Iodinated contrast media-induced nephropathy: pathophysiology, clinical aspects and prevention

Summary— Administration of iodinated contrast media (CM) for radiographic purposes is a preoccupying cause of acute renal failure. This review of the literature deals with what is known about physiopathology, clinical course, risk factors and prevention. Factors involved in the pathophysiology of CM-induced acute renal failure are vasoconstriction, direct tubular cell injury and tubular obstruction by casts. In the case of pre-existing renal hypoperfusion, CM may disturb the complex interaction between factors which modulate renal haemodynamics by increasing vasoconstrictor factors, notably endothelin peptides. The renal medulla, a zone characterized by a high metabolic activity and a low oxygen tension, may be a specific target for CM-induced effects. CM-induced nephropathy (CMN) is essentially observed in patients with one or more associated risk factors (chronic renal failure, dehydration, diabetes mellitus with impaired renal function, multiple myeloma, large CM volume, intra-arterial rather than intravenous route, etc). There is much debate as to whether newer low osmolar CM (LOCM) are better tolerated than conventional high osmolar CM (HOCM). Most of the animal studies clearly demonstrate the advantages of LOCM over HOCM. Clinical literature is far more confusing, although some recent studies and one meta-analysis demonstrate that LOCM are better tolerated in patients with impaired renal function. The low number of comparative clinical trials carried out in high risk patients, wide variability in CMN definitions, limited number of patients enrolled and inadequacy of various selected endpoints may explain difficulties experienced in demonstrating this advantage. Furthermore, while hydration is correctly maintained during clinical trials, this is not always true in clinical practice. Such a discrepancy could lead to underestimation of the potential advantage of LOCM over HOCM. Effective prevention should associate the correct hydration of patients, identification and, when possible, optimal correction of risk factors, avoidance of repeated CM injections within a short period of time and temporary disruption of treatment with other nephrotoxic drugs (non steroidal antiinflammatory drugs, aminoglycosides, etc).     

Late presentation and development of nephrocalcinosis in primary hyperoxaluria

A case of primary hyperoxaluria type 1 with complete deficiency of alanine:glyoxalate aminotransferase that first manifested at the age of 59 with irreversible acute on chronic renal failure is reported. Nephrocalcinosis, initially absent, developed rapidly after renal failure evolved. The possible role of hypovolaemia and contrast nephrotoxicity in precipitating the clinical onset is discussed. Primary hyperoxaluria should be considered in patients of any age presenting with unexplained renal failure, and appropriate systemic pathology of oxalosis. (Aust NZ J Med 1992; 22: 48–50.)     

Isolation, Biological and Antigenic Properties of a Specific Toxin Formed in Thermally Altered Mouse Skin

Abstract. A lipid-protein complex, which has a lethal effect on recipient animals, was isolated from mouse skin exposed to controlled thermal energy. A new isolation procedure was developed, which takes advantage of the toxic activity present in thermally modified skin, to trace the fate of the active compound. A bioassay was designed for this purpose by injecting Thorotrast into the recipient animals. The toxic lipid-protein complex and the corresponding derivative from native skin were shown to have the same lipid (40%) and protein (60%) content. The lipid moieties of both derivatives were made up of six different lipid classes. The toxic compound differed from the non-toxic material only by its larger size and higher density. Equivalent results were obtained on samples isolated, after the removal of surface lipids and soluble cell constituents, from the donor skins prior to the application of thermal energy i.e. processing "skin residues". The biological activity was shown to reside in the apoprotein while the lipid moiety contributes to the toxic activity to a certain extent. The results suggest that the toxic compound is a polymeric form produced by thermal energy from a naturally occurring precursor. The toxin has a specific antigenic property protecting mice after active and passive immunotherapy against a lethal bum injury in vivo. This suggests strongly that the toxic compound is an etiological factor responsible for the high mortality after severe burns. It is significant that, if scalding was applied to the same extent as the dry heat burns in vivo , the injured animals survived. This was interpreted to support the hypothesis of a specific mechanism being responsible for toxin formation. The experimental results suggest that a specific therapy for the "late mortality" after severe human burns might be possible.     

Adriamycin causes hyperlipemia as a consequence of nephrotoxicity

Adriamycin induced hyperlipemia: its features and mechanism(s) in rats were investigated. Massive hyperlipemia occurred 14–21 days after a single dose of adriamycin (7.5 mg/kg i.v.). All lipoprotein fractions were affected. Mild but significant changes in tissues were observed (liver and intestine triglycerides and kidney phospholipids were reduced). Lipid synthesis and secretion was decreased, as shown by the Triton WR1339 test 7 days after treatment, but subsequently returned to normal. Mitochondrial oxidation of long-chain fatty acids was markedly reduced in kidney, and a slight reduction was also observed in heart. Lipoprotein lipase activity was reduced in adipose tissue. These results suggest that adriamycin hyperlipemia is due to reduced lipid storage and utilization. Carnitine did not counteract hyperlipemia and proteinuria after adriamycin. Analogies to hyperlipemia following puromycin aminonucleoside-induced nephrotoxicity are discussed.     

No Effect of Low-dose 1α-Hydroxycholecalciferol Treatment on the Renal Function Deterioration Rate in Long-term Uraemic Rabbits

Abstract: The development of renal function during 18 weeks of oral treatment with 1α-hydroxycholecalciferol was investigated in rabbits with surgically induced chronic renal failure. Renal function was evaluated by the serum creatinine concentration and the ⁵¹Cr-EDTA clearance measured by the single injection technique. Three groups of uraemic rabbits on three different diets with high, medium and low content of calcium and phosphate were studied. The treatment with 0.02 μg/kg/day of 1α-hydroxycholecalciferol did not induce statistically significant changes in the serum concentrations of calcium or phosphate. Compared to placebo 1α-hydroxycholecalciferol did not increase the deterioration rate of renal function in any of the three groups.     

Comparison of the specificity and sensitivity of traditional methods for assessment of nephrotoxicity in the rat with metabonomic and proteomic methodologies

There is currently a great deal of scientific interest and debate concerning the possible advantages that proteomic and metabonomic technologies might have over traditional biomarkers of toxicity (blood and urine chemistry, histopathology). Numerous papers have been published that make impressive claims concerning potential applications for these novel technologies, however there appears to be little hard evidence in the literature of their advantages over the traditional techniques for assessing toxicity. The aim of this review was to evaluate the relative sensitivity and specificity of proteomic and metabonomic techniques, compared with traditional techniques, for assessing xenobiotic-induced nephrotoxicity. A review of studies was performed where both one of the novel methods as well as traditional techniques were used for assessment of xenobiotic-induced nephrotoxicity. There was no consistent evidence from the literature that the novel methodologies were any more sensitive than the traditional methods for assessing nephrotoxicity. This could be due to the relatively small number of studies available for review (n = 13), the fact that generally these studies were not aimed at determining relative sensitivity or specificity and may not be the case with other target organs, such as the liver. However, it was clear that the novel methodologies were able to discriminate between the effects caused by different toxicants. There was evidence both that this discrimination was on the basis of different mechanisms of toxicity and on the basis of different locations of nephrotoxic lesion. A great deal of validation work is necessary before these techniques could gain full acceptance by regulatory authorities, and it is unclear whether their use in anything other than non-regulatory, mechanistic studies is likely to become widespread.     

Effect of endogenous hydrogen sulfide inhibition on structural and functional renal disturbances induced by gentamicin

Animal models of gentamicin nephrotoxicity present acute tubular necrosis associated with inflammation, which can contribute to intensify the renal damage. Hydrogen sulfide (H₂S) is a signaling molecule involved in inflammation. We evaluated the effect of DL-propargylglycine (PAG), an inhibitor of endogenous H₂S formation, on the renal damage induced by gentamicin. Male Wistar rats (N = 8) were injected with 40 mg/kg gentamicin (im) twice a day for 9 days, some of them also received PAG (N = 8, 10 mg·kg⁻¹·day⁻¹, ip). Control rats (N = 6) were treated with saline or PAG only (N = 4). Twenty-four-hour urine samples were collected one day after the end of these treatments, blood samples were collected, the animals were sacrificed, and the kidneys were removed for quantification of H₂S formation and histological and immunohistochemical studies. Gentamicin-treated rats presented higher sodium and potassium fractional excretion, increased plasma creatinine [4.06 (3.00; 5.87) mg%] and urea levels, a greater number of macrophages/monocytes, and a higher score for tubular interstitial lesions [3.50 (3.00; 4.00)] in the renal cortex. These changes were associated with increased H₂S formation in the kidneys from gentamicin-treated rats (230.60 ± 38.62 µg·mg protein⁻¹·h⁻¹) compared to control (21.12 ± 1.63) and PAG (11.44 ± 3.08). Treatment with PAG reduced this increase (171.60 ± 18.34), the disturbances in plasma creatinine levels [2.20 (1.92; 4.60) mg%], macrophage infiltration, and score for tubular interstitial lesions [2.00 (2.00; 3.00)]. However, PAG did not interfere with the increase in fractional sodium excretion provoked by gentamicin. The protective effect of PAG on gentamicin nephrotoxicity was related, at least in part, to decreased H₂S formation.     

Cyclosporin therapy in patients with Alport syndrome

Alport syndrome (AS) is a hereditary disorder of type IV collagen characterized by the association of progressive hematuric nephritis and sensorineural hearing loss. An increase in proteinuria is linked with progressive renal failure. Preliminary data have shown that cyclosporin therapy reduces proteinuria, thereby suggesting that it may also slow the progression of AS nephropathy. We treated nine AS patients manifesting proteinuria >1 g/m²/day and a glomerular filtration rate (GFR) >50 ml/min/1.73 m² with cyclosporin for at least 6 months. At the end of this 6-month period, mean proteinuria had decreased from 2±1.06 to 0.65±0.73 g/day, and mean albuminemia had increased from 29±5.2 to 35±6.5 g/l. Mean inulin clearance had decreased from 102±29 to 74±16.3 ml/min/1.73 m². Cyclosporin treatment was stopped in four patients because of inefficacy or adverse effects and continued in the remaining five patients for an additional 14–42 months. At the end of this second treatment period, control renal biopsies revealed significant lesions of cyclosporin nephrotoxicity in three patients. Based on these results we conclude that while cyclosporin therapy can decrease proteinuria in most patients with AS, it may be associated with nephrotoxicity, thereby precluding its long-term use.     

Renal Transport of Adefovir,Cidofovir, and Tenofovir by SLC22A Family Members (hOAT1, hOAT3, and hOCT2)

Purpose The nephrotoxicity of the nucleotide antivirals adefovir, cidofovir and tenofovir is considered to depend on the renal tubular transport of them. Although it is known that the antivirals are substrates of the human renal organic anion transporter hOAT1 (SLC22A6), there is no information available on other organic ion transporters. The aim of the present study was to investigate whether the other renal organic anion transporter hOAT3 (SLC22A8) and organic cation transporter hOCT2 (SLC22A2) transport the antivirals. Materials and Methods Uptake experiments were performed using HEK293 cells transfected with cDNA of the organic ion transporters. Results The uptake of adefovir, cidofovir and tenofovir in monolayers stably expressing hOAT3 increased time-dependently, compared with control. Probenecid, a typical inhibitor of organic anion transporters, completely inhibited their transport. The amounts of the antivirals taken up by hOAT3 were much lower than those by hOAT1. The transient expression of hOCT2 did not increase uptake of the antivirals. Conclusion These results indicate that adefovir, cidofovir and tenofovir are substrates of hOAT3 as well as hOAT1, but that quantitatively hOAT1 is the major renal transporter for these drugs.