Chronic Kidney Disease (CKD) in the Elderly – a Geriatrician’s Perspective

By Munikrishnappa, Devaraj

Abstract Chronic kidney disease (CKD) is becoming increasingly prevalent among many different populations all over the world, including the US and Europe. Its multitude of complications with devastating outcomes leads to a significantly higher risk for cardio- vascular and all-cause mortality in an individual. However, it is clear now that early detection of CKD might not only delay some of the complications but also prevent them. Therefore, various important public health organizations all over the world have turned their focus and attention to CKD and its risk factors, early detection and early intervention. Nevertheless, the general goals in preventing the increase in CKD and its complications are far from being completely achieved. Why is this so? What is the magnitude and complexity of the problem? How is it affecting the population – are there differences in its affection by age, gender or frail elderly versus the robust? Are we modifying the risk factors appropriately and aggressively? Are there subtle differences in managing the risk factors in those on dialysis versus the non-dialysis CKD patients? Is it important to treat anaemia of CKD aggressively, will it make a difference in the disease progression, its complications or to quality of life? What do these unfortunate individuals commonly succumb to? What do we advise patients who refuse dialysis or those who desire dialysis or transplant? Are there useful non-dialytic treatment recommendations for those who refuse dialysis? What is the role of the physicians caring for the elderly with CKD? When should the primary care givers refer a CKD patient to a nephrologist? The key to eventually controlling incident and prevalent CKD and improve quality of life of affected individuals, lies in not only knowing these and many other vital aspects, but also in applying such knowledge compulsively in day-to-day practice by each and every one us. As CKD is increasingly a disease of the elderly with men being affected more, this review details fairly comprehensively the vital aspects of CKD, especially from a primary care geriatrician’s practical standpoint.

Keywords: Chronic kidney disease, elderly/aged, dialysis, frailty, kidney failure/insufficiency

Introduction

CKD as a health problem in the aging male and frailty

Chronic kidney disease (CKD), particularly end stage renal disease (ESRD), is affecting American adults at an explosive rate, placing a large, growing burden on our society. An estimated 19.2 million American adults have CKD and approximately 0.22% of this population is estimated to have ESRD [1-3]. Compared to just about 14,500 annual new cases of ESRD in 1978, in 2002 it was approximately 100,359 [1,3,4].

Fortunately, recent data from the US Renal Data System (USRDS) is depicting a slower rate than the initial projected estimate of 4.1% increase in incident ESRD cases by 2010 [4,5]. Nevertheless, upstream preventive measures are not yet completely in place and it is a cause for concern, especially in the elderly as CKD affects them disproportionately [I]. For instance, moderate to severely decreased kidney function was noted in as much as approximately 25% of the non-institutionalized US elderly population alone aged 70 years or older [3,6] . The implication of this is even more perturbing if one considers that by 2030, about 70 million Americans would likely be elderly, as compared to about 33 million in 2003 [6] . Similarly, studies from Europe suggest concerning trends in prevalence of CKD, especially so in the elderly [7,8].

Are men, like the elderly, also affected disproportionately compared to women? The prevalence of CKD was higher in men than women among Medicare patients at 4.9% and 3.9% respectively in 2004 [9]. In addition, male gender is associated with worse renal outcomes according to many studies, including higher risk of ESRD and death [10-13]. Possible contributory factors for such poor outcomes in men include gender differences in both kidney changes with aging as well as in CKD progression. The differences between the sexes in glomerular structure, glomerular haemodynamics, diet, variations in the production and activity of local cytokines and hormones on kidney cells may be potentially contributory underlying mechanisms for this gender disparity [14]. Besides, aging men experience greater decrements in renal function and increased glomerular sclerosis than women [15].

Gender differences in progression of CKD are controversial. While the effect of sex on the development and progression of diabetic nephropathy remains inconclusive, in case of non-diabetic kidney disease, men may be at higher risk of more rapid progression of CKD when compared to women [16]. Although it is not fully elucidated as yet, sex hormones may have a role in mediating the effects of gender on CKD through alterations in the renin-angiotensin system, reduction in mesangial collagen synthesis, the modification of collagen degradation, and up-regulation of nitric oxide (NO) synthesis [16].

Functional ability, especially under stress, is an extremely important concern and quality-of-life determinant with both aging and affliction with any disease, including CKD. Diminished ability to perform important practised social activities of daily living under stressful conditions indicates frailty [17] . Objective criteria for diagnosing frailty have been developed by Linda Fried and her colleagues at Johns Hopkins University recently, as: weight loss of more than 10 lb in one year, physical exhaustion by self report, weakness as measured by grip strength, decline in walking speed, and low physical activity [17-19].

Although, men were just half as likely to develop frailty as were women in the data derived from the Cardiovascular Health Study cohort, a significant number of elderly men do become frail [20-22] . This gender dispority could be partly explained by earlier mortality in men succumbing to chronic diseases as compared to women who survive longer with chronic diseases. For older men becoming frail, biological explanations may be possible including declining testosterone with aging [20]. In fact, indirect evidence exists to support the theory that declining testosterone might contribute to gradual decline in muscle strength [20,23,24]. For instance, clinical trials have demonstrated that replacing testosterone in hypogonadal older men improves muscle strength, mass and protein synthesis [20,23,25-29].

What precipitates frailty? Pain and other conditions such as anaemia, peripheral vascular disease, diabetes and depression – all are important precipitants of frailty and are commonly seen in CKD patients [17,30-32]. Besides, CKD itself can contribute to frailty.

Shlipak and colleagues determined from a cross-sectional analysis using baseline data collected from the Cardiovascular Health Study, that elderly persons with chronic renal insufficiency (CRI) were 3 times as likely to be frail as those with normal renal function, an association that remained significant after multivariate adjustment for demographic characteristics and co-morbidity, as well as such potential mediators as inflammation and subclinical atherosclerosis [33] . Interestingly, while only 4% of white men without CRI had frailty in this study, it increased to 10% in those with CRI. In addition, 14% of black men wim CRI were also found to have frailty in this study. Dialysis-treated CKD stage 5 patients were found to have more functionally significant muscle wasting man CKD stage 4 patients with significant uraemia in another study [34]. Although, various factors that are usually associated with CKD including diabetes, inflammation, wasting and others could be contributory, the exact causal relationship needs further study.

Why is frailty so important for physicians to be aware of? Aging and any disease, irrespective of its severity, would have much less of an impact on an individual, if functional ability is not lost due to them. Frailty not only predisposes to disability but also to hospitalization, institutionalization and death [17]. Clearly, CKD in an aging male offers a setting for frailty to occur. For this reason and many others oudined in the following sections, early identification of patients at risk for CKD or in the initial stages of CKD is extremely important and is apdy receiving immense focus of our attention in recent times, with perhaps, some results already evident. For instance, our improved awareness in identifying frail CKD patients has allowed us to intervene wim several strategies including targeted exercise, maintaining adequate nutrition, adequate socialization, increasing mental activity, treating vitamin D deficiency, anaemia, heart failure, diabetes and supplementing testosterone in hypogonadal men [17]. These strategies help delay development of disability and lead to potentially significant improvement in quality of life of these otiierwise unfortunate individuals.

Role of a geriatrician in recognition and management of CKD

CKD places an individual at a significandy higher risk for cardiovascular and all-cause mortality [35,36]. It is, therefore, extremely important for geriatricians to be aggressive in not only preventing incident CKD but also in detecting it early so mat such adverse outcomes are prevented or delayed. In fact, evidence exists to corroborate that this is possible [1,37]. Furthermore, geriatricians can play an increasingly significant role in established CKD patients. As an example, treating anaemia of CKD, which is highly under-treated will improve quality of life (QoL) and cognition among these patients [38,39] . Currendy, a growing number of me elderly are being referred and accepted onto dialysis – the average age of a dialysis patient, in the year 2000, for instance, being 62 years of age [40]. Planning for dialysis oners QoL comparable to that of other diseases whereas an unplanned one severely impairs QoL in an ESRD patient [41,42]. Similarly, referring an eligible patient to dialysis early decreases hospitalization and early mortality [43,44] . Of course, the warmth of a caring and compassionate geriatrician to an elderly patient who has opted either for withdrawing or withholding dialysis cannot be emphasized enough – it can be immensely palliative. Kidney changes with aging

It is suggested that there is a progressive decline of renal function with age after 40 years from cross sectional studies in humans [45]. Aging kidney is able to maintain homeostasis under normal conditions but not so under stress [46]. The important anatomical and physiological changes in kidney with aging are outlined in Tables I and II [7, 13, 16-18,26,42,46-48].

Table I. Anatomical changes in kidney with aging.

Table II. Functional changes in kidney with aging.

Rates of both glomerulosclerosis and tubulointerstitial sclerosis may vary from one individual to another depending on some likely etiologic factors more recently identified by animal models of aging. These include angiotensin II, transforming growth factor-a, nitric oxide (NO), advanced glycosylation end products (AGE), oxidative stress, and lipids. The interplay of these factors may be the reason why two thirds of 254 healthy elderly individuals had a decrease in creatinine clearance while one third had no absolute change in creatinine clearance during longitudinal follow-up over 23 years in a study. It might become clinically important if these factors can be modified to help prevent progressive age-related decline in renal function [46,49].

Diagnosis and management of ckd with focus on the elderly

Chronic kidney disease

Definition. According to the National Kidney Foundation (NKF), irrespective of the diagnosis or cause of CKD, the criteria to define CKD are based on kidney damage and level of function as follows:

1. Kidney damage for >/=3 months with or without decreased GFR. The damage could be functional or structural and, noted either in the form of pathological abnormalities or abnormalities in markers of kidney damage in blood or urine or imaging studies of kidney.

or GFR of <60 mIVmin/1.73 m^sup 2^ for >/=3 months, 2. with or without kidney damage [37,55].

Stages of CKD. Although, the staging is based on arbitrary ‘cut- off levels’ of continuous measures of kidney function, it is required for clinical application to measure clinical performance and initiate quality improvement measures towards overall management of CKD [55]. Terms such as ‘chronic renal insufficiency’ and ‘chronic renal failure’ should be avoided to facilitate use of this classification and thereby enhance standardization of our practice. It is important to remember, staging is but one step in caring for the patient with CKD. The physician still needs to diagnose the cause of CKD, assess its progression, complications and accompanying comorbid conditions of the patient.

Table III. NKF stages of chronic kidney disease and action plan.*

CKD is classified by the National Kidney Foundation (NKF) as in Table III.

Four different scenarios deserve further comments:

1. While stages 1 and 2 require that kidney damage be apparent, criteria for stage 3 and onwards require a level of GFR decrease to < 60 mL/min/1.73 m^sup 2^ for >/=3 months alone with or without apparent kidney damage. The reason is that this level of decline in kidney function or lower indicates that kidney has lost half or more of its adult level of normal kidney function and it may be associated with a number of complications [37,55].

2. Similarly, the reason to include those with GFR > 60 mlvmin/ 1.73 m^sup 2^ in this CKD staging system is that, in some patients, the GFR may be maintained at normal or higher level although kidney damage exists. The kidney damage in such conditions is ultimately associated with an increased risk of decline in kidney function and also of suffering from cardiovascular (CVS) disease.

3. It is important to recognize, especially, from a geriatrician’s perspective that there are some older people who have no recognized kidney damage markers but their GFR is in the range of 60 to 80 mL/min/1.73 m^sup 2^ and are classified as ‘decreased GFR’, not as patients with CKD. The consequences of this scenario in the elderly are not well studied. People who are on vegetarian diets, have unilateral kidney, extra-cellular depletion, and in those with systemic illnesses affecting the kidney perfusion, e.g., heart failure or cirrhosis may also demonstrate low GFR without kidney damage.

4. High blood pressure, a common cause and consequence of CKD, is frequent in the elderly, irrespective of the kidney disease status. And with aging, it is associated with accelerated GFR decline and more marked pathological abnormalities in the kidneys. Although it is not included in the definition of CKD, it is still very important to assess these patients carefully for CKD especially in the presence of decreased GFR [37,55].

Once the CKD in a patient is recognized and staged appropriately, it is important to understand the consequences and act appropriately to decrease the morbidity and mortality from it. As geriatricians, we have a very responsible role here, as we care for a substantially huge number of about 14.2 million patients >/=70 years of age with decreased GFR, who can potentially be prevented from developing further progression and mortality from CKD [37,55]. In order to do so, we need to be aware of the NKF-based recommendations and the metabolic consequences corresponding to the CKD stages as outlined in Table I and apply them clinically. Further discussion on this will be continued under ‘Approach to the patient with CKD’.

Kidney damage markers

Persistent proteinuria, abnormalities in the urinary sediment or blood or abnormalities on imaging studies are all markers of kidney damage, as alluded to earlier, in the definition of CKD. Proteinuria is further discussed here for the following reasons. Persistent proteinuria as a CKD marker has been well studied and to detect it is a simple office procedure. Also, it is an early and sensitive marker of an increase in glomerular permeability for normally non- filtered plasma macromolecules such as albumin. No significant difference in protein excretion exists in the elderly compared to the younger adults.

Table IV. Values for proteinuria [57].

Proteinuria can be detected by various methods. Dipstick is a common method of proteinuria detection that can, in turn, be based on colorimetrie or acid precipitation method. The colorimetrie method mostly detects albumin as opposed to acid one that detects all proteins and trace, 1+, 2+, 3+, 4+ implies <30, +30, 100, 300, 2000 mg/dL respectively in this method [56]. Note that, for the dipstick method to detect proteinuria, an individual with a urine output of 1 litre per day must be excreting nearly 300 mg of albumin per day before proteinuria could be detected. Contrarily, at times, the quantitative amount of proteinuria may be <150 mg/day but if it is a very concentrated urine specimen, the dipstick might still test positive as it can detect urine albumin concentration of as little as 30 mg/dL [56]. This also implies that it is important, therefore, to detect lesser amounts of albumin as in microalbuminuria, albumin- specific dipsticks that detect albumin above a concentration of 3 to 4 mg/dL should be used instead of either of the two dipstick methods mentioned above (colorimetrie or acid precipitation methods).

The other two ways to measure either for total proteins or for albumin specifically, are by the 24-hour excretion method or by spot urine tests (protein – or albumin to creatinine ratio). The values are as shown in the Table IV.

Given the disadvantages of 24-hour urine collections in geriatric settings especially, the measurement of the albumin to creatinine concentration in an untimed random urine specimen could be used. A ratio of > 30 mg of albumin per gram of creatinine correlates very well with a 24-hour urine albumin measurement [56].

Urinary albumin excretion may be seen transiently increased in short-term hyperglycemia, exercise, urinary tract infections, pregnancy, marked hypertension, heart failure, and acute febrile illnesses and as diurnal variation. Therefore confirmation of microalbuminuria requires verification on 2 or 3 collections over 3 to 6 months [56]. Proteinuria helps in the diagnosis of CKD, in its differential diagnosis (as it is not prominent in certain types of CKD such as vascular causes or tubulointerstitial) and is of prognostic importance.

CKD, kidney failure and ESRD [37,55]

It is necessary to understand the difference in these terms to apply them in clinical practice appropriately. Kidney failure is defined by NKF Kidney Disease Quality Outcomes Initiative (K/DOQI) as either (1) a level of GFR of <15 mL/min/1.73 m^ sup 2^, with signs and symptoms of uraemia in most cases, or (2) as a state in which kidney replacement therapy (dialysis or transplantation) has to be initiated for treatment for complications of decreased GFR, in order to prevent an otherwise increase in the risk of mortality and morbidity.

In the US, end-stage renal disease is an administrative term used for payment for health care by the Medicare ESRD Program. It is based on specifically the level of GFR and the occurrence of signs and symptoms of kidney failure necessitating initiation of treatment by replacement therapy. Irrespective of the level of GFR, ESRD includes patients treated by dialysis and transplantation. The K/ DOQI definitions of kidney failure and ESRD differ in two important ways:

1. Individuals with GFR < 15 mIVmin/1.73 m^ sup 2^ or with signs and symptoms of kidney failure but are not treated by dialysis and transplantation should still be considered as having kidney failure.

2. Among patients undergoing renal replacement treatment, kidney transplant recipients have a higher mean level of GFR (usually 30 to 60 mL/min/1.73 m^ sup 2^) and better average health outcomes than dialysis patients. Unless they have GFR < 15 mL/min/1.73 m^ sup 2^ or have resumed dialysis, kidney transplant recipients should not be included in the definition of kidney failure.

Renal function estimation: Which is the recommended method especially in the elderly?

Commonly, serum creatinine or estimation equations from it (Cockcroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) equations in adults) or creatinine clearance measurement by 24-hour urine collection are used to assess renal function. Serum Cystatin C is a novel marker gaining attention in the literature.

GFR is the best index available for level of kidney function in health and disease and is therefore a pan of the definition of CKD. Age, sex and body size influence it [58]. In healthy young adults it is approximately 120-130 ml/min/1.73 m^ sup 2^ and declines with age. It can be assessed directly or indirectly [7], Direct measurement is by inulin clearance considered as ‘gold standard’ but it is impractical for routine use. The alternative for direct measurement is the radioisotopic method (^ sup 51^Cr EDTA, ^ sup 125^I iothalamate) but it is expensive, time consuming and not widely available [7]. So, most prevailing practice among physicians is to estimate it by serum creatinine alone.

GFR estimation based on serum creatinine alone. GFR estimation based on serum creatinine alone is, however, not the best practice, especially so in the elderly. A number of variables like age, sex, muscle mass, diet and medications that block creatinine’s tubular secretion (especially in renal insufficiency) influence it [7]. Cimetidine, trimethoprim and fibric acid derivatives other than gemfibrozil block tubular secretion of creatinine and thereby increase serum levels of creatinine without change in GFR [59]. Cimetidine and trimethoprim, for instance, can result in a self- limited and reversible rise in the plasma creatinine of as much as 0.4 to 0.5 mg/dL [60]. Despite reductions in GFR to < 60 ml per minute per 1.73 m^ sup 2^, serum creatinine levels may not rise noticeably particularly in the elderly [61].

Given the combination of an increasingly aging population, widespread polypharmacy and the silent nature of CKD, one of the most important initial steps to prevent CKD, therefore, is to avoid using serum creatinine alone as the index of kidney function, more so in the older population. This was reflected in a retrospective study conducted by Swedko and colleagues that concluded that serum creatinine is a poor screening test for renal failure in the elderly and leads to marked under-investigation and under-recognition of it [62].

However, it is a good method for monitoring GFR changes in a given patient. The reason is that both the biological variability within an individual and the variation due to assay are low in this scenario. Thus, a change in serum creatinine of > 15% is likely to imply a significant fall in GFR in a given patient rather than due to simple biological and analytical variations [54,60,63]. If the body mass and diet are relatively stable, it could reflect the GFR changes in an individual more closely.

Creatinine clearance can be measured by using 24-hour urine collection but it has inherent inaccuracies, inconvenience and is unpleasant [7]. Except in certain conditions with considerable variations in factors affecting the creatinine clearance (as in extremes of age and body size, disease of skeletal muscle, amputation, malnutrition, muscle wasting or rapidly changing kidney function), it is not a good choice to consider.

GFR estimation by serum cystatin C. Cystatin C (Cys C) is a non- glycosylated basic protein and an important, endogenous cysteine proteinase inhibitor produced by all nucleated cells, freely filtered, reabsorbed and catabolized by the kidney [64,65]. It is involved in extra cellular proteolysis, immune modulation, antibacterial and antiviral activities [66]. It has been proposed as an alternative to serum creatinine as an index of GFR.

Most but not all studies indicate that it is a better index of GFR than serum creatinine alone especially in mild to moderate renal disease [7,67]. The serum cystatin C may rise at a higher level of decline of GFR compared to serum creatinine-this higher clinical sensitivity therefore may help to identify mild renal impairment [68]. In the elderly, mere have been a few studies done that reveal mat cystatin C reflects age related decline in GFR (i.e., decrease in GFR without kidney disease) and is probably a more sensitive marker of renal dysfunction, especially mild dysfunction, than the others [7,61]. If this is confirmed, me potential advantage is that we may be able to avoid the formulaic calculation, probably leading to greater compliance among physicians and nurse practitioners in recognizing CKD early and in considering renal status prior to prescribing relevant medications to the elderly. Serum cystatin C was also found to be a better predictor of mortality and cardiovascular disease than was serum creatinine alone or GFR estimate from it in a 10 year follow-up study of 4637 elderly patients in the Cardiovascular Health Study by Shlipak and colleagues [65,69].

The factors that might influence its levels as well as advantages and disadvantages of its use currently are listed in the following Tables V and VI respectively.

Although question of bias raised by their use of creatinine clearance as the gold standard for kidney function in the study, Knight and colleagues, from Prevention of Renal and Vascular End- Stage Disease (PREVEND) study, concluded mat serum cystatin C could be influenced by factors other than renal function including older age, male gender, greater weight and greater height, smoking and higher C-reactive protein independent of their effects on renal function [74]. Higher levels of cystatin C were associated wim these factors according to this study but most of the other studies have not reported any such association [60,74]. In fact, as mentioned in this study itself, some previous studies have reported contrasting results for some of these factors [74].

Table V. Factors that might influence serum cystatin C levels.

Table VI. Advantages and disadvantages of using cystatin C for estimating GFR.

One recent study by Macdonald and colleagues using measured GFR by inulin clearance as reference showed mat estimating GFR from serum cystatin C is influenced by body composition, especially the total lean mass [75]. They also conclude that by accounting for body composition, GFR estimation from cystatin C can be improved. So overall, we need to be cautious in interpreting this literature and using cystatin C in clinical practice at this time.

GFR estimation from serum creatinine-based equations

There are two popular formulae or equations – the Cockroft-Gault (CG) and the modification of diet in renal disease (MDRD) – for estimating GFR from serum creatinine. These estimating equations use surrogates for the unmeasured physiologic variables such as muscle mass that affect the serum creatinine in an attempt to increase the accuracy of GFR estimate or eGFR (formula-based GFR estimate), as compared to using serum creatinine alone. Comparisons of CG and MDRD formulae reveal certain important inferences as follows:

1. In elderly people, they have a good average agreement but cannot be used interchangeably in an individual, as there is wide discrepancy in such estimates [78,79]. The degree of difference was influenced by age and weight in this estimation bias [78]. Both equations predicted lower renal function, especially in the elderly and women, as could have been judged from serum creatinine alone [79].

2. The CG formula is one of the earliest developed and most widely used formulas for estimating creatinine clearance. It was derived originally from predominantly younger population that included just 4% of females and initially validated against measured creatinine clearance as it was intended to predict creatinine clearance rather than GFR [7,37,55]. Since creatinine clearance over- estimates GFR, equations that accurately estimate creatinine clearance also overestimate GFR [37,55,79]. However, most (median of 75%) of the estimated values using this method were within 30% of the measured GFR. This degree of accuracy is considered sufficient for good clinical decision-making and better than estimating by serum creatinine alone [37,55].

The experience of applying CG to the older individuals, however, has been variable, and comparing studies investigating this aspect has posed difficulties due to lack of uniformity in methodologies or of required information for such comparisons among these studies [7]. Both CG and MDRD equations tended to underestimate GFR in hospitalized older people but the CG formula underestimated the GFR to a greater extent when compared with MDRD equation in this population [78]. Inferences by some authors from other studies indicate that the CG equation overestimates at younger ages, and underestimates at older ages (e.g. > 70 years of age) than that obtained with the simplified MDRD formula [60].

3. The MDRD formula was derived from a study (Modification of Diet in Renal Disease Study) of 1628 middle-aged, non-diabetic, chronic renal insufficiency patients [7,79]. The advantages include that the equation provides a clinically useful estimate of GFR (up to approximately 90 mL/min/1.73 m^ sup 2^) rather than creatinine clearance among adults [37,55,79]. It was originally derived from a study that used GFR measured directly by urinary clearance of ^ sup 125^I-Iothalamate (a validated method to measure GFR); included both European-American and African-American participants and was validated in a large {n > 500) separate group of individuals as part of its development with a wide range of kidney diseases [37,55,80]. Over 90% of the estimates were within 30% of the measured GFR [37,55]. Thus, the MDRD equation is more accurate than CG (or measured urinary creatinine clearance) when compared to the gold standard [37,55,79]. The abbreviated version requires serum creatinine, age, sex, and race and avoids weight which is a difficult parameter to obtain accurately in some of the institutionalized, bedridden elderly. Web-based calculators are available for providing GFR by this method. When the GFR result using MDRD is estimated to >60 mL/min/1.73 m^ sup 2^, no exact result is reported due to lack of precision of the eGFR in higher range. NKF-K/DOQI guidelines have taken this into account while defining GFR criterion for CKD as persistent decrease in GFR to less than 60 mL/min/1.73 m^ sup 2^ [58]. Many national and international organizations of repute recommend using this equation currently.

Commonly used serum creatinine-based equations for estimating GFR

1. Cockcroft-Gault (CG):

a) For men: CrCl (mIVmin) = [(140 - Age in years) x Weight (kg)]/SCr (mg/dL) x 72

b) For women: CrCl = ([(140 - Age) x Weight (kg)]/SCr x 72) x 0.85

Where CrCl is creatinine clearance, SCr is serum creatinine. Note that the body size is not included in Cockroft-Gault equation. While some studies have used lean body mass rather than total weight, others have tried to overcome this issue by standardizing the results for body surface area [37,55].

1. MDRD: GFR= 170 x (SCr)^ sup -0.999^ x (Age)^ sup -0.176^ x (0.762 if patient is female) x (1.18 if patient is black) x (BUN)^ sup -0.170^ x (Alb)^ sup 0.318^

Where BUN is blood urea nitrogen and Alb is albumin.

2. MDRD (Abbreviated version) (mIVmin/1.73 m^ sup 2^): GFR= 186 x (SCr)^ sup -1.154^ x (Age)^ sup -0.203^ x (0.742 if patient is female) x (1.212 if patient is black)

Some of the limitations of the eGFR are shown in Tables VII and VIII.

Limitations of CKD staging and definition [10,37,55,96]

Some important limitations to this proposed definition and staging of CKD by NKF that we need to be aware of include:

1. The MDRD study prediction equation has not been validated extensively at levels of GFR 90 mL/min/1.73 m^ sup 2^; thus, it is difficult to estimate the level of GFR above 90 mL/min/1.73 m^ sup 2^ and it may be difficult to distinguish between stage 1 and stage 2 of chronic kidney disease.

2. The known markers of kidney damage are not sensitive, especially for tubulointersitial and vascular disease and for diseases in the kidney transplant.

3. The cause of age-related decline in GFR and high blood pressure is not known. Possibly, it may be due to chronic kidney disease. If so, it would be more appropriate to classify individuals with GFR 60 to 89 mIVmin/1.73 m^ sup 2^ without apparent markers of kidney damage as having chronic kidney disease rather than ‘decreased GFR’.

Table VII. Limitations of both estimation equations (eGFR).

Table VIII. Limitations of MDRD equation-derived eGFR.

4. The classification offers inadequate information regarding future risk of deterioration in kidney function.

Approach to the patient with CKD

Now that we have reviewed kidney changes in the elderly, how to estimate kidney function using various methods, defined, classified and partly understood consequences of CKD, we will now look into how to approach an elderly patient with possible CKD or its risk factors and apply the NKF recommended action plans.

Action plan at no kidney damage level and GFR normal: Screen for CKD, risk factors reduction. There is accumulating evidence to believe that early detection and appropriate treatment may be effective in delaying the onset of CKD in those at increased risk, and in slowing CKD progression and decreasing the development of cardiovascular disease in people with CKD. However, note that CKD is largely silent in its early stages. Most people have no severe symptoms until late in their kidney disease. As shown in Table III, stage 1 patients will generally present clinically with markers of kidney damage, while stages 2 through 5 will present with mild complications, moderate complications, severe complications and uraemia/cardiovascular disease respectively, some of which are actually manifestations of CKD itself. Therefore, it is extremely important that all patients should be systematically evaluated during every primary care visit starting with history to obtain clues to kidney diseases as shown in Table IX and then identify those at increased risk for CKD as shown in Table X. Once the patients at increased risk for CKD are identified, they need to be further evaluated as shown in Table XI to diagnose it early when they are relatively still asymptomatic and also, attempt to reduce risk factors.

Action plan at stage 1 level: CKD diagnosis and treatment, interventions to slow CKD progression, treat co-morbid conditions and CVD risk reduction. A useful classification of CKD based on etiological diagnoses is shown in Table XII. In adults, especially those older than 60 years of age, the most common aetiology of CKD and ESRD in the US, is diabetic nephropathy [3]. However, there is decline in the rate of incident cases of ESRD from diabetic nephropathy in all ages from approximately 12% in 1995 to 1% in 2001, which may represent strict blood pressure control, glycaemic control and renoprotection with medicines [4,6]. Hypertensive nephrosclerosis is another major cause of CKD and ESRD in all ages.

Table IX. Clues to the diagnosis of chronic kidney diseases from the patient’s history.

Table X. Risk factors for CKD.

Other secondary glomerular syndromes may occur with increasing frequency in the elderly. Examples include vasculitis (pauci-immune segmental necrosis with or without crescents), amyloidosis, and paraprotein-mediated kidney, membranous glomerulonephritis and antiglomerular basement membrane antibody disease [97-99]. Tubulointerstitial patterns of renal injury also occur with increased frequency among the elderly, especially the interstitial nephritis (up to 18%) [97-99]. Polypharmacy may be the probable reason for this as many drugs including sulfa, beta lactams, cephalosporins and diuretics can cause this pattern of injury [6].

Table XI. Clinical evaluation of patients at increased risk of CKD.

Table XII. Simplified classification of CKD based on diagnosis.

Once CKD is diagnosed, treatment to slow disease progression is as shown in Table XV. In addition, treating comorbid conditions and reducing CVD risk reduction should be ongoing.

Action plan at stage 2 level: estimating disease progression. (As mentioned before, patients with GFR between 60 to 89 mL/min/1.73 m^ sup 2^ without evidence of kidney damage are not classified as having CKD per NKF definition. About 48.5% of the elderly aged >/ =70 years may have GFR in this range according to NHANES III data and not all of them have kidney damage evidence. Yet these elderly individuals should also be clinically evaluated for CKD as shown in Table XIII).

Table XIII. Clinical evaluation of elderly individuals with GFR of 60-80 ml/min/1.73 m^ sup 2^.

In those patients with GFR between 60 to 89 mL/min/1.73 m^ sup 2^ with evidence of kidney damage, disease progression should be estimated and interventions to slow the disease progression, treat co-morbid conditions and reduce CVD risk should be ongoing.

Action plan at stage 3 level: evaluating and treating complications. Those with GFR of < 60 ml/min/1.73 m^ sup 2^ need additional interventions, aimed at evaluating and treating complications, as shown in Table XIV.

Action plan at stage 4 level: prepare patients for kidney replacement therapy. At GFR 15-29 mL/min/1.73 m^ sup 2^, further step to prepare patients for kidney replacement dierapy should be started.

Action plan at stage 5 level: kidney replacement therapy. At GFR < 15 mL/min/1.73 m^ sup 2^, kidney replacement therapy has to be generally considered.

As is clearly evident from the above discussion, for geriatric/ primary care physicians to offer excellent care in delaying the incidence or slowing the progression of CKD, a sound knowledge of HTN, DM, CVD and anaemia in CKD is essential. In the next few following sections we will briefly review hypertension, diabetes, CVD and anaemia in CKD patients with focus on geriatric/primary care. In some of these sections, you will note that haemodialysis patients have additional considerations compared to non- haemodialysis CKD patients.

Hypertension in CKD patients

HTN in non-haemodialysis patients. HTN is both a cause and consequence of CKD. Certain antihypertensive agents are said to be preferred if they are known to reduce CVD risk or slow the progression of certain types of kidney disease by mechanisms in addition to lowering blood pressure [10O]. The preferred agents for CVD reduction are well known and include, for instance, in patients with systolic dysfunction CHF, using diuretics, angiotensin converting enzyme inhibitor (ACEI), angiotensin receptor blockers (ARB), beta blockers like metoprolol or Carvedilol and aldosterone antagonists. The preferred agents for slowing CKD are ACEI, ARB and non-dihydropyridine calcium antagonists.

Table XIV. Possible additional parameters to assess (see other guidelines).

Table XV. Treatments to slow the progression of CKD in adults.

Choosing an antihypertensive in CKD. Points to note include: * In patients not treated with any antihypertensive before, an agent from preferred class for CKD, usually, an ACEI or ARB should be the first choice [100].

* In patients treated with other antihypertensive agents, preferred class agent should substitute it or be added to the regimen with dosage adjustment of the existing drug [100].

* A ‘rule of thumb’ frequently used is that addition of a new antihypertensive agent in appropriate dosage lowers systolic blood pressure by approximately 10 mm Hg. If not, rule out non-compliance and other causes before increasing the dose of the preferred agent. Dose escalation should, generally, be no more frequently than every four weeks [100].

* Diuretic should be added if response to the preferred agent is inadequate, even if mere is no volume overload and dose adjusted till patient is euvolemic, target blood pressure is achieved, adverse effects noted or a high dose has been reached. In patients with GFR >/=30 mL/min/1.73 m^ sup 2^ (CKD stages 1-3), thiazide diuretics are preferred, whereas in patients with GFR <30mL/min/ 1.73 m^ sup 2^ (CKD stages 4-5) loop diuretics are preferred and may need to be given higher doses with lower GFRs and may need to be given twice daily. Avoid potassium-sparing diuretics in patients with GFR < 30 mL/min/1.73 m^ sup 2^ and in patients taking ACE inhibitors or ARBs [100]. With extra cellular volume expansion and oedema, loop diuretics given once or twice daily, in combination with thiazide diuretics, can be used [101]. Monitor for GFR change of >/=15%, besides hypokalemia and hypotension with diuretic use [101].

* If additional agents are required, consider medications based on CVD-specific indications to achieve therapeutic and preventive targets, and on avoidance of drug interactions or known sideeffects. As the GFR decreases especially to <30 mL/min/1.73 m^ sup 2^, three or four antihypertensives may be needed in order to reach the desired blood pressure goals. Adding to current regimen should be one new agent at a time, at the lowest recommended dose, and escalated at intervals of 4 to 8 weeks until the desired blood pressure goal is achieved, a high dose is reached, or a side-effect occurs [100].

* Monitor for kidney function in addition to blood pressure and side effects after the antihypertensive medication initiation [100].

* ACEIs and ARBs: Both can be used safely in most CKD patients. They should be used at moderate to high doses. They could be used as alternatives to each other or can be used in combination to lower the blood pressure or proteinuria. Monitor for hypotension, decreased GFR and hyperkalemia. They could be continued if: GFR decline over 4 months is < 30% from baseline value and serum potassium is

* Calcium channel blockers: The nondihydropyridine calcium- channel blockers, diltiazem and verapamil, have beneficial effects on CKD and CVD and are effective in decreasing proteinuria in diabetic kidney disease [103-106]. The combination of lisinopril and verapamil led to a greater reduction in proteinuria than using either drug at twice the dose used in combination therapy [104]. Similar findings were seen with a combination of trandolapril and verapamil [107]. Among the dihyropyridines, the long-acting agents that do not have cardiac depressant effects, i.e. amlodipine and lacidipine, are preferred [100].

* Alpha-adrenergic agents: Although not used as first line agents due to their side effects, both centrally acting sympatholytic agents (methyldopa, Clonidine, guanfacine and guanabenz) and selective alpha-1 blockers may be used for HTN in CKD and they have beneficial effects on lipid metabolism (increase HDL cholesterol levels and decrease LDL cholesterol levels) and improve insulin sensitivity [100].

* Aldosterone antagonists: caution is advised in using these agents especially in those with elevated serum creatinine or potassium at baseline, although they have favourable cardiovascular effects [100].

HTN in haemodialysis patients. Controlling blood pressure in HD patients could be very challenging. It is oudined in greater detail under the section of CVD in dialysis patients as it is the single most important predictor of coronary artery disease in uremic patients [108].

HTN in diabetic kidney disease. Since albuminuria marks the onset of the kidney disease in diabetes, ACEIs or ARBs should be used even if hypertension is not evident. But if it is evident, then the goal is to keep the systolic blood pressure < 130. If need be, add diuretic, then CCBs or beta blocker. Avoid using dihydropyridine CCBs without ACEIs or ARBs. If there is microalbuminuria, use ACEIs or ARBs, irrespective of type I or II DM. If there is macroalbuminuria, ACEI is preferred in Type 1 and ARB in type 2 DM but they could serve as alternatives to each other as well. Systolic BP of < 130 mm of Hg is the goal [109].

HTN in non-diabetic kidney diseases. Non-diabetic kidney diseases include glomerular diseases other than DM, vascular diseases other than renal artery disease, tubulo-intersritial diseases and cystic diseases. Proteinuria level in these diseases has both diagnostic and prognostic significance. The glomerular diseases have more proteinuria than the other diseases. Higher levels of proteinuria have higher rates of progression of the kidney disease and increased risk of CVD. Target blood pressure should be < 130/80 mm Hg. If spot urine total protein to creatinine ratio >/=200 mg/g is noted in non- diabetic kidney disease, ACEI or ARBS should be used with or without co-existing HTN. If HTN is present, add the medications to ACEIs or ARBs, in the following sequence-diuretics, CCBs or beta blockers. If diuretics had been started prior to the proteinuria noted in patients with coexisting HTN, add ACEIs or ARBs, then CCBs or beta blockers. Again, avoid dihydropyridine CCBs without either an ACEI or ARB [110].

DM in CKD

DM in non-haemodialysis patients. The onset of kidney disease in DM (heralded by presence of urinary protein) increases the risk of cardiovascular disease, retinopathy, and other diabetic complications as compared to DM patients without kidney disease [111]. Thus proteinuria reflects a more generalized vascular disturbance affecting multiple organs and therefore is an ominous sign [111-113].

Cardiovascular disease rather than kidney failure in DM (especially type 2) with CKD is responsible for much of the excess mortality. And, almost all of the excess mortality with DM type 1 and type 2 is found in patients with increased albumin/protein excretion [111,114-116]. Therefore it is extremely important to monitor for proteinuria as well as kidney function besides other complications of diabetes [111].

The use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) and strict blood pressure control are especially important, as they may prevent or delay some of the adverse outcomes of both kidney and cardiovascular disease, in the management of DM with CKD patients [111,114].

DM in haemodialysis patients. Haemoglobin A^ sub 1C^ may not be as representative of glycaemic control in patients on HD or PD as in non-dialysis patients [114,117-119]. Due to decreased metabolism, anaemia, and shorter life of red cells, the haemoglobin A^ sub 1C^ may under-represent glycaemic control in dialysis patients. For instance, a level >7% in a dialysis patient may represent glycaemic control similar to a nondialysis patient with a haemoglobin A^ sub 1C^ <7%. Target haemoglobin A^ sub 1C^ that is associated with the best outcome in dialysis patients has not been clearly established.

There may be a substantial change in both insulin doses and oral hypoglycaemic doses during the transition from earlier stages of CKD to dialysis. The insulin requirement is reduced due to decreased catabolism with further loss of kidney function. The dialysate glucose (especially peritoneal dialysate) may increase the requirement of hypoglycaemic agents [111,114]. The newer insulin regimens and insulin preparations with properties that are closer to normal physiology are encouraged to be used more, possibly in consultation with a specialist in diabetes management. Metformin is contraindicated in diabetic haemodialysis patients due to decreased clearance and also due to the possibility of lactic acidosis. Sulphonylureas should be used with caution due to low clearance [111,114].

CVD in CKD

CVD in non-haemodialysis patients. From a mortality stand-point, it is not progression to kidney failure diat is more concerning in CKD patients but progression to cardiovascular disease (CVD). All CKD patients, irrespective of the diagnosis, are at increased risk of CVD, including coronary heart disease, cerebrovascular disease, peripheral vascular disease, and heart failure and should be considered in the ‘highest risk’ group for cardiovascular disease for risk factor reduction, irrespective of levels of traditional CVD risk factors [120].

Both ‘traditional’ (‘traditional’ risk factors are those variables defined in the general population through prospective cohort studies such as the Framingham Heart Study) and ‘chronic kidney disease-related (non-traditional)’ CVD risk factors may contribute to mis increased risk [120]. Therefore assessment of CVD risk factors should include measurement of ‘traditional’ risk factors in all patients and selective measurement of ‘CKD-related’ CVD risk factors in some patients based on individual cases [120].

While traditional CVD risk factors include older age, male gender, white race, hypertension, elevated LDL cholesterol, decreased HDL cholesterol, diabetes mellitus, tobacco use, physical inactivity and family history of CVD, the CKD-related CVD risk factors (non-traditional) include type (diagnosis) of CKD, decreased GFR, proteinuria, reninangiotensin system activity, extracellular fluid volume overload, abnormal calcium and phosphorous metabolism, dyslipidaemia, anaemia, malnutrition, inflammation, infection, thrombogenic factors, oxidative stress, elevated homocysteine and uraemic toxins [120,121]. Some epidemiological studies suggest that there is a paradoxical inverse relation between these traditional risk factors of CVD and mortality in dialysis patients [122]. That is, lower rather than higher blood pressure [123], lower body mass index [124] and lower cholesterol [125] have been shown to be associated with higher mortality. Interestingly enough, this so called ‘reverse epidemiology’ [126] is not unique to the dialysis patients but is also observed in the geriatric population [127] including the elderly living in nursing homes [128].

Exact cause is not known for this observation but there are several explanations, one of which was studied in a long-term, prospective cohort study recently, is that illness, inflammation, and poor nutrition might have confounded the relationship between dyslipidaemia and CVD. This study investigated the association of cholesterol levels with all-cause and CVD mortality in a prospectively followed (median follow up of 2.4 years) cohort of 823 patients who initiated dialysis treatment [129]. An inverse trend for CVD mortality was not found to be statistically significant in the presence of inflammation/malnutrition while a positive association was evident in the absence of inflammation/ malnutrition. This led to the conclusion by the authors that the inverse association of total cholesterol level with mortality in dialysis patients is likely due to the cholesterol-lowering effect of systemic inflammation and malnutrition, not to a protective effect of high cholesterol concentrations. These findings support treatment of hypercholesterolaemia in this population.

Yet another explanation is that while the traditional risk factors and over-nutrition require several years to decades to exert their deleterious effects, the adverse effects of such highly prevalent factors in dialysis patients as inflammation, anorexia, malnutrition and wasting occur rapidly [130,131]. Besides, several increased inflammatory biomarkers associated with anorexia and wasting in these patients may have independent pro-atherogenic properties contributing to higher atherosclerotic events, consequently higher CVD incidence [132,133]. Therefore, dialysis patients may not live long enough to die of obesity or hypertension because they die much faster from consequences of inflammation, anorexia, malnutrition and wasting [130].

Clearly, controversy exists in this subset of population undergoing haemodialysis especially in those with coexistent malnutrition and inflammation as to how aggressive we have to be in controlling the traditional risk factors. Perhaps being less aggressive in controlling traditional CVD risk factors while being more aggressive in controlling such nontraditional factors like malnutrition and inflammation as may be existent, is more prudent in these situations, at least until the latter factors are fully corrected.

CVD in haemodialysis patients. Cardiovascular disease is the leading cause of death in patients receiving maintenance HD, especially in the first year of treatment. The single most important predictor of coronary artery disease in uraemic patients, even more so than cigarette smoking and hypertriglyceridaemia is hypertension [108]. There is more evidence for pulse pressure than mean arterial pressure especially in middle and older age patients as an independent predictor of risk of coronary heart disease [134].

While the target blood pressure for CVD risk reduction in CKD in general should be < 130/80 mm Hg, in dialysis patients, however, predialysis and postdialysis blood pressure goals should be < 140/ 90 mm Hg and < 130/80 mm Hg, (in sitting position) respectively [121,134]. In patients who have undergone multiple surgical procedures for vascular accesses in both arms, blood pressure should be measured in the thighs or legs, with appropriate cuff size and only in supine position [134].

Management of hypertension in dialysis patients could be very challenging and some of the following strategies may be helpful in difficult cases. Administration of antihypertensive medications preferentially at night as compared to the morning before a dialysis session may reduce the nocturnal surge of blood pressure and minimize the intradialytic hypotension. Dialysability of antihypertensive medications should be considered, as it is an important factor often overlooked in patients with difficult-to- control blood pressure. For example, 75% and 53% of atenolol is removed in haemodialysis and peritoneal dialysis respectively, while 50% of lisinopril is removed in haemodialysis [134].

Preferred drugs are those that inhibit the reninangiotensin system (RAS), such as ACE inhibitors or angiotensin II-receptor blockers because they cause greater regression of LVH, reduce sympathetic nerve activity, reduce pulse wave velocity, may improve endothelial function, and may reduce oxidative stress. Consider other anti-hypertensives for further step-wise addition. For example, one algorithm suggests that after lifestyle modifications, if a patient’s blood pressure is not at the goal of < 140/90 mm Hg, initiate medications in the order: stage 1: ACEIs or ARB; stage 2: two-drug combination with usually ACEI or ARB and a CCB. If it is still not at goal, add a beta blocker or Clonidine. The next step, if it's still not at goal is to work up for secondary causes and if that is negative, to add minoxidil [134]. If there is compelling evidence, drug for those compelling indications are recommended to be used. Life style modifications should be considered throughout [134].

Anaemia of chronic kidney disease

The prevalence of anaemia in stage 3 CKD was noted to be 5.2%, rising steeply to 44.1% in stage 4 and was almost universal in stage 5 according to NHANES III data [135]. As geriatricians, we need to be aware that it is not only one of the afflictions of CKD that responds well to treatment generally but also correction of it has positive implications on the functional aspects of the elderly with compromised reserve.

Untreated anaemia can cause a number abnormalities including reduced tissue oxygen delivery and utilization, increased cardiac output, cardiac enlargement, ventricular hypertrophy, angina, congestive heart failure, decreased cognition and mental acuity, decreased nocturnal penile tumescence and impaired immune responsiveness [136-150]. (The data is inconclusive regarding whether or not anaemia causes faster rate of decline of GFR in CKD patients [151]). Appropriate treatment of the anaemia of CKD therefore decreases morbidity and improves survival and quality of life [152-157]. Although, there is far more evidence of treatment benefit for anaemia in dialysis CKD patients than non-dialysis CKD patients, no direct evidence of harm in treating the latter group is demonstrated as long as recommended target goals are followed [158- 163]. Nevertheless, only about 23 to 28% of Medicare-eligible ESRD patients were prescribed treatment with epoetin alfa as noted in recent surveys [164,165]. Nephrologists along with primary care physicians and geriatricians are responsible to treat patients with anaemia of CKD more aggressively.

Causes of anaemia of CKD. Particularly in dialysis patients, these include blood loss (due to dialysis especially, haemodialysis), the ‘uraemic milieu’, inflammation, shortened RBC life span, vitamin deficiencies and erythropoietin deficiency [166]. The iron loss in dialysis patients is 10 to 20 times higher than the normal 1 to 2 mg per day. Besides, the iron homeostasis appears altered in CKD-transferrin levels, for unknown reasons, is reduced to one half to one third the normal levels causing diminished capacity to transport iron, and, impaired iron release from macrophages and hepatocytes is well known. Elevated inflammatory cytokines like interleukin 6 cause poor response to erydiropoietin by impairing bone marrow function. Hepcidin, a newly discovered molecule secreted by the liver, inhibits iron absorption from the gut and iron release from the reticuloendothelial macrophages [166- 168].

Erydiropoietin deficient anaemia is considered the most important cause of anaemia of CKD [166]. Erydiropoietin is produced in response to local tissue oxygenation from specialized interstitial cells in the kidney cortex. Its binding to the receptors on the erythroid colony forming units (CFU-Es) in the marrow prevents the apoptosis of these CFU-Es, thereby permitting their cell survival, division and eventual expansion of erythropoeisis [169].

Approach to investigation and treatment of anaemia of CKD. Evaluation of the cause of anaemia should precede initiation of erythropoeisis stimulating agent (ESA) therapy. First step is to rule out other causes of anaemia, especially if: (1) severity of the anaemia is disproportionate to the deficit in renal function; (2) there is evidence of iron deficiency, or (3) there is evidence of leukopenia or dirombocytopenia [169].

With the work up for anaemia in CKD patients, if iron deficiency is found, search for the cause, supplement iron, follow up for anaemia correction and if not corrected, treat withi ESA. If abnormalities other than CKD or Iron deficiency are found, treat accordingly. If no abnormality is noted in CKD patients with anaemia, treat with erythropoiesis-stimulating agent (ESA), if indicated [166].

Haemoglobin level and not haematocrit is the standard to assess anaemia in these patients for various reasons. Therefore check haemoglobin periodically in all patients of CKD regardless of stage – if

Target iron level, evaluation and management of iron status in anaemia of CKD. Storage iron is reflected by serum ferritin, while adequacy of iron available immediately for erydiropoiesis is best reflected by serum iron and TSAT or when available, by content of haemoglobin in reticulocytes (CHr). A low level of either set of these indices may indicate the need for additional iron. In non- dialysis CKD (ND-CKD) patients, ferritin levels <25 ng/ml in males and 12 ng/ml in females suggest mat storage-iron depletion is contributing to anaemia. In haemodialysis CKD (HD-CKD) patients, serum ferritin is less reliable in the evaluation of iron stores and iron for erythropoiesis is said to be deficient and likely to contribute to anaemia if TSAT results are less than 16% [171,172].

Target iron level is the iron level to achieve and maintain a haemoglobin level of 11 to 12 g/dl, which usually requires a TSAT level of >/=20% and a serum ferritin level of >/=100 ng/mL. If patients with these levels of iron have not reached target haemoglobin with oral iron, intravenous (IV) iron may help. Most haemodialysis patients will, in fact, require IV iron on a regular basis to achieve target Hgb and iron parameters. IV iron in regular small doses may also prevent both functional and absolute iron deficiency. Oral iron usually cannot maintain iron stores, especially in the haemodialysis patients treated with ESA (ESA use causes functional iron deficiency due to increased demand) [171,172].

Monitoring for iron status involves checking TSAT and serum ferritin every month in patients not on IV iron at the initiation of ESA or adjusting its dose and every three months in patients receiving IV iron, until target haemoglobin is reached. Once target Hgb is reached, TSAT and serum ferritin should be checked at least once every three months. If oral iron is given, at least 200 mg of elemental iron in two to three divided doses should be given. It is important to remember, however, that oral iron absorption is inversely correlated with iron body stores. Therefore, increased doses of oral iron are unlikely to be absorbed when the serum ferritin levels exceed approximately 200 ng/mL or the TSAT is >20% [171,172].

Target haemoglobin level. Current recommendation is to initiate ESA when haemoglobin falls below 9.0 g/dl with the target level of 11 g/dl or greater. However, caution is advised if a haemoglobin level of > 13 g/dl is intentionally maintained [125,127]. (Some references suggest that ESA be initiated at Hgb of < 11 g/dl) [132]. Although these recommendations for target haemoglobin were not based on randomized control trials, results of two trials recently published address the optimal target level for haemoglobin in patients with chronic kidney disease not yet in need of renal replacement therapy - the Cardiovascular Risk Reduction by Early Anaemia Treatment with Epoetin beta (CREATE) by Druke and colleagues and the Correction of Haemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial by Singh and colleagues.

The CREATE trial showed early complete correction of anaemia to target haemoglobin level of 13 to 15 g/dl, does not decrease the incidence of cardiovascular events as compared with partial correction of anaemia to target level of 10.5 to 11.5 g/dl. The CHOIR trial showed that a higher target haemoglobin level of 13.5 g/ dl as compared with 11.3 g/dl was associated with increased risks of death, myocardial infarction, hospitalization for congestive heart failure and stroke without improvement in quality of life. Therefore, Singh and colleagues of the CHOIR trial conclude that a target value of 11.0 to 12.0 g/dl should be used while correcting anaemia in CKD [173-175]. Complete correction of anaemia may lead to worsening of blood pressure and also increase the risk of thrombosis and vasoconstriction [174].

Table XVI. Epoetin alfa use in CKD patients [171,172,176].[section]

Erthyropoesis stimulating agents (ESA). In the United States, epoetin alfa and darbepoetin alfa are available as ESAs for the treatment of anaemia of CKD. While the subcutaneous (SC) route is more efficacious, the intravenous (IV) route is more convenient in haemodialysis patients (in the US, over 90% of haemodialysis patients, receive erythropoietin in the IV form) [171,172,176].

Epoetin alfa use is summarized in Table XVI.

Darbepoetin alfa (Aranesp(TM))

Compared to recombinant human erythropoietin (rHuEPO), darbepoetin alfa has higher potency and longer half life. It could be given by IV or SC routes and administered weekly, once in two weeks or even monthly in some patients. In rHuEPO-naive patients with CKD, darbepoetin alfa can be administered 0.45 [mu]g/kg once weekly. In patients who are stabilized on rHuEPO, its equivalent dose could be determined based on published conversion charts. It should be given weekly, in those who received rHuEPO two to three times a week and once every two weeks in those who received rHuEPO once weekly. When switching from rHuEPO to darbepoetin alfa, the same route of administration should be used. The dose of darbepoetin should not be adjusted more than once a month as it might take two to six weeks for the achievement of a steady state Hgb response. The dose should be increased by 25% if Hgb rise is < 1 g/dL over a four- week period and d