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Nephrology beyond JASN |
Both clinical (1) and experimental (2–4) observations indicate that in renal disease atherosclerosis is accelerated—and this not only in end-stage renal disease, but even in early stages of renal dysfunction (2). The clinical importance is illustrated by the finding that the life expectancy of a 20-yr-old dialyzed patient is equivalent to that of an 85-yr-old individual in the general population (5)—consistent with (but not proof for) the hypothesis that aging is accelerated in uremia. This concept would also be supported by our preliminary, unpublished results, which suggest that indeed cellular senescence is a feature of uremia.
Concerning the evolution of the atherosclerotic plaque, there has recently been a paradigm shift: In the past it had been assumed that the atherosclerotic plaque was the result of a progressive and irreversible local response, in part inflammatory, of resident endothelial cells to injury of chemical (lipids, oxidative stress) or physical (turbulence, pressure) origin (6). This reaction has many similarities to wound healing. Recently it has been shown, however, that the evolution of the plaque is not an irreversible one-way process. Bone marrow–derived progenitor cells can repair plaques (7). This observation led to the concept that plaques are the result of a fragile balance between aggression and repair.
It is here that the above study of Karra et al. (8), in a model of spontaneous atherosclerosis, the apolipoprotein E-null (apoE–/–) mouse, brought a definite breakthrough. Using the microarray technique, the authors documented a relationship between progressive stages in the evolution of plaques and the patterns of gene expression. Furthermore, before the appearance of plaques the authors observed the loss of the molecular signature for competent repair, leading to the conclusion that the initiation of atherosclerotic lesions coincided with the "exhaustion" of repair mechanisms. Finally, the authors compared the aortas of animals treated with precursor cells obtained from either young or old donor animals. The differences of the expression patterns between recipients of cells from young and old donors corresponded to the differences seen between plaques in early and advanced stages of their evolution, lending further support to earlier observations that progressive progenitor cell deficits contribute to the development of atherosclerosis (7).
What strategy was used to achieved these results? The authors had recently shown that large-scale microarray analysis identified patterns of gene expression that correlated with the atherosclerotic burden in human aortas (9). Interestingly, they had identified a number of genes that so far had not been implicated in atherogenesis. Expression phenotyping was performed as a function of time in the established atherosclerosis model of the apoE–/– mouse. To assess "early" aortic atherosclerosis without grossly detectable plaques but with monocytes adhereing to the aortic endothelium, the authors studied 6-wk-old apoE–/– mice fed chow diet. To study "advanced" aortic atherosclerosis they studied 12-wk-old apoE–/– mice fed a high-fat diet (10). The extent of atherosclerosis was quantitated using the Oil Red O stain. RNA was extracted for assessment using Affymetrix MG-U74Av2 microarrays (11). Based on gene expression profiling, samples with the same stage of aortic lesions tended to cluster together. Based on the approach of West et al. (12), predictive modeling was used to associate genes with disease stages. Genes were grouped into "metagenes" sharing common expression patterns. The authors identified 197 genes associated with the transition from no aortic lesions to early lesions, 146 genes for the transition from early to intermediate lesions, 110 genes for the transition from intermediate to moderate lesions, and 650genes for the transition from no lesions to moderate lesions. The different stages in the evolution of atherosclerotic plaques were characterized by unique gene expression patterns. There was surprising concordance with the findings previously obtained in human aortae (9). Conservation of the expression signature across species was noted, arguing for the generalizibility of the results. The genes could roughly be grouped into genes relating to "lipid metabolism" (e.g., apoE, ABCA1, and others), to "defense and inflammation" (e.g., ostepontin, MMP12, Il1-RN, CCL8, and others), and to "morphogenesis" (e.g., RXR
, MAFF, EPAS-1 and others).
The hypothetical role of repair in the genesis of atherosclerotic plaques was addressed by experiments where apo E–/– mice were injected weekly with bone marrow–derived progenitor cells obtained from young (3 to 5 wk) or old (>6 mo) apo E–/– mice. These cells homed in on atherosclerotic plaques; most cells obtained from young (but not from old) donors turned into endothelial cells, but a minority wound also up as other cell types of the vessel wall.
What were the expression signatures of animals with no, intermediate, or moderate lesions of the aorta and how did they compare with the expression signatures of animals treated with bone marrow–derived progenitor cells obtained from young or old donors? Without going into details, mice with early lesions had an expression profile similar to that of the aorta of animals treated with bone marrow–derived progenitor cells obtained from young donors. In contrast, mice with intermediate and moderate disease had an expression profile more similar to that of the aorta of animals treated with bone marrow–derived progenitor cells obtained from old donors. Both were characterized by a marked inflammatory response.
Why are these observations of interest to the nephrologist? The demographic data suggest that survival in hemodialyzed patients behaves as if uremia were a state of premature aging (5). It would not be completely unexpected if the same relationship between exhaustion of repair and progression of plaques, as found in the experiment of Karra et al. (8), existed in uremia as well. Conceivably, in uremia with known acceleration of atherogenesis (1,2) not only the quality and intensity of the insult, but also the quality of repair, are abnormal, possibly as the result of premature senescence of the bone marrow–derived precursor cells.
It is known that the number and, less well-documented, the efficacy of hemangiopoietic precursor cells is increased by interventions such as statins (13) or erythropoietin (14). Whether the same beneficial effect occurs in uremic patients or there is a specific defect of these properties requires further study. In nonuremic individuals, precursor cells predict cardiac events (15), and in experimental and clinical studies (16) administration of precursor cells (17) reduced cardiac events. Whether this approach is feasible and efficacious in uremic patient as well will require further studies.
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Lead intoxication has been known for millennia. For instance, it had been postulated that lead poisoning due to the high lead concentration in Roman wines contributed to the downfall of the Roman empire (1) or the terminal illness of Herodes (2). In the 19th century, a high prevalence of occupational lead intoxication had been well documented (3) in addition to its association with renal disease in patients with symptomatic lead intoxication (4,5), which was also investigated in greater detail more recently (6). Meanwhile, symptomatic occupational lead intoxication has virtually disappeared, but asymptomatic, subclinical occupational or environmental lead intoxication is still encountered (7,8): occupational exposure (e.g., in painters and plumbers), environmental exposure (e.g., from remains of ancient mining with contamination of soil, dust in old homes, contamination of soil by leaded fuel), or other types of exposure such as leakage from lead-containing vessels or dishware (9), herbal medicine (10), or leaded paint.
Of more general concern may be the fact that the environmental lead burden has generally increased. This has been documented by studying Greenland ice, the lead content of which rose in 800 BC with the beginning of silver mining, rising further in the 18th century with the beginning of the industrial revolution, and rising dramatically after 1940 after the widespread introduction of leaded gasoline (11). This finding is paralleled by the observation that skeletal lead content is considerably increased in contemporaneous bone samples compared with prehistorical samples, e.g., ancient Peruvians (12).
There has been considerable concern about the effects of low level lead exposure and particularly the neurodevelopmental sequelae of childhood lead exposure (13).
Less spectacular, but of definite relevance to the nephrologist, are the potential sequelae of low-level lead exposure on renal function and BP (14,15).
It had been shown experimentally that lead causes progressive tubular atrophy and interstitial fibrosis (16), overexpression of angiotensin II (17), generation of oxidative stress (18), as well as salt retention, hypervolemia, and hypertension (19).
A number of cross-sectional or retrospective studies had also found that the age-related decline in renal function of the general population correlated with blood lead levels (20–22), although the retrospective design and the incomplete adjustment for confounders limit the validity of these studies.
It had also been noted that low-level environmental lead exposure is associated with more rapid progression of renal failure in patients with primary renal disease and no known exposure to lead (23), and the occurrence of gout de novo may be an indicator of a higher lead burden (24). The relation of lead burden to progression was confirmed in a prospective study, which documented that doubling of serum creatinine or end-stage renal disease was seen more frequently in patients with high-normal as opposed to low body lead burden (25) when assessed by the ethylene diaminotetraacetic acid (EDTA) mobilization test (24). The role of lead is made even more convincing by a further study in chronic kidney disease (CKD) patients: In a first observational phase a higher body lead burden was identified as a predictor of the rate of loss of GFR; in a subsequent phase patients with a high-normal body lead burden were randomized to receive at regular intervals placebo or infusions of calcium disodium EDTA. The authors observed improvement of renal function and slower progression in the patients receiving chelate therapy (26). Admittedly, because of the protean biochemical and cellular effects of EDTA, this observation does not definitely prove causality, i.e., that the benefit was the specific result of removal of lead (27), but it is the most compelling evidence we have so far for a role of lead in CKD progression.
Nevertheless, the renal community did not pay excessive attention to the potential role of low-level environmental lead exposure as a factor promoting progression.
It is against this background that the study of Muntner et al. (28) is a timely reminder. Although environmental exposure to lead has undoubtedly diminished as a result of legal actions banning the use of lead in gasoline, paint, and soldering of cans (29), low-level exposure persists. It is true that the National Health and Nutrition Examination Survey (NHANES) showed a decline in blood lead levels in the US (30), but on the other hand there is no evidence that a safe threshold exists. This consideration prompted the study by Munter and colleagues.
The cross-sectional surveys of NHANES III 1988 to 1994 and NHANES 1999 to 2002 were used to obtain measurements of venous whole blood lead concentrations and to measure serum creatinine levels with the modified Jaffe kinetic method calculating eGFR using a simplified MDRD (Modification of Diet in Renal Disease) equation.
The good news from a public health perspective is that, between 1988 and 1994 and between 1999 and 2002, the age-standardized geometric mean blood lead level decreased by 41%. This was found in each age group, men and women, and in different ethnicities. The frequency of blood lead levels in excess of 10 µg/dl had declined from 3.3% in 1988 to 1994 to 0.7% in 1999 to 2002. High lead levels were more frequent in the elderly, in men, and in minorities, and were associated after multivariable adjustment with cigarette smoking, alcohol consumption, high school education, and the presence of health insurance.
The bad news is that even after appropriate adjustment the prevalence of CKD was progressively higher at higher quartiles of blood lead levels: compared to the first quartile (blood lead < 1.06 µg/dl) with an odds ratio (OR) of 1.0, the OR in the second quartile (1.06 to 1.63 µg/dl) was 1.49, in the third quartile (1.63 to 2.47 µg/dl) it was 1.83, and in the fourth quartile (>2.47 µg/dl) it was 2.72 (P < 0.001). In contrast to previous studies there was no significant association with high BP except in the minorities.
Obviously lead exposure continues to be a problem in the low socioeconomic strata of American society. Although blood lead levels are admittedly not the optimal biomarker, more sophisticated measures such as mobilizable lead and bone lead are impractical for such large population studies. Undoubtedly lead has virtually lost its former role as the cause of renal failure. Nevertheless, the present study adds weight to the notion that apparently it is a factor aggravating progression—a role not on the radar screen of most nephrologists.
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