189 PD vs IHD or CRRT for AKI? Studies are limited. Comparisons have suggested a worse outcome for PD than for CVVHF \200\224 though second-rate PD equipment (rigid cath- eters, home-ma de \202 uids, acetate buffer, no automated cyclers) are often judged against \201 rst-r ate CVVHF technology in highly catabolic patients. However, PD cannot be considered a front -line treatment for AKI in most settings but may be lifesaving if HD/CRRT unavailable. Prescribing acute PD \200 Commercially available dialysate solutions preferable. Warm to body temperature prior to infusion. A correctly positioned catheter should allow in \202 ow and out \202 ow times of <10 \200\223 15min. Both proceed under gravity. Ensure complete drainage (remembe r: more drains out than in if UF has occurred). \200 Dwell times of 1h are typical (<30mi n a waste of time and effort). \200 With non-cuffed rigid catheters, peritonitis risk i d ramatically after 72h. Cuffed catheters offer uninterrupted treatment. Aim for 20 \200\223 24 exchanges/day (although often logistically dif \201 cult). \200 Record the number of exchanges and \202 uid input:output. \200 Continuous equilibrium P D (CEPD), which is similar to standard CAPD, is an alternative. Dwell times are 4 \200\223 6h, allowing more time for solute equi libration between blood and dialysate. Less time \200\230hands on \200\231 the catheter l d risk of infection. Dialysate volume: most patients tolerate 2L exchanges. Larger volumes (up to 3L) can l catheter leaks, hernias, and diaphragmatic splinting. Dialysis dose is increased by i dialysate volume 9 i exchange frequency. Fluid balance. If the patient is euvolaemic, mildly \202 uid-overloaded, or haemodynamica lly unstable, a 1.5% dextrose concentration ( \200\230 light bag \200\231 ) is appropriat e. Check the subsequent drainage volume to assess UF. Use this \201 gure, in combination with repeated clinical assessment, to direct the need for higher dextrose concentrations (u sually 2.5% or 4.25%). Heparin (200 \200\223 500U/L) can be added to the dialysate to prevent plugging of the cat heter with \201 brin clots. It is not absorbed systemically. Commercial PD solutions do not usually contain K + , so if the patient is hypokalaemic or t he serum K + is rapidly falling, potassium chloride may be added (usually 2 \200\223 4mmol /L). 191 Chapter 3 Chronic kidney disease (CKD) What is chronic kidney disease (CKD)? 192 Prevalence of CKD 194 Diagnosis of CKD 196 Cardio vascular disease in CKD 198 Pathogenesis of CKD 200 Progression of CKD: general 202 Progres sion of CKD: antihypertensives in CKD 204 Progression of CKD: miscellaneous 208 Advanced CK D: the uraemic syndrome 212 Complications of advanced CKD 214 Anemia and CKD 216 EPO and th e kidney 218 Erythropoiesis-stimulating agents (ESAs) 220 Prescribing ESAs 222 ESAs: additi onal bene \201 ts 224 ESAs: target hemoglobin 226 Iron 1: metabolism and markers 228 Iron 2: therapy and targets 230 CKD-mineral and bone disorder (CKD-MBD) 232 CKD-MBD: bone diseas e 234 CKD-MBD: physiology 236 CKD-MBD: clinical features 240 CKD-MBD: vascular calci \201 cation 242 CKD-MBD: treatment 244 CKD-MBD: hyperphosphataemia 246 CKD-MBD: vitamin D treatm ent 250 CKD-MBD: calcimimetics 252 CKD-MBD: parathyroidectomy 254 Calci \201 c uraemic art eriolopathy (calciphylaxis) 256 Diet and nutrition in CKD 258 Malnutrition in CKD 260 Endoc rine problems in CKD 262 CKD management overview 264 Advanced CKD care 266 Conservative tre atment of CKD: symptomatic management of ESRD 268 Conservative treatment of CKD: general 27 0 CHAPTER 3 Chronic kidney disease (CKD) 192 What is chronic kidney disease (CKD)? De \201 nition The NKF KDOQI (National Kidney Founda tion Kidney Dialysis Outcomes Quality Initiative) classi \201 cation of chronic kidney dis ease (CKD) has been rapidly adopted internationally. 1 It is simple and useful and has help to raise awareness of kidney disease. CKD is divided into \201 ve stages, according to e stimated GFR. (See Table 3.1.) Table 3.1 NKF KDOQI classi \201 cation of CKD GFR (mL/min/1.73m 2 ) CKD stage Description >90 \200 Normal or increased GFR but other evidence of kidney damage 1 60 \200\223 89 \200 2 Mild reduction in GFR, with other evidence of kidney damage 3A * 3B * 45 \200\223 59 * 30 \200\223 44 * Moderately reduced GFR, with or without other evidence of kidney damage 3 30 \200\223 59 4 15 \200\223 29 Severely reduced GFR 5 <15 End-stage, or approaching end-stage, kidney failure 5D <15 On dialysis \200 Early CKD is not diagnosed on eGFR alone. There must also be evidence of kidney dama ge (see rest of table). Patients with an eGFR of 60 \200\223 89mL/min without kidney damag e do not have CKD. * The subdivision of stage 3 into 3A and 3B is not part of the original KDOQI classi \201 cation but has been advocated by other organizations (e.g. NICE in the U K). It re \202 ects the higher incidence of cardiovascular disease and complications (e.g. anemia) that are more prevalent, as eGFR falls below 45mL/min. Patients with a GFR >60mL/min should not be considered to have CKD, unless there is concomi tant evidence of kidney damage: \200 Urinary abnormalities (proteinuria, haematuria). \200 Structural abnormalities (e.g. abnormal renal imaging). \200 Genetic disease (e.g. APKD). \200 Histologically established disease. The reduced eGFR and/or urinary abnormalities should ideally be present on at least two occasions \211 3 months apart. It has been suggested that the suf \201 x (p) is added to the CKD stage to indicate the pr esence of proteinuria (uACR \211 30mg/mmol or uPCR \211 45mg/mmol). This helps to highl ight the i risk of both progression and CV disease (e.g. stage 3p). Chronic renal failure (CRF) is now an outmoded term that indicates an irreversible decline in GFR. WHAT IS CHRONIC KIDNEY DISEASE (CKD)? 193 3 The majority of patients with CKD stages 1 \200\223 3 do not progress to kidney failure. The risk of death from CV disease is far higher than the risk of progression ( b p. 198). Causes of CKD Accurate data on the causes of early CKD are scarce. Registry data focuses on causes of end-stage renal disease (ESRD). As only a relatively small number progress (and live long enough) to reach dialysis or trans- plantation, it is dif \201 cult to extrapola te back to early CKD. Recent UK and US causes are shown in Table 3.2, but there is consider able variation worldwide. Table 3.2 Causes of CKD \200\224 the US and UK Renal disease UK Renal Registry US Renal Data System (USRDS) Cystic or congenital disorder 7 7 Diabetes mellitus 13 37 Glomerulonephritis a 15 18 Hypertension/atherosclerotic 9 24 Infective or obstructive (including re \202 ux) 12 3 Miscellaneous b 18 7 Unknown 26 4 a May not be histologically proven. b Includes analgesic nephropathy, TB, HIV-related, sick le cell disease, sarcoidosis, acute interstitial nephritis, trauma. Reference 1. National Kidney Foundation (2002). KDOQI clinical practice guidelines for chro nic kidney dis- ease: evaluation, classi \201 cation and strati \201 cation. American Jou rnal of Kidney Diseases , 1 , S1 \200\223 S266. CHAPTER 3 Chronic kidney disease (CKD) 194 Prevalence of CKD \200 The exact prevalence of CKD in the general population remains unknown. \200 A large UK study in primary care suggested an age-standardized prevalence of stages 3 \200\223 5 CKD of 8.5% (10.6% in 5 and 5.8% in 4 ). Over 19 million of the US adult population are thought to have some form of CKD. The most common associations are i BP, diabetes, and vascular disease. \200 In the UK stu dy just mentioned, the age- and gender-adjusted odds ratios were 2.1 for i BP, 1.33 for dia betes, and 1.69 for CV disease. \200 CKD prevalence rises dramatically with age \200\224 from 78 pmp age <40 to 5,900 pmp age >80. Early stages appear common, so the base of the pyramid in Fig. 3.1 should actually be drawn much wider, with a much narrower peak. These colossal estimates of prevalence have led to CKD being proposed as an important public health issue. CKD is more common in many ethnic minorities, e.g. in association with diabetes in South As ian and hypertension in black people. Additional genetic factors are also likely to play a role in the relative over-representation of certain ethnic groups in ESRD programs. Many cases of early CKD are unrecognized. \200 Many cases of advanced CKD are unknown to specialist renal services. Stage 5: 0.2% Stage 4: 0.2% Stage 3: 4.3% Stage 2: 3.0% Stage 1: 3.3% Fig. 3.1 The burden of chronic kidney disease. Data taken from NHANES study in US populatio n. 2 ESRD represents just the tip of the iceberg \200\224 note the large numbers in stages 1 \200\223 3, compared to 4 and 5. All stages have signi \201 cantly increased CV risk. Reference 2. Coresh J, Astor BC, Greene T, et al. (2003). Prevalence of chronic kidney dise ase and decreased kidney function in the adult US population: Third National Health and Nut rition Examination Study. American Journal of Kidney Diseases , 41 , 1 \200\223 12. PREVALENCE OF CKD 195 Criticisms of the KDOQI classi \201 cation Although the 2002 classi \201 cation is now ub iquitous, it is not without its problems. Criticisms include the following: \200 The clas si \201 cation sets out to identify risk yet labels as a disease. \200 It de \201 nes d isease on a laboratory variable alone, with no clinical assessment or correlation. Many patients will be caused unnecessary anxiety. \200 Many live kidney donors have an eG FR <60mL/min post-nephrectomy. Do they have a disease? The MDRD eGFR equation was validated in subjects with renal disease and yet is being used t o evaluate subjects without it. The equation is not suf \201 ciently validated for differences in age, race, and body habitus. MDRD tends to underestimate true GFR (yet the values are generally unconditionally accepted). The vast estimates of CKD prevalence offered by the classi \201 cation are unrealistic and should be viewed as distribution values for eGFR in a particular popula tion, rather than true disease prevalence. The classi \201 cation does not take account of the age-related change in GFR. Many view t his as natural senescence, not pathology ( 7 25% age >70 have an eGFR <60mL/min and 6 kidne y \200\230 disease \200\231 ). The eGFR bands used to de \201 ne stages are arbitrary: Stage 3: a 25-year-old proteinuric 4 whose renal function has rapidly deteriorated to an eGFR of 30 \200\223 35mL/min. Stage 3: a 75-year-old 5 with no other evidence of kidney disease and a stable eGFR of 55 \200\223 59mL/min. Identical stage notwithstanding, the implications for these individuals are very, very different. Is it a useful CV risk assessment tool? Although there is an association between d eGFR, pr oteinuria, and CV risk, a causal link is unproven. Also, this relationship mainly operates at eGFR <45mL/min. The classi \201 cation implies progression from one stage to the next. In reality, this do es not occur. Stage 3 seldom progresses to 4 or 5. \200 It de \201 nes normal function a s >90mL/min and disease as <60mL/min. Neither is particular satisfactory nor evidence-based. It does not give enough weight to microalbuminuria or overt proteinuria, which may be better markers of CV risk (especially in early stages). Many laboratories do not report a value for eGFR when >60mL/min, removing any justi \201 cation for separating stages 1 and 2. Large numbers have been diagnosed with early CKD \200\224 this has diverted specialist time away from kidney failure and its treatment. The term CKD should be reserved for persistent, irreversible renal pathology, not just redu ctions in eGFR \200\224 unless there are pathophysiological consequences, such as anemia o r altered salt and water homeostasis (often not present until eGFR <30mL/min). \200 It ha s been suggested that percentile charts of eGFR in healthy individuals of both sexes, across all ages, and in different populations should be used to de \201 ne an abnormal eGFR. CHAPTER 3 Chronic kidney disease (CKD) 196 Diagnosis of CKD 2 Always assume a d eGFR represents acute kidney injury until proven other wise. Is there a historical eGFR for comparison? Has there been a recent illness or change in medication? If uncertain, repeat within 5 days, and seek specialist help, as necessary. Why is it important to identify patients with CKD? \200 CKD is associated with i CV risk. Modifying CV risk factors ( 2 i BP) would be expected to d morbidity and mortality. Some patients will bene \201 t from further investigation (e.g. renal biopsy) to identify a potentially treatable intrinsic renal disease (e.g. glomerulonephritis) or renal involvem ent in a systemic illness (e.g. myeloma). Whatever the underlying cause, it may be possible to slow or prevent progression to kidney failure. Complications (e.g. anemia) can be identi \201 ed and treated early. \200 Those (relativ ely few) patients who will go on to kidney failure and potentially need dialysis or transplantation can be adequately prepared. Patients with CKD are at higher risk of acute kidney injury. This is often preventable (e.g. after IV contrast administration). eGFR for diagnosis and management of CKD \200 Serum creatinine (SCr) has a non-linear rel ationship with GFR. In early CKD, SCr may remain within the \200\230 normal \200\231 rang e and be misleading. \200 eGFR is calculated from formulas that adjust SCr for age, sex, and race. \200 The most widely used (and foundation of the KDOQI classi \201 cation) is the Modi \201 cation of Diet in Renal Disease (MDRD) equation since it appeared the mos t reliable and reproducible in individual patients. \200 More recently, the CKD Epidemiol ogy Collaboration pooled study data to produce the CKD-EPI equation. This provides a more accurate assessment of GFR in in dividuals with normal or only slightly d GFR. This results in lower estimates of CKD preval ence and more accurate prediction of adverse outcomes. Most laboratories will routinely report an MDRD eGFR, although the use of CKD-EPI is likely to increase. Formulas are available at: M http://www.renal.org/eGFRcalc or M http://www.ki dney.org/ professionals/tools . Several useful free Apps are also available, e.g. MedCalc, QxMD, MedMath, Epocrates (fee-requiring). Normal GFR is 7 100mL/min/1.73m 2 , so eGFR gives a (very) rough percentage of kidney function. Cautions \200 It is only an estimate (con \201 dence intervals are wide; 90% of patients will have a GFR within 30% of their eGFR). eGFR is likely to be inaccurate at extremes of body habitus (malnourished, obese) as well as in amputees and during pregnancy. It is not fully validated in age <18. \200 Race: only validated in Caucasians and black p eople though probably acceptable utility in South Asians ( (cid:2) check whether your lab corrects for race, othe rwise use a correction factor of x 1.21 for black patients). It is not validated if the GFR is rapidly changing (e.g. AKI). DIAGNOSIS OF CKD 197 The MDRD equation tends to underestimate normal renal function. CKD-EPI is more reliable in this situation. It is less accurate in individuals with very poor kidney function. Screening for CKD? There is no evidence that screening of the general population for CKD sa ves lives or money. Screening can be targeted at those at highest risk. Who \200 i BP. \200 Diabetes mellitus. \200 CCF. \200 Atherosclerotic disease (coro nary, cerebral, peripheral). \200 Possible renal involvement in multisystem disease (e.g. SLE, myeloma). \200 Urological problems: bladder out \202 ow obstruction, neurogenic bladder or diversion surgery; renal stone disease. Chronic nephrotoxin use (e.g. NSAIDs, lithium, ciclosporin, ACE-I). \200 Urologically une xplained haematuria. \200 Unexplained oedema. How \200 eGFR, BP, urinalysis for blood 9 protein, uACR, or uPCR (annually). Proteinuria Why is proteinuria so important? \200 It is a marker of chronic kidney damage . \200 It has prognostic value in the progression of CKD. \200 It may itself cause prog ression of CKD ( X ). \200 It is a helpful surrogate treatment target. \200 It is an in dependent CV risk factor. Detection and quanti \201 cation of proteinuria \200 Dipstick: if \211 1+, send MSU to exclude UTI, and repeat after 2 weeks. \200 All with an eGFR <60mL/min (and high-risk pa tients in stages 1 and 2) should have their urinary protein excretion quanti \201 ed. (See Table 3.3.) \200 24h collection unnecessary. Send spot sample (preferably early morning) . \200 The relationship between uACR and uPCR is non-linear. Table 3.3 Approximate equivalent values for proteinuria quanti \201 cation uACR (mg/mmol) uPCR (mg/mmol) Urinary protein excretion (g/24h) 30 50 0.5 70 100 1 uACR is more sensitive for early disease and favored in many guidelines, esp. as an initial test. uPCR is adequate for monitoring. uACR \211 2.5mg/mmol ( 4 ) or \211 3.5mg/mmol ( 5 ) represents microalbuminuria (still a marker of early renal disease and associated with an i CV risk, p articularly in diabetes and i BP). CHAPTER 3 Chronic kidney disease (CKD) 198 2 Cardiovascular disease in CKD CKD patients are at higher risk of CV events, including cor onary disease, CCF, stroke, and peripheral vascular disease (see Table 3.4). Both d eGFR an d proteinuria (itself a marker of generalized endothelial dysfunction) are independently (a nd additively) associated with adverse CV outcomes. Even those with early CKD are at increa sed risk \200\224 most will die a CV death before progressing to kidney failure. (See Tabl e 3.4.) Table 3.4 Percentage of 5-year clinical outcomes in patients with CKD a Endpoint Stage 2 Stage 3 Stage 4 Progression to RRT 1.1% 1.3% 19.9% Death 19.5% 24.3% 45.7% a Keith DS, Nichols GA, Guillion CM, et al. (2004). Longitudinal follow-up and outcomes amo ng a population with chronic kidney disease in a large managed care organization. Arch Inte rn Med , 164 , 659 \200\22363. Take 100 patients with an eGFR <60mL/min. 7 1% will progress to kidney failure each year. H owever, there is a 10% death rate (mainly CV disease), so, after 10 years, 8 patients will require RRT, 27 will have \200\230 smoldering \200\231 CKD, and 65 will be dead! 2 An estimated 8 million people in the USA have an eGFR <60mL/min. Those that survive to st art RRT do so with a high CV disease burden. Dialysis patients are 7 20 x more likely to die a CV death than the general population. A cardiac cause is implicated in >40% of all deaths at ESRD. ESRD 5-year survival (UK data): age 18 \200\223 34 is >90%; age 45 \200\223 54 is 70%; age 65 \200\223 74 is 30%; age >75 is <20%. Managing risk factors \200 X Good evidence for the bene \201 t of many interventions in CKD patients is lacking \200\224 it is often inferred by extrapolation from the non-CKD po pulation. Lifestyle advice: Encourage exercise. \200 Offer smoking cessation help and advice. \200 Healthy diet; ad equate nutrition. \200 Meticulous BP control (<130/80): use ACE-I and ARB to d proteinuri a. Management of lipids, usually with a statin: Evidence of bene \201 t for lipid-lowering therapy in CKD is limited. \200 For example, the Die Deutsche Diabetes Dialyse (4D) study showed no bene \201 t from cholesterol reduct ion by atorvastatin in dialysis patients with T2DM. Explanation: competing CV risk may \200\230 drown out \200\231 the bene \201 t of statins in this very high-risk group. Similarly, AURORA, a RCT of 2,776 HD patients comparing rosuvastatin vs placebo, showed no bene \201 t of LDL reduction against a composite endpoi nt of CV death, non-fatal MI- and non-fatal stroke. CARDIOVASCULAR DISEASE IN CKD 199 However, SHARP, an RCT of 9,438 CKD (dialysis or CKD) with no history of MI or CV revascula rization, compared simvastatin + ezetimibe against placebo, \201 nding a 17% reduction in major vascular events after mean 4.7 years \200\231 follow-up. Recent guidelines, including those for non-CKD populations (e.g. those produced by the Amer ican Heart Association/American College of Cardiology), have moved away from traditional nu meric targets for primary and secondary prevention towards the estimation of risk as the ba sis for treatment (usually a statin). This is also the case in KDIGO lipid management guide lines for CKD (2013). See b p. 205. Glycaemic control; HbA1c <7.0% (if diabetic \200\223but see b p. 612). \200 Aspirin 75mg daily for s prevention unless contraindicated. \200 Appropriate CKD-MBD management ( d va scular calci \201 cation). \200 Appropriate anemia management ( d LVH). \200 Adequate dialysis. \200 No current evidence for homocysteine reduction using folic acid. \200 On going interest in antioxidant therapy (e.g. vitamin E and acetylcysteine) but no compelling evidence to date. Cardiovascular risk factors Traditional cardiovascular risk factors more common in CKD \200 Hypertension (almost always present). \200 Diabetes (common cause of CKD). \200 D yslipidaemia: CKD l d HDL, i IDL, i pro-atherogenic lipid particles, and i oxidation of LDL (all promote atherogenesis). Obesity and reduced physical activity. Risk factors common in (or unique to) advanced CKD \200 Arteriosclerosis. \200 Diastoli c dysfunction. \200 Vascular calci \201 cation (and cardiac valvular calci \201 cation) . \200 Proteinuria. \200 Volume overload. \200 Anemia ( b p. 216). \200 Higher Hb t argets on ESA therapy ( b p. 226). \200 Oxidant stress: i Reactive oxygen species. \200 d Antioxidants (e.g. vitamin E). In \202 ammation ( b p. 261). \200 Malnutrition ( b p. 260). \200 Vitamin D de \201 c iency ( b p. 251). \200 Accumulation of advanced glycation end-products. \200 LVH (a st rong predictor of mortality in ESRD). \200 Hyperparathyroidism. \200 Myocardial \201 brosis and abnormal myocyte function. \200 Carnitine de \201 ciency. \200 Hyperhomocys teinaemia. \200 Asymmetric dimethyl arginine (ADMA) retention. \200 Reduced nitric oxid e bioavailability. \200 Insulin resistance. \200 Renin \200\223 angiotensin system act ivation. CHAPTER 3 Chronic kidney disease (CKD) 200 Pathogenesis of CKD Progression of CKD Once CKD is established, it tends to progress, regar dless of the underlying cause. Decline in GFR tends to be linear over time, unless clinical circum- stances change. Progression of CKD is more often due to s maladaptive haemodynamic and metabolic factors than underlying disease activity (see Fig. 3.2). A series of interac ting processes eventually results in: \200 Glomerulosclerosis (glomerular scarring and ob solescence). \200 Proteinuria. \200 Tubulointerstitial \201 brosis. Mechanisms Raised intra-glomerular pressure \200 As nephrons scar and \200\230 drop out \200\231 , remaining nephrons undergo compensatory adaptation, with i blood \202 ow per nephron and hyper \201 ltration attempting to \200\230 normalize \200\231 GFR (the Brenn er hypothesis). Changes in glomerular capillary wall permeability are a feature of glomerular diseases. Renal vasodilatation may be an initiating event, with the glomerulus exposed to a higher capillary pressure. Glomerular damage \200 i intra-glomerular pressure l i wall stress and endothelial injury . \200 i strain on mesangial cells l i matrix deposition mediated (in part) by angiotensin II and cytokine release (TGF- B , PDGF). Proteinuria may be due to an underlying glomerular lesion or result from raised intra-glome rular pressure. Protein or factors bound to \201 ltered albu- min (such as fatty acids, g rowth factors, or metabolic end-products) may lead to: \200 Direct proximal tubular cell injury. \200 Local cytokine synthesis ( l recruitment of interstitial in \202 ammatory cells). Pro- \201 brotic factors l interstitial scarring. \200 Myo \201 broblast activation and tubular epithelial to mesenchymal transition (EMT) occur, further fueling the \201 broge nic process. Tubulointerstitial scarring \200 The degree of tubulointerstitial damage correlates bette r with long-term prognosis than glomerular damage. Proteinuria may itself be harmful to the tubulointerstitium, but chronic ischaemic damage i s also important: tissue O 2 tension is relatively low in the renal medulla, making tubules sensitive to hypoxic injury. Chronic ischaemia 6 occurs with: \200 Damage to glomerular capillaries (glomerulosclerosis l altered peritubular perfusion). RAS activation l intrarenal vasoconstriction. \200 Intratubular capillary loss and i diff usion distance between capillaries and tubular cells ( l a vicious cycle of hypoxic damage). PATHOGENESIS OF CKD 201 Renal injury Repair Decreased nephron number Phenotypic changes in intrinsic glomerular cells Glomerular hypertension Macrophage recruitment Systemic hypertension Release of cytokines and growth factors Proteinuria Glomerular hypertrophy Hyperlipidemia Increased ECM production Glomerulosclerosis CHRONIC KIDNEY DISEASE Fig. 3.2 Potential \200\230 maladaptive \200\231 responses which contribute to progressio n in CKD. Reproduced from Oxford Desk Reference: Nephrology , Jonathan Barratt, Kevin Harri s, and Peter Topham (2008), with permission of Oxford University Press. CHAPTER 3 Chronic kidney disease (CKD) 202 Progression of CKD: general De \201 ning progression Arbitrary, but progression may be de \201 ned as a decline in eGFR of >5mL/min in 1 year or >10mL/min in 5 years (in the absenc e of other causes of an acute deterioration). Factors in \202 uencing CKD progression Non-modi \201 able \200 Underlying cause of kidney disease (tubulointerstitial disease t ends to progress more slowly than glomerular disease). Race (progression faster in black patients). Modi \201 able \200 BP. \200 Level of proteinuria. \200 Plus: Exposure to nephrotoxic agents. \200 Underlying disease activity (e.g. SLE, vasculitis). \200 Further renal insults (superimposed obstruction, UTI). \200 Hypovolaemia or interc urrent illness. \200 Dyslipidaemia. \200 Hyperphosphataemia. \200 Metabolic acidosis. \200 Anemia. \200 Smoking. \200 Glycaemic control (if diabetic). What can be done to prevent or slow progression? Identify any potentially modi \201 able u nderlying cause \200 Helps determine prognosis. \200 Is speci \201 c intervention/trea tment possible, e.g. immune suppression in immunologically mediated renal disease, relief of obstruction? \200 History: systemic dis ease (e.g. SLE, myeloma), lower urinary tract symptoms, stone disease, review all medications. Examination: BP, hypovolaemia, atherosclerosis, palpable bladder, stigmata of in \202 ammatory disease. Investigation: urinalysis (haematuria and/or proteinuria may suggest a renal or systemic disease that could bene \201 t from speci \201 c intervention), USS ren al tract, renal biopsy. In \202 uence mediators of progression \200 There is considerable overlap in the measure s employed to prevent progression and those used to modify CV risk ( b p. 202). In addition, these often dovetail with a patient \200\231 s existing treatments for CV disease, diabetes, or hypertension. This enables an integrated management program to be developed that is easy for the patient (and physician) to understand and administer. PROGRESSION OF CKD: GENERAL 203 Preventing progression: blood pressure \200 i BP is almost universal in CKD and may be bo th cause or effect. \200 i BP l glomerular \201 ltration pressure and i proteinuria l i renal injury. \200 BP control unequivocally slows progression of CKD and is the main renoprotective strategy. A large body of evidence supports the use of ACE-I and ARBs as \201 rst-line antihyperten sives in both diabetic and non-diabetic CKD, particularly if concomitant proteinuria. These agents: \200 d efferent arteriolar tone l d intra-glomerular pressure and d proteinuria. d A2 activity l A2-induced in \202 ammation l d \201 brosis and scarring. \200 ACE-Is affect both angiotensin type 1 (A1) and type 2 (A2) receptors but may not completely inhibi t A2 formation. ARBs block A1, but not A2, receptors. BP targets are more stringent in CKD (and lower still for patients with proteinuria). (See b p. 204.) The stringent application of current evidence would result in: ACE-I for renoprotection in: (i) T1DM and microalbuminuria or overt diabetic nephropathy; (ii) T2DM with i BP or microalbuminuria; (iii) non-diabetic CKD with proteinuria 0.5g/day. \200 ARBs for renoprotection in T2DM and microalbuminuria or overt nephropathy. Few studies have directly compared ACE-I and ARB treatment in CKD. \200 Combination ACE-I and ARB therapy ( \200\230 dual blockade \200\231 ) reduces BP and proteinuria to a grea ter extent than monotherapy but has not been shown to d CKD progression (see also b p. 614) . There is often reluctance to use ACE-I in more advanced CKD because of fears of i K + or a rapid fall in GFR. However, evidence suggests that the bene \201 t of ACE-I therapy is present, regardless of the initial level of renal function. X There is evidence that dihydropyridine calcium channel blockers (e.g. nifedipine and amlo dipine) may adversely effect the progression of CKD through effects on the renal microcircu lation. They should 6 be avoided as \201 rst-line treatment but are frequently used as pa rt of combination therapy (particularly in patients taking beta blockers where non-dihydrop yridine CCBs are best avoided). Starting an ACE-I or ARB in CKD \200 Clinical trials show a good safety pro \201 le, eve n in higher CKD stages. \200 Ensure patient is well hydrated. \200 Avoid NSAIDs: If on diuretic therapy, consider reducing diuretic dose for 48h, and request \201 rst dose is taken at bedtime. Check eGFR and K + before and 3 \200\223 5 days after. \200 Expect (and allow) a rise in SCr or d eGFR of up to 20%, but recheck within 2 \200\223 4 weeks. If K + >5.5mmol/L, assess diet and other medications. \200 Stop if K + >6.0mmol/L. \200 Measure K + and eGFR during intercurrent illnesses. CHAPTER 3 Chronic kidney disease (CKD) 204 Progression of CKD: antihypertensives in CKD Antihypertensives in CKD: a suggested batting order Expect to need \211 2 agents (warn the patient this is likely to be the case). \200 First, limit Na + intake (<100mmoL/day), and recommend other lifestyle measures ( b p. 259). ACE-I (especially if uPCR >100mg/mmol or uACR >70mg/mmol). \200 Loop diuretic (e.g. furos emide) if evidence of salt and water overload. Thiazide diuretics may be effective in early CKD. Add ARB if uPCR remains >100mg/mmol or uACR >70mg/mmol. \200 Calcium channel blocker: If a beta blocker is likely to be necessary, then use dihydropyridine CCB (e.g. nifedipine, amlodipine); if not, then a non-dihydropyridine (e.g. diltiazem) is preferred. Beta blocker (e.g. atenolol, bisoprolol). \200 Alpha blocker (e.g. doxazosin). \200 Cen trally acting agent (e.g. moxonidine). \200 Vascular smooth muscle relaxant (e.g. minoxid il). Blood pressure targets in CKD KDIGO \200 Recommend a BP target <140/90mmHg for non-diabet ic, nonproteinuric CKD patients. Target <130/80mmHg if proteinuria (>30mg/24h) whether diabetic or not. Tailor treatment regimes for individual elderly patients by carefully 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