considering age, co-morbidities and other therapies. Escalate treatment carefully under app ropriate supervision. UK Renal Association and NICE recommend: \200 Without proteinuria (uPCR <100mg/mmol or uA CR <70mg/mmol): Target 140/90mmHg (NICE suggest target range for SBP 120 \200\223139mmHg and DBP <90mmHg). With proteinuria (uPCR >100mg/mmol or uACR >70mg/mmol): \200 Target 130/80mmHg (NICE sugg est target range for SBP 120 \200\223129mmHg and DBP <80mmHg). Diabetes mellitus: Target 130/80mmHg. d Reduction of proteinuria should also be seen as an important Therapeutic goal (target uPCR <50mg/mmol or uACR <30mg/mmol). Others Recent international guidelines for hypertension from nonnephrologi- cal bodies, suc h as ESH-ESC (and JNC 8 \200\223 in preparation), have, or are expected to, suggest that t he evidence for lower treatment targets, such as <130/80mmHg, in the presence of comorbidit ies such as diabetes and CKD is not currently robust (see b pp. 464 \200\2238). For example ESH-ESC (2013) suggests all patients (apart from the elderly) should be treated to a SBP of <140mmHg. PROGRESSION OF CKD: ANTIHYPERTENSIVES IN CKD 205 Dyslipidaemia \200 In addition to placing CKD patients at i risk of CV disease (b p. 198) , lipid abnormalities may also accelerate progression. Potential mechanisms: mesangial cell proliferation, cytokine expression, LDL oxidation to reactive O 2 species. Treatment has attenuated renal injury in animal models. \200 Patchy evidence from clinica l trials ((cid:2) statins only \200\224not \201 brates). \200 Recent guidelines, includ ing those for non-CKD population (such as those produced by the American Heart Association/American College of Cardiology) have moved away from numeric targets for 1 and 2 prevention and towards the estimation of CV risk . The KDIGO lipid management guidelines for CKD (2013) suggest: Adults aged \211 50 years with eGFR <60 mL/min (not on RRT) are treated with a statin (or statin/ezetimibe combination) (evidence graded 1A). Adults aged \211 50 years with CKD and eGFR \211 60 mL/min are treated with a statin (graded 1B). Adults aged 18 \200\22349 years with CKD (not on RRT) are statin treated if one or more of the following is present (graded 2A). \200\224 Known coronary disease (M I or revascularization). \200\224 Diabetes mellitus. \200\224 Prior stroke. \200\224 Est imated 10-yr incidence of coronary death or MI >10%. \200 Initiation of statin treatment is not recommended for adults on dialysis (2A). Patients receiving statins (or statin/ezetimibe) at the time of dialysis initiation should continue treatment (2C). Statin treatment is suggested for transplant recipients (2B). (cid:2) Statin side effects are more common in CKD. Myalgia and a small rise in creatine ki nase common. 2 More rhabdomyolysis reported. Liver function abnormalities also more common. Hyperphosphataemia ( b p. 246) Calcium phosphate deposition in the renal interstitium may c ontribute to progression of CKD, strengthening the argument for good control of mineral hom eostasis in these patients. Anemia ESA treatment may d progression. Robust evidence is lacking. Acidosis \200 Experimentally, acid in the nephron l complement activation and interstitial damage. A recent RCT has shown that administration of oral sodium bicarbonate signi \201 cantly sl ows CKD progression vs placebo. 3 \200 134 patients, CrCl 15 \200\223 30mL/min, baseline bicarbonate 16 \200\223 20mmol/L \200 Dose: 600mg tds, increased to achieve a bicarbona te of 23mmol/L (500mg capsules are also widely available). 2-year follow-up (exclusions: CCF, uncontrolled i BP). CHAPTER 3 Chronic kidney disease (CKD) 206 Drugs, toxins, and infections Once CKD is established, remaining kidney function is highly susceptible to further (often irreversible) damage. 2 Avoid: \200 Hypovolaemia, obstructi on, recurrent UTIs. \200 Nephrotoxins: drugs (e.g. NSAIDs), radiocontrast. Smoking Smoking l i proteinuria and CKD progression in both diabetic and non-diabetic CKD, adding to the already overwhelming bene \201 ts of smok- ing cessation. Patients should be offered practical help and support to quit. Diabetes Poor glycaemic control is a major determinant of the progression of dia- betic nep hropathy. The evidence is stronger for T1DM. \200 T1DM: in the DCCT trial, intensive trea tment was associated with less microalbuminuria and d progression to macroalbuminuria. In a ddition, the EDIC/DCCT follow-up study cohort has suggested lowering HbA1c preserves GFR in the long term. T2DM: in the UKPDS study, intensive treatment led to a d incidence of microalbuminuria, and other studies have shown reduced progression to macroalbuminuria. UKPDS also demonstrated a reduced decline in GFR. However the ADVANCE and ACCORD studies suggested that intensive treatment of hyperglycemia in T2DM does not always lead to an acceptable risk/bene \201 t ratio. These studies involv ed large populations and used aggressive tactics for glycaemic control. Participants had st rong CV risk pro \201 les (including prior events) and were at high risk of future events. Microvascular end points, including renal outcomes, were improved in both studies. However , primary CV outcomes were not improved by intensive glycaemic therapy and, in ACCORD, inte nsive treatment was associated with a 22% increase in all-cause mortality; i.e. intensive g lucose lowering in high- risk populations, later in the course of T2DM, delivered only a we akly protective effect on CV outcomes. KDOQI practice guidelines recommend maintaining HbA1c at <7%. However, some authorities sug gest a target between 7 \200\2238% in higher risk patients later in the course of their dis ease. Reference 3. de Brito-Ashurst I, Varagunam M, Raftery MJ, Yaqoob MM (2008). Bicarbonate sup plementation slows progression of CKD and improves nutritional status. Journal of the Ameri can Society of Nephrology , 20 , 1869 \200\223 70. PROGRESSION OF CKD: ANTIHYPERTENSIVES IN CKD 207 CHAPTER 3 Chronic kidney disease (CKD) 208 Progression of CKD: miscellaneous Vitamin D \200 Vitamin D has many important paracrine f unctions, with roles in immunity, in \202 ammation, vascular and cardiac function, and ins ulin resistance. In the kidney, it in \202 uences mesangial cell and podocyte proliferation, downregulates RAS (via renin inhibition), prevents glomerular hypertrophy, decreases cytoki ne production, reduces in \202 ammation, and blocks epithelial to mesenchymal transition. There is experimental (and limited clinical) evidence that it may ameliorate proteinuria, g lomerulosclerosis, and tubulointerstitial \201 brosis. Optimum replacement strategies, however, remain unclear (see b p. 250). Dietary protein restriction \200 d Protein intake in animal models protects against glome rulosclerosis. \200 Appears to d intra-glomerular pressure and d glomerular hypertrophy. \200 Non-haemodynamic effects, such as d TGF- B and d matrix accumulation, may also be important. In humans, the bene \201 t of protein restriction is controversial. \200 Although progre ssion may be slowed, a huge investment is required by both patients and dietetic staff. Lon g-term compliance is often poor. At present, optimal dietary protein intake in CKD is uncertain. \200 X A reasonable regim en is an intake of 7 0.8 \200\223 1.0g/kg of protein/day. Lower levels may risk malnutriti on (particularly in advanced CKD or with nephrotic range proteinuria). Diabetic nephropathy may be more responsive. Preventing progression \200\224what \200\231s on the horizon? \200 Endothelin receptor bl ockade l d BP, d renal vasoconstriction, d proteinuria, and d tissue damage in experimental diabetic nephropathy. Vasopeptide inhibitors l d vasoconstrictors (A2) + i vasodilators (natriuretic peptides and bradykinin). Renin inhibitors. Available as antihypertensives. Theoretical bene \201 t would be through aggressive RAS blockade. However, the ALTITUDE study, designed to determin e if a renin inhibitor could reduce CV and renal morbidity and mortality in T2DM when added to conventional treatment (including ACE-I or ARB), was stopped early after more frequent adverse events were reported in the treatment arm. Mineralocorticoid receptor activation l interstitial \201 brosis + vascular damage. Antag onism ( eplerenone/spironolactone ) may 6 be bene \201 cial. \200 Sulodexide , an orally active glycosaminoglycan, reduces proteinuria and is under evaluation in clinical trials. Pirfenidone and hepatocyte growth factor are anti \201 brotic and show experimental promise. BMP-7 antagonizes TGF- B and inhibits the pro- \201 brotic epithelial to mesenchymal cell transition. PROGRESSION OF CKD: MISCELLANEOUS 209 The anti-in \202 ammatory, antioxidant, and possibly anti \201 brotic molecule bardoxolone methyl was associated with an early improvement in eGFR in advanced diabetic ne phropathy. Unfortunately, the subsequent international BEACON trial was terminated, followi ng the reporting of excess of adverse events in the treatment arm. The cardiorenal syndrome (CRS) \200 A newly described syndrome of interdependency. Each d ysfunctional organ can initiate and maintain disease in the other through common haemodynam ic, neurohormonal, and immunological pathways. Five subtypes have been suggested, describing the scenarios in which CRS can occur (and de \201 ning the p and s organ in each case) (see Table 3.5). Signi \201 cant controversy and debate around this topic remains. \200 Cardiac + renal f ailure = magni \201 cation of poor outcomes: Renal failure is as powerful a prognostic marker in CCF as ejection fraction (EF) or NYHA status. i SCr on admission with CCF predicts longer hospital stay, i risk of ITU admission, and i mortality. In parallel, patients with CKD are much more likely to manifest CV disease than the non-CKD population ( b p. 198). Pathophysiology \200 The traditional view that d GFR in CCF is simply a consequence of im paired renal blood \202 ow (RBF) s to impaired LV function is correct, in part, although a gross oversimpli \201 cation. \200 d RBF l RAS stimulation l Na + and water retention. \200 A2 l i cardiac pre- and afterload and i myocardial O 2 demand. \200 A2 also promo tes NADH and NADPH oxidase activation l oxidative stress, d NO ( l endothelial dysfunction) , vascular in \202 ammation, and \201 brosis (both cardiac and renal). Chronic sympathetic nervous system (SNS) activation l d adrenoceptor sensitivity, i LVH, an d i myocyte apoptosis. Elevated venous pressures l intra-abdominal hypertension l further d renal perfusion. Anemia is common and integral to a progressive vicious cycle of organ dysfunction. EPO itse lf may exert anti-apoptotic effects ( b p. 219). Management \200 A heterogeneous group, often excluded from major trials. \200 Diuretics and ACE-I are key components of management but may further d GFR. Physician anxiety means they are often not prescribed \200\224 further in \202 uencing outcomes. Close monitoring is essential. The role of IV iron and ESAs remains contentious ( b p. 226). \200 Future: inotropes, ult ra \201 ltration for diuretic resistance, AVP antagonists, adenosine A 1 antagonists, and BNP analogs have variably been shown to improve symptoms, if not overall outcomes. CHAPTER 3 Chronic kidney disease (CKD) 210 Table 3.5 Subtypes of CRS Name Description Acute cardiac dysfunction l AKI 1. Acute cardiorenal CCF l d GFR (very common) 2. Chronic cardiorenal AKI l acute cardiac dysfunction (e.g. \202 uid overload) 3. Acute renocardiac CKD l cardiac dysfunction (e.g. LVH and diastolic dysfunction) CRS s systemic condition, e. g. septic shock 4. Chronic renocardiac 5. Secondary PROGRESSION OF CKD: MISCELLANEOUS 211 CHAPTER 3 Chronic kidney disease (CKD) 212 Advanced CKD: the uraemic syndrome Uraemia is the metabolic and clinical syndrome caused by a substantial fall in GFR \200\224 it is not a result of i blood urea concentration, but rather of failure to eliminate many potentially toxic small and middle molecules. This lead s to chronic in \202 ammation and oxidative stress, with accumulation of metabolic end-pro ducts, accelerated atherogenesis, disruption of the immune system, and anemia. The retained compounds or toxins have multiple effects: \200 Many remain unidenti \201 ed. \200 Th ey are divided into \200\230 low \200\231 and \200\230 middle \200\231 molecular weight molecules by size (<500Da = low; >500Da = middle). Ur and SCr are routinely measured but are not directly toxic. They act as markers for other LMW substances, including guanidines, such as asymmetric dimethyl arginine (ADMA) \200\224 a potent inhibitor of NO synthase. Retained middle molecules include: B 2 microglobulin (12,000Da) \200\224 a component of MHC (the cause of dialysis-related amyloid). Advanced glycation end-products (AGEs) \200\224 products of non-enzymatic breakdown of sugars. Also retained in normal ageing and diabetes. Linked to a therogenesis and susceptibility to infection. Complement factor D \200\224 may activate the complement system and contribute to chronic in \202 ammation. Cytokines \200\224 may maintain uraemic chronic in \202 ammation and malnutrition (although a short half-life suggests overproduction is more important). \200 Many, many others. i oxidant stress l i oxidation products with d antioxidant levels (in part due to impaired polyamine balance). Phosphate is retained, contributing to hyperparathyroidism, arteriosclerosis, and vascular calci \201 cation ( l d arterial compliance, wide pulse pre ssure, and diastolic dysfunction) ( b p. 242). Uraemic cardiomyopathy Not the result of one speci \201 c uraemic toxin but of a combinati on of factors: \200 i Arterial stiffness. i phosphate l vascular smooth muscle cell transdifferentiation into osteoblast-like cells, causing vascular medial calci \201 cation . This leads to arteriosclerosis, d arterial compliance, and i pulse pressure. This is anal ogous to the arterial changes seen in the elderly but premature. The result is i cardiac wo rkload and worsening LVH and diastolic dysfunction. Cardiac \201 brosis . Local and systemic angiotensin II and PTH l i cardiac stiffness, myocyte injury, and diastolic and systolic dysfunction. Anemia . l i LVH and i cardiac work. \200 Myocyte dysfunction . Myocyte contractility is reduced, possibly as a result of changes in intracellular bioenergetics. ADVANCED CKD: THE URAEMIC SYNDROME 213 The uraemic syndrome Water, electrolyte, and acid \200\223base balance \200 Breathlessnes s s to volume overload, and Kussmaul breathing s to acidosis. Postural hypotension caused by volume depletion. \200 Effects of i or d K + . Hematological system \200 Symptomatic anemia and bleeding tendency. Cardiorespiratory \200 Cardiac failure associated with \202 uid overload, i BP, anemia, and impaired LV function. Accelerated atherosclerosis (angina, stroke, PVD) and vascular calci \201 cation. \200 P leuropericarditis. \200 Cardiac arrhythmias s electrolyte disturbances. Musculoskeletal \200 Weakness, bone pain, and deformity s to osteodystrophy. \200 Gout. Nervous system \200 Hypertensive stroke and encephalopathy. \200 Anxiety, depression, a nd other psychological disturbances. \200 Impaired cognitive function. \200 Peripheral and autonomic neuropathy. \200 Involuntary movements (including restless legs). \200 De creased conscious level and seizures (late). Gastrointestinal \200 Nausea, anorexia, and malnutrition. \200 GI bleeding (peptic ulce ration and angiodysplasia). \200 Fetor, constipation, and diarrhea. Skin \200 Dry skin, nail changes, and pruritus. \200 Bullous eruptions. \200 Pallor, pigmentation, and uraemic frost (late). Eyes \200 Conjunctival calcium deposits and retinal vascular disease. Immunity \200 Impaired cellular and humoral immunity ( l infection and malignancy). Endocrine \200 Aberrant vitamin D and PTH metabolism. \200 Impaired IGF-1 production (g rowth retardation in children). \200 Hyperprolactinaemia (gynaecomastia). \200 Multiple other subclinical abnormalities. Sexual function \200 Sexual dysfunction. \200 Decreased fertility. CHAPTER 3 Chronic kidney disease (CKD) 214 Complications of advanced CKD Fluid overload Salt and water overload is usual in advanced C KD. However, as tubuloint- erstitial scarring progresses, loss of concentrating ability may l \201 xed (and often large) urine volumes and a relative salt-losing state. Such patien ts may be chronically hypo- , rather than hyper volaemic, and require salt and water supple mentation (e.g. NaHCO 3 0.5 \200\223 1.5g PO tds and increased \202 uid intake). Treating salt and water retention in CKD 2 Careful clinical assessment of volume status. \200 Restrict dietary salt ( b p. 259). \200 Restrict \202 uid intake. \200 Start fu rosemide 40mg PO od, and titrate as necessary (max. 250mg daily). Loop diuretics do not have a particularly smooth dose-response curve \200\224 a diuresis/n atriuresis will not occur until a threshold is reached. This means a patient not responding to 40mg furosemide should have the dose, rather than frequency dosing, increased, i.e. i t o 80mg once daily, rather than 40mg twice daily. If poor response, consider thiazide diuretic (metolazone 2.5 \200\223 10mg od) for synergistic effect. (cid:2) Diuresis may be brisk. Beware d Na + , d K + , and volu me depletion (consider admission). Monitor: Daily weight \200\224 the best day-to-day guide of salt and water status. Ask the patient to keep a diary of their weight at home. Weight loss should generally be \211 0.5 \200 \223 1kg/day. \200 BP (esp. postural d BP if overdiuresed). \200 A rise in Ur 9 SCr may restrict dose escalation. If Ur >25mmol/L, consider dose reduction (or cessation), depending on clinical need. (cid:2) Refractory volume overload may signal the need for renal replacement therapy. Hyperkalaemia d Na + delivery to the distal convoluted tubule l d aldosterone-mediated Na + /K + exchange and d K + excretion. 2 i K + is a common, and potentially life-threatening, problem in advanced CKD. Rapid rises in K + are generally more dangerous than gradual ones, as cell membrane stability is more vulnerable to acute changes. The widespread use of ACE- I, ARBs, and, more recently, mineralocorticoid antagonists, such as spironolactone, is chan ging the natural history of CKD-related hyperkalaemia. It is increas- ingly common, with aw areness more important than ever. COMPLICATIONS OF ADVANCED CKD 215 When to worry about the K + level ? Depends on context and chronicity. \200 5.5 \200\223 6.0mmol/L: recheck routinely. Review medications. Arrange dietary advice. 6.1 \200\223 6.5mmol/L: recheck urgently. Review medications (withhold ACE-I, ARB, spironolactone). Arrange dietary advice. >6.5mmol/L: 2 consider admission. Treat as an emergency. Measures to prevent i K + \200 Dietary restriction ( b p. 259). \200 Diuretics: a loop diuretic (e.g. furosemide 40 \200\223 160mg PO od) may promote urinary K + loss (thiazides may be less effective). Drug withdrawal or dose reduction if taking an ACE-I or ARB. Review other contributory drug s (e.g. spironolactone, beta blockers, NSAIDs). Correct acidosis (see Box 3.1). \200 (cid:2) Refractory i K + may indicate the need for d ialysis. Acidosis ( b p. 820 \200\223823) Systemic effects of acidosis \200 Bone . i bone resorption and impaired mineralization, contributing to renal osteodystrophy ( b p. 234). Metabolism. Muscle weakness, fatigue, sense of ill-health. \200 Effects of respiratory co mpensation ( b p. 820). Overventilation; may l symptoms of dyspnoea 9 exhaustion. Hyperkalaemia. Aldosterone-mediated exchange of H + for K + is enhanced in the collecting duct l i K + . Acidosis also lessens K + ingress via cell membra ne Na + /K + pumps. Ionized calcium. i ionized (free) calcium (acidosis l d albumin-bound fraction). (cid:2) Correction of acidosis may l d Ca 2+ and provoke tetany. \200 Nutritio n. Acidosis promotes catabolism by induction of proteolysis and resistance to growth hormone ( l malnutrition). Box 3.1 How to correct acidosis? \200 Treat when venous HCO 3 \200\223 is <21mmol/L. \200 Give NaHCO 3 0.5 \200\223 1.5g/tds as capsules, or 0.6 \200\223 1.8g tds as tablets (start at low dose, and titrate). (cid:2) Na + load may cause or worsen \202 uid overload. Consider concomitant loop diuretic. (cid:2) Refractory acidosis is an indication for dialysis. CHAPTER 3 Chronic kidney disease (CKD) 216 Anemia and CKD Key facts \200 Common; prevalence and severity increase as GFR falls (see Table 3.6). \200 Typically normochromic, normocytic, with normal WCC and platelets. \200 Associated with reduced quality of life and poorer prognosis. \200 Erythropoietin (EPO) de \201 ciency is the dominant, but by no means the only, cause (see Box 3.2). The introduction of human recombinant erythropoietin (hrEPO or epoetin) 7 20 years ago comp letely transformed management. Prior to this, recurrent transfusion was the norm ( l iron o verload, risk of blood-borne viruses, and sensitization to foreign antigens \200\224 with implications for transplantation). Newer therapeutic agents still aim to stimulate red cell production via the EPO receptor but may not be based on recombinant EPO. The term erythropoiesis-stimulati ng agent (ESA) has been introduced to re \202 ect this. Increasing numbers of early CKD patients \200\224 and virtually all dialysis patients \200\224 receive an ESA. Black and diabetic patients tend to have higher rates of anemia for each CKD stage. The target range for Hb is lower than the normal physiological range, e.g. 10 \200\223 12g/dL (UK Renal Association). X Randomized trials have found i CV complication rate with higher Hb targets \200\224 so optimal treatment strategies remain uncertain ( b p. 226). Patients receiving ESAs invariably need concomitant iron therapy \200\224 and iron alone m ay be suf \201 cient to correct anemia in some ( b p. 230). CKD patients require different targets for iron parameters from non-CKD individuals to facilitate optimal red cell production ( b p. 230). The success of ESAs in CKD has led to their use to treat anemia in other contexts, particularly chemotherapy-associated anemia ( X ESAs have been associated w ith i thromboembolic events and d survival in cancer patients and could theoretically stimu late tumor growth). The cost of anemia management is substantial. Table 3.6 Prevalence of anemia from NHANES III ( b p. 228) CKD stage Median Hb in men (g/dL) Median Hb in women (g/dL) Prevalence of anemia a 2 14.9 13.5 1% 3 13.8 12.2 9% 4 12.0 10.3 33% a Hb <12g/dL in 4 ; <11g/dL in 5 . Reprinted from American Journal of Kidney Diseases , 41 , Coresh J, Astor BC, Greene T, et al . Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey, 1 \200\223 12, Copyright (2003), with permission from Elsevier. anemia AND CKD 217 Box 3.2 Differential diagnosis of anemia in CKD patients 2 EPO de \201 ciency is not the o nly cause of d Hb in CKD. Think of the following before commencing ESA therapy and particu- larly if disproportionate anemia or ESA resistance ( b p. 223): \200 Blood loss: Peptic ulcer disease, GI vascular ectasia. d red cell survival: In \202 ammation + oxidative stress + uraemic toxins l RBC membrane and cytoskeletal damage. Haemolysis \200 Related to dialysis: Blood loss during treatment ( \200\230 lost lines \200\231 ). \200 Haemolysis: contamin ated dialysate, hypo-osmolar or overheated dialysate, residual sterilizing agents, trauma i n blood pump, high \202 ow through narrow gauge needles. Haematinic de \201 ciency: \200 Iron de \201 ciency. \200 B12 or folate de \201 cien cy. Impaired bone marrow response: Chronic infection or in \202 ammation. \200 Uraemic toxins (? underdialysis). \200 Hyp erparathyroidism ( l marrow \201 brosis). \200 Carnitine de \201 ciency. \200 Alumin um overload; now rare ( b p. 247). Malnutrition. \200 Relating to underlying or unrelated disease: Myeloma. \200 Myelodysplasia. \200 Sickle cell disease or other haemoglobinopathy. \200 SLE. \200 Autoimmune haemolysis. \200 Coeliac disease. \200 Occult malignancy. \200 Hypothyroidism. \200 Relating to treatment: \200\224 Poor compliance with ESA therapy or incorrect dosing. \200\224 Immune suppressio n. \200\224 ACE-I (several mechanisms, including: d endogenous EPO production and d angiot ensin II stimulation of erythroid precursors). Rarely mandates cessation of treatment. \200\224 Pure red cell aplasia (PRCA) ( b p. 225). CHAPTER 3 Chronic kidney disease (CKD) 218 EPO and the kidney \200 RBC production is tightly regulated by a number of growth factors , including EPO \200\224 a 165 amino acid-secreted glycoprotein (with four complex carbohy drate side chains) that is required for terminal erythrocyte maturation. EPO differs importantly from other hematopoietic growth factors because it is produced in the kidney \200\224 speci \201 cally by the peritubular interst itial \201 broblasts in the outer medulla and deep cortex. Hepatic EPO production is also important in fetal, but not adult, life. \200 The kidney i s ideally placed to regulate RBC production, as it is uniquely able to sense and control both O 2 tension and circulating volume (and to differen tiate between the two): \200 Control of red cell mass is mediated by EPO. \200 Circulat ing volume is regulated by renal salt and water excretion. \200 CKD and renal scarring l d functioning renal tissue l d EPO synthesis l d RBC production l anemia. Exceptions (where EPO may be overproduced) are: APKD, benign renal cysts, renal cell carcinoma, and chronic hypoxia. EPO production (See Fig. 3.3) \200 If GFR is normal, plasma EPO levels are inversely prop ortional to Hb concentration. This relationship breaks down in CKD (where EPO levels are us ually inappropriately in the normal range). \200 Anemia or d environmental O 2 l d blood O 2 content l O 2 -dependent gene expression l i EPO secretion. Central to this are the hypoxia inducible transcription factors HIF-1 and HIF-2. HIF-1 and 2 have an O 2 -regulated A subunit and constitutively expressed B subunit. In states of normal O 2 tension, intracellular HIF-1 and 2 are continuously inactivated by (iron-dependent) proline hydroxylation of their A subunit. Once hydroxylated, they are targeted by the von Hippel \200\223 Lindau protein (pVHL) for ubiquitinization and proteasomal degradation. \200 In hypoxic conditions, A subunit hydro xylation and degradation do not occur, and HIF A remains free to enter the nucleus and form a heterodimer with HIF B . The HIF A + HIF B heterodimer binds the hypoxia response element (HRE) and initiates EPO transcription. Several mechanisms exist to regulate EPO production, including the GATA family of transcription factors hepatocyte nuclear factor 4 (HNF-4) and haematopoi etic cell phosphatase (HCP-1). All are potential therapeutic targets ( b p. 221). During hypoxia, HIF activity is induced in multiple cell types where it activates a panoply of target genes (>100), including those involved in angiogenesis and glycolysis. Genetic m utations in the HIF pathway are responsible for certain congenital polycythaemias. Activation of the EPO receptor (EPO-R) prevents erythroid cell apoptosis through downstream JAK2/STAT5 signaling pathways. EPO AND THE KIDNEY 219 Normoxia Hypoxia HIF HIF Alpha subunit Alpha subunit Beta subunit Beta subunit Fe EPO Degradation of alpha subunit Proline hydroxylation O2 Red cell production in bone marrow VHL protein Ubiquitin ligase Fig. 3.3 Regulation of EPO production. EPO beyond anemia: cytoprotection \200 In addition to the role of EPO in the regulation o f erythropoiesis, there is increasing interest in its potential anti-apoptotic and cytoprotective effect. The EPO-R is widely distributed (e.g. neurons, cardiac myocytes, endothelial cells, hepatocytes, and mesangial cells), and expression is increased in respon se to hypoxic injury. It is hoped this might be therapeutically exploited and that exogenous ESA administration might offer protection from injury in various clinical scenari os. This concept has been successfully explored in numerous animal models of tissue injury, particularly ischaemia reperfusion (including nervous system, card iac, and renal). There are currently a number of trials in progress in a variety of clinical settings, including traumatic brain injury, subarachnoid hemorrhage, myocardial infarction, cardiopulmonary bypass, renal transplantation, sepsis, and many others. However, a recent randomized, placebo-controlled trial of an IV ESA in early acute ischaemi c stroke reported more deaths in the group receiving the ESA. Short-acting ESAs with retained cytoprotective, but reduced erythropoietic, effects are under development. CHAPTER 3 Chronic kidney disease (CKD) 220 Erythropoiesis-stimulating agents (ESAs) At present, no evidence distinguishes ESAs in term s of clinical ef \201 cacy. All have similar issues around cost, complexity of manufacture , routes of administration, storage requirements and potential immunogenicity. See Table 3. 7 for dosing information. Short-acting Epoetin and . EPO- A (Eprex , Epogen , or Procrit ) and EPO- B (NeoRecormon ) have been in use for 7 20 years and are clinically indis- tinguishable. B oth are synthesized in transformed Chinese hamster ovary cells and have identical amino aci d sequences (if different glycosylation pat- terns). Other recombinant epoetins have emerge d, sharing the 165-amino acid structure, e.g. epoetins omega and delta. Biosimilar agents. The term biosimilar is used to describe a generic product that is delibe rately similar to molecules already in clinical use. Manufacturers submit data suggesting t heir agent is chemically and phar- macokinetically identical to a reference drug (usually E PO- A or - B ). Clinical data generated with the original is then extrapolated to the new p roduct. The reduced R&D and marketing costs ensure products are com- mercially competitive, e.g. epoetin-zeta (Retacrit ). Long-acting Darbepoetin (Aranesp ). Recombinant EPO with a twist: \201 ve amino aci ds are substituted away from the EPO-R binding site to allow the inser- tion of two carbohy drate side chains. This signi \201 cantly increases circulating half-life. Table 3.7 ESA dosing Generic name Trade name Half-life Initial dosing Example starting dose 2,000IU 3 x week 2,000IU 3 x week Epoetin A Eprex , Epogen , Procrit 4 \200\223 8h 80 \200\223 120IU/kg in 3 divided doses a Epoetin B NeoRecormon 4 \200\223 12h 80 \200\223 120IU/kg in 3 divided doses a Darbepoetin A Aranesp 21 \200\223 25h 0.45 micro grams/ kg 1 x week b 0.6 micrograms/ kg fortnightly, then monthly (usually at tw ice the fortnightly dose) 30 micro grams 1 x week 50 micro- grams fortnightly Mircera 130h Methoxy polyethylene glycol epoetin B a Increase by 25% for IV dosing. b 1 microgram is equivalent to 200IU of epoetin A or B , t hough there is considerable variability. No dose adjustment SC to IV for darbepoetin. ERYTHROPOIESIS-STIMULATING AGENTS (ESAs) 221 Continuous EPO receptor activator (CERA). Methoxy polyethylene glycol epoetin B (Mircera ) incorporates a large polymer chain to increase its MW to 760kDa (EPO: 30.4kDa). Half-lif e is increased (considerably) to 130h, and it can rapidly dissociate from the EPO-R after b inding. 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).