George A. Porter

Contrast-associated nephropathy.

Contrast nephropathy can be defined as an acute impairment of renal function that follows exposure to radiocontrast materials and for which alternative explanations for renal impairment have been eliminated. Based on reported studies, the incidence of contrast associated nephropathy (CAN) varies from 0 to 22%. This wide variation can be traced to differences in study design and the criteria used to designate significant renal impairment. Irrespective of the exact incidence, 2 defined risk factors have been identified: preexisting renal disease and diabetes mellitus. Whereas preexisting renal insufficiency is the single most influential risk factor for CAN, when diabetes coexists the incidence approaches 100%. The clinical presentation of CAN is distinct, having a temporal relation between the performance of the contrast study in the high-risk patient and the onset of an increase in serum creatinine levels within the next 24 hours. Serum creatinine values greater than 50% of baseline or rising 1 mg/dl or more is diagnostic. The peak serum creatinine level occurs within 3 to 5 days of the contrast study and oliguria is associated in approximately 30% of the cases. Monitoring serum creatinine is the most useful clinical procedure in high-risk patients after angiography. At least 5 potential pathophysiologic mechanisms of CAN have been proposed: interference with renal perfusion, altered glomerular perm-selectivity, direct tubular injury, intraluminal obstruction, and immunologic mechanisms. Support for each mechanism, either singularly or in combination, can be found in published reports; however, none has achieved universal acceptance. The single most important clinical axiom regarding the prevention and management of CAN is, Always use the least invasive diagnostic procedure available.(ABSTRACT TRUNCATED AT 250 WORDS)

Contrast associated nephropathy: Presentation, pathophysiology and management

Contrast-associated nephropathy, a significant rise in serum creatinine 1-5 days following intervascular contrast injection, remains one of the most serious complications of contrast imaging. The reported incidence varies widely; in consecutive random cases ranges from 2 to 7%, but it can increase 5- to 10-fold in high risk patients with serum creatinine > 1.5 mg/dl. Postulated mechanisms of renal damage include vasoconstriction and direct tubular cell injury. The usual clinical presentation is an asymptomatic increase in serum creatinine without oliguria. Residual loss of renal function occurs in principle in patients with preexisting renal impairment. Aggressive prestudy hydration along with selective use of low osmolar contrast media can significantly reduce the risk of contrast nephropathy for patients with either chronic renal failure or diabetic nephropathy.

Novel sorbents for removal of gadolinium-based contrast agents in sorbent dialysis and hemoperfusion: preventive approaches to nephrogenic systemic fibrosis

UNLABELLEDnMany forms of organocomplexed gadolinium (Gd) contrast agents have recently been linked to a debilitating and a potentially fatal skin disease called nephrogenic systemic fibrosis (NSF) in patients with renal failure. Free Gd released from these complexes via transmetallation is believed to be the most important trigger for NSF. In this work, nanostructure silica materials that have been functionalized with 1-hydroxy-2-pyridinone (1,2-HOPO-SAMMS) have been evaluated for selective and effective removal of both free and chelated Gd (gadopentetate dimeglumine and gadodiamide) from dialysate and blood. 1,2-HOPO SAMMS has high affinity, rapid removal rate, and large sorption capacity for both free and chelated Gd, properties that are far superior to those of activated carbon and zirconium phosphate currently used in the state-of-the-art sorbent dialysis and hemoperfusion systems. The SAMMS-based sorbent dialysis and hemoperfusion will potentially provide an effective and predicable strategy for removing the Gd from patients with impaired renal function after Gd exposure, thus allowing for the continued use of Gd-based contrast magnetic resonance imaging while removing the risk of NSF.nnnFROM THE CLINICAL EDITORnChelated gadolinium (Gd) contrast agents have been linked to a debilitating disease called nephrogenic systemic fibrosis (NSF) in patients with renal failure. Free Gd+(3) released from the contrast agents is believed to be the trigger for NSF. In this work, functionalized nanostructured silica materials were evaluated for removal of both free and chelated gadolinium both from dialysate and blood. The new method demonstrated a rapid removal rate and large sorption capacity, and overall was far superior to currently used state-of-the-art sorbent dialysis and hemoperfusion systems.

Experimental contrast-associated nephropathy and its clinical implications

Acute renal failure after contrast media injection has been recognized for at least 35 years but the exact mechanism responsible for the renal injury remains an enigma. The clinical characteristics of contrast-induced nephropathy (CAN) are well-known although more recently the nonoliguric presentation has occurred at an increased frequency--in 70 to 90% of cases. For nonoliguric presentation of CAN, one can expect an asymptomatic increase in serum creatinine, the mean peak occurring at 4.2 days. If oliguric, the fractional excretion of sodium will be less than 1% and resistant to either fluid challenge or loop diuretics. Preexisting renal insufficiency, with or without diabetes mellitus, increases the risk of CAN 6- to 10-fold but recovery is expected, with less than 10% of all patients requiring dialytic support. Despite the growing body of published reports, the lack of a suitable animal model to evaluate various proposed mechanisms of renal injury has compromised our ability to devise a technique for preventing CAN. A popular scheme has been proposed to describe the possible sequence by which ischemia or nephrotoxins, or both, induce acute renal failure. In particular, a vascular mechanism (i.e., ischemia), is an appealing explanation for CAN since acute changes in renal hemodynamics after contrast media injection have been confirmed by several animal experiments. Unlike other vascular beds in which contrast media induce acute vasoconstriction followed by vasodilatation, the initial effect on the renal circulation is acute vasodilatation, followed by progressive vasoconstriction, increasing renal vascular resistance and a concomitant decrease in both renal blood flow and glomerular filtration rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Urinary biomarkers and nephrotoxicity

Biomarkers represent measurable changes in biologic systems or samples which correlate with an organisms altered biochemical or cellular function. For the kidney urine is the usual body fluid sampled. The principle processes which are evaluated are filtration/elimination and reabsorption/secretion. Proteins, either abnormal in type or amount, and enzymes have dominated interest in this field for many years. However, application of monoclonal antibody techniques, along with an understanding of the role of cytokiness, growth factors, collagen matrix and lipid mediators have rapidly expanded the field of new candidates for urinary biomarkers.

Urinary Enzymes as Biomarkers of Renal Injury in Experimental Nephrotoxicity of Immunosuppressive Drugs

Urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) and of alanine-aminopeptidase (AAP) was studied after administration of cyclosporine A (CSA A), FK 506, or the corresponding vehicles to salt-depleted rats. On days 7, 14, and 28 after treatment for CSA and day 14 after treatment for FK 506, measurements of the urinary enzymes, serum creatinine (SCr), creatinine clearance (ClCr), and blinded renal histology were done. After 1 week on CSA there was a dramatic increase of 489% in the urinary excretion of AAP (162.6 IU/g Cr, CSA vs. 27.6 IU/g Cr control, p < .03), a significant decrease of 32% in ClCr, a significant increase of 41% in SCr, and mild proximal tubular atrophy and vacuolization. After 2 or 4 weeks of CSA treatment there were no more differences in the urinary AAP between CSA and control rats, but the urinary excretion of NAG was increased: 29.6 IU/g Cr, CSA vs. 20.9 IU/g Cr, control, p < .03 on day 14 and 26.9 IU/g Cr, CSA vs. 21.5 IU/g Cr, control, p < .008 on day 28. At the same time there was a progressive decline of the ClCr, a progressive increase in the SCr, and an increase in the severity of the histological lesion. After 14 days of treatment with FK 506 we observed a striking elevation in urinary AAP (62.6 IU/g Cr, FK 506 vs. 36.0 IU/g Cr, control, p < .01) consistent with a significant decrease in ClCr, a significant increase in SCr, and a moderate proximal tubular vacuolization and atrophy.(ABSTRACT TRUNCATED AT 250 WORDS)

Non-contrast-enhanced computerized tomography and analgesic-related kidney disease: report of the national analgesic nephropathy study.

Previous studies suggested that the non-contrast-enhanced computerized tomography (CT) scan is a highly reliable tool for the diagnosis of analgesic-associated renal disease. However, this issue has not been addressed in the US population. A total of 221 incident patients with ESRD from different regions of the United States underwent a helical CT scan and detailed questioning about drug history. Specific renal anatomic criteria were developed to determine whether a constellation of CT findings (small indented calcified kidneys [SICK]) is linked to analgesic ingestion. For approximating use before the onset of renal disease, only analgesic ingestion at least 9 yr before starting dialysis was considered relevant. Fifteen patients met the criteria for SICK. This represented 7% of the enrolled patients and approximately 1% of the total ESRD population. There was a significant increase in the estimated risk among patients with a history of heavy aspirin ingestion (odds ratio [OR] 7.4 [95% confidence interval (CI) 1.2 to 43] for > or =1 kg lifetime; OR 8.8 [95% CI 1.2 to 66] for > or =0.3 kg/yr). Total analgesic ingestion of > or =0.3 kg/yr also was significantly associated with SICK (OR 8.2; 95% CI 1.5 to 45). These findings were accounted for largely by combination products that contained aspirin and phenacetin (used by three patients with SICK), which are no longer available. In addition, the CT finding of SICK was present only in a minority of heavy analgesic users, yielding a sensitivity of 5 to 26%. Findings of SICK are infrequent in the US ESRD population and do not occur among a sufficient proportion of heavy analgesic users to render the non-contrast-enhanced CT scan a sensitive tool to detect analgesic-associated kidney injury.

Relationship Between Elevated Serum Troponin Values in End-Stage Renal Disease Patients and Abnormal Isotopic Cardiac Scans Following Stress

One hundred asymptomatic high-risk renal transplant candidates were screened for asymptomatic coronary artery disease using stress cardiac isotopic imaging. The cardiac markers, serum cTnT, cTnI, and CKMB, were collected pre and post stress testing. Of the 99 patients whose cardiac scans were technically satisfactory, 32 were normal, 49 had a definite imaging abnormality and the scan was indeterminate in the remaining 18 patients. Based on these results, patients were stratified into either normal, indeterminate or abnormal scan groups. They then were analyzed to detect any correlations between cardiac perfusion defects and either elevated pre-stress cardiac markers or consistent changes 24 h after stress testing. While the mean pre-stress serum values for both cardiac troponin T (0.117 ± 0.12 µg/L) and cardiac troponin I (0.235 ± 0.89 µg/L) were increased in the abnormal cardiac scan group, only the cTnT value proved to differ significantly from the normal group (p<0.01). For the indeterminate group neither marker was different from the normal scan group. Only an elevated serum cTnT>0.1 µg/L (OR 3.042, p = 0.030) proved to discriminate an abnormal scan in this population. It is concluded that the increase in pre-stress serum cTnT encountered in patients with chronic renal failure, with or without evidence of overt, symptomatic coronary artery disease, may represent a combination of subclinical myocardial damage and a prolonged half-life of the marker in the serum. Because of the frequency of elevated serum concentrations of cTnT and, to a lesser degree cTnI, the physician should exercise caution when interpreting a single elevated Troponin value during the evaluation of chest pain in patients with end-stage renal disease. A cTnT>0.1 µg/L increases the likelihood of finding significant coronary artery disease three fold in high-risk ESRD patients being evaluated for renal transplantation.

Non-steroidal anti-inflammatory drugs

Introduction ___________________________________________________________ 419 Prostaglandins and renal function __________________________________________ 420 The prostaglandin pathway 420 Renal prostanoid receptors 421 Cyclooxygenase isoforms _________________________________________________ 422 Factors regulating isoform expression 422 Distribution within the kidney 422 Mechanism of action of NSAIDs ____________________________________________ 422 Renal syndromes associated with NSAIDs ____________________________________ 423 Acute deterioration of renal function 424 Salt and water retention 428 The concept of “renal sparing” NSAIDs 430 Nephrotic syndrome with interstitial nephritis 431 Chronic renal failure/papillary necrosis 432 Other NSAID-induced renal syndromes 434 Renal effects of COX-2 inhibitors ___________________________________________ 435 Effects on renal function: GFR/urinary sodium excretion 435 Incidence of adverse cardio-renal events 436 Concurrent use of an oral synthetic prostaglandin analog with a NSAID ___________ 444 Conclusions and future challenges _________________________________________ 445 References _____________________________________________________________ 449

Effect of Amiloride on Experimental Gentamicin Nephrotoxicity

Potassium and magnesium deficiency have been reported as risk factors for experimental gentamicin nephrotoxicity. Amiloride, a potassium-sparing diuretic, also leads to increased renal magnesium reabsorption. Amiloride, 2 mg/kg/day, was given to groups of 8-12 Fischer 344 rats receiving gentamicin, 20 mg/kg b.i.d., for 3, 7, 10 and 14 days. Control animals received the vehicle for gentamicin, amiloride alone or gentamicin alone. The degree of renal failure and weight loss were similar in gentamicin and gentamicin + amiloride groups at all time points despite increases in serum potassium and magnesium in the amiloride-treated animals. Tubular dysfunction as assessed by depression of renal cortical slice uptake of p-aminohippurate and N-methylnicotinamide was not improved by the addition of amiloride. In addition, a comparable degree of tubular necrosis and regeneration was observed in all gentamicin-treated groups. Maximum gentamicin concentrations in the renal cortex did not differ. Thus, despite reduction of urinary losses of potassium and magnesium with resultant increased serum values, amiloride did not protect against experimental gentamicin nephrotoxicity. The tubular electrolyte wasting noted clinically is likely to be a result, rather than a cause of proximal tubular cell damage.