Structural and functional changes in the aging kidney Under normal circumstances, the elder ly kidney is capable of maintaining \202 uid and electrolyte balance and the physi- ologi cal changes associated with age are clinically silent. However, the capacity to adapt is re duced and the response rate to change is slower, thus making the elderly kidney more suscep tible to developing AKI. Being less able to adapt to sudden changes in blood \202 ow or s alt and water balance leads to: CHAPTER 10.13 Acute kidney injury in the elderly 385 Glomerulonephritis There is an increased incidence of rapidly progressive glomerulonephriti s (RPGN) due to small vessel vasculitis in patients aged >60 years. RPGN consistently accou nts for approximately a third of cases in renal biopsy series in the elderly. Lupus nephrit is is very rarely found in renal biopsies in older populations. Table 10.13.1 Causes of AKI occuring more frequently in the elderly Prerenal AKI (all forms more common in the elderly) True hypovolemia Reduced intravascular volume (functional hypovolemia) NSAID- or ACEI/ARB-induced hemodynamic changes Renal artery thrombosis Cholesterol embolization Acute tubular necrosis Acute tubular necrosis (ATN) is the commonest cause of AKI in both y oung and elderly populations, particularly for those patients who require ITU admission. Al though a distinction is frequently made between ischemic, nephrotoxic and septic ATN, in re ality, ATN com- monly results from a mixture of insults. The elderly also have an increased prevalence of comorbid conditions predisposing them to develop ATN (diabetes mellitus, hyp ertension, CKD and heart failure). Ischemic ATN is more common in elderly populations where approximately one-third of cases are the conse- quence of surgical intervention. Raised se rum creatinine or urea preoperatively strongly predict the likelihood of developing worseni ng renal function postoperatively. Cardiac and vascular surgery are most likely to result i n postoperative AKI. Septic ATN is common in younger adults as well as the elderly. Multipl e organ failure in the elderly most frequently results from infection, and the development of AKI is a strong predictor of mortality in this age group. The interaction of nephrotoxin s and renal hypoperfusion is at least additive in the development of AKI and may be synergi stic. Risk factors for the development of nephro- toxic ATN in the elderly are: \200 Intrinsic renal AKI Rapidly progressive glomerulonephritis Focal segmental glomeruloscleros is Ischemic ATN Nephrotoxic ATN Myeloma Postrenal AKI Benign prostatic hyperplasia or prostate cancer Abdominal/pelvic malignancy Prerenal AKI Prerenal AKI is more common in the elderly and also more common in community-a cquired AKI. It may result from a number of causes. Hypovolemia The elderly are more susceptible to true hypovolemia due to reduced maximal con centrating ability, reduced sodium reabsorption capacity, a reduced thirst impulse and an i ncreased prevalence of diuretic usage. Functional hypovolemia (interpreted by the kidney as a reduction in intravascular volume) from pre-existing conditions such as heart failure is also more common in the elderly. radiocontrast use (prevalence increasing as more inter- ventions carried out); an increased prevalence of polypharmacy; injudicious use of nephrotoxic drugs especially when dosage is not adjusted for the reduction in GFR. Aminoglycosides in particular are associated with a n increased incidence of AKI amongst the elderly and should be avoided unless absolutely ne cessary where- upon monitoring of drug levels is essential. Hemodynamic Impaired renal blood flow autoregulation leaves the elderly kidney at increased risk from superadded hemo- dynamic effects from drug therapy. Age alone, however, has not been shown to be a risk factor for AKI following either NSAIDs or ACEIs/ARBs. Risk factors for NSAID-induced AKI include patient aged >60 years with concomitant cardiovascular diseas e, CKD and renal hypoperfusion. Risk factors for ACEI/ARB-induced AKI include the pres- enc e of renal artery stenosis, severe chronic heart failure, polycystic kidney disease and int ra-renal nephrosclerosis (often undiagnosed). \200 Acute interstitial nephritis The overall incidence of acute interstitial nephritis is not h igher in the elderly, but theoretically they are more at risk due to the higher prevalence of polypharmacy. If diagnosis is suspected, renal biopsy should be performed promptly as ea rly treatment with corticosteroids may improve renal recovery. Renovascular disease Both renal artery thrombosis and cholesterol embolism are more common in the elderly. Cholesterol embolization is an important cause of AKI in the elderly. It mo st commonly occurs after vascular inter- ventions with AKI, generally occuring up to 2 \200 \2234 weeks after the procedure. It is thought to be responsible for a third of cases of AK I following AAA repair. Cholesterol emboliza- tion can also arise spontaneously in an indiv idual with severe atherosclerotic disease, or following anticoagula- tion or thrombolysis. Intratubular obstruction This is less common than urethral/ureteric obstruction. Intratubul ar obstruction due to myeloma (light chain precipitation) is more common in the elderly. Ot herwise the causes of intratubular obstruction are similar to the general population. Postrenal AKI Obstructive renal failure is more common in the elderly than in younger adult s. The incidence in the general population is quoted as 1 \200\22310% but in elderly popula tions the incidence is increased to 9 \200\22322%. Intrinsic renal AKI Rapidly progressive glomerulonephritis, renovascular disease and myelom a are all seen more frequently in the elderly. R. WESTACOTT 386 AKI only develops where there is bilateral obstruction or obstruction to a single functioni ng kidney. CT scan An enhanced CT scan should be considered if renal artery occlusion is suspected. Urethral/ureteric obstruction This is an important cause of AKI in the elderly and is often amenable to treatment. Important causes to consider in the elderly patient are: \200 Renal biopsy There is no excess risk in performing a renal biopsy in the elderly patient an d much potentially to be gained if a treat- able condition is diagnosed. A biopsy should th erefore be performed if clinically indicated. Interpretation of the biopsy can sometimes be more dif \201 cult due to the presence of age-related changes such as glomerulosclerosis. However, this should not be used as a reason for not per- forming a biopsy if it is otherw ise indicated. The most common diagnoses seen in renal biopsy series in elderly patients wi th AKI are: \200 \200 \200 \200 prostatic disease (benign prostatic hyperplasia and pros- tate cancer); intra-abdominal mal ignancy; retroperitoneal malignancy. \200 Presentation of AKI The presentation of AKI in the elderly as in the general population is often nonspeci \201 c. However, the elderly are more likely to have an atypical presentati on of AKI such as an acute confusional state. Physical signs can also be misleading in the elderly. In particular: \200 RPGN (one-third of all renal biopsies in the elderly); ATN; renovascular disease; acute int erstitial nephritis. loss of skin turgor is a common \201 nding in the elderly and may be a re \202 ection of aging rather than hydration status; orthostatic hypotension may occur in elderly patients without hypovolemia; edema may occur in the absence of \202 uid overload. One renal biopsy study in the elderly noted that the histo- logical diagnosis was different from the clinical diagnosis in 33% of cases, emphasizing the importance of biopsy in this population. Treatment There are currently no evidence-based guidelines for the management of AKI in the elderly. The following principles are based on expert opinion. Investigations In general, AKI occurring in an elderly patient should be investigated in th e same way as in the general adult population. The following pertain to issues speci \201 cally related to the elderly population. Fluid management As the elderly are more prone to volume contraction, initial rehydration i s an important \201 rst step when AKI is suspected (and there are no signs of \202 uid overload). This should occur regardless of urinary indices. Reversibility of renal impairme nt in response to fluid replacement is the most reliable indicator of prerenal AKI. Whereas rehydration rapidly reverses prerenal AKI in the young, the elderly are likely to respond more slowly to a \202 uid challenge. Furthermore, the cardiovascular system is frequently more rigid in older populations leading to an increased risk of \202 uid overload. For t hese reasons, the assessment of fluid balance is often more dif \201 cult in elderly patie nts and generally CVP monitoring will be required to guide \202 uid resuscitation. Care s hould be taken with fluid management in the elderly patient with obstructive AKI, being ale rt to the possibility of: \200 Blood tests The following should always be considered: \200 serum immunoglobulins, serum protein electrophoresis and urine electrophoresis to exclude m yeloma; ANCA and anti-GBM Ab (see below); LDH if renal infarction is suspected (raised in a bsence of LFT derangement). \200 Urinary electrolytes The value of urinary indices in distinguishing types of AKI is controv ersial. A high urine osmolality (>500 mosmol/kg) and a fractional excretion of sodium (FENa ) <1% suggest pre-renal AKI. Such parameters may be even less useful in elderly patients be cause FENa >1% and a urine osmolality <500 mosmol/kg can occur in pre-renal AKI in the elde rly in the presence of: \200 a decrease in the maximal concentrating ability of the kidney (with or without underlying C KD); an inability to maximize sodium reabsorption; diuretic use. Postobstructive diuresis (>4 L/day): \202 uid and electrolyte replacement needs to be car efully managed due to reduced urinary concentrating and diluting ability and blunted maxima l response to alterations in sodium concentration. Hyperkalemic (type IV) renal tubular aci dosis: the elderly are more susceptible (reduction in renin and aldosterone activity), and it may persist after correction of the obstruction. \200 Conversely, FENa <1% may also be seen in intrinsic AKI in: \200 \200 \200 \200 \200 early obstruction; acute glomerulonephritis; hepatorenal syndrome; following radiocontrast administration; sepsis. Renal replacement therapy Indications for dialysis are no different from the general popula tion and individual patient characteristics and local service provision rather than age sho uld determine the dialysis modality chosen. Radiological investigations Abdominal ultrasound USS is imperative to diagnose or exclude o bstructive AKI and should be performed without delay. CHAPTER 10.13 Acute kidney injury in the elderly 387 There is currently no convincing evidence that elderly patients with AKI requiring RRT have a signi \201 cantly worse outcome than their younger counterparts and dialysis should the refore not be withheld on the basis of age alone. 13% Recovery Crescentic (rapidly progressive) glomerulonephritis Any form of RPGN has a much poorer prog nosis in patients aged >60 years. However, the decision to treat patients aged >60 years wi th aggressive immunosuppression should be considered carefully as it is associated with a s igni \201 - cantly increased relative risk of death compared with patients aged <60 years. Partial recovery 48% 28% ESRD Death 11% Prognosis It is dif \201 cult to estimate immediate mortality risk or long- term prognosis for an individual patient due to the diver- sity of the different data series, re \202 ec ting the heterogeneity of both the underlying causes of AKI and population groups studied. Whereas increasing age is associated with a worse out- come in the ITU population, there is no consensus as to whether mortality rates from AKI in the elderly are higher than the ove rall population. Mortality is lower in obstruc- tive AKI and more common in elderly populat ions, which may have a bearing on mortality rates. Mortality rates range from 40 to 65% but studies on AKI in the elderly are generally small. Mortality is often not related to AKI p er se. The major causes of mortality in elderly patients with AKI published in the literatu re are: \200 \200 \200 \200 Fig. 10.13.1 Prognosis of AKI in patients aged >65 years. Renal function is taken from the time of discharge from hospital. Data are taken from two studies with 137 patients in total : Baraldi et al. (1998) and Klouche et al. (1995). Further reading Baraldi A, Ballestri M, Rapan R, et al. Acute renal failure of medical ty pe in an elderly population. Nephrol Dial Transplant 1998; 13(Suppl 7): 25 \200\22329. Feest TG, Round A, Hamad S. Incidence of severe acute renal failure in adults: results of a community based study. Br Med J 1993; 306: 481 \200\223483. Haas M, Spargo BH, Ernst-Jan C, et al. Etiologies and outcome of acute renal insuf \201 ci ency in older adults: a renal biopsy study of 259 cases. Am J Kidney Dis 2000; 35: 433 \200 \223447. Hegarty J, Middleton RJ, Krebs M, et al. Severe acute renal failure in adults: place of car e, incidence and outcomes. Q J Med 2005; 8: 661 \200\223666. sepsis; multiple organ failure; GI bleeding; cardiac failure and arrhythmias. Klouche K, Cristol JP, Kaaki C, et al. Prognosis of acute renal failure in the elderly. Nephrol Dial Transplant 1995; 10: 2240 \200\2232243. Lameire N, Van der Noortgate N, Vanholder RC. The elderly. In: Davison AM, et al. (eds), Ox ford textbook of nephrology, 3rd edn. Oxford: Oxford University Press; 2005. Prognostic factors Many studies have looked for factors which have prognostic signi \201 c ance for AKI in the elderly. Although no consensus exists, the following (in decreasing ord er) are those factors considered to have a negative prognostic significance, for which most agreement exists: \200 \200 \200 \200 \200 \200 Metcalfe W, Simpson M, Khan IH, et al. Scottish Renal Registry. Acute renal failure requiri ng renal replacement therapy: incidence and outcome. Q J Med 2002; 95: 579 \200\223583. Internet resources Acute Dialysis Quality Initiative: primary diagnosis or underlying cause of AKI; increasing number of failing organ systems; r equirement for dialysis; oliguria; hypotension; pre-existing cardiac disease. http://www.ADQI.net See also The aging kidney, p. 18 Clinical approach to acute kidney injury, p. 318 Renal rep lacement therapies in acute kidney injury, p. 328 Urinary tract obstruction, p. 652 Crescen tic glomerulephritis, p. 120 Recovery of renal function Renal tubular recovery is slower in the elderly and, although th ere is no \201 rm evidence to suggest that the proportion of patients remaining dialysis dependent is different in young and elderly adults, studies suggest that full recovery of r enal function occurs less often in elderly patients. Figure 10.13.1 combines the outcomes o f 137 patients from two studies of AKI in elderly patients. This page intentionally left blank 389 Chapter 11 Chronic kidney disease (CKD) Chapter contents Assessment of chronic kidney disease 390 Endocrine disorders in chronic kidney disease 398 Sexual disorders in chronic kidney disease 402 Hypertension in chronic kidney disease 406 C ardiovascular risk factors in chronic kidney disease 412 Gastrointestinal disorders in chro nic kidney disease 418 Liver disorders in chronic kidney disease 422 Hematological disorder s in chronic kidney disease 426 Skeletal disorders in chronic kidney disease 432 B2-Microgl obulin amyloidosis in chronic kidney disease 436 Immune function in chronic kidney disease 440 Coagulation disorders in chronic kidney diesase 444 Dermatologic disorders in chronic k idney disease 450 Neuropsychiatric disorders in chronic kidney disease 454 K. HARRIS 390 Assessment of chronic kidney disease Introduction Chronic kidney disease (CKD) is a long-term condition which can arise from dam age to the kidneys from a variety of diseases. When mild it results in few symptoms and may frequently go undetected. For such patients the major issue is the associated increased mo rbidity and mortality from cardiovascular disease (CVD). In an important minority of people CKD is progressive and results in end-stage renal disease (ESRD). This is fatal unless tre ated by renal replacement therapy (RRT) \200\223 either dialy- sis or kidney transplantati on. Such treatment is expensive, consuming a disproportionate amount of healthcare resource (in the UK >2% of the NHS budget is spent on the 0.1% of patients who receive RRT). The nu mber of patients receiving RRT around the world is rising rapidly and is unlikely to reach steady state for many years. Many healthcare economies are currently putting in place syste ms to allow the early detection of CKD. At the same time guidelines for CKD management are being imple- mented with the aim of either preventing or delaying the onset of associated c ardiovascular complications as well as progression of CKD to a more advanced stage. Generally, cross-sectional population studies in a number of countries suggest an overall p revalence of CKD 1 \200\2235 of >10%. CKD stage 5 is relatively rare, but lesser degrees of CKD are frequently found in the community and are frequently asymptomatic. Reported commun ity prevalence of the various stages of CKD is typically of the order: \200 \200 \200 \200 \200 CKD 5: 0.1% CKD 4: 0.2% CKD 3: 5% CKD 2: 3% CKD 1: 3% However, in assessing the burden of disease it is important to understand the characteristi cs of the population since the prevalence of CKD is affected by: \200 Increasing age: exponentially increasing so that 30 \200\22340% of population >75 years hav e CKD 3 \200\2235 (mostly CKD 3). Ethnicity: several-fold more common in Afro-Caribbean and South East Asian populations. Presence of comorbidities: higher prevalence in those with h ypertension, diabetes, vascular disease, ischemic heart disease and heart failure. Social d eprivation: increases with increasing deprivation. First-degree relatives of a patient with ERF have a higher risk of developing CKD. Data from the US (National Health and Nutrition Examination Surveys: NHANES) suggests that the preva- lence of CKD has increased from 10% t o 13% between 1988 \200\2231994 and 1999 \200\2232004. This may be partly explained by an i ncrease in the risk factors for CKD including an aging population and increasing prevalence of diabetes and hypertension. Typically in a cohort of patients with CKD 3 \200\2235: \200 \200 \200 De \201 nitions In 2002 the K/DOQI Clinical Practice Guidelines provided a de \201 nition of CKD which is now widely used around the world. To diagnose CKD there must be: \200 Kidney damage for \211 3 months de \201 ned as either struc- tural or functional abnormal ities such as urinary sedi- ment abnormalities or albuminuria. GFR may or may not be reduce d. GFR \211 60 mL/min/1.73m2 for \211 3 months with or without evidence of structural dam age. CKD is classi \201 ed into \201 ve stages according to the level of GFR irrespective of the underlying diagnosis (Table 11.1.1). It is essential to exclude causes of acute kidney injury (AKI) before classifying a patient as having CKD, or acute on chronic kidney before determining the stage of CKD. Stage 5 CKD may be called established renal failure (ERF) or ESRD and re \202 ects progression of CKD to a point where RRT may be required to maintain life. It is irreversible. As understanding of the epidemiology of CKD has devel- oped, modi \201 cations of the above classi \201 cation have been suggested in order to allow impro ved risk strati \201 cation of patients with CKD. These include: Subdivision of stage 3 in to: \200 60% will be aged >70 years; 25% will be known to have diabetes; 75% will have a history of hypertension. CKD appears to be an independent and signi \201 cant risk fac- tor for progressive CVD. CV D accounts for 50% of the deaths in patients with CKD. The relative risk of death from CVD increases with decreasing GFR even when adjusted for comorbidities such as known cardiovas cular disease, hypertension and diabetes. This relationship is maintained (although less pr onounced) even into the 9th decade of life. stage 3A: a lower risk group with an eGFR of 45 \200\22359 mL/ min/1.73 m2; stage 3B: a hig her risk group with an eGFR of 30 \200\22344 mL/ min/1.73 m2. Etiology There are many causes of CKD. These include: \200 systemic diseases: diabetes, hypertension, immunological disease; glomerular diseases: resu lting in so-called \200\230chronic glomerulonephritis \200\231; tubulointerstitial disease s; AKI, which does not recover. Applying the suf \201 x \200\230p \200\231 to all stages re \202 ects the importance of proteinuria/albuminuria as an independent risk factor for adverse outcomes in CKD. \200 Epidemiology CKD is increasingly recognized as a public health problem. Mild-to-moderate CK D is very common in unselected populations; some surveys have suggested that as many as 16% of the adult population have CKD. The various causes of CKD are described in depth else- where in this book. CHAPTER 11.1 Assessment of chronic kidney disease 391 Table 11.1.1. Classi \201 cation of CKD based on the NKF K/DOQI recommendations GFR (mL/min/1.73 m2) CKD stage Description Kidney damage with a normal or increased GFR There must be other evidence of kidney damage: \200 persistent microalbuminuria \200 persistent proteinuria \200 persistent hematur ia \200 structural abnormalities of the kidneys demonstrated \200 on USS or other radio logical tests \200 biopsy-proven chronic glomerulonephritis Kidney damage with mild reduc tion in GFR There must be other evidence of kidney damage (as above) >90 1 60 \200\22389 2 Moderate reduction in GFR 30 \200\22359 3 Severe reduction in GFR 15 \200\22329 4 Kidney failure <15 (or dialysis) 5 There appears to be wide variation in the causes of CKD in different parts of the world. Th is may re \202 ect geographical differences in the prevalence of the causative diseases wh ich can lead to CKD or different racial susceptibilities to the adverse renal effects of th ose diseases. However, the causes of CKD as listed within National Registries are frequentl y based on clinical assessment with- out histological examination of the kidney (the \200 \230gold stand- ard \200\231). This can result in misclassi \201 cation \200\223 for exam ple most patients with CKD will be hypertensive, but it would be wrong to conclude that hyp ertension had caused the CKD without a thorough assessment. Many patients present late in t he course of their disease; a histological diagnosis is either not justi \201 ed or not te chni- cally possible due to small, shrunken kidneys. In such cases the cause of CKD should be listed as \200\230cause unknown \200\231. The cause of CKD is unknown in 20 \200\22330% of patients start- ing RRT in the UK. The increasing prevalence of diabetes means this is now the single commonest cause of CKD in the Western world. In the UK, 19 \200\22320% of pa tients start dialysis as a result of diabetes, and in the USA the rate is nearer 50%. When the process is long-standing and the damage advanced it may be dif \201 cult to ident ify the primary renal disease with certainty. At the same time the \201 brotic process re sults in a loss of renal cortex and a contraction in the size of the kidneys (Fig. 11.1.1). Thus in advanced CKD a renal biopsy is rarely indicated since it may be both technically d if \201 cult and unlikely to yield information that would be diagnostically or therapeu- t ically useful. Clinical features Patients with CKD are frequently asymptomatic until the disease is advanc ed. Symptoms related to progressive loss of tubular function may be seen in early CKD. The loss of urinary concentrat- ing ability (lack of response to ADH) results in polyuria which may manifest itself as nocturia in adults or enuresis in children. However, it is possible for the majority of the kidney \200\231s excretory function (GFR) to be lost without the p atient experiencing any symptoms. Symptoms are frequently not seen until CKD 4 and even at that stage they are often nonspeci \201 c. They may include: Pathophysiological changes within the kidney Most forms of chronic injury to the kidney ini tiate a series of pathological events which result in the functional unit of the kidney (th e nephron) being replaced by scar tissue. This appears to be a nonspeci \201 c response to injury, but as a result renal function is lost resulting in CKD. The pathological changes within the kidney are character- ized by: Glomerulosclerosis: this is considered the histol ogical hall- mark of CKD. It is characterized by expansion of the glomerular mesangium and deposition of extracellular matrix. Tubulointerstitial \201 brosis: there is tubular atro phy, an intersti- tial in \202 ammatory cell in \201 ltrate and deposition of extracellu- lar matrix within the interstitium. A number of studies have demonstrated that tubulointer stitial disease correlates bet- ter with the level of renal function than glomerular diseas e. Because of the nonspeci \201 c nature of the response the his- tological changes seen i n the end-stage kidney are similar irrespective of the primary cause of the renal injury. Fig. 11.1.1 Macroscopic section of a normal kidney (left) and a small, shrunken, end-stage kidney (right). K. HARRIS 392 lethargy and tiredness: at least in part related to renal anemia; pruritis: an ill-understo od symptom but a cause of sig- ni \201 cant morbidity to the patient; skin pigmentation: a combination of deposition of mela- nin due to increased melanocyte-stimulating hormone and retained urochromes; easy bruising: due to platelet dysfunction; generalized aches and pai ns: a result of disturbed bone and mineral metabolism and secondary hyperparathy- roidism; loss of appetite and nausea: often associated with a metallic taste; vomiting: unusual unti l CKD is advanced; sleep disturbance. Proteinuria is better quanti \201 ed on a spot (ideally early morning) urine sample by mea suring either: \200 \200 albumin:creatinine ratio (ACR); protein:creatinine ratio (PCR). ACR and PCR results correlate well with those obtained from \200\230gold standard \200\231 24 h urine samples. As the latter are dif \201 cult to perform reliably in clinical pract ice they should not be routinely undertaken. \200 Table 11.1.2 Situations which may cause the eGFR to be unreliable When the true GFR is normal In particular values \211 60 mL/min/ 1.73 m2 should be interpreted with caution \200 States of reduced muscle mass Muscle wasting disease states When the GFR is extremely low (<5 mL/min) the patient may develop: \200 Amputees neurological disturbances (signs of neuropathy, altered conscious level, \201 tting and c oma); \200\230uremic \200\231 pericarditis; a uremic \200\230frost \200\231 (deposits of urea and urate on the skin, especially around the mucous membranes). Malnourished patients Edematous states Where there is an abnormal volume of distribution for creatinine \200 Pregnancy (MDRD should not be used to estimate GFR in pregnancy) With the routine availability of RRT, the symptoms and signs of preterminal uremia are now rarely seen except in patients being treated conservatively. Frequently and especially in t he early stages of CKD there may be little to \201 nd on examination other than hyperten- sion (which is found in the majority of patients with CKD). Some patients will also have s igns of salt and water reten- tion (edema, pulmonary edema) or signs relating to any underl ying systemic disease which has caused the CKD. At extremes of body size At extremes of age Children require speci \201 c formulas (for example the Schwartz equation) MDRD underestimates GFR in the elderly In particular ethnic groups Formulas have not generally been validated in all ethnic groups Ideally blood samples for GFR estimation should be obtained without the person having eaten any meat in the previous 12 h When there is a high or low dietary intake of creatinine or creatine Early detection of CKD Several types of intervention have been shown to reduce the risk of CVD, decrease the rate of progression of CKD and reduce mortality in CKD. Thus some countri es have highlighted the early identi \201 cation of CKD as a priority (including in the UK by the National Service Framework for Renal Services). CKD may be detected by simple and r eadily available tests. These include: \200 \200 \200 Technical issues Appropriate calibrated creatinine assays must be used and blood samples should be processed by the laboratory within 12 h Measuring renal function Measurement of GFR is considered the \200\230gold standard \200 \231 assessment of kidney function but this is both expensive and complex to perform. Tradi tionally, clinicians have relied on serum creatinine to assess renal function. However, the serum creatinine level depends not only on renal function but also on muscle mass and, for a given level of renal function, serum creatinine will vary accord- ing to factors such as age, sex, body mass and ethnic origin since these are surrogate markers of an individual \200\231s muscle mass. GFR may be estimated from the creatinine (eGFR) using a number of di fferent formulas. For adults the four-variable MDRD formula has been most widely adopted (s ee Appendix) since it relies only on: \200 \200 \200 measurement of blood pressure; testing the urine; measuring the renal function. Urine testing Testing the urine for the presence of: \200 \200 \200 protein; albumin; erythrocytes. This can be conveniently undertaken on a spot urine sam- ple using a commercially available reagent strip ( \200\230dipstick \200\231). Persistent abnormalities provide evidence of k idney dam- age (although urological causes of hematuria need to be considered and excluded where appropriate). In routine clinical practice, dipstick testing is a more relia- ble way of detecting hematuria than urine microscopy because of cell lysis during transportation o f the sample to the laboratory. Dipsticks for proteinuria provide semiquantitative informa- tion and have limitations due to false-positive results. creatinine; age; sex. This allows it to be reported automatically by laboratories when serum creatinine is reques ted. A correction for black race must be applied manually. CHAPTER 11.1 Assessment of chronic kidney disease 393 The widespread introduction of automated eGFR report- ing has made the true prevalence of C KD readily apparent to clinicians. It is important to remember that formulaic estimates of GFR do have limitations and may have wide con \201 dence limits (Table 11.1.2). They must therefore be interpreted in the clinical context. Formal measurement of GFR should only be required where a high degree of accuracy is needed such as for dos- ing of drugs with a nar row therapeutic window during chemotherapy or in the evaluation of renal function in potent ial living donors. PTH should also be measured in people with CKD 4/5. The frequency of testing of these parameters should be determined in the light of the initi al values, the clinical cir- cumstances and any treatments that are initiated. Patients wit h CKD should be investigated for other end- organ damage related to hypertension. This may include an ECG and echocardiography looking for evidence of LV hypertrophy. In addition, be cause of the high risk of death from CVD it is essential to fully assess cardiovascular ris k factors (includ- ing lipids) in patients with CKD. However, it is important to recognize that cardiovascular risk tables signi \201 cantly under- estimate risk of death from CVD i n people with CKD. Other complications of CKD which may require further speci \201 c inves tigation include malnutrition and neuropathy. Who to screen for chronic kidney disease Screening the general population for CKD is not ju sti \201 ed. However, targeted investigation of groups at high-risk of CKD does allow the majority of cases to be identi \201 ed at an early stage and enables timely therapeutic in tervention. The following groups should be tested for CKD: \200 \200 \200 Progression of CKD CKD is a potentially progressive disease. Experimental studies and obser vational data in humans suggest that CKD may progress as a result of both: \200 ongoing i njury from the primary renal insult; \200 a maladaptive response that is initiated within the kidney following a renal injury. patients with hypertension; patients with diabetes (types 1 and 2); patients with cardiovas cular disease (ischemic heart dis- ease, chronic heart failure, peripheral vascular disease and cerebral vascular disease); anyone found to have hematuria or proteinuria on an incide ntal medical examination; patients receiving drugs known to be potentially nephro- toxic (N SAIDs for example); patients known to have structural renal tract disease, renal calculi or prostatic hypertrophy; people with a family history of stage 5 CKD or heredi- tary kidney disease. Once a critical reduction in renal mass has occurred it appears that CKD progresses inexora bly even if the initiat- ing insult has resolved. This has led to the concept that a \200 \230maladaptive \200\231 response occurs within the kidney which in turn leads to further d amage (Fig. 11.1.2). There is a large body of experimental work which has examined potentia l maladaptive responses. Suggested mechanisms include: Hemodynamic factors: \200 \200 Further investigations Further investigations should initially be directed at identi- fying the underlying cause of CKD. This may require several different biochemical and immu- nolo gical tests as well as some radiological interventions. A renal USS is not justi \201 ed i n all patients with CKD but should be undertaken in anyone with: \200 \200 \200 \200 \200 systemic hypertension; intraglomerular hypertension. Nonhemodynamic factors: \200 \200 \200 \200 \200 \200 proteinuria; hyperlipidemia; glomerular hypertrophy; mesangial cell activation and prolifer ation; biologically active in \201 ltrating cells; production of prosclerotic cytokines an d growth factors. CKD stage 4 or 5; visible or invisible hematuria; symptoms of renal tract obstruction; rapi dly declining GFR; family history of polycystic kidney disease; The extent to which any of these factors contributes to the progression of CKD in humans is unknown. Observational studies suggest that whereas some patients with CKD experience a li near and predictable decline in renal function with time, others (possibly the majority) ma y have extended periods during which their renal func- tion is completely stable but which are punctuated by sud- den and stepwise decrements in renal function. Longitudinal studies suggest that renal function declines with age. Whether this is part of the natural aging pr ocess (and therefore should be considered normal) or a patho- logical condition remains con troversial. Such studies have generally included those at risk of CKD (diabetes, hyper- ten sion) and therefore the findings of an age-related decline in renal function may re \202 e ct unrecognized CKD in an aging population with comorbidity. Studies of people without como rbidities generally support the view that renal function declines only very slowly with age and that In patients with unexplained CKD and a normal renal tract, renal biopsy may be required. Th ese investigations are discussed in detail elsewhere in this book in the relevant chapters. Patients with CKD should also be investigated for complications of CKD, principally anemia and renal bone disease. Epidemiological data suggest that the prevalence of CKD- associate d complications increases sharply once GFR declines to <45 mL/min/1.73 m2. Therefore such p atients should have the following measured: \200 hemoglobin to identify anemia \200\223 other causes of non- CKD-related anemia should also be considered and excluded where necessary; calcium, phosphate and alkaline phosphatase; K. HARRIS 394 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. 11.1.2 Potential \200\230maladaptive \200\231 responses which contribute to progressi on in CKD. \200 \200 diabetes; smoking; Afro-Caribbean or South East Asian. GFR can remain normal into the 9th decade of life. Hence age alone is not a justi \201 cat ion for dismissing the \201 nding of CKD as unimportant. The K/DOQI classi \201 cation d e \201 nes CKD at a given point in time. Clinically it is more useful to understand how CK D is progressing with time in order to focus efforts on those in whom a rate of decline of GFR would lead either to com- plications of CKD or to the need for RRT within their lifetim es This requires repeated measurement of renal function and for the results to be interpret ed in the clinical context of the individual patient. For example, young patients with CKD 4 progressing at a slow rate may be at greater risk of requiring RRT within their lifetimes than eld- erly patients with CKD 2 progressing at the same or an even faster rate. What co nstitutes progression of CKD is controversial. NICE has recently suggested that progression of CKD should be de \201 ned as a decline in GFR of: \200 Assessment of proteinuria Either urinary protein or albumin excretion must be quan- ti \201 ed in patients with CKD. The level that constitutes \200\230signi \201 cant proteinu ria \200\231 and hence would trigger further intervention is debated but typically guidelin es suggest a total protein excretion of 1 g/24 h (equivalent to a PCR of 100 mg/mmol or ACR of 70 mg/ mmol) in non diabetic CKD, although NICE has recently proposed a lower protein e xcretion threshold of 0.5 g/24 h. In diabetics, microalbuminuria (ACR \211 2.5 mg/mmol in men and ACR \211 3.5 mg/mmol in women) is an indication for the use of ACEIs or ARBs. Treatment The speci \201 c goals of treatment in CKD should be to: \200 >5 mL/min/1.73 m2 within 1 year minimize the risk of any additional renal injury (in par- ticular nephrotoxic drugs should be avoided); reduce the risk of death from CVD; reduce the rate of progression; manage the complications of CKD. or \200 \200 \200 >10 mL/min/1.73 m2 within 5 years in the absence of other causes of an alternative acute de terioration in renal function. Progression of CKD is more likely when the following risk factors are present: \200 \200 \200 Cardiovascular disease It is important to remember that at any stage of CKD the risk of pre mature cardiovascular death is far greater than the risk of progression. cardiovascular disease; proteinuria; hypertension; CHAPTER 11.1 Assessment of chronic kidney disease 395