time spent on dialysis. Post-mortem studie s indicate a prevalence of 20% after 1 year on dialysis rising to >90% after 9 years. Clin ical or radiological features are unlikely before 5 years on dialysis but then rise to 50% at 15 years. Histological detection is much greater than that found on clinical or radiolo gical grounds. Changes in practice would imply that greater clearances of B2M will result i n a falling prevalence. Pathogenesis B2M is a nonglycosylated polypeptide of 11.8 kDa. It is a component of the cla ss I major histocompatibility complex and is present on the cell surface of virtually all n ucleated cells. Clearance occurs by glomerular \201 ltration followed by proximal tubular cell (PTC) uptake and catabolism. A raised serum level of B2M is a prerequisite for AB2M f ormation. This can result from increased production or decreased clearance of the molecule. Causes of increased B2M production include: \200 Clinical features The major clinical features of AB2M relate to the muscu- loskeletal syste m. Carpal tunnel syndrome (CTS) This is one of most frequently encountered manifestations of A B2M. On the basis of neurological involvement it is clinically indistinguishable from other causes of CTS. It is, however, more likely to be exacerbated by dialysis ses- sions and at night. A high index of suspicion should remain for other causes of CTS in renal patients ( diabetes mellitus, myeloma and AL-amyloid). lymphoid cell activation (clonal B-cell disorders, various viral infections, rheumatoid art hritis, Crohn \200\231s disease and systemic lupus erythematosus); interferon-A therapy; \200 \200 metabolic acidosis; \200 bioincompatibility of HD membranes. Factors affecti ng clearance of B2M include: \200 \200 falling GFR; the mode of dialysis in ESRD. Scapulohumeral periarthritis The most commonly affected joint in AB2M is the shoulder. Amyl oid deposits are found in the synovial tissue and sub- acromial bursa. A seemingly trivial residual GFR in ESRD can signi \201 cantly increase renal clearance of B2M. Although raised serum B2M levels are a prerequisite this alone is insuf \201 cient t o initiate AB2M. Generation of amyloid \201 brils Although it is well-documented that B2M can spontane- ously assemble into amyloid \201 brils in vitro there is discord- ance bet ween the physicochemical conditions required for this and those that would occur pathophysi ologically. It is unclear how \201 bril seeds form in vivo although transient unfolding o f the native protein under mildly acidic condi- tions has been suggested. Once formed, \201 bril seeds can be stabilized by biologically relevant molecules (serum amyloid protein , apolipoprotein E, glycosaminoglycans, collagen and prostaglandins). Such seeds then provi de a focus for further elongation into \201 brils using B2M. This process may be enhanced by the addition of uremic serum. At a histological level these deposits will eventually di srupt tissue architecture and have a deleterious effect on func- tion. There is also eviden ce that amyloid-derived \201 brils are able to modify cell function at a much earlier poi nt in the natural history, before clinical disease becomes apparent. Effusive arthropathy This is commonly bilateral and affects the knees and shoulders. It is characterized by restricted movement and pain. It is exacerbated during dialysis and is wor se at night. Amyloid deposits may be found in the synovial \202 uid. Bone cysts These occur at the ends of long bones and contain amyloid deposits. They may cau se pathological fractures. Spondyloarthropathy This is radiologically characterized by cysts and narrowing of the inte rvertebral space. Osteophytes are not a feature. It can be compounded by coexistent hyperpa rathyroidism and aluminum overload. It is associated with back pain of variable severity. CHAPTER 11.10 b2-Microglobulin amyloidosis in chronic kidney disease 437 Scintigraphy Serum amyloid P (SAP) is a liver synthesized glycoprotein that binds noncovale ntly and in a calcium-dependent man- ner to virtually all forms of amyloid \201 brils. Us e of radiolabelled SAP for the detection of AB2M has been limited largely by the poor sensi tivity and speci \201 city of the investigation. Use of [131I]B2M has produced mixed resul ts. Generally the sensitivity and speci \201 city are better than the combined use of clin ical and radiological evidence. The high cost of the investigation precludes its widespread use in clinical practice. Rarely encroachment on the spinal cord may result in paralysis or a cauda equine syndrome. Visceral involvement Visceral involvement at postmortem is well-described though the functi onal consequences of such in \201 ltration are less clear. GI tract Involvement is serosal rather than mucosal and at post- mortem this gives a ripple d appearance to the entire GI tract. It can cause bleeding, pseudo-obstruction, perforation , infarction and diarrhea. Cardiovascular system The literature is not extensive but the predominant sites of involvem ent are the walls of the small blood vessels sup- plying the myocardium. These changes have been reported at postmortem but there is no information on any func- tional correlation. R isk factors for cardiac involvement are age at onset of dialysis and the duration of dialys is treatment. Treatment Medical management Simple analgesia Intra-articular corticosteroid injections are useful when a single joint is affected. As with all joint injections their effect is trans itory and carries a de \201 nite risk of septic arthritis. Oral prednisolone (0.1 mg/kg/da y) may be helpful. Respiratory system It is a rare cause of pulmonary hypertension but has been described as a cause of exudative pleural effusions in long- term hemodialysis patients. Surgical management The natural history is for nerve entrapment syndromes to be progressive and therefore early intervention is war- ranted to prevent permanent neurological de \201 cit. Arthroscopic or open surgery for affected shoulder joints and removal of affected syn ovium has a marked analgesic effect. Curettage of cysts within the femoral head and subsequ ent bone grafting has been reported to reduce hip pain. Prosthetic replacement of affected joints may be consid- ered on an individual basis and may result in bene \201 cial effects on pain and mobility. Skin Cutaneous involvement has been described although it is rare. Investigations Histology The \200\230gold standard \200\231 remains the histological exami nation of affected tissue. In common with other forms of amyloid, AB2M stains with Congo Re d and there is apple-green birefringence under polarized light. Joint aspiration may yield AB2M in synovial tissue fragments. Biopsy of rectal mucosa is of low yield and may re \202 ect the serosal rather than mucosal pattern of involvement.