From secondary to primary prevention of progressive renal disease: The case for screening for albuminuria
2004; Elsevier BV; Volume: 66; Issue: 6 Linguagem: Inglês
10.1111/j.1523-1755.2004.66001.x
ISSN1523-1755
AutoresPaul E. de Jong, Barry M. Brenner,
Tópico(s)Dialysis and Renal Disease Management
ResumoFrom secondary to primary prevention of progressive renal disease: The case for screening for albuminuria. Many subjects nowadays present with end-stage renal failure and its attendant cardiovascular complications without known prior renal damage. In this report we review the evidence available to strongly suggest that the present practice of secondary prevention in those with known prior renal disease should be extended to primary prevention for those subjects in the general population who are at risk for progressive renal failure, but who had never suffered from a primary renal disease. We show that such subjects can be detected by screening for albuminuria. Elevated urinary albumin loss is an indicator not only of poor renal, but also of poor cardiovascular prognosis. In addition to diabetic subjects who are at risk for albuminuria, we also show that hypertensive, obese, and smoking subjects are more susceptible. We suggest that therapies that have been shown to lower albumin excretion, such as ACE inhibitors, angiotensin II receptor antagonists, and statins be started early in such patients to prevent them from developing clinical renal disease and its attendant cardiovascular complications. From secondary to primary prevention of progressive renal disease: The case for screening for albuminuria. Many subjects nowadays present with end-stage renal failure and its attendant cardiovascular complications without known prior renal damage. In this report we review the evidence available to strongly suggest that the present practice of secondary prevention in those with known prior renal disease should be extended to primary prevention for those subjects in the general population who are at risk for progressive renal failure, but who had never suffered from a primary renal disease. We show that such subjects can be detected by screening for albuminuria. Elevated urinary albumin loss is an indicator not only of poor renal, but also of poor cardiovascular prognosis. In addition to diabetic subjects who are at risk for albuminuria, we also show that hypertensive, obese, and smoking subjects are more susceptible. We suggest that therapies that have been shown to lower albumin excretion, such as ACE inhibitors, angiotensin II receptor antagonists, and statins be started early in such patients to prevent them from developing clinical renal disease and its attendant cardiovascular complications. Historically, nephrology expanded greatly after the development of the artificial kidney and the introduction of renal transplantation. Due to the great demand for renal replacement therapy, little effort was given to primary or secondary prevention of progressive renal disease. Fortunately, however, in the last decade much has been achieved in secondary prevention in subjects who had been diagnosed with already established renal damage due to glomerular or tubulointerstitial renal diseases. This secondary prevention aimed at preventing progressive renal function loss in these patients with prior renal disease. Low-protein diets1Pedrini M.T. Levey A.S. Lau J. et al.The effect of dietary protein restriction on the progression of diabetic and non-diabetic renal diseases: A meta-analysis.Ann Intern Med. 1996; 124: 627-632Crossref PubMed Scopus (575) Google Scholar (although in clinical practice difficult to achieve), and antihypertensive agents, in general2Parving H.H. Andersen A.R. Smidt U.M. Svendsen P.A. Early aggressive antihypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy.Lancet. 1983; 1: 1175-1179Abstract PubMed Scopus (779) Google Scholar, but angiotensin-converting enzyme (ACE) inhibitors3Lewis E.J. Hunsicker L.G. 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De Zeeuw D. et al.Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med. 2001; 345: 861-869Crossref PubMed Scopus (5795) Google Scholar,7Lewis E.J. Hunsicker L.G. Clarke W.R. et al.Renoprotective effects of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.N Engl J Med. 2001; 345: 851-860Crossref PubMed Scopus (4761) Google Scholar, in particular, appeared especially effective in retarding a further progressive renal function decline. Recent, yet not thus far confirmed data suggest that the use of lipid-lowering agents8Bianchi S. Bigazzi R. Caiazza A. et al.A controlled prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease.Am J Kidney Dis. 2003; 41: 565-570Abstract Full Text Full Text PDF PubMed Scopus (321) Google Scholar, weight reduction9Morales E. Valero A. Léon M. et al.Beneficial effects of weight loss in overweight patients with chronic proteinuric nephropathies.Am J Kidney Dis. 2001; 41: 319-327Abstract Full Text PDF Scopus (249) Google Scholar, and cessation of smoking10Schiffl H. Lang S.M. Fischer R. Stopping smoking slows accelerated progression of renal failure in primary renal disease.J Nephrol. 2002; 15: 270-274PubMed Google Scholar may also be beneficial in secondary prevention. With such interventions it is possible to retard the progressive decline in renal function: the slope of glomerular filtration rate (GFR) over time becomes less steep, and the time elapsing before renal replacement therapy is started has been extended significantly. Some reports even document the reversal of prior renal function decline11Ruggenenti P. Perna A. Benini R. et al.In chronic nephropathies prolonged ACE inhibition can induce remission: Dynamics of time-dependent changes in GFR.J Am Soc Nephrol. 1999; 10: 997-1006PubMed Google Scholar,12Brenner B.M. Remission of renal disease: Recounting the challenge, acquiring the goal.J Clin Invest. 2002; 110: 1753-1758Crossref PubMed Scopus (79) Google Scholar. Despite successes in slowing progression after renal injury has already occurred, we are still faced with increasing numbers of patients requiring renal replacement therapy. The increasing demand for these services is partly related to the fact that dialysis and renal transplant techniques have improved and are now extended to those who are elderly or suffer systemic diseases (i.e., diabetes and generalized atherosclerosis). Whereas diabetes now constitutes the major cause of end-stage renal disease (ESRD) in many national registries, it should be noted that the number of patients reaching ESRD without a renal diagnosis is also increasing dramatically. Besides diabetes, the importance of generalized atherosclerosis and hypertension to insidious loss of renal function, therefore, cannot be neglected13Mailloux L.U. Napolitano B. Belluci A.G. et al.Renal vascular disease causing end-stage renal disease. Incidence, clinical correlates and outcomes: A 20 year experience.Am J Kidney Dis. 1994; 24: 622-629Abstract Full Text PDF PubMed Scopus (358) Google Scholar. In this paper we will (1) consider the mechanisms underlying the progressive decline in renal function observed in subjects with preexisting renal disease. Cognizant of these mechanisms, we will (2) examine the factors likely to be responsible for initiating loss of renal function in the general population; (3) review the options available to detect subjects at risk for early loss by screening for albuminuria; and (4) consider whether strategies that have been proven effective in secondary prevention will also be effective as primary prevention, that is, prevention of progressive renal function loss in those not known to have prior renal disease, and at a time when renal function loss is not yet manifest. Such preventive efforts should ultimately improve long-term health and greatly reduce the economic burden related to renal replacement therapy. Considering the evidence available, we believe it is essential for large ongoing and future epidemiologic studies that focus on risk factors for, and treatment of, cardiovascular disease to add albuminuria measurements to their protocol. Additionally, it would be of great benefit for optimizing cardio- and renoprotective therapies in primary health care to include albuminuria measurements in the routine follow-up of patients. At present, much is known about the mechanisms underlying the progressive decline in renal function in patients with known renal disease. It has been well documented that the hemodynamic adaptations of glomerular hypertension and hyperfiltration in remnant nephrons (i.e., those nephrons not damaged by the initiating renal disease) ultimately prove detrimental. They suffer progressive glomerulosclerosis, a process that sets into motion a vicious cycle of nephron loss. The more initial nephrons lost, the more the hemodynamic burden to the remaining ones14Brenner B.M. Meyer T.W. Hostetter T.H. Dietary protein intake and the progressive nature of kidney disease: The role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease.N Engl J Med. 1982; 307: 652-659Crossref PubMed Scopus (128) Google Scholar. The ensuing protein leakage through these affected glomeruli results in enhanced tubule protein reabsorption, which initiates progressive tubule atrophy and interstitial fibrosis15Abbate M. Zoja C. Corna D. et al.In progressive nephropathies, overload of tubular cells with filtered proteins translates glomerular permeability dysfunction into cellular signals of interstitial inflammation.J Am Soc Nephrol. 1998; 9: 1213-1224PubMed Google Scholar. Clinically, the most important factors promoting this final common pathway of progressive nephron loss are hypertension16Oldrizzi L. Rugiu C. De Biase V. Maschio G. The place of hypertension among the risk factors for renal function in chronic renal failure.Am J Kidney Dis. 1993; 21: S119-123Abstract Full Text PDF PubMed Scopus (34) Google Scholar, proteinuria17Williams P.S. Fass G. Bone J.M. Renal pathology and proteinuria determine progression in untreated mild/moderate chronic renal failure.QJM. 1988; 67: 343-354PubMed Google Scholar, hyperlipidemia18Maschio G. Oldrizzi L. Rugiu C. et al.Factors affecting progression of renal failure in patients on long term dietary protein restriction.Kidney Int. 1987; 32: S49-52Google Scholar, and genetic factors, such as race19Perneger T.V. Whelton P.K. Klag M.J. Race and end-stage renal disease. Socioeconomic status and access to health care as mediating factors.Arch Int Med. 1995; 155: 1201-1208Crossref PubMed Scopus (161) Google Scholar and ACE gene polymorphism20van Essen G.G. Rensma P.L. De Zeeuw D. et al.Association between angiotensin converting enzyme gene polymorphism and failure of renoprotective therapy.Lancet. 1996; 347: 94-95Abstract PubMed Scopus (168) Google Scholar. Other factors such as obesity21Bonnet F. Deprele C. Sassolas A. et al.Excessive body weight as a new independent risk factor for clinical and pathological progression in primary IgA nephritis.Am J Kidney Dis. 2001; 37: 720-727Abstract Full Text PDF PubMed Scopus (233) Google Scholar, smoking22Orth S.R. Ritz E. Schrier R.W. The renal risks of smoking.Kidney Int. 1997; 51: 1669-1677Abstract Full Text PDF PubMed Scopus (199) Google Scholar, low birth weight23Brenner B.M. Chertow G.M. Congenital oligonephropathy and the etiology of adult hypertension and progressive renal injury.Am J Kidney Dis. 1994; 23: 171-175Abstract Full Text PDF PubMed Scopus (465) Google Scholar, male gender24Silbiger S.R. Neugarten J. The impact of gender on the progression of chronic renal disease.Am J Kidney Dis. 1995; 25: 515-533Abstract Full Text PDF PubMed Scopus (311) Google Scholar, and high salt intake25Cianciaruso B. Bellizzi V. Minutolo R. et al.Salt intake and renal outcome in patients with progressive renal disease.Miner Electrolyte Metab. 1998; 24: 296-301Crossref PubMed Scopus (124) Google Scholar are also likely to be associated with a worse outcome in subjects with preexisting renal disease. The potential for hyperfiltration also occurs in other “physiologic” circumstances, such as congenital reduction in nephron number, sickle cell anemia, and following uninephrectomy (i.e., after kidney donation). Does glomerular hyperfiltration also explain the GFR decline in normal aging? In the normal population, GFR decreases from the age of 30 by about 0.8 mL/min/year26Lindeman R.D. Shock T.J. Longitudinal studies on the rate of decline in renal function with age.J Am Geriatr Soc. 1985; 33: 278-285Crossref PubMed Scopus (1166) Google Scholar. Assuming that a 30-year-old subject has a normal GFR of about 120 mL/min, his/her GFR will be about 70 mL/min at the age of 80. A renal biopsy in a kidney from that 80-year-old person will typically reveal some atrophic glomeruli with tubule atrophy, other glomeruli showing signs of glomerulosclerosis, and still others showing glomerular enlargement and hypertrophy. It has been shown that the age-related decline in renal function, as well as in renal cortical thickness is accelerated in cases of generalized atherosclerosis27Bax L. van der graaf Y. Rabelink A.J. et al.Influence of atherosclerosis on age-related changes in renal size and function.Eur J Clin Invest. 2003; 33: 34-40Crossref PubMed Scopus (37) Google Scholar. If an elevated GFR by itself bears the risk of later progressive renal function loss, we should question whether screening for hyperfiltration would be of help to detect subjects at risk. Screening for glomerular hyperfiltration with accurate renal function studies is, however, not feasible in population studies. Measuring creatinine clearance is also difficult to perform in population studies, and an elevated creatinine clearance in a single subject does not allow investigators to conclude that hyperfiltration exists in that subject because of possible inaccuracies in 24-hour urine collections. Finally, indirect GFR estimates such as the Modification of Diet in Renal Disease (MDRD) formula or the Cockroft-Gault formula have never been tested in the range of normal to elevated GFRs. Thus, the detection of glomerular hyperfiltration in population studies is difficult to achieve. With regard to the relationship between initial glomerular hyperfiltration and subsequent loss of renal function, we should learn from the experience in diabetes mellitus, especially type 1 diabetes. This is the condition in which the course of GFR in the long run is best studied, and in which the relation between hyperfiltration and albuminuria has been well established. If such an association also holds true for the general population, the screening for microalbuminuria may be appropriate. It is well known that glomerular hyperfiltration exists in the initial years after onset of hyperglycemia both in type 128Mogensen C.E. Andersen M.J.F. Increased kidney size and glomerular filtration rate in early juvenile diabetes.Diabetes. 1973; 9: 706-712Crossref Scopus (294) Google Scholar,29Christiansen J.S. Gammelgaard J. Frandsen M. Parving H.-H. Increased kidney size, glomerular filtration rate and renal plasma flow in short-term insulin-dependent diabetics.Diabetologia. 1981; 20: 451-456PubMed Google Scholar and type 2 diabetes30Vora J.P. Dolben J. Dean J.D. et al.Renal hemodynamics in newly presenting non-insulin dependent diabetes mellitus.Kidney Int. 1992; 41: 829-835Abstract Full Text PDF PubMed Scopus (129) Google Scholar,31Palmisano J.J. Lebovitz H.E. Renal function in black Americans with type II diabetes.J Diabet Complications. 1989; 3: 40-44Abstract Full Text PDF PubMed Scopus (33) Google Scholar. This increase in GFR is related to both a rise in renal plasma flow and in filtration fraction, caused by afferent, but not efferent, vasodilatation and increased glomerular capillary pressure. Without treatment, this phase continues for about a decade before urinary albumin loss commences and rises to the level of microalbuminuria (defined as urinary albumin excretion of 20–200 μg/min or 30–300 mg/day). At this time, GFR declines to normal and then subnormal levels, and ultimately progresses to end-stage renal failure. This latter phase coincides with a further increase in albuminuria, often to more than 2 g/day. This longitudinal pattern of changes in GFR and albuminuria in type 1 diabetes is illustrated in Figure 132Mogensen C.E. Prediction of clinical diabetic nephropathy in IDDM patients. Alternatives to microalbuminuria.Diabetes. 1990; 39: 761-767Crossref PubMed Google Scholar. Data on the time course of GFR and albuminuria in type 2 diabetes are sparse. It has been shown that GFR increases during follow-up in Pima Indians with impaired glucose tolerance and recently detected type 2 diabetes (at the time where there is not yet albuminuria), whereas GFR is stable during the period of microalbuminuria and diminishes as macroproteinuria develops33Nelson R.G. Bennet P.H. Beck G.J. et al.Development and progression of renal disease in Pima Indians with non–insulin-dependent diabetes mellitus.N Engl J Med. 1996; 335: 1636-1642Crossref PubMed Scopus (379) Google Scholar. The experience in diabetes can be used as a model to study the impact of an increased albumin excretion in nondiabetic subjects, as well. Indeed, a similar association between albuminuria and creatinine clearance was observed in a large cohort of about 8000 nondiabetic subjects of the general population. The presence of albuminuria in the high normal range (15–30 mg albumin per day), or the so-called “micro” albuminuria range (30–300 mg per day) was associated with glomerular hyperfiltration34Pinto-Sietsma S.J. Janssen W.M.T. Hillege H.L. et al.Urinary albumin excretion is associated with renal functional abnormalities in a non-diabetic population.J Am Soc Nephrol. 2000; 11: 1882-1888PubMed Google Scholar. In contrast, the subjects with macroproteinuria (>300 mg per day) showed an impaired GFR. These data indicate that the presence of an elevated albumin excretion can be used to identify subjects with glomerular hyperfiltration. Although these latter data are cross-sectional, they are in agreement with the longitudinal data shown in Figure 1. The emphasis we give to the relation between glomerular hyperfiltration and an increased urinary albumin excretion does not imply that hyperfiltration is the only mechanism of albuminuria. The scope of this review, however, is not to extensively review the various pathohysiologic mechanisms underlying glomerular albumin leakage and tubular handling of proteins, which are well studied in primary glomerular diseases. To that purpose, we refer to extensive in-depth reviews that have been published recently35D'Amico G. Bazzi C. Pathohysiology of proteinuria.Kidney Int. 2003; 63: 809-825Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar,36Russo L.M. Bakris G.L. Comper W.C. Renal handling of albumin: A critical review of basic concepts and perspective.Am J Kidney Dis. 2002; 39: 899-919Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar. In diabetes, prevention of microalbuminuria to macroalbuminuria is considered as secondary prevention, and prevention of normoalbuminuria to microalbuminuria can be considered as primary prevention. In line with the pattern observed in Figure 1, it could thus be argued that the detection of a subject with glomerular hyperfiltration (with a shift from normo via “high-normal” to microalbuminuria) makes him/her suitable for primary prevention. In contrast, detecting him/her at the time when glomerular hyperfiltration is no longer manifest (that is, when microalbuminuria shifts to macroalbuminuria) makes him/her suitable only for secondary prevention. What conditions then, besides diabetes, are associated with increased urinary albumin excretion, and what is the evidence that these conditions are also associated with glomerular hyperfiltration? Table 1 summarizes the various risk factors associated with albuminuria. They are grouped as either non-modifiable or modifiable by therapeutic approaches, and further subdivided as to whether the risk has been well documented or is likely, when adequately studied, to prove to be associated. It is evident that many of the reported risk factors overlap with those already known to be associated with progression of established renal disease. Indeed, most of the factors mentioned have also been shown in diabetes to favor the development of microalbuminuria. 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