Renal Division, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA
Keywords: ACEI; ARB; chronic kidney disease; ESRD; non-renal factors; renal failure progression
Over the last decade the number of patients receiving treatment for end-stage renal disease (ESRD) has steadily increased, partly due to an increase in the rate of ESRD incidence [1,2]. An increase in diabetes and poorly controlled hypertension can only partly account for the increase. The role of other risk factors for progressive loss of renal function other than factors directly linked to kidneys may provide additional explanation. That these factors that are seemingly unrelated to the kidneys such as patients' physical characteristics, genetics, environment, race, education, socioeconomic status, drug dependence and health care utilization could have important implication for renal failure progression is not widely appreciated. After a terse remark on the role of angiotensin converting enzyme (ACE) inhibition in renal failure progression, this commentary will focus entirely on non-renal risk factors.
Recent clinical studies have established the therapeutic efficacy of ACE inhibitors (ACEI) and angiotensin II receptor blockers (ARB) in slowing the rate of renal failure progression [36]. Their use is rapidly becoming the standard of therapy for patients with chronic renal failure. However, the effect of these agents in reducing the rate of progression is modest, and in clinical studies a statistically significant reduction in progression is demonstrated only by designing studies with large numbers of patients. In the captopril study, conducted in 409 patients with diabetic renal failure by Lewis et al. [3], the absolute risk reduction for reaching ESRD between captopril and placebo group was 0.0568 or 5.68%. In this study, the number of patients needed to be treated to prevent one patient reaching ESRD (1/absolute risk reduction) was 1/0.0568=17.60. Knowing that the majority of diabetic patients with renal impairment will progress to ESRD, it may not be incorrect to interpret this finding that despite captopril therapy the majority of the patients will still progress to ESRD. A similar interpretation is also possible for the recent ARB studies [6,7] as well for the African American Study of Kidney Disease and Hypertension (AASK) study [8]. This less optimistic interpretation of the effect of ACEI and ARB therapy on renal failure progression is not dissimilar to clinical experience with these agents and is not inconsistent with the projection of a dramatic increase in ESRD in the US in the year 2010 [2]. The alternative perspective that ACE inhibition is not a panacea for renal failure progression, a contentious issue among Italian nephrologists earlier [9], should not be viewed as an attempt to stifle the importance of angiotensin blockade in renal failure. Rather, it should serve as a reminder of the complex nature of renal failure progression (Figure 1) and the need for the continued search for additional strategies to halt renal failure progression. A number of non-renal risk factors discussed below may contribute to the progression of renal failure and should receive more attention while we attempt to halt the progression of renal failure in the ACE inhibition era.
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Studies suggest that familial aggregation of renal disease in excess of that predicted by clustering of diabetes and hypertension does occur within families [10]. This observation supports many nephrologists' long held clinical view that in many patients either genetic susceptibility or environmental exposures shared within families increases the risk for ESRD clustering. While it is currently not known whether familial clustering of renal disease is a risk factor for rapid progression, with the recent deciphering of human genome and the purported availability of rapid and affordable gene sequencing, this and other information regarding genotypes and renal injury and best treatment options tailored for genotypes might become available sooner than we think. In this regard, studies are already underway examining the interaction between ACE gene polymorphism and the beneficial effect of ACEIs in renal failure progression.
ACE genotype
One component of the genetic risk for diabetic renal disease may be the ACE genotype. In some studies, the DD polymorphism in patients with type 2 diabetes has been associated with a greater risk for diabetic nephropathy [11]; other studies however, fail to confirm such an association [12]. Similarly, the role of ACE genotype in the progression of non-diabetic renal failure also remains uncertain. The findings from the Ramipril Efficacy in Nephropathy (REIN) trial suggest that the ACE genotype per se may not be a crucial determinant of progression, but the presence of DD but not II or ID genotype is a strong predictor for the positive renal response to ACE inhibitor therapy [13]. Such a suggestion, albeit inchoate, again underscores the variable effect one observes in clinical practice with ACE inhibition on renal failure progression.
Low-birth weight
In 1997 Brenner and Mackenzie [14] proposed that reduction in the nephron number, including congenital deficits, might be a risk factor for progression of renal disease. A recent study by Lackland et al. [15] supports this intriguing concept and found that low-birth weights contribute to high rates of early-onset chronic renal failure in the southeastern US. Because the association occurred irrespective of the cause of renal damage, the authors have suggested that an adverse environment in utero impairs kidney development and makes it more vulnerable to damage from a range of pathological processes. Future prospective studies are required to clarify this issue as this retrospective study could be flawed with selection bias. However, if the premise that low-birth weight and renal failure are linked is substantiated, then strategy to prevent or limit renal failure has to begin in utero at least in certain subgroups of population.
Hyperglycaemia and advanced glycosylation end product-related oxidative and carbonyl stress
The prospective Diabetes Control and Complications Trial (DCCT) provided evidence that strict glycaemic control can both delay the onset of microvascular complications and slow the rate of progression of already established complications. Strict glycaemic control can reduce the development of microalbuminuria and development of diabetic nephropathy [16]. An area of intense experimental research interest is in the role of advanced glycosylation end products (AGEs) in the causation of diabetic complications. Circulating AGE concentrations are increased in diabetic patients, particularly those with renal insufficiency, as AGEs are normally excreted in the urine. However, the importance of these heterogeneous compounds in causing human vascular or renal disease has yet to be established [17]. Chronic uraemia has been shown to cause increased reactive carbonyl modification of protein, indirectly leading to advanced glycation or lipoxidation of proteins that are implicated in dialysis-associated amyloidosis and accelerated atherosclerosis [18]. Compared with matched normal subjects, cardiovascular disease (CVD) mortality in renal failure patients was between 10 and 20 times higher, and this was almost 100 times higher in the presence of diabetes. One intriguing possibility for the synergistic interaction between these two conditions may be the ability of each of these conditions to promote oxidative and carbonyl stress, which then leads to increased lipid peroxidation, atherosclerosis, and greater CVD mortality.
Hyperlipidaemia
An intriguing but murky issue is the role of hyperlipidaemia in renal failure progression. Hyperlipidaemia is common in patients with nephrotic syndrome, but its incidence is quite variable in non-nephrotic patients. In addition to accelerating the development of systemic atherosclerosis, experimental studies suggest that high lipid levels may also promote progression of renal disease. The major evidence in support of this hypothesis is the observation in experimental animals that cholesterol loading enhances glomerular injury, and that reducing lipid levels with drugs such as lovastatin slows the rate of progression of injury [19]. The factors responsible for the lipid effects are incompletely understood and may involve a rise in intraglomerular pressure, lipid-mediated mesangial cell activation and proliferation and increased cytokine, growth factor and free radical production. The applicability of these findings to human disease is unclear. In a study by Massy et al. [20] high triglycerides and low HDL cholesterol, but not LDL cholesterol was found to predict increased risk of renal dysfunction. Overall, the lack of well-controlled clinical intervention studies precludes any firm conclusion on the role of hyperlipidaemia in renal failure progression.
Obesity
Several nutritional surveys have shown that weight gain is such a common problem that a larger proportion of the general population is now overweight and obese. Focal segmental glomerulosclerosis (FSGS) has become the leading form of glomerulonephritis in the US, and whether this is related to the obesity epidemic in the US is not clear. Obesity is associated with glomerulosclerosis, which is reported to be a milder form of glomerulosclerosis than the idiopathic variety of FSGS [21]. Obesity may contribute to progression of renal failure and whether this occurs through the effect of obesity per se or through hypertension, insulin resistance and hyperglycaemia is not known. At any rate, obesity and being overweight in renal failure patients should become a concern also for nephrologists attempting to halt the progression of renal failure.
High dietary protein intake
The tangible benefit of marked dietary protein restriction in the clinical practice setting remains controversial. Although the benefit may be sufficient to delay dialysis, there is a large cost in terms both of effort on the part of the medical team and patient and of the relatively poor palatability of food with severe protein restriction. In renal transplant patients with proteinuria and impaired renal function, a short-term high-protein diet was accompanied by a significant worsening of glomerular permselectivity, indicated by an increase in the fractional renal clearance of both albumin and globulin [22]. Loss of glomerular permselectivity, that is, non-selective proteinuria, is a well-known predictor of progression of renal failure. Thus, patients who might regularly consume a high-protein diet, for example 2 g/kg body weight might be at higher risk for renal progression and should be advised for moderation in protein intake.
Smoking
Chronic cigarette smoking is a well-known risk factor for vascular disease because of its ability to induce atherosclerosis and vascular occlusion. Similar histological changes along with reduced renal blood flow have been reported in the kidneys of chronic smokers [23,24]. Furthermore, continued prevalence of cigarette smoking was purported as a reason for the unabated increase in renal failure incidence, despite awareness of and treatment for hypertension. Thus, smoking remains a clearly modifiable risk factor in patients with renal failure.
Socioeconomic status, educational achievement and health care access
These non-biological variables that are socioeconomic status, educational achievement and health care access are seldom discussed in the scientific context of renal failure progression. Yet these factors undoubtedly influence disease management and its outcomes, especially in many indigent and racial minority patients [25,26]. A recent study reported that lower socioeconomic status and suboptimal health care access accounted for most of the rapid renal progression noted in blacks vis-a-vis whites in the US [27]. Patients from such susceptible cohorts should be specifically targeted for more frequent clinic visits and aggressive health education whenever possible.
In summary, a number of non-renal factors such as obesity, poorly controlled hypertension and diabetes, smoking, genetic and racial factors and factors involving socioeconomic status, educational achievement and health care access contribute to renal failure progression. The overall clinical finding that angiotensin inhibition slows the rate of progression is heartening. However, the use of angiotensin inhibition should not lessen the importance of rigorous control of systemic factors such as hyperglycaemia, hypertension, smoking and obesity and should not lessen the additional focus required on certain groups of vulnerable patients.
Notes
Correspondence and offprint requests to: Abdulla K. Salahudeen, MD, MSc, FRCP, Professor of Medicine, Renal Division, Department of Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505, USA. Email: asalahudeen{at}medicine.umsmed.edu
References
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