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. Calcimimetic therapy ( b p. 252) may prove to have a role in reducing the need for parathyr oidectomy and may be an alternative in those in whom surgery has failed, is refused, or is deemed too high risk. Inappropriate parathyroidectomy may have deleterious consequences for the skeleton ( l low turnover disease). Pre-op considerations Imaging. Isotope scans (e.g. MIBI) allow localization of the parathyr oid glands prior to surgery and identify ectopic (e.g. retrosternal) tissue. USS and CT can also be helpful (speak to your surgeon). ENT. All patients should have their vocal cords v isualized preopera- tively \200\224 there is a risk of damage to the recurrent laryngeal n erve during surgery, so pre-existing dysfunction needs documentation. Prevention of \200 \230 hungry bone syndrome \200\231 . Most likely if bone turnover is very high ( i alkalin e phosphatase or subperiosteal resorption on X-ray. High doses of active vitamin D pre-op ( e.g. alfacalcidol 5 micrograms daily for 5 days) attenuates/prevents rapid and severe falls in Ca 2+ post-operatively (caused by calcium in \202 ux into bone). Post-op considerations Hemorrhage. Rare but may cause tracheal compression. Monitor drains carefully. Hypocalcaemia. May be profound in the days following surgery. Check Ca 2+ 2 \200\223 4h post-op, then 12h for 2 \200\223 3 days. Give calcitriol or alfacalcidol 0.5 \200\223 2.0 micrograms/day, with oral calcium (1 \200\223 3g in divided doses). If serum Ca 2+ falls below 1.8mmol/L or tetany develops, administer IV cal- cium (see Box 3.4), and continue high-dose oral vitamin D. PTH. Measured post-operatively to con \201 rm success ( can also be meas- ured intra-operatively). Box 3.4 IV calcium post-parathyroidectomy 2 Start IVI 10% calcium gluconate 50mL in 500mL 5 % glucose or 0.9% saline, initially at 50mL/h. Recheck Ca 2+ at +1h, and adjust infusion ra te accordingly. Cardiac monitoring required. 22 If tetany, give 10mL 10% calcium gluconate 10mL (2.2mmol) IVI over 3min ( (cid:2) extrav asation \200\224 central vein preferable). Repeat if necessary or infusion as described. C ardiac monitoring required. CKD-MBD: PARATHYROIDECTOMY 255 Parathyroidectomy technique The amount of parathyroid tissue removed at operation can be va ried. Partial parathyroidectomy. Parathyroid tissue is deliberately left behind in an attempt to avoid the deleterious consequences of absent PTH (prin- cipally ABD). Unfortunately, furthe r autonomous PTH secretion often necessitates repeat (and technically more dif \201 cult) surgery. Total parathyroidectomy with reimplantation. Parathyroid tissue is implanted into an extraparathyroid site (usually the arm). This tissue is then more easily accessible if r ecurrent hyperparathyroidism develops. Unfortunately, parathyroid regrowth in the neck rema ins common; the implant may fail to \200\230 take \200\231 , or the implant itself may be come autonomous or even locally invasive. Total parathyroidectomy. Attempted removal of all parathyroid tissue. Leaves the patient hypoparathyroid, with risk of ABD. Serum calcium is subsequently maintained with calcitriol or alfacalcidol. Regrowth of islands of parathyroi d cells is not uncommon. Small nests of residual cells often mean that serum PTH will incre ase with time. Radiological ablation. Ultrasound localization and ablation through eth- ano l injection has met with limited success. Direct injection of active vitamin D compounds in to the largest gland(s) is successfully used in some countries. CHAPTER 3 Chronic kidney disease (CKD) 256 Calci \201 c uraemic arteriolopathy (calciphylaxis) De \201 nition Calci \201 c uraemic arteriolopathy (CUA), or calciphylaxis, is a small vessel vasculopathy involving mural calc i \201 cation, with intimal proliferation, \201 brosis, and thrombosis. It occurs predom inantly in individuals with renal failure and results in ischaemia and necrosis of skin, so ft tissue, visceral organs, and skeletal muscle. Incidence First described in 1962, but better recognition in recent years has con- tributed to an increasing incidence. However, recent estimates of a 4% prevalence in ESRD programs are probably too high (closer to 7 1%). 2 Mortality 7 45% at 1 year (almost always due to s epsis). Pathogenesis is poorly understood. Abnormal skeletal and mineral metabolism certainly appea rs to play an important role, but many patients do not have uncontrolled CKD-MBD at the tim e of presentation. Reduction in key inhibitors of calci \201 cation (e.g. fetuin-A, matrix Gla pro- tein), an increase in reactive oxygen species, and in \202 ammatory cytokines all contribute. Multi ple risk factors, some of which are iatrogenic, have been documented. What creates a \200 \230 perfect storm \200\231 for the development of CUA in an individual patient remains un determined. Risk factors \200 Uraemia (though also seen post-transplantation and in primary HPT). \200 5 > 4 . \200 Diabetes mellitus. \200 i Calcium phosphate product. \200 i PTH. \200 Duration of dialysis therapy. \200 Vitamin D analog and calcium-based phosphate bin der usage. \200 Elevated alkaline phosphatase. \200 Caucasian race. \200 Obesity. \200 Malnutrition and low serum albumin. \200 Warfarin. \200 Protein C and/or S de \201 ciency. \200 Liver disease. \200 Corticosteroid treatment. Presentation \200 Painful erythematous livedo reticularis-like skin patches and plaques, with violaceous mottling and subsequent ulceration. Panniculitis and s infection follow. Surrounding soft tissue often feels hard and plaque-like. \200 Two overlapping patterns h ave been described: Ulcers on the trunk, buttocks, or thighs (over adipose tissue in more obese patients). CALCIFIC URAEMIC ARTERIOLOPATHY (CALCIPHYLAXIS) 257 Ulceration on the extremities (often in thinner malnourished patients). Not just a cutaneous disease \200\224 may occur in arterioles supplying other organs (lung calci \201 cation on the CXR is common). \200 Bone scans often show increas ed uptake over lesions. \200 Awareness is often half the journey to diagnosis. \200 Ski n biopsy is characteristic: medial calci \201 cation of cutaneous arterioles, intimal hyperplasia, endovascular \201 brosis, in \202 ammation, thrombosis, luminal occlusion, necrosis, and panniculitis. Calcium stains should be undertaken. Differential diagnosis: vasculitis, pyoderma gangrenosum, ulceration s to macrovascular disease, cholesterol emboli. Treatment (cid:2) No treatment is of proven bene \201 t. \200 2 Appropriate analgesia. \200 Scrupulous wound care and avoidance of trauma (e.g. subcutaneous injections). Aggressive treatment of sepsis. \200 Lower CaxP: avoid calcium-based binders; discontinue vitamin D analogs; daily dialysis; lower dialysate Ca 2+ . Aggressive control of PO 4 with non-calcium-based binders and dietary restriction. Parathyroidectomy (or cinacalcet) may help if i PTH and i CaxP. \200 Optimize tissue perf usion; revascularize, as necessary. \200 Stop warfarin. \200 Investigate for primary hy percoagulable/prothrombotic state. \200 Hyperbaric oxygen has been used successfully. \200 Interest in sodium thiosulphate has grown recently. Case series have demonstrated enh anced pain relief and wound granulation. Administered IV, with minimal side effects at low infusion rates ( l nausea, abdominal pain, diarrhea). Two mechanisms of action: \200 It i s a powerful antioxidant. \200 It sequesters calcium ions to form soluble calcium thiosul phate complexes, thus preventing calcium deposition. Bisphosphonates have been used but may have deleterious effects on bone metabolism in patie nts with pre-existing low turnover disease. Steroids probably of no bene \201 t ( (cid:2) sepsis). There are several calciphylaxis registries to which clinicians are encour- aged to submit b oth patient data and tissue specimens. For example, the UK calciphylaxis registry is part o f the international collaborative calciphylaxis network and can be accessed at M http://www .calciphy- laxis.org.uk . CHAPTER 3 Chronic kidney disease (CKD) 258 Diet and nutrition in CKD Dietary advice is extremely important in the management of CKD an d the maintenance of broader health in CKD patients. Measurement of nutritional status 2 No single parameter should be considered in isolation. Assessment should include: History and examination to identify ongoing medical problems that may limit nutritional int ake \200\224 psychosocial issues may be important. Dietary interview or diary. Quantitative intake of nutrients. \200 Subjective global asse ssment (SGA). SGA is based on subjective and objective assessment of several patient parame ters, including factors in the history and examination, GI symptoms, body weight patterns, functional capacity, and the presence of comorbid conditions that may in \202 uence nutrit ional requirements. Patients are assigned to one of three nutritional states: (i) well nour ished; (ii) mild to moderately malnourished, or (iii) severely malnourished. This simple sc ore is well validated in CKD and powerful enough to predict outcome. 4 Anthropometric measurements . BMI, skinfold thickness, estimated % weight loss, and mid-arm muscle circumference. Serum albumin. Re \202 ects not only protein intake, but susceptible to changes with in \202 ammation or infection. 2 A strong predictor of future mortality in ne w starters on dialysis. Adequacy of dialysis. Inadequate dialysis is a common contributing factor to malnutrition (uraemic toxins are anorectic and proin \202 ammatory). Dialysis ad equacy should be assessed in conjunction with the normalized protein catabolic rate (nPCR), which is a measure of the rate of urea formation. When a patient is in steady state, urea formation correlates with protein intake and protein breakdown. Fluid restriction \200 CKD stages 4 \200\223 5. Fluid and salt restriction are often imp ortant to prevent volume overload. On dialysis. When the urine output drops, \202 uid restriction is vital to minimize weigh t gains. Aim for weight gains of 1 \200\223 1.5kg or less/day. In an anuric patient, this means a \202 uid restriction of 750 \200\223 1,000mL. 2 This must be combined with salt restriction. Protein intake \200 Intake averages 7 80g/day in the developed world, although requirements may be only 50g. A low-protein diet has been shown to slow the progression of renal failure in patients with CKD ( b p. 208). Set against this is the danger of patients reaching dialysis with signi \201 cant malnutrition. Most advocate no more than moderate p rotein restriction. Daily protein targets: \200 0.8 \200\223 1.0g/kg per day for CKD sta ges 4 \200\223 5. \200 1.2g/kg per day when on dialysis. Protein sources include meat, \201 sh, eggs, milk, nuts, pulses, and beans. DIET AND NUTRITION IN CKD 259 Carbohydrate intake \200 Adequate energy intake is essential for patients with CKD, espec ially those undergoing protein restriction. Target 30 \200\223 35kcal/kg per day. \200 Sources: mainly complex carbohydrates, some f rom mono- or polyunsaturated fats. Combining a diabetic diet with a renal diet can be dif \201 cult and requires expert support. Examples: sugar, jams, marmalade, specialist high-energy renal drinks. Phosphate restrictio n (see also b p. 246) \200 The kidney is the main route of phosphate excretion. Aim to re strict dietary phosphate to 0.8 \200\223 1g/day, and target a serum phosphate in the norma l physiological range. Prescribe phosphate binders if dietary restriction alone fails ( b p. 246). Phosphate-rich foods include all protein-containing foods, making phosphate restriction dif \201 cult to achieve. Examples: milk, cheese, custard, yogurt, ice cream, cola, chocolate drinks, beer, liver, baked beans, dried peas and beans (e.g. chick peas), nuts, wholegrain products, bran cereals, and, many, many convenience foods. Potassium restriction \200 Typical UK intake 7 50 \200\223 120mmol/day. With failing ren al function, K + excretion falls, making restriction necessary (esp. in patients taking ACE -I, ARBs, and/or mineralocorticoid antagonists, such as spironolactone). K + -rich foods include dairy products, potatoes (baked, chips, and crisps), some fruits (bananas, grapes, dried fruit, fresh pineapple), fresh fruit juice, to matoes, sweet corn, mushrooms, chocolate, and coffee. Salt restriction \200 Typical UK intake 7 150 \200\223 200mmol/day (or 9 \200\223 12g). \200 This is a vast excess over physiological needs. \200 Salt restriction is helpful if i BP volume overload (helps reduce thirst and hence \202 uid intake). Aim for an in take of <100mmol/day (5 \200\223 6g). Na + -rich foods include cheese, salted butter/margarine, salted meat (bacon, ham, corned a nd luncheon meats), tinned meat, vegetables and soups, crisps, soy sauce, many breads and c ereals, salted nuts, processed foods, and packaged meals. There are several resources on the internet that can help patients and their families to un derstand and adjust to these dietary restrictions. The nutrition section of the US National Kidney Foundation website is a good starting point (M http://www.kidney.org ), and several cookbooks are available. Reference 4. Steiber A, Kalantar-Zadeh K, Secker D, et al . (2004). Subjective Global Asses sment in chronic kidney disease: a review. Journal of Renal Nutrition , 14 , 191 \200\223 200. CHAPTER 3 Chronic kidney disease (CKD) 260 Malnutrition in CKD Malnutrition is common in CKD (affecting up to 50% of dialysis patients ) and a powerful predictor of survival. Contributors include: \200 Anorectic uraemic toxi ns (e.g. leptin). \200 Chronic low-grade in \202 ammation. \200 Dietary restrictions ( low-protein diet, unbalanced low-phosphate diet). \200 Medication (phosphate binders, ora l iron). \200 Dialysis itself (esp. CAPD where protein losses into the dialysate may be 1 \200\223 2g/L or 7 10g/day; this would be considered nephrotic range if lost in the u rine!). Managing malnutrition in the CKD patient \200 Assess the severity of malnutrition ( b p. 258). \200 Measure current nutritional intake. \200 Address correctable factors: 2 Correct under-dialysis (e.g. change modality, improve access, increase treatment time). Seek and treat occult infection. \200 Investigate and treat GI problems, e.g. gastropares is. \200 De \201 ne and intervene if psychosocial problems. Consider dietary supplements: Wide range available. \200 Renal-speci \201 c oral supplements are low in K + and PO 4 a nd are also concentrated (limiting the volume of \202 uid). Overnight nasoenteral (or PEG) feeding may be bene \201 cial in more severe cases of malnu trition when adequate oral intake cannot be maintained. IDPN (intradialytic parenteral nutrition). Given on dialysis, it provides amino acids, glucose, and lipids. It is not a substitute for oral supplements but can deliver 7 1,500kcal/session (of which at least 7 500kcal are lost in dialysate!). Howev er, it can be a useful adjunct if the patient is able to manage 50% of the desired daily in take by mouth. Expensive. X Amino acid containing PD solutions (Nutrineal ) may offer bene \201 t in malnourished PD patients. Total parenteral nutrition (TPN) should be reserved for those who cannot be fed enterally. Electrolyte quantities (particularly potassium, phosphate, and mag nesium) should be reduced and monitored daily. X Appetite stimulants/anabolic agents are of uncertain bene \201 t: \200 Growth hormone (costly and long-term bene \201 t uncertain). \200 Nandrolone (an androgen). MALNUTRITION IN CKD 261 In \202 ammation in CKD Patients with CKD have ongoing low-grade in \202 ammation, with i acute phase proteins (CRP, ferritin), i in \202 ammatory cytokines, hypoalbumi- naemia, a nd hypercholesterolaemia. Contributors include: \200 Repeated infections. \200 Oxidant stress ( d levels of antioxidants, i oxidative and carbonyl stress). Accumulation of AGEs. \200 Arteriosclerosis and abnormal endothelial function. \200 Mal nutrition (both a cause and an effect of chronic in \202 ammation). Protein \200\223 energy malnutrition may coexist \200\224 there is increasing evi- dence that chronic in \202 ammation and oxidant stress increase metabolic demands and predispose to malnutrition. The triad of malnutrition, in \202 ammation, and accelerated atheroscler osis has been labeled the MIA syndrome. A vicious cycle may ensue, often culminating in dea th from cardiac disease. This may account for the apparent paradox that patients on dialysi s with a higher BMI tend to survive longer. CHAPTER 3 Chronic kidney disease (CKD) 262 Endocrine problems in CKD Thyroid function Tests may be dif \201 cult to interpret, as thy roid-binding globulin is lost in the urine if heavy proteinuria, causing a d measured T4. C linical assess- ment and measurement of T3 and TSH may be necessary for correct interpretat ion. Adrenal axis function Addison \200\231 s disease is dif \201 cult to diagnose in the cont ext of CKD, espe- cially in dialysis patients, as the characteristic electrolyte changes ma y be masked by renal dysfunction and dialysis. Suspect if persistent hypotension (or postur al hypotension). Many renal patients have received corticoster- oid therapy, with consequen t steroid-related side effects. Sexual dysfunction ( 5 ) Reduced libido frequent. Comorbidi ty (vascular disease, diabetes) and concomitant drug treatment may be relevant. Altered bod y image and self-perception may also play a role, as may depression and anxiety. Offer coun seling. 2 Anemia contributes to reduced libido and should be corrected. Disturbances in men struation and fertility are common. Amenorrhoea is virtually ubiquitous at ESRD. Gynecologi cal assessment is often helpful. Sexual dysfunction ( 4 ) Erectile dysfunction is common. I t may be multifactorial (arterial dis- ease, neuropathy, psychological factors, side effect s of drug treatment). Where possible, treat the underlying cause. Testosterone de \201 cie ncy is not uncommon in dialysis patients and should be corrected with replacement therapy. Phosphodiesterase inhibitors, such as sildena \201 l, are effective but should be avoided in patients on nitrates, with signi \201 cant coronary artery disease or hypotension. Vacu um devices or penile implants may be useful, especially if a physical cause for impotence. Hyperprolactinaemia Elevated circulating prolactin concentrations, s to i secretion and d c learance, are common in advanced CKD. Causes galactorrhoea ( 5 ) and gynaecomastia ( 4 ). B romocriptine or cabergoline may normalize levels. The contribution of i prolactin to sexual dysfunction in both sexes is unclear. Other causes, such as drugs (e.g. tricyclics, metocl opramide) or a prolactinoma, may need exclusion. Early menopause Not associated with CKD per se but may occur in patients treated with cyclo phosphamide or other cytotoxic agents. ENDOCRINE PROBLEMS IN CKD 263 Growth retardation in CKD Resistance to growth hormone (GH) is an important consequence of advanced CKD. Although circulating GH levels are normal (or elevated), resistance to its ac tion causes growth retardation in children and muscle wasting in adults. This resistance is the consequence of multiple defects in the GH/IGF-1 axis: GH receptor expression is downre gulated, as is the activity of the downstream JAK/STAT signal transduction pathway. The exp ression and activity of IGF-1 (a major mediator of GH action) are also signi \201 cantly r educed. Growth delay can now be treated with recombinant GH. Other contributors to growth r etardation are steroid therapy, malnutrition, and osteodystrophy. CHAPTER 3 Chronic kidney disease (CKD) 264 CKD management overview General advice (all stages) \200 Exclude AKI. \200 Explanation, education, and reassurance regarding the causes and consequences of CKD. Smoking cessation. \200 Weight reduction if obese. \200 Encourage aerobic exercise. \200 Aspirin 75mg, according to 10-year CV risk estimate. \200 Treat lipids, according t o best practice guidelines. \200 Avoid NSAIDs and other nephrotoxic drugs. \200 Limit a lcohol to <3 units per day ( 4 ) or 2 units per day ( 5 ). \200 Vaccination against in \202 uenza and pneumococcus. CKD stages 1 \200\2233 \200 2 Most of these patients will not progress to kidney failure, so the emphasis should be on CV risk reduction. Can usually be effectively managed in primary care setting. \200 Suggested criteria for r eferral to a specialist renal service are shown on b p. 265. Stages 1 \200\223 2 \200\224 at least annual follow-up: \200 eGFR, urinalysis, and uACR /uPCR. \200 Meticulous BP control; use ACE-I (see b p. 204 for targets). Stage 3 \200\224 at least 6-monthly follow-up: USS of urinary tract if lower urinary tract symptoms. \200 eGFR, urinalysis, and uACR/uPC R. \200 Meticulous BP control; use ACE-I (see b p. 204 for targets). \200 Anemia manage ment. If Hb <11g/dL, exclude other causes; check iron stores, and refer for consideration o f IV iron and ESA therapy ( b p. 222). 6-monthly check of serum calcium and phosphate. \200 PTH at baseline; 6 \200\223 12-mont hly if abnormal. CKD stages 4 \200\2235 \200 Refer to a specialist unit ( 2 urgently if stage 5). Late ref erral of patients with advanced CKD is associated with poor outcomes. Full dietary assessment ( b p. 258). \200 Anemia management. \200 CKD-MBD management ( b p. 249). \200 Correct acidosis ( b p. 205). \200 Immunize against hepatitis B. \200 Information and discussion regarding future treatment choices; dialysis modalities, options for transplantation, or conservative/palliative treatment ( b p. 266). CKD MANAGEMENT OVERVIEW 265 When to refer to specialist care \200 What do nephrologists do for patients with CKD? \200 Diagnose and manage treatable kidney disease. \200 Identify and control risk factor s for progression. \200 Manage s complications, such as anemia. \200 Plan for RRT in pa tients progressing to kidney failure. It is not possible, or necessary, for all CKD patients to be seen in specialist clinics. Referral guidelines Even if seen for specialist review, subsequent follow-up can continue i n primary care, with appropriate shared care protocols. Consider referral if: \200 eGFR < 30mL/min. \200 eGFR <60mL/min, and any of : Progressive fall (>5mL/min in 1 year or >10mL/min in 5 years). \200 Microscopic haematuri a. \200 Proteinuria (uACR >70mg/mmol, uPCR >100mg/mmol) unless known to be due to diabetes and appropriately treated. >15% decline in eGFR with commencement of an ACE-I or ARB (? renovascular disease). Suspected systemic illness (e.g. SLE, myeloma). \200 Hb <11g/dL, with no other explanatio n. \200 Abnormal calcium, phosphate, or PTH. \200 Refractory i BP (>150/90 despite thre e antihypertensive agents). eGFR >60mL/min and other evidence of renal disease/damage: uACR >70 or uPCR >100mg/mmol. \200 uACR >30 or uPCR >50mg/mmol and microscopic haematuria . \200 Abnormal renal imaging, e.g. renal cysts. Other indications: 2 Suspected acute kidney injury. CHAPTER 3 Chronic kidney disease (CKD) 266 Advanced CKD care The transition from CKD to ESRD is a physically and psychologically deman ding time (see Fig. 3.8). Such patients are best cared for by a mul- tidisciplinary team (s ee 7 6-weekly, more often in the latter stages), with attention to: \200 Ongoing measures to minimize rate of progression. \200 Dietary intervention. \200 Active management of complications (anemia, CKD-MBD, malnutrition). \200 Pre-dialysis counseling: choice of di alysis modality, individualized advice and support in the decision-making process. Pre-dialysis and pre-transplant information and support sessions. Ideally involving expert patients (peer supporters); see \200\230Education \200\231. \200 Preparation for transplantation: education; identify potential living donors. 2 Pre-emptive transplantation should be the goal, if possible. \200 Formation of dialysis access (surgical review at least 6 months prior to start of dialysis is desirable). Access to palliative services for those who elect not to undertake dialysis treatment or to help manage symptom burden. \200 Timing initiation of dialysis \200\224 avoid symptomatic uraemia. Composition of an advanced CKD clinic \200 Nephrologist. \200 Specialist nurses (e.g. p re-dialysis counseling, anemia management, pre-transplant assessment, dialysis access preparation, palliative care). Renal dietitian. \200 Vascular access and transplant surgeon. \200 Pharmacist. \200 S ocial worker. \200 Counselor. Education \200 De \201 ned education program, involving specialist nurses and expert patients (peer support). Start when eGFR \211 20mL/min (ideally 12 months prior to RRT). \200 Use a variety of t echniques to impart information \200\224 1:1 sessions, group education, culturally appropr iate written material, visual aids (DVDs, image library), practical demonstrations, web-bas ed material. Include information on: Functions of the kidney. \200 Implications of impaired kidney function. \200 Cardiovasc ular risk and lifestyle modi \201 cation. \200 Symptoms to expect as function declines. \200 Concept of integrated care \200\224 they may need to move between different treatment modalities over time. Detailed discussion on different dialysis options, with practical demonstrations and visits to PD and HD departments. Transplant options. De \201 ne treatment plan when eGFR approaches 15mL/min \200\224 allows for timely access preparation and assessment for a home-based therapy, if required. ADVANCED CKD CARE 267 When to start dialysis \200 The IDEAL study compared \200\230 early \200\231 (eGFR 10 \200\223 15mL/min) vs \200\230 late \200\231 (5 \200\223 7mL/min) commencement of dialys is and showed no survival bene \201 t. However, quality of life is just as important a con sideration. \200 Guidelines recommend considering the commencement of dialysis when GFR < 15mL/min. However, this requires careful discussion with the patient and consideration of t he risks and bene \201 ts associated with RRT. Symptoms and signs of advanced CKD (e.g. pe rsistent nausea and vomiting, anorexia, malnutrition, volume overload, restless eggs), como rbidity, functional status, and physical and the psychological and social consequences of s tarting dialysis all need to be taken into account. GFR \211 5 \200\223 7mL/min, whether symptomatic or not. \200 Refractory hyperkalaemia , acidosis, pulmonary oedema, pericarditis, encephalopathy, and neuropathy are all (urgent) indications for dialysis (the aim should be to start dialysis before these are present). 2 Pre-emptive transplantation is the treatment of choice of ESRD. Consider when GFR <20mL/m in. If not possible, discuss whether a home-based therapy (HD or PD) is suitable. Early pla nning leads to improved choice. Fig. 3.8 A pathway of care for advanced CKD. \200\230 Crash landers \200\231 (or unplanne d starters): these individuals are unknown to renal services and present as emergencies wit hin 90 days of needing RRT ( 7 25 \200\223 30% of patients entering ESRD programs annually ). They miss out on pre-emptive education, usually start on HD with temporary vascular acce ss, and have worse outcomes in general. Reproduced from Focus on Preparing for End Stage Re nal Disease with kind permission of the NHS Institute for Innovation and Improvement. CHAPTER 3 Chronic kidney disease (CKD) 268 Conservative treatment of CKD: symptomatic management of ESRD As CKD advances, so does the symptom burden. Over half of patients who follow a conservative (i.e. non-dialytic) managem ent pathway report poor mobility, weakness, pain, and pruritus, and over one-third report p oor appetite, dif \201 culty sleeping, drowsiness, dyspnoea, and constipation. With proact ive identi \201 cation and management, the distress and disability caused by these symptom s can be considerably eased (see Table 3.17). Many units now run a service speci \201 call y for such patients, concentrating resources and care to provide physical and social suppor t. Patients may become increasingly reliant on family members and other carers. District nu rses, social workers, home care teams, physiotherapists, occupational therapists, and hospi ce services should be involved, as required. Table 3.17 Symptom control in advanced CKD Symptoms Causes Treatments Comment Relax dietary restrictions Anorexia Constipation, oesophagitis, nausea, dry mouth, gastroparesis, oral candidiasis, dysphagia, anxiety Arti \201 cial saliva, ice to moisten mouth Dexamethasone 2 \200\223 4mg od for up to 4 weeks Medroxyprogesterone 100 \200\223 200mg daily Mode of action unknown. Avoid if thromboembolic risk Thalidomide 100mg od SE: neuropathy Fluconazole 50 \200\223 100mg od If oral candidiasis Taste disturbance Consider trial of a zinc salt, e.g. zinc sulfate Dyspepsia Lansoprazole 30mg od or other PPI Ranitidine 150mg bd Lactulose 10 \200\223 20mL bd Osmotic Constipation Multifactorial Adequate \202 uid intake and dietary advice are important Senna 2 \200\223 4 tablets bd Stimulant Bisacodyl 5 \200\223 10mg od/bd Stimulant Docusate sodium 100 \200\223 200mg bd Stimulant and softener; good choice with opiates Macrogols 1 \200\223 3 sachets daily Osmotic CONSERVATIVE MANAGEMENT OF CKD 269 Symptoms Dyspnoea Causes Treat anemia, \202 uid overload, acidosis, anxiety Treatments IV iron and ESAs, diuretics, bronchodilators, O 2 advice on sleeping position Comment Lorazepam 0.5mg sublingual 4 \200\223 6h Midazolam 2.5mg SC 4 \200\223 6h Benzodiazepines can be a useful adjunct in dyspnoea, especially if anxiety a factor Nausea and vomiting Multifactorial Haloperidol 0.5 \200\223 2mg PO od Metoclopramide 5 \200\223 10mg tds PO Domperidone 10 \200\223 20mg tds PO Ondansetron 4 \200\223 8mg bd PO Constipating Dry skin and pruritus Control PO 4 and i PTH Emollients (e.g. aqueous cream, E45 , Diprobase ), Oilatum in bath water Antihistamines, e.g. cetirizine 5 \200\223 10mg od, chlorphenamine 4mg qds Capsaicin 0.025% cream if localized SE: burning sensation Thalidomide 100mg nocte if intractable SE: neuropathy Anxiety and depression Expert counseling and psychological support Anxiety Lorazepam 0.5 \200\223 1mg PO prn SSRIs (e.g. citalopram 20mg od) Low mood Metabolic (e.g. d Na + , i Ca 2+ ) 2 Check for reversible causes Confusion Constipation Drug toxicity Has an incorrect dose been prescribed for level of renal function? Restless legs Correct anemia, iron de \201 ciency and i PO 4 Clonazepam 250 \200\223 500 micrograms nocte Co-careldopa 12.5/50 nocte May give short-term relief, then exacerbate Pergolide 25 micrograms nocte SE: nausea CHAPTER 3 Chronic kidney disease (CKD) 270 Conservative treatment of CKD: general The decision not to have dialysis \200 Patients wh o start dialysis with signi \201 cant comorbidity and functional dependence typically have a short survival time, which may be \201 lled with hospital admissions, painful illnesse s, and unpleasant procedures. For such patients, continuing supportive care without commencing dialysis may allow a better quality of life, with little or no reduction in life expectancy . The decision whether to commence dialysis at ESRD is ultimately made by the patient (assumi ng the patient has capacity). The renal team has a duty to ensure that this decision is as informed as possible by explaining the implications of withholding dialysis and the pros an d cons of commencing it. Family members should also be involved. \200 The process cannot be rushed. A decision not to accept dialysis