Hot Topics in Internal Medicine

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  • Neutrophil gelatinase-associated lipocalin, or NGAL [1], belongs to the lipocalin family of proteins. These are typically small secreted proteins characterized by their ability to bind small, hydrophobic molecules in a structurally conserved pocket formed by b-pleated sheet and to form macromolecular complexes. Many lipocalins also bind to specific cell-surface receptors, but so far no NGAL receptor has been identified. NGAL has many synonyms: it is also known as neutrophil lipocalin (NL or HNL for the human form) [2], lipocalin 2, oncogene protein 24p33 or uterocalin [4] in the mouse, and neu-related lipocalin [5] or 25 kDa a2-microglobulin-related protein [6] in the rat. Human NGAL consists of a single disulfide-bridged polypeptide chain of 178 amino-acid residues with a calculated molecular mass of 22 kDa [1], but glycosylation increases its apparent molecular mass to 25 kDa. In neutrophils and urine it occurs as monomer, with a small percentage of dimer and trimer, and it also occurs as a complex with 92-kDa human neutrophil type IV collagenase, also called gelatinase B or matrix metalloproteinase-9 (MMP-9) [1,7]. Human NGAL was originally isolated from the supernatant of activated neutrophils [1], but it is also expressed at a low level in other tissues including the kidney, prostate and epithelia of the respiratory and alimentary tracts [8, 9]. It is strongly expressed in adenomas and inflamed epithelia of the bowel [10], adenocarcinomas of the breast [11] and urothelial carcinomas [12]. Because of its small molecular size and resistance to degradation, NGAL is readily excreted and detected in the urine, both in its free form and in complex with MMP-9. Urinary levels correlate with plasma or serum levels whatever the cause of increased NGAL production (own data), but particularly high urinary levels can be expected when it is released directly into the urine by the kidney tubules or urothelial carcinomas. It is uncertain how far NGAL-MMP-9 complexes from sources remote from the urinary tract are excreted as such into the urine or reform in the urine after independent excretion of NGAL and MMP-9 [7]. While the functions of NGAL are not fully understood, it appears to be upregulated in cells under "stress", e.g. from infection, inflammation, ischemia or neoplastic transformation, or in tissues undergoing involution, such as the postpartum mouse uterus and mammary glands on weaning. In relation to a possible antibacterial role, it binds enterobactin and other siderophores, depriving the microorganisms of Fe3+, an important nutritional requirement [13]. Its complex formation with MMP-9 appears to protect MMP-9 enzymatic activity from degradation [7]. The upregulation of NGAL in involuting tissues has led to the postulation of a role in apoptosis, but it appears more likely that NGAL is associated with a survival response [14]. This seems to be so in the kidney, where NGAL-siderophore-iron complex rescues the mouse kidney from ischemic injury [15]. NGAL in inflammation or infection NGAL is released from the secondary granules of activated neutrophils [1] and plasma levels rise in inflammatory or infective conditions, especially in bacterial infections [16]. Thus the level of NGAL in plasma or serum has been proposed as a marker of infection. However, as levels of NGAL may also be raised in neoplastic conditions and renal disorders independently of any infective process, this proposed application should be treated with caution. NGAL may also be raised in infections in patients with an uncountably low number of neutrophils due to leukemia or treated leukemia, showing that the source of the raised NGAL in infections is not only the neutrophils. Indeed, serum NGAL levels correlate very poorly with the neutrophil count in unselected critically ill patients (own data). In view of the possible release of NGAL from the kidney (see below) when sepsis becomes severe enough to affect it, data on NGAL in sepsis should by reassessed to take this into account. NGAL and neoplasia The various types of cancer in which NGAL may be upregulated (often with MMP-9) have been referred to above. This has been shown by its expression in tumor cells and its high urinary levels, both in the free form and complexed with MMP-9 [7]. Indeed, it has been proposed that urinary NGAL-MMP-9 complexes may serve as a marker of disease status for breast cancer patients [17]. Plasma levels have not usually been measured in these cases. NGAL and the kidney Even before NGAL had been isolated from human neutrophils, its mouse homologue 24p3 was known to be expressed by kidney cells and to undergo an early, dramatic upregulation (14- to 20-fold) in response to SV 40 viral infection [18]. A similar early and dramatic upregulation was later observed in rat proximal tubule cells after ischemia-reperfusion injury [19], and raised plasma levels of NGAL were found to be strongly correlated with decreased renal function in patients with renal damage due to systemic vasculitis [20]. The results for renal ischemia-reperfusion injury were subsequently confirmed and extended to nephrotoxic agents [21, 22, 23]. It has been suggested that urinary NGAL levels may serve as an early marker for ischemic renal injury in children after cardiopulmonary bypass [24]. Raised urinary and serum NGAL levels have also been observed in patients with established renal failure (own data) and patients with functioning renal grafts also showed urinary levels that were sufficiently raised to be readily detectable by Western blotting [12]. It is therefore apparent that a large variety of renal disorders are associated with raised plasma and urinary levels of NGAL. While plasma and urinary NGAL levels are closely correlated in acute conditions, it is to be expected that urinary NGAL levels will be particularly high after ischemic renal injury severe enough to result in acute renal failure, acute tubular necrosis or acute tubulo-interstitial nephropathy. However, the use of urinary NGAL as a potential marker for these conditions is subject to the proviso that the presence of concurrent conditions that are independently associated with raised NGAL levels must be taken into account. NGAL quantification In many of the above studies on NGAL, the protein has been quantified by immunoblotting. However, some research groups have developed specific ELISAs, based on polyclonal and/or monoclonal antibodies to NGAL [16, 25]. The recent development of a commercial sandwich ELISA that measures NGAL in urine, plasma or serum, should make it easier for clinical investigators to assess the potential of this interesting molecule, either as a diagnostic marker for different pathologies, or as a marker of disease progress or response to treatment. Some NGAL may be released from neutrophils during the preparation of serum, making it generally preferable to use plasma, and urine should be centrifuged to remove neutrophils in cases of urinary tract infection. NGAL as a potential diagnostic marker It is apparent that a variety of independent pathologies are associated with raised levels of urinary or plasma NGAL. Therefore the finding of a raised level cannot be independently diagnostic of any one of these pathologies. Other information on the patient must be taken into account in order to assess the significance of the result. As other quite effective marker molecules are available to assess inflammatory and infective states (e.g. procalcitonin as a sepsis marker), and as more specific markers are available for many of the cancers in which NGAL is raised, it seems likely that the interest in NGAL will center chiefly on its role as a marker of kidney damage, where its early and marked response to the insult (within 2 hours [24]) makes it one of the best markers hitherto studied. It is to be expected that serial rather than isolated single measurements of NGAL, whether in urine or plasma, will provide the most useful data on patients with several concurrent pathologies.
  • In general, the higher the osmolality of contrast media, the higher the nephrotoxicity. A meta-analysis published in 1992 evaluated the relative nephrotoxicity of high-osmolar contrast media and low-osmolar contrast media (LOCM). The pooled odds ratio for the prevalence of contrast-induced AKI events (rise in serum creatinine of >44.2 µmol/L [>0.5 mg/dL]) in 25 trials was 0.61 (95% confidence interval, 0.48–0.77), indicating a significant reduction in risk with LOCM ( 43 ). Studies published since this meta-analysis generally support these findings ( 44 ). Most studies comparing different LOCM have been small trials that have not shown clinically relevant variation between the renal effects of different LOCM, and there is insufficient evidence to draw definitive conclusions about possible differences ( 7 ). Evidence to date suggests isosmolar contrast medium (IOCM) is the least nephrotoxic ( 45–47 ). In a pooled analysis of 16 trials (2,727 patients) of intraarterial contrast medium, the incidence of contrast-induced AKI was significantly lower with iodixanol than with the comparator LOCM ( Fig. 3 ) ( 47 ). Another systematic review was also consistent with a low rate of contrast nephropathy with iodixanol (IOCM) ( 48 ). A total of 17 prospective clinical trials (1,365 patients) were included, but only two of these trials were randomized comparisons of LOCM and IOCM, and the other data came from the placebo arms of 13 trials of preventive strategies for contrast-induced AKI and the LOCM arms of two trials comparing LOCM and high-osmolar contrast media. Finally, a meta-analysis of the renal tolerability of another IOCM, iotrolan 280, provides further evidence that IOCM are associated with a lower risk of postprocedure renal impairment ( 49 ). In an analysis of 14 double-blind studies, it was found that iotrolan had less effect on renal function than the LOCM with which it was compared (iopamidol, iohexol, iopromide). There are no currently approved pharmacologic agents for the prevention of AKI. With iodinated contrast, the pharmacologic agents tested in small trials that deserve further evaluation include theophylline, statins, ascorbic acid, and prostaglandin E1 ( 10 ). Only one uncontrolled study has been published of pharmacologic treatment in ICU patients, and this showed that the incidence AKI after contrast exposure was very low (2%) in patients who received prophylactic intravenous theophylline before the administration of contrast medium ( 64 ). Although popular, N-acetylcysteine has not been consistently shown to be effective. Nine published meta-analyses were identified in the review ( 10 ), all documenting the significant heterogeneity between studies and pooled odds ratios for N-acetylcysteine approaching unity. Importantly, only in those trials in which N-acetylcysteine reduced serum creatinine below baseline values because of decreased skeletal muscle production did renal injury rates seem to be reduced. Thus, N-acetylcysteine seems to falsely lower creatinine and not fundamentally protect the kidney against injury. However a recent study suggested that the use of volume supplementation with sodium bicarbonate together with N-acetylcysteine was more effective than N-acetylcysteine alone in reducing the risk of CIN ( 65 ). Fenoldopam, dopamine, calcium channel blockers, atrial natriuretic peptide, and l-arginine have not been shown to be effective in the prevention of contrast-induced AKI. Furosemide, mannitol, and an endothelin-receptor antagonist are potentially detrimental ( 10 ). Stacul F, Adam A, Becker CR, et al: Strategies to reduce the risk of contrast-induced nephropathy. Am J Cardiol 2006; 98:59K–77K
  • In our meta-analysis of 41 randomized trials, we found that preprocedural treatment with N -acetylcysteine effectively reduced the risk for contrast-induced nephropathy. Theophylline also produced larger risk reductions than previously mentioned; however, the effects of this agent were not significant. Not all agents analyzed had beneficial effects—fenoldopam; furosemide; mannitol; and the combination of furosemide, dopamine, and mannitol had odds ratios greater than 1. Our findings for N -acetylcysteine support previous studies (60–63) . To date, no meta-analyses have studied preprocedural dopamine or statins for the prevention of contrast-induced nephropathy. Our findings for theophylline support previous studies that showed a risk reduction (64) . However, the effects of theophylline were not statistically significant in our study. In contrast, Ix and colleagues (64) found borderline statistical significance when they limited their analysis to studies using concomitant intravenous fluids or contrast volumes greater than 100 mL and no statistical significance when their analysis was limited to studies of only coronary angiography patients or where the theophylline was given within 1 hour of the procedure. Bagshaw and Ghali (65) , however, did not find a statistically significant effect, similar to our findings. N -Acetylcysteine is extremely inexpensive at 23 cents for a 500-mg tablet (price as of 17 January 2007 at http:// www.shopping.com ), is readily available, and is easily administered. Side effects and drug interactions are very rare with continued use and are highly unlikely to result from the limited use for renal protection. Therefore, although no formal cost-effective analysis has been performed to date, these findings support the use of N -acetylcysteine in selected at-risk patients. Hydration and iso-osmolar or low-osmolar contrast agents, such as iodixanol, are all associated with a decreased incidence of contrast-induced nephropathy in patients with renal impairment (creatinine clearance <1 mL/s [<60 mL/min]) (44) . In a recent meta-analysis, McCullough and colleagues (15) found that although low-osmolar contrast agents reduced the risk for contrast-induced nephropathy by two thirds, they did not totally eliminate the risk. Thus, protective agents must still be considered for patients with severe renal impairment who are to receive large volumes of contrast agents. Our meta-analysis has several limitations. All included trials evaluated the surrogate end point of contrast-induced nephropathy as the primary outcome. Contrast-induced nephropathy was defined as an increase in serum creatinine of more than 44.2 µmol/L (>0.5 mg/dL) or 25% from baseline values, which represents a minor deterioration in renal function in patients with chronic renal failure. Even in high-risk patients, contrast-induced nephropathy is almost always transient and only rarely requires dialysis. Only the trial by Kay and colleagues (46) examined length of hospital stay as an end point and found a significant reduction in length of stay among patients given N -acetylcysteine. Despite the reported association of contrast-induced nephropathy with impaired outcomes, no trial has examined clinical end points, such as dialysis dependency or in-hospital morbidity and mortality. The clinical relevance of the renoprotective effects of N -acetylcysteine, dopamine, and other agents is therefore debatable, whereas periprocedural hydration is of proven benefit (66) . In addition, it is possible that we did not detect a significant effect for theophylline because of study heterogeneity or insufficient data. Because we primarily identified and used published studies, our results are weighted on the findings of published trials. The exclusion of unpublished data is generally associated with an overestimate of the true effect in meta-analysis (67) . The single most common reason for inability to publish a trial is the lack of statistical significance, although some have suggested that the quality of unpublished data is not comparable to that accepted by peer-reviewed journals (68) . In addition, many of the included studies did not have high quality scores, and many did not specify that they met the quality criteria, with the true quality remaining uncertain. Strengths of our study include the comprehensive search strategy and the careful statistical methods used. We identified 41 trials with a total of 6379 patients and evaluated multiple therapeutic agents within 1 analysis framework, allowing side-by-side comparison of the efficacies across agents. Our meta-analysis shows that N -acetylcysteine is the most effective agent for preventing contrast-induced nephropathy in patients with chronic renal insufficiency. Whether this risk reduction translates into a benefit in clinical outcomes remains to be proven. The reported association of contrast-induced nephropathy with increased morbidity, mortality, and hospital stay might justify the use of N -acetylcysteine as a routine intervention for prophylaxis of contrast-induced nephropathy, given that N -acetylcysteine is readily available and inexpensive and has a favorable side effect profile. The results of this meta-analysis should be evaluated in head-to-head empirical studies of active agents to identify the most efficacious regimen for preventing contrast-induced nephropathy. However, our findings indicate that the use of such oral agents as N -acetylcysteine is reasonable in high-risk patients who are to receive large or repeated volumes of contrast agents. We believe that the lack of significant side effects and the low cost justifies use of these agents while empirical data on clinical outcomes mature.

Transcript

  • 1. Hot Topics in Internal Medicine Molly Cooke MD Chair-elect, Board of Governors
  • 2. Questions
    • Does intensive glucose control improve outcomes in Type 2 diabetes?
    • What is the optimal prophylaxis to prevent contrast-induced acute kidney injury?
    • Do inhaled medications increase morbidity and/or mortality in patients with COPD?
  • 3. Questions
    • Does intensive glucose control improve outcomes in Type 2 diabetes?
    • What is the optimal prophylaxis to prevent contrast-induced acute kidney injury?
    • Do inhaled medications increase morbidity and/or mortality in patients with COPD?
  • 4. Does intensive glucose control improve outcomes in Type 2 diabetes?
    • ACCORD Effects of intensive glucose lowering in Type 2 diabetes N Engl J Med 2008; 358: 2545-59
    • The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with Type 2 diabetes. N Engl J Med 2008; 358:2560-72
    • Duckworth W et al. Glucose control and vascular complications in veterans with Type 2 diabetes. N Engl J Med 2009; 360:129-39.
  • 5. Background
  • 6. ACCORD 2008
    • RCT 10,251 patients
    • Intensive therapy HgbA 1 c 6.4%
    • vs. standard therapy HgbA 1 c 7.5%
    • Terminated early after 3.5 years
  • 7. ADVANCE 2008 RCT 11,140 patients Median follow up 5 years Intensive control HgbA 1 c 6.5% Standard control HgbA 1 c 7.3%
  • 8. ADVANCE 2008
  • 9. Glucose control and vascular complications (Duckworth) 2008
    • RCT 1791 veterans, median follow up 5.6 years
    • Intensive therapy HgbA 1 c 6.9% vs. standard therapy HgbA 1 c 8.4%
    • Adverse effects, particularly hypoglycemia, 17.6% in standard therapy vs. 24.1% in intensive therapy
  • 10. Questions
    • Does intensive glucose control improve outcomes in Type 2 diabetes?
    • What is the optimal prophylaxis to prevent contrast-induced acute kidney injury?
    • Do inhaled medications increase morbidity and/or mortality in patients with COPD?
  • 11. Risk of death associated with medications for recently diagnosed COPD Lee 2008
  • 12. Inhaled corticosteroids in patients with stable COPD Drummond Ann Intern Med 2008
  • 13. Long-term daily erythromycin and COPD exacerbations Seemungal Am J Resp Crit Care Med 2008
  • 14. Questions
    • Does intensive glucose control improve outcomes in Type 2 diabetes?
    • What is the optimal prophylaxis to prevent contrast-induced acute kidney injury?
    • Do inhaled medications increase morbidity and/or mortality in patients with COPD?
  • 15. Summary
    • Does intensive glucose control improve outcomes in Type 2 diabetes?
      • No, and it is associated with excess morbidity and mortality
    • What is the optimal prophylaxis to prevent contrast-induced acute kidney injury?
      • Discontinuation of NSAID’s, pre-procedure hydration, possibly possibly sodium bicarbonate > sodium chloride, probably N-acetylcysteine
    • Do inhaled medications increase morbidity and/or mortality in patients with COPD?
      • Inhaled steroids are associated with increased pneumonia
      • Ipatropium may be associated with increased mortality
      • Daily macrolide prophylaxis appears to decrease exacerbations
  • 16. Acute Kidney Injury
    • Sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury
    Nickolas T, et al. Ann Intern Med 2008; 148(11):810-819
  • 17. Neutrophil Gelatinase-Associate Lipocalin (NGAL)
    • Small protein belonging to the lipocalin family of proteins
    • Expressed by neutrophils and various epithelia, including the renal proximal tubules
    • Functions are not completely understood
      • Upregulated in cells under “stress”
      • Released from secondary granules of activated neutrophils
      • Initially proposed as a marker for infections and certain adenocarcinomas
    • NGAL has an early and dramatic rise in urine
    • after renal injury
  • 18.  
  • 19. Print Nikolas et al Ann Intern Med 2008
  • 20.
      • A single measurement of urinary NGAL helps to distinguish acute injury from normal renal function, prerenal azotemia, and CKI
      • This may help patient disposition from the ED to home, observation unit for hydration, versus full admission
  • 21. Acute kidney injury with iodinated contrast McCullough PA. Crit Care Med 2008; 36(4Suppl):S204-211
  • 22. Acute Kidney Injury
  • 23. Meta-analysis - Nephrotoxicity of high- and low- osmolality iodinated contrast medium Barrett 1993, as presented in McCullough 2008
  • 24. Acute Kidney Injury
    • Prevention, incidence, and outcomes of contrast-induced acute kidney injury
    Weisbord SD, et al. Arch Intern Med 2008; 168(12):1325-32
  • 25. Use of preventive therapy is variable Weisbord SD, et al. Arch Intern Med 2008; 168(12):1325-32
  • 26.  
  • 27.  
  • 28. Acute Kidney Injury (AKI)
    • Meta-analysis: effectiveness of drugs for preventing contrast-induced nephropathy
      • Kelly AM, et al. Ann Intern Med 2008; 148(4):284-294.
  • 29. Dopamine Fenoldopam Furosemide N-Acetylcysteine Theophylline 0.62 (0.44-0.88)
  • 30. Acute Kidney Injury (AKI)
    • Bottomline
      • CIAKI is associated with poor outcomes
      • Need to standardize contrast induced acute kidney injury (CIAKI) prophylaxis
      • Patients with risk factors for CIAKI (chronic kidney disease and diabetes) should receive non-ionic contrast
      • NAC is more effective in preventing CIAKI injury than hydration alone
  • 31. Summary
    • Does intensive glucose control improve outcomes in Type 2 diabetes?
    • What is the optimal prophylaxis to prevent contrast-induced acute kidney injury?
    • Do inhaled medications increase morbidity and/or mortality in patients with COPD?
  • 32.
    • Systematic abstracting of papers from > 130 journals
    • Ratings of each article for quality and newsworthiness
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    • Cumulative searchable database of alerts from 2003
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