Giorgio Savazzi

Facts and fallacies concerning the prevention of contrast medium-induced nephropathy

Objective:The aim of this article is to extract from recent medical literature and nephrologic practice the facts and fallacies concerning the possible prophylaxis of contrast medium–induced nephropathy. Data Sources, Study Selection, and Data Extraction:A MEDLINE/PubMed search (1985 to January 2006) was conducted, including all relevant articles investigating the pathogenesis and prevention of contrast medium–induced nephropathy from a nephrologic critical point of view. Data Synthesis:Considerable efforts have been made to develop pharmacologic therapy for the prevention of contrast medium–induced nephropathy, especially in patients at risk, such as elderly subjects and those with preexisting renal impairment, hypovolemia, or dehydration. There is general consensus that hydration protocols implemented before and after imaging with contrast medium may be effective in preventing contrast medium–induced nephropathy. However, definitive and convincing data related to amounts to be infused, infusion timing, and type of solutions (half-isotonic, isotonic saline solution, or bicarbonate) are lacking. Forced diuresis with furosemide or mannitol and use of dopamine, together with concomitant hydration, have been proved to be ineffective or even more risky in the event of inadequate maintenance of euvolemia. Various direct or indirect vasodilators have been investigated (atrial natriuretic peptide, calcium channel blockers, angiotensin-converting enzyme inhibitors, and endothelin receptor antagonists), yet results have been inconsistent and inconclusive. Recent large meta-analyses concerning the protective role of antioxidant action of N-acetylcysteine have led to the conclusion that the statistical significance of the results is borderline. Preventive hemodialysis has not proved to be useful; on the contrary, it might worsen the clinical conditions by inducing hypotension. Hemofiltration, despite some positive studies, is too complex and cannot be used extensively. Conclusions:It is believed that prevention is actually achieved by correcting hypovolemia, dehydration, or both. Normalization of body fluids is probably the true objective to be achieved by preventive measures in all patients, not only in those at risk. Because limited data have been collected in intensive care units, at present, no firm or specific recommendations can yet be provided for the critically ill. LEARNING OBJECTIVESOn completion of this article, the reader should be able to: Identify risk factors for contrast medium-induced nephropathy (CMIN). Describe effective prophylaxis for CMIN. Use this information in a clinical setting. All authors have disclosed that they have no financial relationships with or interests in any commercial companies pertaining to this educational activity. Lippincott CME Institute, Inc., has identified and resolved all faculty conflicts of interest regarding this educational activity. Visit the Critical Care Medicine Web site (www.ccmjournal.org) for information on obtaining continuing medical education credit.

Cerebral Imaging Changes in Patients with Chronic Renal Failure Treated Conservatively or in Hemodialysis

Background: Nonuremic patients with apparently normal memory and behavior, studied by means of cerebral computed tomography and found to have cerebral atrophy (CA), evidenced functional intellectual deficits when they underwent psychometric testing. The finding of CA has been repeatedly reported in limited case groups of uremic patients who also demonstrated functional intellectual deficits on the basis of the same tests. This retrospective study considered all diagnostic cerebral computed tomography scans done in our department between 1981 and 1998. Fifty-five uremic patients in conservative treatment (CT) and 111 patients in hemodialysis treatment (HT) were selected on the basis of the following two criteria: primary nephropathy as the cause of uremia and an age ≤55 years to exclude involutive brain changes occurring with age. Aims: The aims of the study were to determine the percent of uremic patients with CA, the characteristics of their CA (cortical or subcortical), and eventual associated morphological lesions. Results: CA was detected in 50.9% (cortical atrophy in 47.3% and subcortical atrophy in 3.6%) of the uremic patients in CT and in 77.5% of those in HT (cortical atrophy in 65.7% and subcortical atrophy in 7.7%). The average degree of CA was 0.872 in the patients in CT and 1.765 in the patients in HT. Thirty-four of the patients in the CT group and 46 in the HT group were hypertensive: these patients had a more severe degree of CA than the nonhypertensive subjects. In the CT group, the degree of CA in the hypertensive patients was 1.205 versus 0.428 for the nonhypertensive subjects. In the HT group, the degree of CA was 2.087 for the hypertensive patients versus 1.538 for the nonhypertensive patients. Of the overall population, 7.8% had ischemic lesions, 9.6% had endocranial calcifications, and 5.4% evidenced periventricular white matter hyperintensities. Conclusions: The high percent of CA found in young uremic patients increased in subjects in HT and, even more so in hypertensive patients. Vascular calcifications, focal ischemia and leukoaraiosis, well-known expressions of a chronic state of cerebrovascular insufficiency, were also found in HT patients; hypertension alone is a recognized accelerator of vascular damage. Thus, early and severe atherosclerosis and related hypoperfusion can be considered as the paramount causes of parenchymal cerebral damage in uremia.

Hypertension as an Etiopathological Factor in the Development of Cerebral Atrophy in Hemodialyzed Patients

Twenty-five patients on long-term regular hemodialysis treatment (RDT) at our dialysis unit who underwent diagnostic cerebral computed tomography (CCT) participated in a study aimed at clarifying the pathogenesis of cerebral atrophy occasionally found at their original scan. The upper age limit was 55 years to exclude the physiological involutive brain changes occurring with age. Cerebral atrophy (CA), as defined morphologically (enlargement of cerebral sulci or an increased Evan’s Index), was detected in all cases. Seventeen patients underwent magnetic resonance imaging (MRI) to define possible white matter changes more accurately. No significant correlation was found between the degree of atrophy and the following uremia-altered hematoseric parameters: creatinine, hematocrit, cholesterol, triglyceridemia, albumin, PTH, calcium, inorganic phosphate. There was no correlation between degree of atrophy and number of months the patients had been on RDT or time that passed between the finding of a creatinine clearance <30 ml/min and the start of RDT. Very high correlations were found between the degree of CA and predialytic blood pressure values, and between CA and the duration of hypertension (n = 13, r = 0.66, p < 0.013). Thus, hypertension seems to be an early cause of cerebral parenchymal damage in RDT patients, and should be promptly corrected.

Progression of Cerebral Atrophy in Patients on Regular Hemodialysis Treatment: Long-Term Follow-Up with Cerebral Computed Tomography

Fifteen patients (10 males, 5 females) on regular hemodialysis treatment (average age 43.6 +/- 4.0 years, average time on dialysis 100.7 +/- 62.8 months) underwent cerebral computed tomography between 1981 and 1984. Ten patients showed mild cerebral atrophy (CA) on the basis of cortical sulci exceeding 3 mm in breadth and an Evans ratio exceeding 0.31, for a total of 14 degrees of CA (mean 0.9 +/- 1). The same 15 patients underwent a second cerebral computed tomography during 1991/92 (101 +/- 23.7 months later). At that time, the patients exhibited a degree of CA of 2.6 +/- 1.4, for a total of 39 degrees with an overall increase of 25 degrees. Since CA is not detected before the age of 55 years in the normal population, we conclude that the CA in this patient group can only be attributed to uremia-related pathology and that it tends to worsen as regular hemodialysis treatment continues. Nevertheless, no evident cognitive, affective, or behavioural changes were verified in these patients. To our knowledge, this is the first presentation of radiologically documented progression of CA in the same patient population over time.

Sarcoid Granulomatous Nephritis with Isolated and Reversible Renal Failure

A case of reversible renal failure due to sarcoid granulomatous nephritis is described. The patient, a 21-year-old student, was admitted with renal insuffciency (GFR = 25 ml/min); no damage was found in any organ except for slightly enlarged pulmonary hilar lymph nodes. Repeated percutaneous renal biopsies showed an interstitial noncaseating granulomatous nephritis. Steroid therapy provided rapid improvement and the diagnosis of sarcoidosis was established. Complete recovery of renal function with normal urinalyses was seen.

Renal effects of captopril, indomethacin and nifedipine in nephrotic patients after an oral protein load

BACKGROUND In this study we investigated whether the increase in proteinuria induced by an oral protein load may be prevented by the angiotensin-converting enzyme inhibitor (ACEI) captopril in patients with nephrotic syndrome, and whether the effects of captopril on renal haemodynamics and/or glomerular selectivity are comparable to those obtained with the nonsteroidal anti-inflammatory drug (NSAID) indomethacin and the calcium-channel blocker (CaCB) nifedipine. METHODS Twelve subjects underwent the following treatments: (1) low-protein meal (0.2 g protein/kg body wt), (2) high-protein meal (1.3 g protein/kg body wt), (3) high-protein meal plus oral captopril (50 mg), (4) high-protein meal plus oral nifedipine (10 mg), (5) high-protein meal plus oral indomethacin (50 mg). Urine and blood samples were obtained after meals and tested for total protein, immunoglobulin G and albumin. GFR and renal plasma flow (RPF) were calculated from iothalamate and p-aminohippuric acid clearances respectively. RESULTS Mean arterial pressure decreased significantly after both captopril (-4%, P = 0.001) and nifedipine (-5%, P = 0.0019). Compared with the low-protein meal, mean values of GFR and RPF increased significantly after the high-protein meal alone (+21%, P = 0.0002; +10%, P = 0.0491 respectively), and after captopril (+18%, P = 0.0025; +24%, P = 0.0034 respectively) or nifedipine administration (+30%, P = 0.0001; +21%, P = 0.0036 respectively), whereas they remained unchanged after the high-protein meal plus indomethacin administration. FF did not change significantly under the five experimental conditions. The increase in urinary protein excretion induced by the meat load (total protein +18%, P = 0.0102; albumin +26%, P = 0.0316; IgG +28%, P = 0.0203) was entirely blocked by both captopril and indomethacin, whereas it was further increased by nifedipine administration. CONCLUSIONS Both captopril and indomethacin, but not nifedipine, are able to prevent the increase in urinary protein excretion rate following a meat meal. The antiproteinuric effect of captopril is comparable to that of indomethacin, but the renal haemodynamic changes induced by these drugs differ considerably, because the filtration capacity and the renal functional reserve were preserved by captopril and decreased by indomethacin. The reduction in systemic blood pressure following administration of both captopril and nifedipine does not account for changes in proteinuria, since, with a similar degree of blood pressure lowering, urinary protein excretion is reduced by captopril and increased by nifedipine.

Physiopathology and Clinical Aspects of Diabetic Nephropathy

End-stage renal failure is a severe and relatively frequent complication of insulin-dependent diabetes, also representing the only growing cause of uremia requiring replacement therapy in Western countries. Five principal pathogenic factors are to be considered: genetic, immunologic, hemorheologic, biochemic, and hemodynamic; of these, nonenzymatic glycosylation of proteins and glomerular hyperfiltration appear to be most important. In the last few years, a better understanding of the natural history of type I diabetes has been gained, with particular significance attributed to the stage of the disease defined as incipient diabetic nephropathy which is characterized by microalbuminuria. However, advances in pathophysiologic notions have not always been followed by corresponding results in the prevention and therapy of diabetic nephropathy; possible reasons for this are briefly discussed. In spite of these uncertainties, the importance of achieving the best possible correction of glycemic homeostasis and of albeit initial elevations in the arterial pressure appears to be well established.

Acute Renal Failure and Piromidic Acid

A case of nonoliguric acute renal failure after treatment with piromidic acid and acetylsalicylic acid is reported. The histological picture of acute interstitial nephritis and a positive leukocyte in

Brain atrophy in uremia. Research of the causes and future perspectives.

Accessible online at: www.karger.com/journals/nef Dear Sir, We would like to reply to the points raised by P. Scarpelli et al. in their letter ‘Brain atrophy in uremia: its underevaluated meaning and consequences’ [Nephron 2002; 90:510] in reference to our paper ‘Cerebral imaging changes in patients with chronic renal failure treated conservatively or in hemodialysis’ [Nephron 2001;89:31–36]. When we divided the patients, those in conservative and those in hemodialysis treatment, into patients positive or negative for cerebral atrophy (CA), both groups showed cholesterol and triglyceride blood values compatible with dyslipidemia. However, there was no statistical significance between the two groups. The same lack of correlation was observed for PTH, Ca and PO4. On the contrary, there was a striking correlation between CA and hypertension. It should be noted that these results are in line with our previous observations concerning 30 hemodialysed patients [1], none of whom were included in the present work. The letter by Scarpelli et al. stimulates us to make some further clinical considerations regarding other morphological changes found in our patient population, i.e. focal areas of clinically silent ischemia and leukoaraiosis. These findings have notoriously been correlated to a chronic state of cerebral vascular insufficient blood flow. Areas of focal ischemia were found in 13 (11.7%) of our 166 patients, while stroke was reported in only 6 patients of the group in hemodialysis treatment (it occurred in 3 patients at the end of a dialysis session). Of these 6 patients, 2 had cerebrovascular calcifications. Stroke is generally the result of acute regional cerebral hypoperfusion (embolism or sudden thrombosis). Stenosis or occlusion of the internal carotid artery as a long-term change is accompanied by important hemodynamic changes and is a known major cause of chronic cerebral hypoperfusion, morphologically compatible with silent areas of focal ischemia. Both distal perfusion pressure and cerebral blood flow may be normal if collateral circulatory pathways remain adequate [2]; furthermore, if collaterals are inadequate, autoregulatory dilatations of resistance vessels contribute to maintain normal blood flow. Oxygen extraction increases only when autoregulatory vasodilatation fails and blood flow decreases [3]. We speculate that both collateral circulatory pathways and autoregulatory vessel dilatation are decreased in uremic patients and chronic cerebral hypoperfusion is widespread early in the course of uremia parallel to dysionism of divalent ions and hyperphosphoremia. We believe that further studies should focus on compensatory mechanisms of cerebral blood flow that depend on autoregolatory vessel dilatation and collateral circulatory pathways. In addition, ischemic changes observed in the uremic patients are frequently located in cerebral parenchymal areas between the supply areas of the two major arterial territories, e.g. the anterior and middle cerebral arteries. In contrast to brain infarcts confined to a single arterial territory, generally intended as stroke due to thromboembolism, the border-zone infarcts are associated with hemodynamic factors [4–6]. A further difficulty in the final interpretation of borderzone infarcts is that there exist large anatomical variations in vascular territories of the major brain artery [7]. Further, studies – if possible, noninvasive – are needed to enable assessment of functional compensation mechanisms in chronic hypoperfusion of the uremic brain and, of course, to gain better understanding of their alterations. These could be carried out by the overlapping of echotomography on the large vessels with combined diffusion/ perfusion MR techniques. Our group is presently working in this new frontier area.

Patients at risk for contrast-induced acute kidney injury

Subjects with hypovolemia and/or dehydration and pre-existing renal failure are considered at highest risk for radiocontrast-medium-induced acute kidney injury (RCI-AKI), and this risk increases in the presence of glomerular filtration rate or creatinine clearance rates lower than 60 mL/min (stage 3-5 chronic kidney disease according to the National Kidney Foundation). The authors critically review the evidence-based literature on RCI-AKI, its diagnosis, epidemiological aspects, predisposing conditions, and markers of risk, including advanced age. Procedures requiring the use of iodinated contrast media are increasingly performed in patients over 70 years of age, and there is no definitive consensus regarding the role of advanced age as a marker of risk for RCI-AKI.