Mayer Brezis

Potential deleterious effect of furosemide in radiocontrast nephropathy

The purpose of the study was to determine the efficacy of furosemide in addition to intravenous fluids in the prevention of radiocontrast nephropathy. 18 patients, referred to a radiocontrast study, considered at risk because of preexisting renal insufficiency, were enrolled in a prospective, randomized, controlled trial, performed at the secondary care center of a 1,100-bed private university hospital. In addition to fluids, the treatment group received furosemide (mean dose 110 mg) intravenously 30 min prior to the injection of contrast material. The control group received fluids (mean 3 liters). Radiological studies were mostly angiographies performed with both ionic and non-ionic contrast material, at an average dose of 245 ml. Renal function significantly deteriorated in the group pretreated with furosemide (p < 0.005 by ANOVA), with a rise in serum creatinine from 145 +/- 13 to 182 +/- 16 mumol/l at 24 h, while no change occurred in the control group (from 141 +/- 6 to 142 +/- 7 mumol/l). Renal failure was associated with weight loss in the furosemide-treated group. Furosemide may be deleterious in the prevention of radiocontrast nephropathy.

Pathophysiology of radiocontrast nephropathy: a role for medullary hypoxia.

Recent experimental data underlies the role of hypoxic tubular injury in the pathophysiology of radiocontrast nephropathy. Although systemic transient hypoxemia, increased blood viscosity, and a leftward shift of the oxygen-hemoglobin dissociation curve may all contribute to intrarenal hypoxia, imbalance between oxygen demand and supply plays a major role in radiocontrast-induced outer medullary hypoxic damage. Low oxygen tension normally exists in this renal region, reflecting the precarious regional oxygen supply and a high local metabolic rate and oxygen requirement, resulting from active salt reabsorption by medullary thick ascending limbs of Henles loop. Radiologic contrast agents markedly aggravate outer medullary physiologic hypoxia. This results from enhanced metabolic activity and oxygen consumption (as a result of osmotic diuresis and increased salt delivery to the distal nephron) because the regional blood flow and the oxygen supply actually increase. The latter effect may result in part from the activation of various regulatory mediators of outer medullary blood flow to ensure maximal regional oxygen supply. Low-osmolar radiocontrast agents may be less nephrotoxic because of the smaller osmotic load and vasomotor alterations. Experimental radiocontrast-induced renal failure requires preconditioning of animals with various insults (for example, congestive heart failure, reduced renal mass, salt depletion, or inhibition of nitric oxide and prostaglandin synthesis). In all these perturbations, which resemble clinical conditions that predispose to contrast nephropathy, outer medullary hypoxic injury results from insufficiency or inactivation of mechanisms designed to preserve regional oxygen balance. This underlines the importance of identifying and ameliorating predisposing factors in the prevention of this iatrogenic disease.

Chronic cyclosporine-induced nephropathy in the rat : a medullary ray and inner stripe injury

Cyclosporine CsA nephrotoxicity was examined in male Sprague-Dawley rats with or without prior uninephrectomy, injected daily with 12.5 mg/kg CsA, and fed a salt-depleted or normal diet for 3-10 weeks. Control rats received the CsA vehicle. CsA induced a fall in creatinine clearance in salt-depleted rats, from 1.3 +/- 0.1 to 0.8 +/- 0.1 ml/min (P less than 0.001), and in normally fed rats from 1.8 +/- 0.2 to 1.0 +/- 0.2 ml/min (P less than 0.02). Vehicle treatment had no effect. The most striking morphologic changes were those of thick ascending limb cell atrophy with concomitant fibroblastic proliferation and collagen formation; these alterations were present in the inner stripe of the outer medulla and the medullary ray. The medullary-ray findings included S2-S3 degenerative changes as well and apparently correspond to the striped fibrosis described in human CsA nephropathy. The alterations were specific to the CsA group, progressive, and most severe in the salt-depleted, CsA-injected rats (on a scale of 0-4: 1.7 +/- 0.2 for medullary rays, and 2.0 +/- 0.2 for inner stripe, P less than 0.001). Morphologic changes predicted renal failure (r = 0.3, P less than 0.01 for cortical alterations, and r = 0.5, P less than 0.001 for medullary alterations). Prior uninephrectomy did not enhance these changes. Thus, chronic CsA administration impaired kidney function and induced morphologic alterations found in regions characterized by, and in nephron segments particularly vulnerable to, limited O2 availability. Salt depletion appears to accelerate the development of chronic CsA renal injury in the rat.

Protective Role of Furosemide and Saline in Radiocontrast-Induced Acute Renal Failure in the Rat

Acute renal failure (ARF) can be produced in rats by a combination of insults which augment transport activity and blunt regulatory mechanisms designed to maintain medullary oxygen sufficiency. This type of ARF is characterized by necrosis of medullary thick ascending limbs (mTALs). Uninephrectomized, salt-depleted rats injected with indomethacin (10 mg/kg) develop ARF following the administration of the radiocontrast agent, iothalamate. Furosemide (20 mg/kg, intravenous), administered immediately before the contrast material, attenuated the severity of ARF and reduced mTAL necrosis. Treatment with furosemide and/or normal saline prevented both the decline in renal function and mTAL injury. It is concluded that furosemide and normal saline may ameliorate the course of ARF if administered before radiocontrast.

Effects of ioversol versus iothalamate on endothelin release and radiocontrast nephropathy.

RATIONALE AND OBJECTIVES.Certain radiocontrast agents, including iothalamate, iohexol, and ioxaglate, release the renal vasoconstrictor peptide endothelin from vascular endothelium in a way that might contribute to radiocontrast nephropathy. The effects of the nonionic, low osmolar agent, ioversol, on endothelin release and renal function are investigated. METHODS.Effects of ioversol were compared with equiiodine doses of iothalamate when applied to cultured bovine aortic endothelial cells or injected into normal rats and rats preconditioned by uninephrectomy, salt depletion, and indomethacin (USIC) to develop radiocontrast nephropathy. RESULTS.In comparison with iothalamate, ioversol had a greatly reduced propensity to stimulate the release of endothelin, from cultured cells and when injected into anesthetized rats. Ioversol produced less renal vasoconstriction than did iothalamate, in control and in USIC rats, and the development of radiocontrast nephropathy, assessed by creatinine clearance and morphologic damage to the renal medulla, was largely avoided. CONCLUSIONS.These results strengthen the hypothesis that endothelin release induced by radiocontrast agents is correlated with their renal toxicity and therefore, may play a role in radiocontrast nephropathy.

Effect of Glycine and Hypertrophy on Renal Outer Medullary Hypoxic Injury in Ischemia Reflow and Contrast Nephropathy

Glycine preserves tubular cell integrity under hypoxic and toxic conditions in vitro. It also ameliorates cisplatin nephrotoxicity in vivo. We studied the effect of glycine on tubular necrosis from ischemia reflow and on inner stripe injury in an animal model of radiocontrast nephropathy. In all experiments, glycine (75 mg/100 g/h) increased tubular damage in the inner stripe. In the model of radiocontrast nephropathy, the percentage of medullary thick ascending limb (mTAL) necrosis at 24 hours increased from 22% +/- 6% to 41% +/- 9% or 55% +/- 7% with glycine infusion of 75 or 135 minutes, respectively (mean +/- SE, P less than 0.05, analysis of variance [ANOVA]). Renal function was not significantly affected. In rat kidneys subjected to ischemia reflow, mTAL injury following glycine increased from 1% +/- 0% to 12% +/- 6% (P less than 0.05) and from 8% +/- 5% to 49% +/- 8% (P less than 0.01) 24 hours after 30 minutes and 45 minutes ischemia, respectively. Tubular injury in the inner stripe was maximal in the deep interbundle zone, typical of hypoxic, rather than reperfusion, injury. Prior uninephrectomy increased inner stripe damage, but protected the proximal tubules. Both uninephrectomy and glycine infusion were found to contribute to mTAL necrosis. The infusion of glycine for 1 hour in intact rats increased renal blood flow by 44% and tripled urine volume (P less than 0.01). A parallel increase in glomerular filtration rate GFR; by 22% over 90 minutes) fell short of statistical significance.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II augments medullary hypoxia and predisposes to acute renal failure

The effects of angiotensin II (AII) upon medullary hypoxic injury and kidney function were investigated in vitro and in vivo. Synthetic AII added to perfusate of isolated rat kidneys reduced perfusion flow from 48 ± 2 ml min−1 (±SE) to 19 ± 1 (P < 0·001) without altering glomerular filtration rate (GFR), raising filtration fraction from 1% to 3% (P < 0·001). AII‐extended hypoxic injury to medullary thick ascending limbs (mTAL) from 66 ± 4% of tubules to 79 ± 3 (P < 0·05) in correlation with filtration fraction (r = 0·8, P < 0·001). Addition of indomethacin (10−4 mol 1−1) further extended medullary hypoxic damage to 89 ± 2% of mTAL (P < 0·001).

EXPERIMENTAL NEPHROTOXICITY OF THE RADIOCONTRAST AGENTS IOHEXOL, IOXAGLATE, AND IOTHALAMATE : AN IN VITRO AND IN VIVO STUDY

The authors compared the renal toxicity of the low osmolality radiocontrast agents, iohexol and ioxaglate, and the ionic agent, iothalamate, at equivalent iodine dose, using experimental models in vitro and in vivo. In isolated perfused rat kidneys, all agents induced comparable biphasic hemodynamic changes, associated with similar declines in glomerular filtration rate (GFR) and tubular necrosis. In two different in vivo models (using multiple insults combined with the administration of radiocontrast), iothalamate appeared to induce more severe morphologic injury. Despite similar nephrotoxic potential in vitro, the newer radiocontrast agents, iohexol and ioxaglate, cause in vivo less renal injury than iothalamate in the experimental models.

Mannitol Treatment for Acute Compartment Syndrome

Accessible online at: http://BioMedNet.com/karger Dear Sir, A 19-year-old generally healthy male soldier was diagnosed with heat stroke complicated by rhabdomyolysis and acute renal failure following a 90-km march in the Negev desert. On admission, blood pressure was 150/60 mm Hg, temperature 42°C, pulse rate 120, and respiratory rate 40. The patient exhibited delirium without meningeal or focal neurological signs. Laboratory results were as follows: sodium 123 mmol/l, potassium 4.9 mmol/l, creatinine 141 Ìmol/ l, urea 8.5 mmol/l, creatine kinase 6,957 U/l, and serum myoglobin 8,830 ng/ml (normal 0–120). Shortly after admission he developed generalized tonic-clonic seizures. Treatment included cooling, intravenous hypertonic saline, bicarbonate and diazepam. Approximately 12 h after admission his delirium resolved accompanied by improvement in renal function, electrolyte, myoglobin, and creatine kinase abnormalities. Two days later he complained of right anterior tibial pain, swelling, and limitation of movement. Physical examination showed localized tenderness and edema encompassing the right anterior tibial area associated with drop foot and pain exacerbation with passive movement. Abnormal conduction along the right common peroneal nerve was demonstrated on nerve conduction studies. No sensory deficit was elicited. An ultrasound duplex examination of the right lower extremity veins was normal. A diagnosis of anterior tibial compartment syndrome was made. Mannitol treatment was started, as illustrated in figure 1, with subsequent reduction Fig. 1. Effect of mannitol upon compartment syndrome. ▼

Medullary injury in the ageing rat kidney: functional–morphometric correlations

Urinary concentrating ability decreases with age in both humans and animals. This phenomenon is not yet clearly explained or corroborated by morphological findings, often focused on glomerular changes. In rats aged 5–22 months, semi‐quantitative and quantitative morphometric analysis was performed to score cortical and medullary changes. Morphological data were related to renal functional parameters. Three stages of tubulointerstitial injury were observed: minimal findings (stage I); mild fibrosis with atrophy and casts in medullary thick ascending limbs (stage II); extensive fibrosis and atrophy with large cast formation (stage III). Maximal urinary osmolality decreased in correlation with the stage of tubulointerstitial injury (r = −0.8, P < 0.0001), from 3735 mosmol L−1 at stage I to 2807 at stage II and 1567 at stage III. A dissociation was observed in the rate of progression with age between tubulointerstitial injury and glomerular sclerosis. Whereas sclerosis was observed in only 2–3% of glomeruli at both stages I and II of tubulointerstitial injury, damage to thick ascending limbs significantly increased from 2% of tubules at stage I to 11% at stage II (P < 0.002). At stage III, both extensive glomerular sclerosis (53%) and tubular injury (32%) were present. Uninephrectomy accelerated both morphological injury and functional compromise. We conclude that, in the early stages of renal ageing, injury to medullary tubules may be more prevalent than injury to glomeruli and could be responsible for the reduction in concentrating ability.