Biologic Markers in Urinary Toxicology (1995) / Chapter Skim
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2 TOXIC EXPOSURE OF THE URINARY TRACT
2 TOXIC EXPOSURE OF THE URINARY TRACT
Pages 23-52
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From page 23... ...
However, many forms of acute and chronic renal failure occur for unknown reasons, and the incidence of end-stage renal disease (ESRD) has mariced racial and regional differences, so nephrotoxicants might well present a serious health hazard.
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From page 24... ...
Such fine adjustment rarely occurs; the presence of a substantial amount of structural and functional damage might be impossible to determine precisely with standard tests of renal function. Finally, there are almost no epidemiologic data on the number of people who develop ESRD as a result of acute or chronic exposure to environmental nephrotoxicants.
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From page 25... ...
THE URINARY TRACT To understand the inherent limitations in the detection of early renal injury, we consider here several elements of normal renal function. In the sections that follow, we treat the mechanisms that lead to renal toxicity once exposure to a nephrotoxic substance occurs, the host factors that modify the response and the nature ant!
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From page 26... ...
The major extrarenal hormones aldosterone, vasopressin, and parathyroid hormone modulate the excretion of sodium, water, and phosphorus, respectively. Intrarenal hormones such as renin, prostaglandins, and kallilcreinsaffect renal blood flow, gIomerular fiItration, and tubular function.
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From page 27... ...
MECHAIlISMS OF RENAL TOXICITY Susceptibility to Injury The susceptibility of the kidney to toxic damage is related to various aspects of renal function. First, because blood flow to the kidney per gram of tissue is greater than that to most other organs, the total amount of toxicant delivered can be disproportionately high.
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From page 28... ...
Renal 7ubular-Cell Injury The most firmly established effects of nephrotoxicants are on renal tubular epithelial cells, in particular those of the proximal tubule. Indeed, toxicity might be limited to a specific cell type or to a particular organelle in the cell.
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From page 29... ...
Environmental agents can also have a primary effect on other antibody-antigen interactions, favoring the formation of complexes of such a size or composition that nephritogenic immune reactions occur. Apart from those considerations is the possibility that the Type IV mechanism, once thought to be of little importance in the development of renal injury, plays a role in some forms of interstitial disease.
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From page 30... ...
Apoptosis has been clemonstrated in oxidant injury to renal tubular epithelial cells, renal arterial stenosis, ischemia-reperfusion injury, hydronephrosis, polycystic lcidney disease, glomerulonephritis, lead nitrate injury, radiation nephropathy, and analgesic nephropathy. Further research on the mechanism of apoptosis might identify means of reversing this process and preventing atrophy.
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From page 31... ...
The gIomerular filtration rate also decreases with age, as does the ability to conserve sodium and the ability to produce maximally concentrated urine. With regard to the decrease in the glomerular filtration rate, it shouldd be noted that muscle mass and creatinine production also decrease, so the serum creatinine concentration remains constant; this is why the serum creatinine concentration cannot be used reliably as a measure of gIomerular function in the elderly.
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From page 32... ...
With prolonged maInutrition, although renal blood flow and glomerular filtration rate are thought to be normal, other physiologic measures might be adversely affected. In particular, abnormal responses to salt and wa 32 ter loads are reflected in a propensity for edema.
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From page 33... ...
, and age-related loss of renal function is faster in North American blacks than in whites (Boyle, 1970~. Acute Renal Disease A combination of insults, which by themselves are milct and individually well tolerated, can result in unexpectectly severe acute renal failure.
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From page 34... ...
~. Factors Associated with Progressive Loss of Renal Function A concern over the early detection of renal injury is appropriate and is height ened by the propensity of many forms of renal disease, once established, to progress relentlessly.
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From page 35... ...
Acute renal failure is often but not always accompanied by a reduction in urinary output to less than 500 cm3/day. Even if urinary flow is unaltered, inevitable compositional changes in the urine reflect parenchymal injury and tend to separate postischemic and nephrotoxic renal failure from reduction in renal function that occurs merely as a result of alterations in systemic hemodynam~cs.
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From page 36... ...
Cadmium-procluced injury to proximal tubular epithelial cells also results in the presence of aminoaciduria, enzymuria, and glycosuria. A decrease in the tubular reabsorption of phosphorus, an increase in the fractional excretion of uric acid, and an increase in cadmium excretion can be present.
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From page 37... ...
Lacking such a complication, the diagnosis might not be suspected until an abnormal urinary sediment is seen during routine examination. In patients with chronic renal failure, the progressive decline in the giomerular filtration rate is too slow and the cleviation from the steady-state condition too small to result in day-to-day changes in the serum creatinine or blood urea nitrogen concentration.
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From page 38... ...
Patients with primary glomerulonephritis and progressive 38 renal failure have heavier hydrocarbon exposure and worse renal impairment at presentation than those with stable or improving function (Yaqoob et al., 1993~. Moreover, patients with declining renal function were more lilcely to have continued occupational hy(lrocarbon exposure after the diagnosis of glomerulonephritis.
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From page 39... ...
Hypertension The association between kidney function and hypertension is based on both clinical and experimental observations reported over the last 150 years. Renal disease in the form of diabetic nephropathy, glomerulonephritis, interstitial nephritis, obstructive uropathy, polycystic lcidney disease, pyelonephritis, and vasculitis is the most common cause of secondary hypertension in humans.
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From page 40... ...
Today, a multitude of antihypertensive drugs are available, so virtually any hypertensive patient can be successfully treated without intolerable side effects of administered drugs. Long term studies are being conducted to evaluate the effectiveness of antihypertensive treatment in preserving renal function and preventing renal damage.
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From page 41... ...
Bladder cancer presents an interesting paradigm of the mechanism by which environmental or occupational toxicants can be initiators or promoters of cancer development or factors in its progression. Indeed, bladder cancer is highly correlated with occupational exposure to xenobiotics.
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From page 42... ...
a few are documented human carcinogens (Anonymous, 1990~. A list of compounds classified by IAlRC as human bladder carcinogens is contained in Table 2-2.
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From page 43... ...
It is possible that injury to these cells and exposure to urine trigger rapid growth. Bladder cancer, lilce many other cancers, occurs as a result of the interaction of genetic predisposition, occupational exposure, and a variety of cofactors.
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From page 44... ...
"Unless otherwise specified, relative risks. CCI = confidence interval; NS = not statistically significant; PMR = proportional mortality ratio; SMR = standardized mortality ratio; PCMR = proportional cancer mortality ratio.
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From page 45... ...
, but an increased incidence of renal cancer has also been reported among lead-exposed workers without statistically increased rates of chronic renal disease (Steeniand et al., 1992~. The role of renal leacl-binding proteins that both animals and humans mediate indivi(lual susceptibility to renal cancer from lead has been hypothesized (Fowler et al., 1994)
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From page 46... ...
The retinoblastoma gene binds to the adenoviral E1A oncogenic protein, thus inactivating it and allowing the cells to enter the cell cycle continuously. Both alleles at the retinoblastoma-gene locus on chromosome 13 are defective in retinoblas toma and other cancers, including prostatic and bladder cancer (DeCaprio et al., 1 989~.
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From page 47... ...
Unsubstantiated evidence that occupational exposure is a factor in renal carcinoma indicates that development of biologic markers for individual risk assessment might assist in identification. The increased incidence in males might be attributed to the hormonal milieu or to smoking, which has been more frequent in men in the past.
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From page 48... ...
The gland contains neuroenclocrine cells, basement-membrane cells, associated stromal cells, and, of great importance for the continued reproductive success of the species, functional epithelial cells. Any of the several cellular types can abort normal regulatory control and participate in a new program of tumorigenesis.
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From page 49... ...
Second, low concentrations of TGF are involved in a negative-feedback mechanism for the control of growth of prostatic stroma and epithelial cells. Obliteration of androgens-either surgically by orchiectomy or medically by use of a dihydroxysterone antagonist-results in prostatic-cell involution; this is followed by an increase in the prostatic growth factors, receptors, and cofactors, such as EGF and IGFs (Fiorelli et al., 1991a,b)
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From page 50... ...
signals; an example of the former is platelet-derived growth factor, and an example of the latter is TGF although, to complicate the picture, TGF can inhibit epithelial cells and stimulate fibroblasts. Receptor processing at the membrane is complex, involving a receptor, a transmembrane domain, and an intracellular domain; the latter procluces changes in cellular second messengers and modulates proteins, such as the ras p21 protein and other G proteins.
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From page 51... ...
Although the etiology of interstitial cystitis is not lcnown and there is no firm evidence that it results from xenobiotic exposure, the economic and human import of this condition merits attention and consideration of all possible causes. ANIMAL MODELS OF INTERSTITIAL CYSTITIS Several animal models of various aspects of interstitial cystitis have been reported recently.
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From page 52... ...
There are several well-establishe(1 associations between xenobiotic exposure and the development of chronic renal failure, as exemplified by exposures to lead and cadmium. The association of bladder cancer ant!
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