Effect of initiating biologics compared to intensifying conventional DMARDs on clinical and MRI outcomes in established rheumatoid arthritis patients in clinical remission: Secondary analyses of the IMAGINE-RA trial.

OBJECTIVES: To compare the effect of treat-to-target-based escalations in conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologics on clinical disease activity and magnetic resonance imaging (MRI) inflammation in a rheumatoid arthritis (RA) cohort in clinical remission. METHOD: One-hundred patients with established RA, Disease Activity Score based on 28-joint count-C-reactive protein (DAS28-CRP) < 3.2, and no swollen joints (hereafter referred to as 'in clinical remission') who received csDMARDs underwent clinical evaluation and MRI of the wrist and second to fifth metacarpophalangeal joints every 4 months. They followed a 2 year MRI treatment strategy targeting DAS28-CRP ≤ 3.2, no swollen joints, and absence of MRI osteitis, with predefined algorithmic treatment escalation: first: increase in csDMARDs; second: adding a biologic; third: switch biologic. MRI osteitis and Health Assessment Questionnaire (HAQ) (co-primary outcomes) and MRI combined inflammation and Simplified Disease Activity Index (SDAI) (key secondary outcomes) were assessed 4 months after treatment change and expressed as estimates of group differences. Statistical analyses were based on the intention-to-treat population analysed using repeated-measures mixed models. RESULTS: Escalation to first biologic compared to csDMARD escalation more effectively reduced MRI osteitis (difference between least squares means 1.8, 95% confidence interval 1.0-2.6), HAQ score (0.08, 0.03-0.1), MRI combined inflammation (2.5, 0.9-4.1), and SDAI scores (2.7, 1.9-3.5). CONCLUSIONS: Treat-to-target-based treatment escalations to biologics compared to escalation in csDMARDs more effectively improved MRI inflammation, physical function, and clinical disease activity in patients with established RA in clinical remission. Treatment escalation in RA patients in clinical remission reduces clinical and MRI-assessed disease activity. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01656278.

MRI bone oedema is the strongest predictor of subsequent radiographic progression in early rheumatoid arthritis. Results from a 2-year randomised controlled trial (CIMESTRA).

OBJECTIVE: To identify predictors of radiographic progression in a 2-year randomised, double-blind, clinical study (CIMESTRA) of patients with early rheumatoid arthritis (RA). METHODS: Patients with early RA (n = 130) were treated with methotrexate, intra-articular betamethasone and ciclosporin/placebo-ciclosporin. Baseline magnetic resonance imaging (MRI) of the wrist (wrist-only group, n = 130) or MRI of wrist and metacarpophalangeal (MCP) joints (wrist+MCP group, n = 89) (OMERACT RAMRIS), x-ray examination of hands, wrists and forefeet (Sharp/van der Heijde Score (TSS)), Disease Activity Score (DAS28), anti-cyclic citrullinated peptide antibodies (anti-CCP), HLA-DRB1-shared epitope (SE) and smoking status were assessed. Multiple regression analysis was performed with delta-TSS (0-2 years) as dependent variable and baseline DAS28, TSS, MRI bone oedema score, MRI synovitis score, MRI erosion score, anti-CCP, smoking, SE, age and gender as explanatory variables. RESULTS: Baseline values: median DAS28 5.6 (range 2.4-8.0); anti-CCP positive 61%; radiographic erosions 56%. At 2 years: DAS28 2.0 (0.5-5.7), in DAS remission: 56%, radiographic progression 26% (wrist+MCP group, similar for wrist-only group). MRI bone oedema score was the only independent predictor of delta-TSS (wrist+MCP group: coefficient = 0.75 (95% CI 0.55 to 0.94), p<0.001; wrist-only group: coefficient = 0.59 (95% CI 0.40 to 0.77), p<0.001). Bone oedema score explained 41% of the variation in the progression of TSS (wrist+MCP group), 25% in wrist-only group (Pearson's r = 0.64 and r = 0.50, respectively). Results were confirmed by sensitivity analyses. CONCLUSION: In a randomised controlled trial aiming at remission in patients with early RA, baseline RAMRIS MRI bone oedema score of MCP and wrist joints (and of wrist only) was the strongest independent predictor of radiographic progression in hands, wrists and forefeet after 2 years. MRI synovitis score, MRI erosion score, DAS28, anti-CCP, SE, smoking, age and gender were not independent risk factors. TRIAL REGISTRATION NUMBER: NCT00209859.

Nephrogenic systemic fibrosis: more questions and some answers.

Nephrogenic systemic fibrosis (NSF) is a fibrosing disorder that may develop in patients who have advanced reduction in renal function. A causal relation between gadolinium (Gd(3+))-based contrast agents (Gd-CA) and NSF is probable and is supported by the accumulating data in the literature. From those data, the prevalence of NSF is seen to be significantly higher after exposure to gadodiamide than any other gadolinium-based agent. Gd-CA are either linear or macrocyclic chelates and are available as ionic or non-ionic preparations. The molecular structure, whether cyclic or linear, and the ionicity determine the stability of Gd-CA. Linear chelates are flexible open chains which do not offer a strong binding to Gd(3+). In contrast, the macrocyclic chelates offer a strong binding to Gd(3+) by the virtue of being pre-organised rigid rings of almost optimal size to cage the Gd(3+) atom. Non-ionic preparations are also less stable in comparison to the ionic ones, as the binding between Gd(3+) and the negatively charged carboxyl groups is stronger than that with amides or alcohol in the non-ionic preparations. According to stability constants and kinetic measurements, the most stable Gd-CA is the ionic-macrocyclic chelate Gd-DOTA and the least stable agents are the non-ionic linear chelates gadodiamide and gadoversetamide. The stability of Gd-CA seems to be an important factor in the pathogenesis of NSF. Gd-CA of low stability are likely to undergo transmetallation and release free Gd ions that may deposit in tissues and attract circulating fibrocytes to initiate the process of fibrosis. There have been no cases of NSF reported in the peer-reviewed literature after the exclusive use of the stable macrocyclic Gd-CA. This minireview covers the clinical and pathological features of NSF and updates the current understanding of the pathophysiology of this condition.

Clinical manifestation of gadodiamide-related nephrogenic systemic fibrosis.

AIMS: To further characterize the clinical signs and symptoms of nephrogenic systemic fibrosis, a new and serious disease affecting renal failure patients and caused by some Gd-containing contrast agents, including gadodiamide. MATERIAL: 22 cases of gadodiamide-related nephrogenic systemic fibrosis followed at the nephrology department of Copenhagen University Hospital Herlev. METHOD: Retrospective cohort study based on medical records, personal interviews and physical examinations. RESULTS: Typical first signs of the disease were skin discoloration, induration and warmth, itching, constant pain and other neuropathic symptoms localized to the lower legs. First sign appeared in a median of 14 days (range 0 â 53 days) after gadodiamide exposure. Associated early symptoms included sleeplessness and transient, diffuse hair loss. The predominant late symptom was symmetrical skin stiffness of extremities with or without restricted joint motion. Ten of 22 patients (45, 95% CI: 27 â 66%) were severely disabled due to contractures on the average of 29 months after being exposed to gadodiamide. Four patients died (18, 95% CI: 6 â 41). Patients perceived that intensive physiotherapy was effective in limiting disabling contractures. CONCLUSIONS: Signs and symptoms of nephrogenic systemic fibrosis vary over time and between patients. The disease leads to severe disability in a significant proportion of affected patients. Intensive physiotherapy may limit the development of contractures.

Contrast-induced nephropathy: the wheel has turned 360 degrees.

Contrast-induced nephropathy (CIN) has been a hot topic during the last 5 years due its association with increased morbidity and mortality. CIN is an important complication, particularly in patients with advanced chronic kidney disease (CKD) associated with diabetes mellitus. Methods to diminish the incidence of CIN have been highly contentious. They include choice of contrast, pharmacologic manipulation, and volume expansion. The pathophysiology of this complication remains uncertain, but reduction in renal blood flow and direct toxicity of tubular cells has been implicated. More than 900 publications under the heading CIN have been published during the last 5 years. Fewer than 5% of these publications are randomized prospective controlled studies. In spite of the large number of reports on CIN, very little has been changed. The use of the smallest possible dose of low- or iso-osmolar contrast media, volume expansion, stopping nephrotoxic drugs, and avoiding repeat contrast injections within 48 hours remain the most effective approach to reduce the risk of CIN.

Unenhanced computed tomography in acute renal colic reduces cost outside radiology department.

BACKGROUND: Unenhanced multidetector computed tomography (UMDCT) is well established as the procedure of choice for radiologic evaluation of patients with renal colic. The procedure has both clinical and financial consequences for departments of surgery and radiology. However, the financial effect outside the radiology department is poorly elucidated. PURPOSE: To evaluate the financial consequences outside of the radiology department, a retrospective study comparing the ward occupation of patients examined with UMDCT to that of intravenous urography (IVU) was performed. MATERIAL AND METHODS: A total of 594 consecutive patients were admitted for renal colic during two 6-month periods. One hundred seventy-three consecutive patients were examined with IVU in 2000 and 421 with UMDCT in 2005. The only difference between the two groups was the imaging procedure. The duration of hospital stay and pathology findings were registered. RESULTS: In 50% of the patients undergoing UMDCT, a stone was found; a stone was found or suspected in 40% of patients undergoing IVU. Patients undergoing IVU stayed significantly longer in the ward than patients examined by UMDCT (P<0.0001). The new procedure (UMDCT) saved the hospital USD 265,000 every 6 months compared to the use of IVU. CONCLUSION: Use of UMDCT compared to IVU in patients with renal colic leads to cost savings outside the radiology department.

1H-MRS measured ectopic fat in liver and muscle is associated with the metabolic syndrome in Danish girls but not in boys with overweight and obesity.

BACKGROUND: The metabolic syndrome (MetS) is a complication to overweight and obesity, which can be observed already in childhood. Ectopic lipid accumulation in muscle and liver has been shown to associate with the development of insulin resistance and dyslipidemia. Thus, the interaction between MetS and ectopic fat may offer clinical relevance. OBJECTIVES: To investigate the prevalence of MetS, or components hereof, and ectopic fat accumulation in liver and skeletal muscle tissue in children, as well as interactions between these. METHODS: Two-hundred-and-sixteen children and adolescents (95 boys) with overweight/obesity were investigated, as well as 47 controls (22 boys) with normal weight. The assessments included anthropometry, fasting blood biochemistry and blood pressure measurements. Liver and muscle lipid contents were assessed by proton magnetic resonance spectroscopy. RESULTS: We observed an odds ratio in girls with overweight/obesity of 12.2 (95% confidence interval: [3.8; 49.0]) for exhibiting MetS when hepatic steatosis was present, whereas no association was observed in boys with overweight/obesity (odds ratio 0.7 [0.2; 2.7]). The odds ratio of exhibiting MetS in the presence of muscular steatosis was 3.5 [1.4; 9.5] in girls with overweight/obesity and 1.0 [0.2; 5.6] in boys with overweight/obesity. Similar results were seen for girls with overweight/obesity exhibiting concurrent hepatic and muscular steatoses. CONCLUSION: Hepatic and muscular steatoses were associated with MetS among girls, but not among boys with overweight/obesity.

Monitoring of pancreas-graft perfusion by radionuclide and digital subtraction angiography.

The vascularity of a kidney transplant can be evaluated by intravenous radionuclide angiography. A normal functioning transplant should have an isotope histogram with a well-defined peak. Accordingly, a transplanted pancreas may be evaluated in the same way. By intravenous digital subtraction angiography and small amounts of contrast medium, arterial and venous structures can be visualized without catheterization of the arterial system. Five patients had combined kidney and pancreas transplantation. Intravenous angiography with 99mTc-pertechnetate was performed three times a week for the first 5 postoperative wk. Digital subtraction angiography with an intravenous bolus of 80 ml of a low-osmolar nonionic contrast medium (iopamidol) was performed late in the postoperative course or when severe impairment of pancreas-graft perfusion was discovered by radionuclide angiography. One patient had two episodes and three patients one episode of rejection of both kidney and pancreas. Impairment of the pancreas-graft perfusion always preceded or was associated with deterioration of the graft function. In all patients, digital subtraction angiography demonstrated the graft vessels in sufficient detail. No thrombotic complications were observed. We conclude that these two methods can be used for monitoring the kidney and pancreas-graft perfusion. The methods may be of great value, especially in the early postoperative period, when problems with organ function are frequent and early intervention is essential.

The limited value of routine chest X-ray in the follow-up of stage II breast cancer.

In 280 patients with stage II breast cancer, chest X-ray was performed at 6 and 12 months and yearly thereafter to the 6th year or until recurrence, another cancer was detected, the patient refused further follow-up or died. Among 1289 scheduled chest X-rays, malignant changes were found in 20 patients, of which only 3 had pulmonary symptoms. In a further 14 patients malignant changes were suspected, but follow-up examinations could not prove malignancy. 26 patients presented within 12 months after the last scheduled X-ray with pulmonary symptoms and a work-up chest X-ray revealed malignant changes. Thus, in only 1.3% of the scheduled X-rays were unsuspected malignant changes diagnosed. Median survival of patients with malignant chest X-rays found at scheduled controls versus between scheduled controls did not differ significantly (P = 0.26). It is concluded that routine chest X-ray is not indicated in patients with stage II breast cancer.

Report of the Radionuclides in Nephrourology Committee on renal clearance.

The need for simple and accurate methods to measure renal function is self-evident. This need increases as techniques for intervention become available. The demand for evaluation of individual kidney function has increased with its role in the diagnosis and follow-up of unilateral renal disease and in decision making for conservative or surgical treatment based on residual renal function. The role of nuclear medicine in this area has been inhibited by confusion about conflicting methodologies. This report is meant to provide guidance to those centers that would like to initiate clearance procedures but have difficulty in choosing appropriate methodology.

Estimation of glomerular filtration rate from low-dose injection of iohexol and a single blood sample.

Clearance of a small dose of iohexol (7 g I) was compared with the glomerular filtration rate (GFR) marker 51Cr EDTA in 11 healthy volunteers. The two tracers were injected simultaneously. The plasma concentration of iohexol was measured with x-ray fluorescence technique. Glomerular filtration rate was determined using blood samples drawn three and four hours after injection. An excellent correlation (0.92 less than r less than 0.97) between iohexol clearance and 51Cr EDTA clearance was found. Glomerular filtration rate can be reliably determined with a low dose of iohexol and a single blood sample obtained three hours after the injection in persons with normal serum creatinine. This new method is a good alternative to the methods using radiopharmaceuticals; it causes no radioactive burden to the patients, increases patient comfort, reduces costs, and requires no special license.

Quality of urography and renal clearance of ionic and nonionic contrast media.

The authors evaluated whether urographic quality correlated with patient hydration and the level of their renal function, depending on whether they received ionic or nonionic contrast media. One hundred patients with normal serum creatinine levels were randomly assigned to receive intravenous urography with either an ionic high-osmolar or a nonionic low-osmolar contrast medium. Patient hydration was evaluated by measuring urine osmolality in a sample voided just before the examination. The plasma concentration of iodine was determined in a single blood sample drawn approximately 3 hours later. From these determinations the plasma clearance of contrast medium was calculated. The urograms were assessed blindly with regard to nephrographic and pyelographic opacification, as well as overall diagnostic quality. The clearance varied between 42 and 115 mL x minutes-1 x 1.73 m-2. No systematic correlation of practical significance was found between the clearances and the urogram quality. A high urinary osmolality before the examination tended to improve quality with both media. It is not possible to assess glomerular filtration rate from nephrographic and pyelographic opacification, or from overall quality of routine urograms in patients with normal serum creatinine levels.

Pyelorenal backflow in normal and ischemic rabbit kidneys.

Pyelorenal backflow during retrograde pyelography was studied in 68 kidneys of anesthetized rabbits. Thirty-three of the experiments were performed during or shortly after temporary renal arterial clamping. Pyelosinous backflow was observed in 67 and pyelovenous backflow in 65 of the 68 kidneys, occurring at an average intrapelvic pressure of 70 mmHg. This was true in intact kidneys and during arterial occlusion. Intrarenal backflow--intrusion of contrast material into the renal parenchyma--could be produced in only one of 35 experiments on intact kidneys, and occurred at an intrapelvic pressure of 119 mmHg. During arterial clamping, intrarenal backflow was observed in eight of nine experiments, occurring at intrapelvic pressures of about 70 mmHg. After removal of the clamp, intrarenal backflow was less frequent with shorter periods of arterial clamping and longer time between restoration of arterial flow before pyelography. Subcapsular extravasation of the medium with total blurring of the kidneys shadow and a prompt fall in intrapelvic pressure was the ultimate result of prolonged and extreme overdistension of the renal pelvis. It occurred at an average intrapelvic pressure of 80 mmHg. Histologic examination revealed tears in the fornix of the pelvic cavity in cases with pyelosinous backflow. If intrarenal backflow was present, there were tears leading from the pelvic cavity into the renal parenchyma. Supplementary experiments using a contrast material that could be demonstrated histologically (barium sulfate with gelatin) showed that the contrast filled the intertubular capillaries and venules. There was no evidence of backflow through the canalicular route.

Urine profiles and kidney histology following intravenous diatrizoate and iohexol in the degeneration phase of gentamicin nephropathy in rats. Effects on urine and serum profiles.

Urine chemical profiles were followed for three or nine days after intravenous injection of diatrizoate, iohexol, or saline in 30 rats, where a tubulointerstitial nephropathy was induced by gentamicin given over an eight-day period. Another ten rats injected with saline served as controls. Compared to injection of saline, both iohexol and diatrizoate induced dysfunction. The excretion of the cytoplasmic enzyme lactate dehydrogenase was significantly greater following iohexol than following diatrizoate. No significant differences between the two media were shown by the various serum components examined. Among the gentamicin-treated rats, light microscopy showed prolonged occurrence of tubular necrosis and a more intensive round cell infiltration following iohexol than following diatrizoate and saline. Both contrast media induced further temporary renal dysfunction in rats with gentamicin nephropathy; iohexol induced more morphologic changes than diatrizoate.

Intrarenal backflow during retrograde pyelography with graded intrapelvic pressure. A radiologic study.

Intrarenal backflow (IRB)--a form of pyelorenal backflow where contrast material appears in the renal parenchyma during retrograde pyelography--seems to be the same phenomenon as intrarenal reflux (IRR), sometimes observed during micturating cystography in children or animals with vesicoureteral reflux. Retrograde pyelography experiments were performed on baby pigs to study the relationship between renal pelvic pressure and IRB. Intrapelvic pressure was raised to 30-35 mm Hg (moderate) or 70-75 mm Hg (high) for 5 minutes. IRB developed in only four of 12 kidneys at moderate pressure but in all six kidneys at high pressure. Similar experiments were conducted on kidneys which had been rendered temporarily ischemic prior to retrograde pyelography. Twenty-seven kidneys were so studied 30 minutes after a 30- or 60-minute period of ischemia. With moderate and high pressure retrograde pyelography, all kidneys developed IRB. The most intense and widespread IRB occurred after 60 minutes of ischemia and at high pressure. IRB localized to the upper pole most frequently but was also observed in other portions of the kidney. The effect of IRB upon renal blood flow (RBF) was determined with electromagnetic flow probes during the same experiments. IRB caused a 16% mean decrease in RBF at moderate pressures and a 57% mean decrease in RBF at high pressures and was independent of preceding ischemia. It is concluded that both raised intrapelvic pressure and preceding renal ischemia are important factors determining the degree of IRB during retrograde pyelography and that backflow itself causes decreased RBF.

Pretreatment with steroids before intravenous injection of diatrizoate or iohexol. Effects on urine and serum profiles.

The effects on urine and serum profiles of intravenous injection of diatrizoate, iohexol, or saline were studied in male rats pretreated with steroids or saline. Using urinary albumin, glucose, sodium, and the enzymes lactate dehydrogenase (LDH), gamma-glutamyltransferase (GGT), and N-acetyl-beta-D-glucosaminidase (NAG) as markers of glomerular and tubular function, it was found that diatrizoate caused temporary glomerular and tubular dysfunction; the effect was independent of the kind of pretreatment. Iohexol did not cause increased glomerular permeability in steroid- and saline-pretreated rats. When used following saline, iohexol induced increased excretion of three tubular components, whereas iohexol plus steroids caused increased excretion of all five tubular components. The dysfunctional effect of iohexol plus steroids was less than that of diatrizoate plus steroids. The serum components revealed no abnormalities induced by either contrast media or methylprednisolone. Pretreatment with steroids has no effect on the glomerular or tubular dysfunctional effect of diatrizoate, whereas it worsens the temporary tubular dysfunctional effect of iohexol in rats.

Renal clearance of an ionic high-osmolar and a nonionic low-osmolar contrast medium.

One hundred patients with normal serum creatinine concentration underwent intravenous urography with either an ionic high-osmolar (diatrizoate) or a nonionic low-osmolar (iopamidol) contrast medium after randomization. Before injection of the contrast medium, a blood sample was drawn for determinating serum creatinine concentration, and a urine sample for measurement of urine osmolality. Using x-ray fluorescence, the plasma concentration of iodine (contrast medium) was determined on blood samples drawn approximately 3 and 4 hours after injection of the contrast medium. The glomerular filtration rate was calculated by two different formulas: one requiring only a single sample and one requiring at least two samples (standard). There were poor correlations between the standard contrast medium clearance and the serum creatinine concentration, the estimated creatinine clearance (calculated from a nomogram), as well as the urine osmolality. The 3-hour and the 4-hour single-sample values correlated well with the two-sample values for both contrast media. In patients with normal serum creatinine, the glomerular filtration rate determined by measuring the contrast medium concentration in a single plasma sample obtained at 3 hours, is almost identical to the value determined from two samples. Consequently, two samples are unnecessary.

Do contrast media aggravate Fanconi's syndrome in rats? A comparison of diatrizoate, iohexol, and ioxilan.

Urine profiles (albumin, glucose, N-acetyl-beta-D-glucosaminidase [NAG], lactate dehydrogenase [LDH], L-gamma-glutamyltransferase [GGT], sodium, and phosphate) were followed for seven days after intravenous (IV) administration of either diatrizoate, iohexol, ioxilan, or saline in 24 Wistar rats with a tubular dysfunction induced by IV sodium maleate. Ioxilan and saline had a similar effect on albumin excretion, iohexol had an intermediate effect, and diatrizoate increased it significantly from day 2 to day 7. Glucosuria was significantly greater after diatrizoate than after the nonionic contrast media (CM) or saline. Diatrizoate delayed normalization of enzymuria, whereas iohexol and ioxilan did not. None of the CM affected urinary sodium or phosphate excretion. It is concluded that Fanconi's syndrome is significantly aggravated only by diatrizoate.

Urine profiles following intravenous diatrizoate, iohexol, or ioxilan in rats.

The effects of intravenous diatrizoate, iohexol, ioxilan, or saline on albumin, glucose, sodium and the enzymes N-acetyl-beta-D-glucosaminidase (NAG), lactate dehydrogenase (LDH), and L-gamma-glutamyltransferase (GGT) in the urine of 24 normal Wistar rats were followed for seven days. During the first two hours after administration of diatrizoate, all profile components changed markedly; the albumin excretion was significantly greater than following ioxilan and iohexol; glucose, LDH, and GGT excretions were significantly greater than following ioxilan. Iohexol and ioxilan caused a higher excretion of albumin, LDH, and GGT than saline. Iohexol also increased glucose and sodium levels. Glucose and GGT were significantly higher following iohexol than following ioxilan. Both high osmolar and low osmolar contrast media may cause temporary glomerular and tubular damage. Urine profile components are affected most by diatrizoate, less by iohexol, and least by ioxilan.

Urine profiles and kidney histologic findings after intravenous injection of mannitol and iohexol in the degeneration phase of gentamicin nephropathy in rats.

RATIONALE AND OBJECTIVES: Previous studies have shown that iodinated contrast media may cause further renal dysfunction in tubulointerstitial nephropathy induced by gentamicin. The current investigation was undertaken to study whether the dysfunction after intravenous injection of a low-osmolar contrast medium is due to a chemotoxic and/or an osmotic effect. METHODS: Urine profiles were followed for 3 or 9 days after intravenous injection of saline, mannitol, and varying dosages of iohexol (1, 2.5, 5, and 10 mL/kg body weight (BW); 350 mg I/mL) in 60 rats, in which intramuscular injection of 40 mg/kg BW gentamicin had been administered daily nine times. A seventh group of 10 rats was given 20 mg/kg BW gentamicin and 5 mL/kg BW of 350 mg I/mL iohexol. Another 10 rats injected with saline served as controls. RESULTS: Both mannitol and iohexol increased the excretion of albumin and the enzyme N-acetyl-B-D-glucosaminidase (NAG) temporarily; the effect was independent of the dose of iohexol. There was a dose-dependent effect on the transient increase in excretion of the enzymes lactate dehydrogenase (LDH), gamma glutamyltransferase (GGT), and alkaline phosphatase (ALK); mannitol did not increase the excretion of these enzymes. In the group given 20 mg/kg BW gentamicin, only the dose-dependent effects of iohexol were seen. Neither various plasma components nor light/electron microscopy showed any changes that could solely be related to the contrast medium. CONCLUSIONS: Iohexol produces transient renal effects in gentamicin nephropathy, which may be due to both chemotoxic and osmotic mechanisms.