Clinically important renal impairment in various ...

ORIGINAL PAPER

æ

Clinically important renal impairment in various groups of old persons Harald A. Nygaard1, Mala Naik2, Sabine Ruths1 and Kjell Kru¨ger2 1

Section for Geriatric Medicine, Department of Public Health and Primary Health Care, University of Bergen, 2Geriatric Section, Deaconess Hospital, Bergen, Norway.

Scand J Prim Health Care Downloaded from informahealthcare.com by Swets Information Services on 10/22/12 For personal use only.

Scand J Prim Health Care 2004;22:152 /156. ISSN 0281-3432

Objective / To assess renal function in various groups of elderly persons, and to determine the proportion of patients with clinically important renal impairment. Design / Cross-sectional study. Participants / Three geriatric populations aged 70 years and over, representing increasing levels of care/treatment: community-dwelling elderly referred to a geriatric outpatient department, inpatients on a geriatric ward, and nursing home patients. Main outcome measures / Cockroft and Gault’s formula was applied to calculate glomerular filtration rate (GFR). Differences in GFR between age groups and between care levels were explored. Results / Altogether 288 elderly persons were included in the study. We observed a general age-related decline of renal function. Only 2% of the participants had normal renal function (GFR /90 ml/min), 13% had light (GFR 60 / 89 ml/min), 68% moderate (GFR

The influence of the ageing process on organ systems leading to impaired function is well known. In 80year-old persons, the renal function is on an average 40 /50% lower than in 35-year-olds (1). Renal function, however, varies considerably between individuals and in the healthy elderly renal function is better preserved than previously assumed (2). Diabetes and hypertension are the most common causes of renal failure in the Western world (3,4). Renal failure may seriously affect bodily functions. There is an interaction between the development of renal failure and hypertension, decreased glomerular filtration rate (GFR) being an independent risk factor for cardiovascular disease and mortality (5). Anaemia, which is a common complication of renal failure, adds to an increased risk of heart failure and mortality (6,7). Furthermore, renal failure contributes to vitamin D deficiency, affecting muscle strength and leading to an increased risk of falling (8). Although reduced GFR is often considered to be a normal feature of the ageing process, it is associated with an increased risk of drug toxicity (4). Impaired elimination of drugs and metabolites that are predominantly excreted by the kidneys necessitates dosing adjustment of drugs in order to preclude adverse drug reactions and drug-related morbidity caused by accumulation of active substances (9). This applies in Scand J Prim Health Care 2004; 22

30 /59 ml/min), and 17% severe (GFR 15 /29 ml/min) impairment in GFR. Moderate or severely decreased GFR was observed in 75% of the outpatients, 78% of the patients from the geriatric ward, and 91% of the nursing home patients. Altogether 99% of patients aged 85/ had renal impairment necessitating dosing adjustment for drugs that are mainly eliminated through renal excretion. Conclusion / Clinically important renal impairment is common in old age, especially in the frailest elderly living in nursing homes. This finding underlines the necessity for close supervision of drug treatment based on renal function in old age.

Key words: renal impairment, glomerular filtration rate, drug dosing, elderly persons. Sabine Ruths, Section for Geriatric Medicine, Department of Public Health and Primary Health Care, University of Bergen, Kalfarveien 31, NO-5018 Bergen, Norway. E-mail: [email protected]

particular for elderly persons who are receiving multiple drug regimens, which includes an increased risk of potentially harmful drug interactions (10). In adults, serum creatinine (S-Cr) is considered an acceptable measure of renal function. However, S-Cr remains fairly stable throughout life, despite the decline in renal excretory capacity (1). Hence S-Cr is not a reliable predictor of renal function in the elderly (11). Sophisticated methods to measure renal function are not feasible in everyday practice, particularly in old people. Hence formulae have been developed to

Renal impairment in elderly persons is associated with an increased risk of drug toxicity. . Renal impairment, in terms of decreased glomerular filtration rate (GFR), increases with ageing despite normal serum creatinine. . 85% of patients over 70 years and 99% aged 85/ had moderate or severe renal impairment. . Very old patients are at highest risk and GFR should therefore be closely monitored with regard to drug treatment. DOI 10.1080/02813430410006468

Clinically important renal impairment in old persons


estimate the GFR, e.g. by Cockroft & Gault (C-G) (12,13), providing an acceptable measure of GFR (14). The clinical importance of reduced renal function for drug treatment in acute and chronic medical care for elderly people has been widely stressed in the pharmacological and medical literature. However, assessment of GFR is still not commonly implemented in general practice, hospitals, or nursing homes. The present study aims to assess GFR in three groups of elderly persons, and to establish the proportion of patients with clinically important renal impairment as regards drug treatment.

MATERIAL AND METHODS The study comprises three groups of elderly persons aged 70 years and over, recruited from three different care levels. Two groups were recruited from the Deaconess Hospital, Bergen, Norway: geriatric outpatients (GOPs) referred for dementia assessment, and inpatients on the geriatric ward (GWPs). A third group constituted nursing home patients (NHPs) participating in a longitudinal study of patients recently admitted for permanent stay. Blood pressure measurements (systolic blood pressure, SBT, and diastolic blood pressure, DBT) were performed at the initial assessment of GODs and NHPs, as was the presence of diabetes mellitus. S-Cr was measured identically on all sites (colorimetrically by means of the alkaline picrate method, reference 55 /115 mmol/l). GFR was calculated according to the formula developed by C-G (12): GFR /1.23 ((140age)*weight (kg))/S-Cr (for women: multiplied by 0.85). Staging of GFR was defined according to the K/DOQI guidelines (14): normal GFR ]/90 ml/min, mild decrease in GFR 60 /89 ml/min, moderate decrease 30/59 ml/min, severe decrease 15 /29 ml/ min, kidney failure GFR B/15 ml/min. The NH study was approved by the Regional Ethics Committee and by the Norwegian Data Inspectorate, and all participants gave their informed consent.

153

Information regarding patients from the Deaconess Hospital (age, sex, weight, blood pressure, S-Cr) was based on results from routine assessments. Statistical analyses Chi-squared tests were applied to compare proportions, and analysis of variance (ANOVA) and Student’s t-test were undertaken to compare continuous variables between age groups and between care levels. Finally, the relationship between GFR (dependent variable) and age, sex, treatment level and blood pressure was studied in multiple linear regression models. For this purpose, coding was applied for sex (men /0, women /1) and care level (GOPs /0, GWPs/1, NHPs /2). The distributions of age, blood pressure, S-Cr and GFR were significantly skewed (Kolmogorov /Smirnov, p B/0.02). Hence, statistical analyses were executed on log10 transformed data. Statistical significance was set to 5%. RESULTS Data for 288 patients (107 men, 181 women), mean age 81.6 years (range 70 /102), were eligible for analysis. NHPs were significantly older than the other patients (Table I). Mean S-Cr did not differ between care levels, while NHPs had a lower mean GFR compared with GOPs (Bonferroni test p B/0.001) (Table I). Blood pressure measurement was available for 127 GOPs and 63 NHRs, revealing a mean SBT of 145.9 Hg (range 85 /230) and a mean DBT of 78.5 mm Hg (range 50/120). The mean GFR of residents with available blood pressure measurement did not differ from that of residents from whom no blood pressure measurement was available, t/0.89, p/0.38. For the total study population, a small but nonsignificant age-associated increase in S-Cr was observed (ANOVA: F /1,307, p /0.08) (data not shown). Measurement of GFR revealed a significant age-associated decline for the total study population, for men as well as for women (Table II). Women had

Table I. Patient characteristics (sex, age), serum-creatinine (S-Cr), and glomerular filtration rate (GFR), according to care level (geriatric outpatient department, geriatric hospital ward, and nursing home).

Geriatric outpatients Geriatric ward Nursing home All patients 1 2 3 4

Comparison Comparison Comparison Comparison

of of of of

Sex1 (n) all (men/women)

Age2 (years) mean (range)

136 83 69 288

79.9 81.8 84.6 81.6

(53/83) (33/50) (21/48) (107/181)

(70 /95) (71 /96) (70 /102) (70 /102)

S-Cr3 (mmol/l) mean (range)

GFR4 (ml/min) mean (range)

92 100 92 95

45.4 41.3 37.1 42.1

(59 /204) (64 /247) (47 /196) (47 /247)

(20.1 /82.0) (15.4 /100.8) (15.5 /115.9) (15.5 /115.9)

sex between treatment levels, x2 /1.77, df. 2, p/0.41. age between treatment levels, ANOVA F /(1, 27.5) pB/0.001. S /Cr between treatment levels, ANOVA F /(1, 0.22) p/0.64. GFR between treatment levels, ANOVA F/(1, 15.70) p B/0.001. Scand J Prim Health Care 2004; 22

154

H.A. Nygaard et al.

Table II. Glomerular filtration rate (GFR) in geriatric patients (n/288) according to age group. Age group

All patients GFR1 (ml/min)

n 70 /74 75 /79 80 /84 85/ All patients

43 64 83 98 288

55.9 50.0 42.3 33.0 42.1

(32.6 /115.9) (21.7 /100.8) (20.1 /92.1) (15.4 /66.9) (15.4 /115.9)

Women n 20 36 55 70 181

Men

GFR2 (ml/min) 53.2 44.9 40.9 31.4 38.7

n

(38.9 /75.8) (21.7 /91.3) (20.1 /81.3) (15.4 /66.9) (15.4 /91.3)

23 28 28 28 107

GFR3 (ml/min) 58.3 57.5 45.4 37.5 48.5

(32.6 /115.9) (25.1 /100.8) (22.2 /92.1) (16.8 /59.2) (16.8 /115.9)

Differences between age groups (ANOVA): All patients: F /1, 121.3, p B/0.001; 2women: F/1, 71.1, pB/0.001; 3men: F/1, 37.2, pB/0.001.


1

about 20% lower GFR than men (t /5.4, pB/0.001). Altogether 85% of the patients had moderate or severe impairment in GFR (Table III). Moderate or severe decrease in GFR was measured in 75% of the GOPs, 78% of the GWPs, and 91% of the NHPs. Only 2% of the patients had GFR ]/90 ml/min. Factors that might influence the GFR were subsequently studied in two linear regression models (Table IV). The influence of sex, age, and care level was tested in the initial model, revealing age and female sex as independent predictors of decreased GFR. Care level was not significantly associated with GFR. When diabetes and blood pressure were entered into the model, the results remained largely unchanged. Neither blood pressure nor diabetes was significantly associated with GFR. DISCUSSION The present study confirms an age-related decline in renal function, in terms of decreased GFR (13,15/17) and that elderly women in general have lower GFR than men (11,15,18). Altogether 85% of the study population, and 99% of patients aged 85 and over, had moderate or severe reduction in GFR (GFR B/60 ml/ min). This is defined as a limit for considering proper and individualized actions, particularly adjusting dosage of drugs that are mainly eliminated by renal excretion (14). Our findings in various geriatric populations appear reasonable as compared with a

26% prevalence of renal impairment (GFR B/60 ml/ min) in the general population over 70 years (14), and with a 47% prevalence (GFR 5/50 ml/min) in over 70year-old patients with normal S-Cr (19). In the present study, no associations of renal function with blood pressure or diabetes were observed, supporting the results of a Belgian study (20). This may partly be due to the small sample size. Death at younger age among diabetics and persons with hypertension may also be a contributing factor. In line with other studies, we observed only a slight age-related increase in S-Cr (15,18,21). We were not able assess other complications of impaired renal function, e.g. anaemia. The prevalence of inappropriate drug dosage in elderly patients with renal impairment has been examined in a few studies. However, comparisons between studies are hampered because different cutoff points for GFR have been applied to define degrees of renal impairment. In long-term care residents with GFR B/50 ml/min, 45% of the prescribed drugs with mainly renal elimination were dosed inappropriately relative to GFR (22). A GFR of B/40 ml/min predicted elevated plasma levels for several commonly used drugs (enalapril, cefotaxime, frusemide, spironolactone, hydrochlorothiazide) with a mean sensitivity of 90% and specificity of 83% (23). Among frequently prescribed antibiotics, a 34% dosing error rate relative to GFR has been reported (24). In a French hospital study examining potentially nephrotoxic drugs and

Table III. Stages of renal function (glomerular filtration rate, GFR) in geriatric patients (n /288) according to age group. Age group

Stages of renal function (GFR) Patients n

70 /74 75 /79 80 /84 85/ All patients

43 64 83 98 288

Severe decrease (15 /29 ml/min) / 6 9 34 49 (17%)

Linear association for trend x2 /50.9, df 1, pB/0.001. Scand J Prim Health Care 2004; 22

Moderate decrease (30 /59 ml/min) 29 40 65 63 197 (68%)

Light decrease (60 /89 ml/min) 13 14 8 1 36 (13%)

Normal (/90 ml/min) 1 4 1 / 6 (2%)

Clinically important renal impairment in old persons

155

Table IV. Linear regression models for association of glomerular filtration rate (GFR) with age, sex, care level and blood pressure, respectively. Model 11 Beta


Constant Age Women Care level Diabetes mellitus

6.35 /2.45 /0.06 /0.01

95% CI

Beta

95% CI

5.49 /7.22 /2.91 / /1.99 /0.09 / /0.03 /0.03 /0.007

5.45 /2.26 /0.04 /0.008 /0.01

4.26 /6.58 /2.77 / /1.74 /0.07 / /0.004 /0.03 /0.012 /0.06 /0.41

Blood pressure Systolic Diastolic 1 2

Model 22

0.04 0.26

/0.04 /0.31 /0.40 /0.55

288 patients. 190 patients in whom information with regard to diabetes and blood pressure measurement was available.

drugs mainly eliminated through renal excretion, 34% of inappropriate prescriptions relative to renal function were identified (25). A controlled study of individual feedback on drug dosages by a clinical pharmacist to the attending physician revealed 81% dosage adjustments in the intervention group, compared with 33% in the control group (26). It has been objected that true GFR is underestimated by endogenous creatinine clearance, and even more by its surrogate calculated GFR (27). Some studies suggest that the true GFR is underestimated when calculated GFR /60 ml/min, due to too strong effects of age in the formula, while calculated GFR provides a good estimate when GFR is B/60 ml/min (16,17,28). In this study, calculation of GFR has not been adjusted for body surface area. However, the unadjusted C-G is fairly robust, and not much affected by body surface area (17). This method is also recommended by K/DOQI (14). CONCLUSION Clinically important renal impairment is common in old age, particularly in the frailest elderly living in nursing homes. Our findings underline the necessity of close supervision of drug treatment based on renal function in old age. REFERENCES 1. Beck L. Aging changes in renal function. In: Hazzard W, Blass J, Ettinger W, Halter J, Ouslander J, editors. Principles of geriatric medicine and gerontology, 4th edn. New York: McGraw-Hill, 1999:767 /76. 2. Lindeman R, Tobin J, Shock N. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 1985;33:278 /85. 3. Remuzzi G, Schieppati A, Ruggenenti P. Nephropathy in patients with type 2 diabetes. N Engl J Med 2002;346:1145 / 51.

4. Levey A. Nondiabetic kidney disease. N Engl J Med 2002;347:1505 /11. 5. Manjunath G, Tighiouart H, Coresh J, MacLeod B, Salem D, Griffith J, et al. Level of kidney function as a risk factor for cardiovascular outcomes in the elderly. Kidney Int 2003;63:1121 /9. 6. Al-Ahmad A, Rand W, Manjunath G, Konstam M, Salem D, Levey A, et al. Reduced kidney function and anemia as risk factors for mortality in patients with left ventricular dysfunction. J Am Coll Cardiol 2001;38:955 /62. 7. Chae C, Albert C, Glynn R, Guralnik J, Curhan G. Mild renal insufficiency and risk of congestive heart failure in men and women ]/70 years of age. Am J Cardiol 2003;92:682 /6. 8. Janssen H, Samson M, Verhaar H. Vitamin D deficiency, muscle function, and falls in elderly people. Am J Clin Nutr 2002;75:611 /5. 9. Turnheim K. Drug dosage in the elderly. Is it rational? Drugs & Aging 1998;13:357 /79. 10. Bjerrum L, Andersen M, Petersen G, Kragstrup J. Exposure to potential drug interactions in primary health care. Scand J Prim Health Care 2003;21:153 /8. 11. Swedko P, Clark H, Paramsothy K, Akbari A. Serum creatinine is an inadequate screening test for renal failure in elderly patients. Arch Intern Med 2003;163:356 /60. 12. Cockroft D, Gault M. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31 /41. 13. Gault M, Longerich L, Harnett J, Weslowski C. Predicting glomerular function from adjusted serum creatinine. Nephron 1992;62:249 /56. 14. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Kidney Disease Outcome Quality Initiative. Am J Kidney Dis 2002;39:S1 /S246. 15. Fastbom J, Wills P, Cornelius C, Viitanen M, Winblad B. Levels of serum creatinine and estimated creatinine clearance over the age of 75: a study of an elderly Swedish population. Arch Gerontol Geriatr 1996;23:179 /88. 16. Clase C, Garg A, Kiberd B. Prevalence of low glomerular filtration in nondiabetic Americans: Third National Health and Nutrition Examination Survey (NHANES III). J Am Soc Nephrol 2002;13:1338 /49. 17. Verhave J, Balje´-Volkers C, Hillige H, De Zeeuw D, De Jong P. The reliability of different formulae to predict creatinine clearance. J Intern Med 2003;253:563 /73. Scand J Prim Health Care 2004; 22


156

H.A. Nygaard et al.

18. Papaioannou A, Ray J, Ferko N, Clarke J-A, Campbell G, Adachi J. Estimation of creatinine clearance in elderly persons in long-term care facilities. Am J Med 2001;111:569 /73. 19. Duncan L, Heathcote J, Djurdjev O, Levin A. Screening for renal disease using serum creatinine: who are we missing? Nephrol Dial Transplant 2001;16:1042 /6. 20. Van Den Noortgate N, Janssens W, Afschrift M, Lameire N. Renal function in the oldest-old on an acute geriatric ward. Intern Urol Nephrol 2001;32:531 /7. 21. Finney H, Bates C, Price C. Plasma cystatin C determinations in a healthy elderly population. Arch Gerontol Geriatr 1999;29:75 /94. 22. Papaioannou A, Clarke J-A, Campbell G, Be´dard M. Assessment of adherence to renal dosing guidelines in long-term care facilities. J Am Geriatr Soc 2000;48:1470 /3. 23. Mu¨hlberg W, Platt D. Age-dependent changes of the kidneys: pharmacological implications. Gerontology 1999;45:243 /53.

Scand J Prim Health Care 2004; 22

24. Hu K-T, Matayoshi A, Stevenson F. Calculation of estimated creatinine clearance in avoiding drug dosing errors in the older patient. Am J Med Sci 2001;322:133 /6. 25. Salomon L, Deray G, Jaudon M, Chebassier C, Bossi P, Launay-Vacher V, et al. Medication misuse in hospitalized patients with renal impairment. Int J Qual Health Care 2003;15:331 /5. 26. Falconnier A, Haefell W, Schoenenberger R, Surber C, Martin-Facklam M. Drug dosage in patients with renal failure optimized by immediate concurrent feedback. J Gen Intern Med 2001;16:369 /75. 27. Drusano G, Muncie H, Hoopes J, Damron D, Warren J. Commonly used methods of estimating creatinine clearance are inadequate for elderly debilitated nursing home residents. J Am Geriatr Soc 1988;36:437 /41. 28. Van Den Noortgate N, Janssens W, Dalanghe J, Afschrift M, Lameire N. Serum cystatin C concentration compared with other markers of glomerular filtration rate in the old old. J Am Geriatr Soc 2002;50:1278 /82.