Classifying kidney problems: can we avoid framing risks as diseases?
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《英国医生杂志》
1 Department of Medicine, McMaster University, Hamilton, Ontario, Canada, 2 Department of Medicine, University of Western Ontario, London, Ontario, Canada, 3 Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
Correspondence to: C M Clase, Suite 708, 25 Charlton Ave East Hamilton, Ontario L8N 1Y2, Canada clase@mcmaster.ca
A new international classification system for kidney problems is currently being developed. How can it meet the challenges of avoiding labelling all patients with low function as having kidney disease and being usable in countries with limited resources?
Introduction
End stage renal disease, defined as kidney function so low that dialysis or transplantation is needed, currently affects 404-1022 people per million population in Europe.1 The burden is large for both patients, whose quality of life and life expectancy are impaired,2 and society because of the high cost of renal replacement therapy.3
Low kidney function refers to abnormalities in clearance of uraemic toxins, often assessed as creatinine clearance or glomerular filtration rate. Low clearance, or low glomerular filtration rate, is commonly known as chronic renal failure. The term chronic renal insufficiency is also widely used; it may have been coined to reduce the apparent severity of this diagnosis. A standard definition does not exist for either term.4
Our understanding of the progression of low glomerular filtration rate derives from observational studies and randomised trials conducted in patients referred for specialist care; these have shown falls in glomerular filtration rate of about 7 to 8 ml/min.5 Until recently it was assumed that all patients with low glomerular filtration would continue to lose function and develop end stage renal disease within about 10 to 20 years. A creatinine clearance of 150 ml/min (standard deviation 20 ml/min) is generally considered normal for men aged 20-30, and longitudinal studies of ageing show that clearance falls by 0.75 ml/min a year.6 On this basis, average clearances of 90-100 ml/min are expected in healthy elderly people. However, recent analyses of data from the third national health and nutrition survey (NHANES III)—a population based survey conducted in the United States—have shown that raised creatinine concentration7 w1 w2 and low glomerular filtration rate7-10 w2 are prevalent, especially in elderly people (figure).
Weighted distribution of predicted glomerular filtration rate by the modification of diet in renal diseases equation, by age (in decades), for non-diabetic adults in third national health and nutrition examination survey. (Estimates are calculated after subtraction of 20.3 μmol/l from serum creatinine concentration to account for differences between White Sands and Cleveland clinic laboratories). Values are given in ml/min/1.73 m2. Modified from Clase et al9
This unexpected finding generated controversy in the nephrology community. Some argued that since the incidence of end stage renal failure is increasing rapidly in most developed counties, the high prevalence of low glomerular filtration rate represents an epidemic of chronic kidney disease. This led to recommendations that people with low glomerular filtration rate should be aggressively identified and treated.7 However, a large disparity exists between the prevalence of low kidney function and that of end stage renal failure and large differences are also seen in the prevalence of proteinuria in studies of referred patients and community studies. We therefore believe it is unlikely that low glomerular filtration rate always carries the same prognosis.9 Recent data on the rate of progression in unreferred patients with low glomerular filtration rate has confirmed this hypothesis.11 Thus current evidence suggests low glomerular filtration rate should not always be considered a disease. In addition, because the evidence for differential management of low glomerular filtration rate is limited to highly selected patient groups,12 13 further data are needed before recommendations for health policy can be made.8 w3
Classification of kidney disease
The current US classification is one of "chronic kidney disease." However, chronicity, a function of time, could better be considered an optional separate dimension. This would allow the classification to be used in non-chronic situations and in cross sectional studies in which chronicity cannot be established. Individual observational data sets and specific clinical questions will require different definitions of chronicity. The classification could suggest a definition of chronicity for use in prospective studies (for example, based on two measurements at least three months apart), but it need not be prescriptive.
The word "kidney," however, is an excellent choice and likely to convey more information than alternatives such as renal. In other languages, the word chosen should similarly be based on common usage.
Recent evidence suggests not all patients with low kidney function require treatment to prevent end stage disease
Credit: SIMON FRASER/RVI, NEWCASTLE
The word "disease" presents more problems. It is defined in the Oxford English Dictionary as "A condition of the body, or of some part or organ of the body, in which its functions are disturbed or deranged; a morbid physical condition; a departure from the state of health, especially when caused by structural change." The word carries connotations that we believe are out of keeping with our current knowledge about many kinds of kidney problems. For example, cut-off points distinguishing abnormal from normal glomerular filtration rate at the upper end of the scale are highly debatable, even kidney function that is indubitably abnormal often does not cause ill health, and proteinuria is only a disease when it leads to symptomatic nephrotic syndrome. Low glomerular filtration rate is a risk factor for severe complicated kidney failure and end stage renal disease14 and may be a causal risk factor for cardiovascular events15; however, it remains a risk factor, and not a disease. A clinically useful classification scheme must consider and minimise the possibility of labelling effects that might influence psychosocial wellbeing and insurability16 and must avoid the promotion of disease to people who do not have symptoms (disease mongering).17
Measurement of kidney health
End stage renal disease (requirement for dialysis or transplantation) does not fit happily within the lowest category of glomerular filtration rate in the US classification.7 We suggest that haemodialysis, peritoneal dialysis, and transplantation be regarded as additional separate categories, although patients with functioning transplants could be further categorised using the kidney function and proteinuria dimensions of the scale. We would add further categories for patients who would benefit from renal replacement therapy but are not receiving it because of a doctor's recommendation or for personal or economic reasons. This would allow researchers to distinguish patients with very low glomerular filtration rate who do not yet require dialysis from those who are pursuing a palliative or conservative care.
Proteinuria
Blood pressure, diabetic status, age, race, aetiology of kidney disease, and structural abnormalities are all important in predicting progression. However, classification systems for these variables already exist and can be combined with one or both dimensions of the kidney classification proposed here as needed.
Stages or groups?
The classification scheme we propose provides a snapshot of kidney health at an instant or over a few months. Previous progression is likely to be a strong predictor of future progression, though direct data to support this hypothesis are not, to our knowledge, available. Because we do not know the relation between past and future progression or whether threshold effects are present (that is, whether there is a rate of loss of glomerular filtration rate above which further clinically important loss is very likely), we do not have sufficient data to suggest categories for this dimension at present.
Separating classification from healthcare recommendations
ERA-EDTA Registry: Annual report, 2003. Amsterdam: Academic Medical Center, 2003.
Khan IH, Garratt AM, Kumar A, Cody DJ, Catto GR, Edward N, et al. Patients' perception of health on renal replacement therapy: evaluation using a new instrument. Nephrol Dial Transplant 1995;10: 684-9.
Lamping DL, Constantinovici N, Roderick P, Normand C, Henderson L, Harris S, et al. Clinical outcomes, quality of life, and costs in the North Thames Dialysis Study of elderly people on dialysis: a prospective cohort study. Lancet 2000;356: 1543-50.
Hsu CY, Chertow GM. Chronic renal confusion: insufficiency, failure, dysfunction, or disease. Am J Kidney Dis 2000;36: 415-8.
Trivedi H, Pang M, Campbell A, Saab P. Slowing the progression of chronic renal failure: economic benefits and patients' perspectives. Am J Kidney Dis 2002;39: 721-9.
Lindeman RD, Tobin J, Shock NW. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 1985;33: 278-85.
National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis 2002;39(suppl 1):S1-266. (Also available at www.kidney.org/professionals/kdoqi/guidelines_ckd/toc.htm, accessed 3 Sep 2004).
Clase CM, Garg AX, Kiberd BA. Prevalence of low glomerular filtration rate in non-diabetic Americans: Third National Health and Nutrition Examination Survey (NHANES III). J Am Soc Nephrol 2002;13: 1338-49.
Clase CM, Garg AX, Kiberd B. Estimating the prevalence of low glomerular filtration rate requires attention to the creatinine assay calibration. J Am Soc Nephrol 2002;13: 2812-6.
Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 2003;41: 1-12.
John R, Webb M, Young ASPE. Unreferred chronic kidney disease: a longitudinal study. Am J Kidney Dis 2004;43: 825-35.
Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329: 1456-62.
Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M, et al. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 1999;354: 359-64.
Iseki K, Iseki C, Ikemiya Y, Fukiyama K. Risk of developing end-stage renal disease in a cohort of mass screening. Kidney Int 1996;49: 800-5.
Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med 2001;134: 629-36.
Haynes RB, Sackett DL, Taylor DW, Gibson ES, Johnson AL. Increased absenteeism from work after detection and labeling of hypertensive patients. N Engl J Med 1978;299: 741-4.
Moynihan R, Heath I, Henry D. Selling sickness: the pharmaceutical industry and disease mongering. BMJ. 2002;324: 886-91.
Iseki K, Ikemiya Y, Fukiyama K. Risk factors of end-stage renal disease and serum creatinine in a community-based mass screening. Kidney Int 1997;51: 850-4.
Iseki K, Ikemiya Y, Iseki C, Takishita S. Proteinuria and the risk of developing end-stage renal disease. Kidney Int 2003;63: 1468-74.
Kannel WB, Stampfer MJ, Castelli WP, Verter J. The prognostic significance of proteinuria: the Framingham study. Am Heart J 1984;108: 1347-52.(Catherine M Clase, associ)
Correspondence to: C M Clase, Suite 708, 25 Charlton Ave East Hamilton, Ontario L8N 1Y2, Canada clase@mcmaster.ca
A new international classification system for kidney problems is currently being developed. How can it meet the challenges of avoiding labelling all patients with low function as having kidney disease and being usable in countries with limited resources?
Introduction
End stage renal disease, defined as kidney function so low that dialysis or transplantation is needed, currently affects 404-1022 people per million population in Europe.1 The burden is large for both patients, whose quality of life and life expectancy are impaired,2 and society because of the high cost of renal replacement therapy.3
Low kidney function refers to abnormalities in clearance of uraemic toxins, often assessed as creatinine clearance or glomerular filtration rate. Low clearance, or low glomerular filtration rate, is commonly known as chronic renal failure. The term chronic renal insufficiency is also widely used; it may have been coined to reduce the apparent severity of this diagnosis. A standard definition does not exist for either term.4
Our understanding of the progression of low glomerular filtration rate derives from observational studies and randomised trials conducted in patients referred for specialist care; these have shown falls in glomerular filtration rate of about 7 to 8 ml/min.5 Until recently it was assumed that all patients with low glomerular filtration would continue to lose function and develop end stage renal disease within about 10 to 20 years. A creatinine clearance of 150 ml/min (standard deviation 20 ml/min) is generally considered normal for men aged 20-30, and longitudinal studies of ageing show that clearance falls by 0.75 ml/min a year.6 On this basis, average clearances of 90-100 ml/min are expected in healthy elderly people. However, recent analyses of data from the third national health and nutrition survey (NHANES III)—a population based survey conducted in the United States—have shown that raised creatinine concentration7 w1 w2 and low glomerular filtration rate7-10 w2 are prevalent, especially in elderly people (figure).
Weighted distribution of predicted glomerular filtration rate by the modification of diet in renal diseases equation, by age (in decades), for non-diabetic adults in third national health and nutrition examination survey. (Estimates are calculated after subtraction of 20.3 μmol/l from serum creatinine concentration to account for differences between White Sands and Cleveland clinic laboratories). Values are given in ml/min/1.73 m2. Modified from Clase et al9
This unexpected finding generated controversy in the nephrology community. Some argued that since the incidence of end stage renal failure is increasing rapidly in most developed counties, the high prevalence of low glomerular filtration rate represents an epidemic of chronic kidney disease. This led to recommendations that people with low glomerular filtration rate should be aggressively identified and treated.7 However, a large disparity exists between the prevalence of low kidney function and that of end stage renal failure and large differences are also seen in the prevalence of proteinuria in studies of referred patients and community studies. We therefore believe it is unlikely that low glomerular filtration rate always carries the same prognosis.9 Recent data on the rate of progression in unreferred patients with low glomerular filtration rate has confirmed this hypothesis.11 Thus current evidence suggests low glomerular filtration rate should not always be considered a disease. In addition, because the evidence for differential management of low glomerular filtration rate is limited to highly selected patient groups,12 13 further data are needed before recommendations for health policy can be made.8 w3
Classification of kidney disease
The current US classification is one of "chronic kidney disease." However, chronicity, a function of time, could better be considered an optional separate dimension. This would allow the classification to be used in non-chronic situations and in cross sectional studies in which chronicity cannot be established. Individual observational data sets and specific clinical questions will require different definitions of chronicity. The classification could suggest a definition of chronicity for use in prospective studies (for example, based on two measurements at least three months apart), but it need not be prescriptive.
The word "kidney," however, is an excellent choice and likely to convey more information than alternatives such as renal. In other languages, the word chosen should similarly be based on common usage.
Recent evidence suggests not all patients with low kidney function require treatment to prevent end stage disease
Credit: SIMON FRASER/RVI, NEWCASTLE
The word "disease" presents more problems. It is defined in the Oxford English Dictionary as "A condition of the body, or of some part or organ of the body, in which its functions are disturbed or deranged; a morbid physical condition; a departure from the state of health, especially when caused by structural change." The word carries connotations that we believe are out of keeping with our current knowledge about many kinds of kidney problems. For example, cut-off points distinguishing abnormal from normal glomerular filtration rate at the upper end of the scale are highly debatable, even kidney function that is indubitably abnormal often does not cause ill health, and proteinuria is only a disease when it leads to symptomatic nephrotic syndrome. Low glomerular filtration rate is a risk factor for severe complicated kidney failure and end stage renal disease14 and may be a causal risk factor for cardiovascular events15; however, it remains a risk factor, and not a disease. A clinically useful classification scheme must consider and minimise the possibility of labelling effects that might influence psychosocial wellbeing and insurability16 and must avoid the promotion of disease to people who do not have symptoms (disease mongering).17
Measurement of kidney health
End stage renal disease (requirement for dialysis or transplantation) does not fit happily within the lowest category of glomerular filtration rate in the US classification.7 We suggest that haemodialysis, peritoneal dialysis, and transplantation be regarded as additional separate categories, although patients with functioning transplants could be further categorised using the kidney function and proteinuria dimensions of the scale. We would add further categories for patients who would benefit from renal replacement therapy but are not receiving it because of a doctor's recommendation or for personal or economic reasons. This would allow researchers to distinguish patients with very low glomerular filtration rate who do not yet require dialysis from those who are pursuing a palliative or conservative care.
Proteinuria
Blood pressure, diabetic status, age, race, aetiology of kidney disease, and structural abnormalities are all important in predicting progression. However, classification systems for these variables already exist and can be combined with one or both dimensions of the kidney classification proposed here as needed.
Stages or groups?
The classification scheme we propose provides a snapshot of kidney health at an instant or over a few months. Previous progression is likely to be a strong predictor of future progression, though direct data to support this hypothesis are not, to our knowledge, available. Because we do not know the relation between past and future progression or whether threshold effects are present (that is, whether there is a rate of loss of glomerular filtration rate above which further clinically important loss is very likely), we do not have sufficient data to suggest categories for this dimension at present.
Separating classification from healthcare recommendations
ERA-EDTA Registry: Annual report, 2003. Amsterdam: Academic Medical Center, 2003.
Khan IH, Garratt AM, Kumar A, Cody DJ, Catto GR, Edward N, et al. Patients' perception of health on renal replacement therapy: evaluation using a new instrument. Nephrol Dial Transplant 1995;10: 684-9.
Lamping DL, Constantinovici N, Roderick P, Normand C, Henderson L, Harris S, et al. Clinical outcomes, quality of life, and costs in the North Thames Dialysis Study of elderly people on dialysis: a prospective cohort study. Lancet 2000;356: 1543-50.
Hsu CY, Chertow GM. Chronic renal confusion: insufficiency, failure, dysfunction, or disease. Am J Kidney Dis 2000;36: 415-8.
Trivedi H, Pang M, Campbell A, Saab P. Slowing the progression of chronic renal failure: economic benefits and patients' perspectives. Am J Kidney Dis 2002;39: 721-9.
Lindeman RD, Tobin J, Shock NW. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 1985;33: 278-85.
National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis 2002;39(suppl 1):S1-266. (Also available at www.kidney.org/professionals/kdoqi/guidelines_ckd/toc.htm, accessed 3 Sep 2004).
Clase CM, Garg AX, Kiberd BA. Prevalence of low glomerular filtration rate in non-diabetic Americans: Third National Health and Nutrition Examination Survey (NHANES III). J Am Soc Nephrol 2002;13: 1338-49.
Clase CM, Garg AX, Kiberd B. Estimating the prevalence of low glomerular filtration rate requires attention to the creatinine assay calibration. J Am Soc Nephrol 2002;13: 2812-6.
Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 2003;41: 1-12.
John R, Webb M, Young ASPE. Unreferred chronic kidney disease: a longitudinal study. Am J Kidney Dis 2004;43: 825-35.
Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329: 1456-62.
Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M, et al. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 1999;354: 359-64.
Iseki K, Iseki C, Ikemiya Y, Fukiyama K. Risk of developing end-stage renal disease in a cohort of mass screening. Kidney Int 1996;49: 800-5.
Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med 2001;134: 629-36.
Haynes RB, Sackett DL, Taylor DW, Gibson ES, Johnson AL. Increased absenteeism from work after detection and labeling of hypertensive patients. N Engl J Med 1978;299: 741-4.
Moynihan R, Heath I, Henry D. Selling sickness: the pharmaceutical industry and disease mongering. BMJ. 2002;324: 886-91.
Iseki K, Ikemiya Y, Fukiyama K. Risk factors of end-stage renal disease and serum creatinine in a community-based mass screening. Kidney Int 1997;51: 850-4.
Iseki K, Ikemiya Y, Iseki C, Takishita S. Proteinuria and the risk of developing end-stage renal disease. Kidney Int 2003;63: 1468-74.
Kannel WB, Stampfer MJ, Castelli WP, Verter J. The prognostic significance of proteinuria: the Framingham study. Am Heart J 1984;108: 1347-52.(Catherine M Clase, associ)