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Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
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2


Characterization of Renal Toxicity

In 2009, the National Research Council (NRC) Committee on Contaminated Drinking Water at Camp Lejeune reviewed the scientific evidence on the association between renal toxicity and exposure to the solvents found in the drinking water at Camp Lejeune. That committee began its work by reviewing a 2003 Institute of Medicine (IOM) report on solvent exposure and possible health effects, and it also reviewed new toxicologic and epidemiologic studies published from 2003 through 2008. The NRC report included an in-depth examination of both human and animal studies of the renal toxicity induced by exposure to two solvents: trichloroethylene (TCE) and perchloroethylene (1,1,2,2-tetrachloroethylene, or PCE). The few animal data available on the kidney toxicity of 1,2-dichloroethylene, 1,1-dichloroethylene, methylene chloride, benzene, and vinyl chloride were also considered. In general, these studies found that high-dose solvent exposures were necessary to produce acute renal effects and that the effects of such exposures were variable among species. The 2009 NRC report concluded that there was limited/suggestive evidence of an association between exposure to mixed solvents and renal toxicity.

Few new data have been published concerning the renal toxicity of the Camp Lejeune drinking water contaminants, other than TCE and PCE, since 2008. This chapter reviews new information, which has come primarily from animal and human toxicity studies with TCE and PCE, and it discusses that new information in the context of the previous conclusions concerning the renal toxicity of the contaminants.

The chapter begins with a summary of the previous assessments of the association between solvent exposure and renal toxicity. A description of possible mechanisms for this toxicity follows. The committee then reviews recent animal and epidemiologic studies of the associations between solvents and renal effects and it draws conclusions about the association between solvent exposure and specific renal effects. Finally, the chapter discusses the U.S. Department of Veterans Affairs (VA) clinical guidance and algorithm K for renal toxicity for the Camp Lejeune program and suggests a modified algorithm. Kidney cancer, one of the cancers covered by the Janey Ensminger Act (P.L. 112-154), is discussed in Chapter 4 in the section on “Cancers and Related Conditions.”

PREVIOUS ASSESSMENTS

This committee conducted an extensive literature search for new information published between 2008 and 2014 to help define the renal toxicity that might result from exposure to the solvents found in the drinking water at Camp Lejeune. The studies reviewed in the previous IOM and NRC reports were not reassessed but rather were used to provide the appropriate background for interpreting new evidence on the renal toxicity of the Camp

Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
×

Lejeune drinking water contaminants to humans. The 2003 IOM and 2009 NRC committees’ evaluations of and conclusions about human renal toxicity based on the available epidemiological studies are summarized below.

2003 IOM Report

In 2003, the IOM released a report that assessed the long-term health consequences that might occur in veterans of the 1990–1991 Gulf War who may have been exposed to solvents during their deployment to the Persian Gulf. Many of the studies reviewed were of occupational exposures to a variety of solvents and solvent mixtures. Studies of the effects of short-term and long-term solvent exposure on renal function below the threshold of clinical disease provided some support for an association between exposure to high concentrations of solvents and acute tubular necrosis. A series of case-control studies that evaluated chronic glomerulonephritis, an immune-mediated disease, in relation to nonspecific solvent exposure provided inconsistent evidence of an association; however, several reasonably strong studies showed dose–response gradients. One large study (Steenland and Palu, 1999) reported a reasonably strong association between an exposure to solvents used for cleaning and degreasing and end-stage renal disease (ESRD), and the study by Porro et al. (1992) reported an association between “degreasing agents” and ESRD. The IOM study concluded that there was limited/suggestive evidence of an association between exposure to solvent mixtures and chronic glomerulonephritis (see Chapter 1, Box 1-1 for a description of the categories of association). It noted that although several studies had addressed the effect of solvent exposure on indicators of renal function, these studies used various magnitudes of exposure and the quality of the exposure assessments varied. None of the studies addressed TCE or PCE directly.

2009 NRC Report

The 2009 NRC report did not identify any new studies of solvent exposure and glomerulonephritis. A large, occupational cohort study of aircraft-maintenance employees did find a nearly two-fold increase in the odds of ESRD (OR [odds ratio] = 1.91, 95% CI [confidence interval] 1.08–3.38) among workers exposed to TCE but not among those exposed to PCE (Radican et al., 2006). A study of renal function in electronics workers who were exposed to TCE (mean concentration 32 ppm [parts per million]; range 0.5–252 ppm) showed decrements in renal function in the clinically normal range. While a small effect on renal function was observed, these effects were not related to extent of exposure and led the authors to conclude that there was no evidence of kidney toxicity under the exposure conditions studied (Green et al., 2004).

The report concluded “that there continues to be limited/suggestive evidence of an association between mixed solvent exposure and chronic glomerulonephritis but inadequate/insufficient evidence to determine whether an association exists specifically between TCE or PCE and chronic glomerulonephritis” (NRC, 2009, p. 158). The report further concluded that animal studies had found high concentrations of TCE and PCE to result in renal tubular cell damage, and that epidemiologic studies provided limited/suggestive evidence of an association between chronic high-level exposures to solvents (but not chronic low-level exposure) and acute renal tubular necrosis (NRC, 2009).

Mechanism of Nephrotoxicity

TCE has been assessed in lifetime carcinogenic bioassays in rats and mice by the National Cancer Institute (NCI, 1976) and the National Toxicology Program (NTP, 1988, 1990); the NTP has also assessed the lifetime carcinogenicity of PCE (NTP, 1986). Those studies found kidney cancer in both species, which stimulated research to characterize the toxicity and potential mechanisms, or modes of action, for both chemicals. Several epidemiological studies were undertaken to characterize the effects on humans of occupational exposures to these chemicals.

The effects of TCE and PCE on kidney function have both been studied in animal models, primarily rodents. Such studies allow measurements of multiple aspects of renal function with varying exposure durations and help elucidate the production of TCE and PCE metabolites. In vitro studies are particularly useful for assessing potential toxic pathways, including the generation of reactive metabolites, the disruption of cellular energy processes, and the

Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
×

production of oxidative stress. These studies have shown that acute exposure to high doses of TCE causes tubular necrosis localized to the proximal sections of the nephron, which results in impaired reabsorption of solutes, including glucose, protein, and water (Chakrabarti and Tuchweber, 1988). Intrarenal control mechanisms constrict blood flow to the glomeruli of the damaged tubules, decreasing the glomerular filtration rate (GFR). Chronic (2-year) and subchronic (13-week) exposures to high doses of either TCE or PCE (generally 300–1000 mg/kg/d) cause kidney pathology, reported as cytomegaly, karyomegaly, and necrosis of the tubular epithelium, particularly in the inner cortical tubular area. In these studies, pathology was determined immediately after exposure.

Studies using experimental animals and cultured cells (including human) have shown that, as with other solvents, neither TCE nor PCE itself is toxic, but rather each is metabolized to chemically reactive intermediates. TCE and PCE are different from many toxicants in that both oxidative and conjugation reactions are required to produce toxic metabolites. A simplified pathway for TCE metabolism is shown in Figure 2-1.

TCE metabolism was reviewed in Lash et al. (2000) and NRC (2006). TCE is metabolized by cytochrome P450 to oxidative metabolites and, by conjugation, to glutathione (see Figure 2-1). The oxidative metabolites are chloral, chloral hydrate, trichloroethanol (TCOH), and trichloroacetic acid (TCA). The glutathione conjugate, dichlorovinyl glutathione (DCVG), is metabolized by γ-glutamyltranspeptidase (γGTP) to dichlorovinylcysteine (DCVC). DCVC has multiple fates. It can be further metabolized to dichlorovinylthiol (DCVT) by cysteine conjugate β-lyase; to dichlorovinylcysteine sulfoxide (DCVCS) by flavin-containing monooxygenase 3 (FMO3), or by N-acetyltransferase (NAT) to N-acetyl dichlorovinylcysteine (NAcDCVC) and then to N-acetyl dichlorovinylcysteine sulfoxide (NAcDCVCS) by cytochrome P4503A (CYP3A). The toxicity of all these metabolites to kidney

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FIGURE 2-1 Metabolic pathway for TCE.
SOURCE: Adapted from NRC, 2006.

Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
×

cells has been well established in both in vivo and in vitro studies; however, DCVC and its subsequent metabolites account for the majority of the renal toxicity.

PCE metabolism was also reviewed by NRC (2010). PCE is metabolized by the same routes as TCE to reactive and toxic metabolites, specifically trichlorovinylcysteine (TCVC), N-acetyl trichlorovinylcysteine (NAcTCVC), and then N-acetyl trichlorovinylcysteine sulfoxide (NAcTCVCS).

REVIEW OF RECENT ANIMAL STUDIES

Metabolism

Recent research indicates that different TCE metabolites are selective for different subregions within the rat kidney, and therefore different segments of the nephron. Irving and colleagues (2013) administered specific metabolites to rats. They reported that NAcDCVC increases urine output somewhat (0.32 dL, compared with 0.20 dL for saline control), whereas DCVCS causes a dramatic drop in urine volume (0.05 dL, 2 animals were anuric). Histopathologically, the N-acetylated derivatives damage the corticomedullary junction whereas DCVCS targets the outer cortex. Massive glycosuria was observed with the N-acetylated derivatives of DCVC and DCVCS (approximately150 mg/24 hr, on average) whereas glycosuria was only slightly increased (10 mg/24 hr) following DCVC. These results indicate that different metabolites of TCE have relative selectivity for different segments of the proximal tubule.

Individual variation in the abundance of the enzymes involved in TCE metabolism—or the presence of other agents such as drugs that alter metabolism by these enzymes—would be expected to result in different patterns of tubular toxicity. Human variation in these enzymes is known to occur. FMO3 is a polymorphic drug-metabolizing enzyme found in the liver and, to a lesser extent, in the kidneys (Yamazaki and Shimizu, 2013).

NAT exists as both cytosolic and microsomal forms and both metabolize nephrotoxic halogenated cysteine conjugates (Altuntas and Kharasch, 2002). Rats, mice, and humans each have two forms of cytosolic NAT, denoted as 1 and 2 (National Center for Biotechnology Information Entrez Gene database). The substrates metabolized by each isoform are different in each species, so that a given substrate may be metabolized by, for example, isoform 1 in rats and isoform 2 in humans. In humans, NAT1 and NAT2 both have rapid phenotypes, and each is associated with an increased risk of renal toxicity upon exposure to drugs or other chemicals (Walker et al., 2009). NAT8 is the microsomal form. Recent studies have associated a mutation in NAT8 (rs 13538) with decreased kidney function in a resequencing study focused on NAT8 (Juhanson et al., 2008) and in genome-wide association studies (Kottgen et al., 2010). Veiga-da-Cunha and colleagues (2010) used HEK293T cells to express NAT8 and rs 13538 mutant (phenylalanine replaced by serine at position 143). They reported decreased activity, due to decreased expression, of the mutated enzyme. Altuntas and Kharasach (2002) reported N-acetylation of cysteine conjugates by both cytosolic and microsomal fractions of human kidney to be highly variable, across twenty samples, and to differ with substrate. Thus, the signs and symptoms of renal toxicity will vary depending on an individual’s metabolic pattern, which implies that a finding in rats may or may not reliably predict acetylation in humans.

Excretion

Using an in vitro model of renal tubular epithelium (cell culture) with cells expressing Mrp2, Tsirulnikov et al. (2010) showed that NAcDCVC undergoes basolateral to apical transport. Mrp2 is a member of the adenosine triphosphate (ATP)-binding cassette class of active transporters that perform the secretion of intracellular NAcDCVC across the apical membrane into the tubular urine, that is, the second step in the movement of TCE metabolites from blood to urine. Mrp2 transported most of the NAcDCVC (Tsirulnikov et al., 2010). Human MRP2 is known to have genetic variants (see, for example, OMIM, 2014), and it is subject to induction by substrates such as rifampin, dexamethasone, and phenobarbital and to inhibition by substrates such as vinca alkaloids, anthracyclines, and cisplatin. Thus, individuals may differ in their ability to transport intracellular NAcDCVC out of the cell. Individuals with less capacity to transport NAcDCVC out of the cell will have greater exposure to this toxic agent, resulting in increased toxicity to the tubular cells.

Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
×

Guinea Pig Sensitization Model

Yu and co-workers (2012) assessed the renal effects of a TCE challenge in guinea pigs that had been previously sensitized to TCE (via injection of Freund’s complete adjuvant and TCE). This experiment was motivated by the observation of an “occupational medicamentosa-like dermatitis” in Chinese workers that was sometimes fatal. The TCE challenge to sensitized guinea pigs (those that exhibited allergic reactions to intradermal injection of TCE) produced histopathological lesions and an impairment of renal function (increased blood urea nitrogen, increased excretion of proteins in urine, including beta-2-microglobulin, alkaline aminopeptidase, and gammaglutamyl transpeptidase). Histopathological tubular changes included the necrosis of cells, the loss of the brush border, mitochondrial damage (vacuolar swelling), and the fusion of foot processes in the glomeruli. These results suggest that in the presence of Freund’s complete adjuvant exposure to TCE can lead to an immune response upon subsequent challenge. Freund’s complete adjuvant is an emulsion of antigen in mineral oil, and it is used because it is effective in stimulating cell-mediated immunity, thus enhancing the biological response so that events occur more frequently and can be better studied. The applicability of this research model to human exposure via water consumption, without the stimulating effect of Freund’s adjuvant is not known. Thus, TCE’s glomerular effects are unknown.

Conclusions from Animal Studies

The metabolic pathways of TCE and of PCE have been well characterized in animal models. Humans have similar enzymes and, in general, produce the same metabolites as in the animal models. Some of these enzymes, however, have polymorphisms in the human population. The secretion of metabolites into urine is mediated by MRP2, known to be affected by drugs in common use (see earlier section on “Excretion”). The variability in the processes involved in producing and eliminating the TCE and PCE metabolites would be expected to result in variability in the magnitude of responses after exposure to these chemicals. Furthermore, each reactive metabolite has a different toxicity so the observed effects would also be expected to vary between and among humans and animals. Although studies support the existence of this intra- and inter-species variation in the toxic response to exposure to TCE or PCE, the variation is not sufficiently well characterized to allow easy extrapolation from animals to humans and vice versa. Finally, in spite of the number of animal studies on the renal toxicity of TCE and PCE, neither the 2009 NRC committee nor this committee identified any animal studies with exposures similar to those that occurred at Camp Lejeune, that is, that assessed long-term renal effects following short-term exposure to the solvents as either immature or adult animals.

REVIEW OF RECENT EPIDEMIOLOGICAL STUDIES

In reviewing the recent literature related to the renal effects of the drinking water contaminants at Camp Lejeune, the committee identified three new epidemiological studies on TCE and one on PCE. In addition one review assessed the updated Integrated Risk Information System (IRIS) report on the human health risk assessment of TCE, prepared by the U.S. Environmental Protection Agency (EPA). These studies are reviewed below.

Calvert et al. (2011) examined the incidence of and mortality from ESRD in workers exposed to PCE only or PCE plus other solvents (most likely Stoddard’s solvent). This study was the third mortality update (as of 1977) on a cohort of 1,704 dry-cleaning workers in four U.S. cities (Chicago, Detroit, New York, and San Francisco/Oakland). Although ESRD from all causes in the entire cohort was nonsignificantly elevated (standardized incidence ratio [SIR] 1.34, 95% CI 0.90–1.91), hypertensive ESRD morbidity was elevated in the entire cohort (SIR = 1.98, 95% CI 1.11–3.27) as well as those employed in PCE-only dry-cleaning establishments for greater than 5 years (SIR = 3.39, 95% CI 1.10–7.92). In addition, the underlying cause-of-death standardized mortality ratio (SMR) for PCE-only workers for acute glomerulonephritis, nephrotoxic syndrome, and acute renal failure was nonsignificantly increased (two deaths; SMR = 2.60, 95% CI 0.31–9.39), while mortality from chronic and unspecified nephritis, renal failure, and other renal sclerosis in the entire cohort was decreased nonsignificantly (two deaths, SMR = 0.42, 95% CI 0.05–1.52). The authors concluded that the increased risk for hypertensive ESRD among workers

Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
×

with PCE-only exposure, particularly for those workers with a longer duration of solvent exposure, supported the conclusion that PCE exposure, rather than lifestyle or socioeconomic factors, was associated with renal toxicity.

Earlier assessments of TCE had suggested that renal toxicity in humans might occur at high exposure levels on the basis of increased urinary protein excretion (NRC, 2009). Using a panel of novel sensitive nephrotoxicity markers, Vermeulen et al. (2012) examined renal toxicity in 80 Chinese factory workers exposed to TCE at concentrations below the permissible exposure level of 100 ppm (8-hour time-weighted average) set by the U.S. Occupational Safety and Health Administration (OSHA). The six factories selected for study used TCE in manufacturing processes but had no detectable levels of benzene, styrene, ethylene oxide, formaldehyde, or epichlorohydrin, and they had low to negligible levels of methylene chloride, chloroform, and PCE. The control set of factories from the clothing and food industries did not use TCE. For exposed workers, the average length of TCE exposure was 2 years, and the mean exposure concentration was 22 ppm; the 45 control workers had been employed an average of 2.3 years in their factories but had negligible TCE exposure. The authors found that one sensitive urinary protein biomarker of proximal tubular injury—kidney injury molecule-1 (KIM-1)—was significantly increased (p = 0.01) in exposed workers compared with controls. A second urinary biomarker—Pi-glutathione S transferase (Pi-GST)—was increased in exposed workers, but the increase did not reach statistical significance (p = 0.09). Pi-GST was considered to be a borderline indicator of renal toxicity. Other urinary markers of renal function (creatinine, alpha-GST, N-acetyl-β-D-glucosaminidase [NAG]) did not differ between TCE-exposed and unexposed workers. The authors concluded that renal toxicity, as evidenced by elevated KIM-1 and possibly Pi-GST urinary excretion, could occur at TCE concentrations below the OSHA exposure limit.

In 2011, EPA published an updated IRIS report on the human health risk assessment of TCE (EPA, 2011). The IRIS report contained a detailed review of literature concerning health risks associated with TCE exposure. It was noted that workers highly exposed to TCE exhibited evidence of tubular and possible glomerular damage, based on the presence of increased urinary excretion of α1-microglobulin, NAG, Pi-GST, or total protein. However, not all exposed groups exhibited the same patterns or degree of urinary protein excretion, and some workers were exposed to mixed solvents rather than TCE alone. These observations provide further support for the conclusions on proteinuria in the 2009 NRC report.

Bove et al. (2014a) reported on the causes of mortality for marine and Navy personnel who began service between 1975 and 1985 and were stationed at Camp Lejeune (n = 154,932) or at Camp Pendleton, California (n = 154,969) during those years; the mortality follow-up period was 1979–2008. The authors reported on mortality due both to kidney disease and to cancer. There were fewer deaths than expected from kidney diseases for both the Camp Lejeune cohort (SMR = 0.50, 95% CI 0.35–0.68) and the Camp Pendleton cohort (SMR = 0.52, 95% CI 0.37–0.71) compared with U.S. mortality rates, while there were more deaths than expected from kidney cancer in the Camp Lejeune cohort (SMR = 1.16, 95% CI 0.84–1.57), but fewer than expected in the Camp Pendleton cohort (SMR = 0.89, 95% CI 0.61–1.25). The risk of dying from kidney disease was the same for Camp Lejeune as for Camp Pendleton (hazard ratio [HR] = 1.00, 95% CI 0.63–1.63), and the Camp Lejeune cohort had a nonsignificant increased risk of dying from kidney cancer (HR = 1.35, 95% CI 0.84–2.16). The results suggest that the Camp Lejeune cohort did not have an increased risk of chronic renal toxicity leading to death or an increased risk of kidney cancer. The authors noted that 97% of the Camp Lejeune cohort was under the age of 55 and only 6% of the cohort had died of any cause by the end of the study; they cautioned that long-term follow up would be needed for a comprehensive assessment of the effects of exposure to the contaminated water at Camp Lejeune.

In a separate report, Bove et al. (2014b) compared the mortality of 4,647 civilian workers at Camp Lejeune during 1973–1985 with 4,690 nonexposed workers at Camp Pendleton during the same time; the mortality followup period was again 1979–2008. No significant kidney effects were found. There were fewer deaths than expected from kidney diseases in both the Camp Lejeune (SMR = 0.78, 95% CI 0.34–1.54) and Camp Pendleton (SMR = 0.50, 95% CI 0.22–1.00) cohorts compared with U.S. mortality rates. Deaths from kidney diseases were not associated with cumulative or average exposure to the drinking water contaminants. Deaths from kidney cancer were higher than normal (SMR = 1.30, 95% CI 0.52–2.67) at Camp Lejeune but not at Camp Pendleton (SMR = 0.82, 95% CI 0.30–1.80). The hazard ratios for deaths due to kidney diseases and kidney cancer at Camp Lejeune and Camp Pendleton both had nonsignificant effects (kidney diseases: 1.23, 95% CI 0.39–3.87; kidney cancer: 1.92, 95% CI 0.58–6.34). The authors noted that the study’s limitations included the small numbers for most causes

Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
×

of death (e.g., each camp had seven deaths from kidney disease) and a potential exposure misclassification bias. Because only 14% of the Camp Lejeune and 18.5% of the Camp Pendleton subjects had died by the end of the study, the authors called for long-term follow-up studies to provide a comprehensive assessment of the effect of drinking water exposures at Camp Lejeune.

Summary of Human Studies

Calvert et al. (2011) found an increased risk of morbidity from solvent-induced hypertensive ESRD in workers with increasing years of exposure, but the number of workers with this outcome was small. The researchers failed to find any increase in mortality in the solvent-exposed workers from chronic and unspecified renal nephritis, renal failure, or other renal sclerosis. Studies by Bove et al. (2014a,b) did not demonstrate any increase in mortality from kidney disease in marine or Navy personnel or in civilian workers at Camp Lejeune, although longer-term follow up is needed. Nevertheless, these results do not support the existence of an increased risk of chronic renal toxicity leading to death in the military and civilian Camp Lejeune cohorts.

CONCLUSIONS FROM ANIMAL AND HUMAN STUDIES

Based on the evidence reviewed here and in previous reports (IOM, 2003; NRC, 2009) there appears to be strong evidence for an association between acute exposure to high levels of TCE or PCE and acute tubular toxicity in both rodents and humans, although humans metabolize these chemicals to a lesser extent and are thus more resistant to adverse effects. There is accumulating evidence that acute renal injury, as might occur soon after exposure, significantly increases the incidence of chronic kidney disease (CKD) many years later (Chawla et al., 2014). Such an effect could occur even if the acute injury were subclinical and thus not detected.

The evidence for an association of TCE or PCE with CKD is less clear, although there does appear to be an association between exposure to high levels of these solvents and ESRD (Calvert et al., 2011; Radican et al., 2006; Steenland et al., 1990). However, the documented levels of PCE and TCE in the drinking water at Camp Lejeune were much lower than those in the animal and human studies discussed here, and it is expected that the exposure duration (median of 36 months in the military cohort; see Bove et al., 2014a) would have been much shorter as well. There is no evidence for an increased incidence of CKD in those who served at Camp Lejeune during the time of the contaminated drinking water.

In humans, exposure to TCE and PCE occurs in complex settings where other etiologies of kidney disease may coexist. The present literature in humans does not permit one to distinguish whether TCE and PCE cause renal disease on their own, or interact with other causes of renal disease, enhancing their toxicity. Although the committee notes that kidney disease, including chronic glomerulonephritis and tubular necrosis, in those who resided at Camp Lejeune will likely be due to causes other than TCE or PCE exposure, it is not possible to rule out a role for solvent exposure. This is a common problem when seeking causes of kidney disease where there is no specific diagnostic histopathology. That kind of renal damage, should it occur, would present clinically as CKD, which describes any type of permanent kidney damage that may progress to ESRD (American Kidney Fund, 2012).

DISCUSSION OF GUIDANCE AND ALGORITHM

In this section, the committee assesses the VA clinical guidance and algorithm K on renal toxicity. The following discussion pertains to the proposed changes in the text of the guidance, the algorithm, and the annotations to the algorithm. Figure 2-2 shows a revised algorithm K that incorporates these suggested changes.

The VA’s clinical guidance specifies that CKD, defined as a chronic decrease in kidney function, or proteinuria should be the clinical endpoints of concern for renal toxicity resulting from solvent exposure at Camp Lejeune. The committee finds CKD to be an appropriate endpoint to represent possible kidney damage potentially caused by exposure to contaminated water at Camp Lejeune.

The guidance asks first whether the patient has evidence of renal injury, when the onset of CKD occurred, and if the patient has other comorbid conditions. The clinician then assesses whether it is probable that the CKD

Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
×

img

FIGURE 2-2 Revised algorithm K.

Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
×

is attributable to a known cause other than solvent toxicity. If there is no evidence for another cause, CKD could be due to toxic exposure. The committee notes, however, that there are several reasons why there may be a lack of evidence of acute renal toxicity at the time of exposure: Renal toxicity did not occur; it did occur but the patient was asymptomatic and therefore there was no indication that the necessary laboratory tests should be conducted; or the tests were conducted but were not sensitive enough to detect mild disease. Thus, the committee finds that a patient should not be ineligible for the VA program because of a lack of documented evidence of kidney disease during or shortly after residence at Camp Lejeune.

If there is no history of acute renal injury around the time of residence at Camp Lejeune, the guidance asks clinicians to consider whether the patient has diabetes mellitus or hypertension (common causes of CKD) or other conditions associated with CKD (such as diabetic neuropathy, obstructive uropathy, hypertensive nephrosclerosis, sickle cell kidney disease, HIV-associated nephropathy, and drug-induced kidney disease) (see Table 2-1). If evidence for such conditions exists and the patient’s course is consistent with those conditions (that is, the “renal disease is as likely as not associated” with those conditions), CKD should be attributed to those entities and the patient would not be accepted into the Camp Lejeune program. Conversely, if no other causes of CKD are probable, patients would be accepted into the program. Similarly, the guidance states that if the patient’s disease is “atypical, in that the progression of their kidney disease is faster than expected, then exacerbation by TCE, PCE or other organic solvents in the contaminated water should be considered” and the patient should be admitted to the program.

Algorithm K addresses renal disease and reflects slightly different and more detailed information than the text in the guidance (see Table 2-1). The first step in the original algorithm directs a clinician to identify data for kidney damage such as eGFR (estimated glomerular filtration rate), serum creatinine, or other indicators of kidney

ANNOTATIONS FOR REVISED ALGORITHM K:
K1—Diagnosis of kidney disease: (1) Applicant has a history of renal toxicity or kidney disease concurrent with Camp Lejeune residence or shortly after the time of possible exposure to contaminated water at Camp Lejeune, or (2) applicant has evidence of chronic kidney disease (CKD).
The two most common causes of CKD are diabetes and hypertension. In most instances, it will be possible to identify the most likely cause of CKD using history, physical examination, laboratory testing, and imaging tests. A kidney biopsy should be considered for patients with nephrotic range proteinuria (urine to creatinine ratio > 3.5), particularly in the absence of diabetes, to determine the histopathology of the kidney disease. The decision to perform a kidney biopsy should be based on the need to provide optimal care to the patient.
K2—Applicant is still administratively eligible for the Camp Lejeune program but does not have evidence of renal toxicity as a covered condition.
K3—Applicant has a history of renal toxicity or kidney disease concurrent with Camp Lejeune residence or shortly after the time of possible exposure to contaminated water at Camp Lejeune. If this cannot be attributed to other known causes of kidney disease, it should be presumed that any subsequent kidney disease may be related to toxin exposure at Camp Lejeune, and the patient should be accepted into the program.
K4—Applicant has no history of renal toxicity or kidney disease concurrent with Camp Lejeune residence or around the time of possible exposure to contaminated water at Camp Lejeune. Applicant has evidence of kidney disease due to long-standing diabetes or refractory hypertension, which are common causes of kidney failure and are not related to exposure to the contaminants in the water at Camp Lejeune. Applicant does not have a covered condition and is not eligible for coverage by the Camp Lejeune program at this time.
K5—Applicant has no history of renal toxicity or kidney disease concurrent with Camp Lejeune residence or around the time of possible exposure to contaminated water at Camp Lejeune. Applicant has evidence of kidney disease consistent with a secondary condition that is not related to exposure to the contaminants in the water at Camp Lejeune. Current kidney disease is due to another cause other than exposure to contaminated water at Camp Lejeune. Applicant does not have a covered condition and is not eligible for coverage by the Camp Lejeune program at this time.
K6 [New]—Applicant has CKD of uncertain etiology, possibly related to exposure to contaminated water at Camp Lejeune. Applicant has a covered condition, renal toxicity, and is accepted into the Camp Lejeune program.

Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
×

TABLE 2-1 Possible Exclusionary Causes of CKD as Given in the Clinical Guidance, the Original Algorithm K, and the Revised Algorithm K

Guidance Text Algorithm (original) Algorithm (revised)

Diabetes

Diabetes

Diabetic kidney disease

Hypertension/hypertensive nephrosclerosis

Hypertension

Hypertensive kidney disease

Obstructive uropathy

Urinary tract obstruction

Urinary tract obstruction

Sickle cell kidney disease

Sickle cell kidney disease

HIV-associated nephropathy

HIV-associated nephropathy

Drug-induced kidney disease

Acute tubular necrosis occurring in the setting of hypotension or nephrotoxic agents, such as radiocontrast, antibiotics, or chemotherapy drugs

Acute tubular necrosis occurring in the setting of hypotension, rhabdomyolysis, or nephrotoxic agents (e.g., chemotherapeutics, IV radiocontrast media, immunosuppressives)

Acute interstitial nephritis, often due to drugs such as NSAIDs or antibiotics

Volume depletion, severe heart failure

Interstitial renal disease

Allergic, analgesic agents

Prerenal disease: volume depletion, congestive heart failure, liver failure

Atheroembolic disease

Glomerulonephritis

IgA nephropathy, post-infection, membranous, membranoproliferative, associated with systemic diseases

Immune-mediated renal disease

Polycystic kidney disease

Vasculitis

Light chain disease

NOTE: HIV = human immunodeficiency virus; IgA = immunoglobulin A; IV = intravenous; NSAIDs = nonsteroidal anti-inflammatory drugs.

failure in the patient’s medical record; these indicators are not specified in the original guidance. The committee finds that this step is unnecessary and therefore that it could be deleted from the algorithm.

The second step in the original algorithm (Box 2 in the guidance and Annotation K1)—and the first step in the revised algorithm—specifies that kidney disease be diagnosed on the basis of an eGFR of less than 60 mL/minute or the presence of proteinuria. The second step and annotation K3 in the revised algorithm specify that if evidence of renal toxicity or kidney disease was present while the patient resided at Camp Lejeune or shortly thereafter, and is probably not due to known causes such as diabetes and hypertension, CKD should be assumed to be due to contaminated drinking water exposure.

In the original algorithm, clinicians are expected to determine the cause of CKD on the basis of “history, physical examination, laboratory testing, and imaging tests.” In some cases a kidney biopsy may be indicated, such as for nephrotic range proteinuria in the absence of diabetes. However, the committee notes that a kidney biopsy should only be performed when medically indicated for the care of the patient and although it may inform adjudication decisions, it should never be performed solely for the purpose of determining whether the patient should be accepted to the Camp Lejeune program (see revised annotation K1 for algorithm K, Figure 2-2).

The third and fourth steps in the original algorithm K ask the clinician to rule out common causes of CKD (hypertension or diabetes) or other causes (such as volume depletion, severe heart failure, urinary tract obstruction, acute tubular necrosis occurring in the setting of hypotension or nephrotoxic agents, or acute interstitial nephritis often due to drugs) that differ from the text in the guidance (see Table 2-1). Furthermore, the annotations that accompany algorithm K provide much more detail on the clinical signs that may be indicative of other possible causes for CKD than does the text in the guidance. The committee finds that the information presented in the guidance and information presented in the original algorithm K are not parallel.

Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
×

Similar to previous recommendations made by the NRC (2009), this committee concludes that patients with CKD should have a thorough evaluation. If the evaluation shows that the patient’s kidney disease is compatible with another etiology such as diabetic nephropathy or hypertensive nephrosclerosis, the conclusion should be reached that solvent exposure at Camp Lejeune was not the causative agent. If the evaluation does not suggest another etiology, or if the clinical course is atypical for the identified etiology, the patient should be given the benefit of doubt and the conclusion reached that a toxicant exposure at Camp Lejeune may have played a role in the development of CKD. Therefore, the committee finds that the VA’s general approach to the guidance and algorithm regarding renal toxicity is appropriate.

Neither the guidance nor the original algorithm K includes other indicators of acute renal injury. Abnormal urinalysis results, serum creatinine, or blood urea nitrogen around the time of exposure and documented in medical records may help a clinician establish that acute effects occurred at or around the time of exposure that later resulted or contributed to CKD. The committee finds that these types of tests, conducted while a patient was in residence at Camp Lejeune, should be considered when determining whether the patient’s CKD is related to exposure to contaminated drinking water while at Camp Lejeune. The differences between the guidance text and algorithm K may lead to some confusion and inconsistent conclusions about whether or not a patient’s CKD is related to his or her time at Camp Lejeune.

Therefore, the committee recommends that VA consider modifying the guidance and algorithm K—as suggested in revised algorithm K—to indicate that patients presenting with defined reductions in GFR or proteinuria AND who had abnormal renal function tests or urinalysis of unknown etiology while residing at Camp Lejeune should be accepted to the program. The committee also recommends that VA consider accepting into the Camp Lejeune program patients with chronic kidney disease, but without evidence of kidney damage during or around the time of residence at Camp Lejeune, if there are no other more likely causes of their kidney disease.

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Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
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Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
×
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Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
×
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Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
×
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Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
×
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Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
×
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Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
×
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Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
×
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Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
×
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Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
×
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Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
×
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Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
×
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Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
×
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Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
×
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Suggested Citation:"2 Characterization of Renal Toxicity." Institute of Medicine. 2015. Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation. Washington, DC: The National Academies Press. doi: 10.17226/18991.
×
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U.S. Marine Corps Base Camp Lejeune, located in eastern North Carolina, is a large installation that covers 156,000 acres and is home at any given time to a population of about 170,000 active-duty personnel, family members, retirees, and civilian employees living on base or in the surrounding community. Between 1957 and 1987, the ground water at Camp Lejeune was inadvertently contaminated with chemicals, primarily industrial solvents that are now known to cause cancer and other health problems. In 1980, drinking water contaminants, primarily trichloroethylene (TCE) and perchloroethylene (PCE), as well as other solvents, were first detected at Camp Lejeune in treated drinking water. The contaminated wells were closed in 1987. In 1989, the U.S. Environmental Protection Agency placed Camp Lejeune on the National Priorities List, also known as Superfund. It is estimated that between 500,000 and 1,000,000 people may have used the contaminated water and many of them continue to have concerns about the long-term effects that might result from that exposure.

In 2012 Congress passed the Honoring America's Veterans and Caring for Camp Lejeune Families Act. The law provides health benefits to veterans and family members who have any of 15 health outcomes associated with exposure to TCE, PCE, or solvent mixtures. At the request of the Veteran's Administration, Review of the VA Guidance for the Health Conditions Identified by the Camp Lejeune Legislation reviews the latest scientific literature to ensure that the clinical guidance provided for the 15 covered medical conditions is scientifically sound. This report also describes the medical conditions that result from renal toxicity due to solvent exposures and characterizes neurobehavioral effects as mandated for coverage in the law.

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