Cast nephropathy

Viscosity of THP solutions increases markedly when the sodium chloride concentration is > 60 mM. Increasing the concentration of calcium and/.or a reduction in pH also increase viscosity and may account for the involvement of THP in the pathogenesis of cast nephropathy and tubulointerstitial nephritis. THP appears to have an inhibitory effect on urinary crystal arrgegation [154] and may play a role in preventing renal stone formation [155]. In some humans with calcium oxalate nephrolithiasis, a molecular abnormality of THP has been detected [156]. Other studies showed decreased urinary levels of THP in patients with nephrolithiasis [157, 158]. A relative deficiency in THP has been associated with impaired inhibition of crystal adhesion to renal epithelial cells instone formers [159]. 

Koss MN, Pirani CL, Osserman EF. Experimental Bence Jones cast nephropathy. Lah Invest 1976 34 579-91. 

Smolens P, Venkatachalam M, Stein JH. Myeloma kidney cast nephropathy in a rat model of multiple myeloma. Kidney Int 1983 24 192-204. 

Smith KD, Wrenshall LE, Nicosia RF, Pichler R, Marsh CL, Alpers CE, Polissar N, Davis CL. Delayed graft function and cast nephropathy associated with tacrolimus plus tapamycin use. J Am Soc Nephrol (2003) 14, 1037 5. 

Chronic exposure of both rats and mice resulted in tubular nephropathy in both males and females. In rats, lesions were present in 45-66% of the males when they were sacrificed at 110 weeks after receiving 212 and 423 mg/kg/day hexachloroethane for 66 weeks of a 78-week exposure period (NTP 1977 Weisburger 1977). The renal lesions were characterized by hyperchromic regenerative epithelium, necrosis, interstitial nephritis, fibrosis, focal pyelonephritis, tubular ectasis, and hyaline casts. Lesions were also present in females but had a lower incidence (18% and 59%) for the two dose groups. Two-year exposures of male rats to much lower doses (10 and 20 mg/kg/day) resulted in similar effects on the kidneys (NTP 1989). Minimal to mild nephropathy was present in females for doses of 80 and 160 mg/kg/day. Over 90% of the male and female mice exposed to 590 and 1,179 mg/kg/day hexachloroethane for 78 weeks displayed tubular nephropathy when sacrificed at 90 weeks (NTP 1977 Weisburger 1977). Regenerative tubular epithelium was visible and degeneration of the tubular epithelium occurred at the junction of the cortex and the medulla. Hyaline casts were present in the tubules, and fibrosis, calcium deposition, and inflammatory cells were noted in the kidney tissues. 

Animal data suggest that renal and liver effects may occur in humans exposed to high doses of hexachloroethane. Kidney and liver effects are not specific to hexachloroethane. Lesions of the kidney (nephropathy, linear mineralization, and hyperplasia) were reported at 10 mg/kg/day or greater in male rats (NTP 1989). Urinalysis also revealed granular and cellular casts in rats exposed to hexachloroethane (47 mg/kg/day or greater) for 13 weeks (NTP 1989). Because other compounds cause similar effects and because some of these effects are unique to male rats, they are not valuable as biomarkers for human hexachloroethane exposure. 

Renal effects have been observed in both male and female rats in a chronic-duration oral study. Male Fischer 344 rats exposed to 1,4-dichlorobenzene at 150 and 300 mg/kg/day for 2 years exhibited nephropathy, epithelial hyperplasia of the renal pelvis, mineralization of the collecting tubules in the renal medulla, and focal hyperplasia of the tubular epithelium. Each of these effects was associated with hyalin droplet formation. There were also increased incidences of nephropathy in female Fischer 344 rats dosed with 1,4-dichlorobenzene at 300 and 600 mg/kg/day. Histopathologically, the nephropathy was characterized by degeneration and regeneration of the tubular epithelium, tubular dilatation with attenuation and atrophy of the epithelium, granular casts in the tubules of the outer stripe of the medulla, thickening of the basement membranes, and minimal accumulation of interstitial collagen (NTP 1987). 

Loop agents can increase the rate of urine flow and enhance K+ excretion in acute renal failure. However, they do not shorten the duration of renal failure. If a large pigment load has precipitated acute renal failure (or threatens to), loop agents may help flush out intratubular casts and ameliorate intratubular obstruction. On the other hand, loop agents can theoretically worsen cast formation in myeloma and light chain nephropathy. 

A 45-year-old man with insulin-dependent diabetes associated with nephropathy, neuropathy, and retinopathy was given dextran 40 (25ml/hour) after orthopedic surgery (20). His urine output fell from 2 to 3 liters on postoperative day, 1 0 ml/day on day 2, and his creatinine clearance fell from 54 to 32ml/min-ute. There were many casts in the urine. Dextran was withdrawn, but his creatinine clearance fell to 12 ml/minute on day 5. On day 6 a large hematoma in the rectus sheath was drained, followed by plasmapheresis (to remove dextran) and hemodialysis. Over the next 24 hours, his urine output increased to 2.21/day... 

Acute exposure to unleaded gasoline and a variety of light hydrocarbons present in gasoline produces a nephropathy in male rats characterized by (1) an excessive accumulation of protein (hyaline droplets) in epithelial cells of proximal tubule, (2) accumulation of casts at the corticomedullary junction, and (3) evidence of mild tubular regeneration. This nephropathy only occurs in male rats female rats and mice do not show any renal pathology. A number of chemicals present in unleaded petrol when tested alone have been shown to produce nephropathy and, in particular 2,2,4-trimethylpentane and decalin have been used as model compounds. Certain other industrial chemicals (1,4-dichlorobenzene and isophorone), natural products (o-limonene), and pharmaceuticals (levamisole) also produce this male-rat-specific nephropathy. Chronic exposure of male rats to unleaded petrol, 1,4-dichlorobenzene, isophorone, or o-limonene ultimately leads to the induction of a low incidence of renal adenomas and carcinomas. 

This MRL was based on a NOAEL of 0.23 mg Hg/kg/day for renal effects in rats administered mercuric chloride 5 days a week for 6 months (Dieter et al. 1992 NTP 1993). This dose was duration-adjusted for a 5 day/week exposure and divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability). Increased absolute and relative kidney weights were observed in rats exposed to 0.46 mg Hg/kg/day, the next higher treatment level. At higher doses, an increased incidence of nephropathy (described as foci of tubular regeneration, thickened tubular basement membrane, and scattered dilated tubules containing hyaline casts) was observed. Renal toxicity is a... 

In addition to heavy proteinuria, urinalysis often reveals lipiduria and oval fat bodies. Microhematuria is seen in fewer than 25% of patients, and gross hematuria and red cell casts are rare. In idiopathic membranous nephropathy, the serum complement concentrations are normal. Low levels of complement should alert one to search for secondary causes, such as lupus, hepatitis B infection, or an alterna-... 

Pathologically and clinically, analgesic-associated nephropathy is primarily a tubular-interstitial disease. The initial lesions appear to involve the renal papillae whith focal areas of necrosis, followed by scarring of the medullary interstitium and later by the changes of chronic interstitial nephritis in the cortex. The pathognomonic lesion is sclerosis of the lower urinary tract capillaries (Mithatsch et al. 1979). Mild to moderate pyuria (1.0 g/day) is usually present, but no red cell casts are found in the sediment. 

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