Acute kidney injury survivors should have long-term follow-up

Acute kidney injury (AKI) is a frequently occurring complication in ICU patients and is associated with decreased short- and long-term survival. Gammelager and colleagues showed that AKI patients are at increased risk for developing heart failure and myocardial infarction at long-term follow-up. Their study provides strong epidemiological data on cardiorenal syndrome type 3, and their findings help explain the worse long-term survival of AKI patients. Finally, it also highlights the need for specific follow-up programs for ICU survivors.In a recent article, Gammelager and colleagues [1] investigated the association between acute kidney injury (AKI) and long-term cardiac morbidity and stroke in a representative ICU cohort. AKI occurs in one- to two-thirds of ICU patients and is associated with worse outcome [2,3]. Short-term worse outcomes can be explained by the effects of decreased kidney function, such as volume overload and retention of uremic toxins [4]. Long-term outcomes are probably affected by development of chronic kidney disease [5]. Recently, there has been increased interest in the complex interaction between the kidney and heart. AKI leading to acute cardiac events has been termed cardiorenal syndrome type 3 (CRS-3) [6]. At present this concept is only sparsely supported by human data [7]. The study by Gammelager and colleagues is one of the first providing high-quality data on CRS-3 in ICU patients.Several groups, including the group of Gammelager and colleagues, have demonstrated worse long-term outcomes for AKI patients [3,8-11]. The present study by Gammelager and colleagues demonstrates that cardiovascular disease may contribute to these worse outcomes. Over a 3-year period, AKI stage 1 and greater was associated with heart failure (hazard ratio 1.33), and AKI stages 2 and 3 were associated with myocardial infarction (hazard ratio 1.51). Similar findings were reported before by James and colleagues [12] in a cohort of non-ICU patients after coronary angiography. The paper by Gammelager and colleagues is one of the first providing long-term epidemiologic data on CRS-3 in ICU patients. Importantly, it shows that CRS-3 is also relevant for patients discharged from the ICU, a less well-recognized aspect of CRS-3.These findings are strengthened by the methodological quality of the study. Selection bias was limited by including a large multicenter ICU cohort, and a population-based medical registry guaranteed virtually complete patient follow-up. Studies using different AKI definitions cannot be compared. Therefore, it is crucial that the universally accepted KDIGO (Kidney Disease: Improving Global Outcomes) definition for AKI was used [13].A limitation is that administrative data were used for recoding of the endpoints. Administrative databases may be limited by both over- and under-reporting, and also miss detailed information on, for example, severity of heart failure. Also, an epidemiologic study can only demonstrate an association, rather than prove a causal effect, in this case between AKI and cardiac events. These data on CRS-3 are therefore hypothesis generating and should prompt further research on the pathophysiologic mechanisms explaining the worse cardiovascular outcomes.How can we explain this increased risk for cardiovascular events? This may be mediated, especially in the long-term, by chronic kidney disease developing after AKI, but other factors may also play a role [5]. In the acute phase, AKI may exert a negative impact on the heart, leading to cellular response with apoptosis, remodeling and fibrosis, which may ultimately lead to arrhythmias, conduction abnormalities, heart failure, and ischemia [7,14].The study by Gammelager and colleagues is also one of the few that reports on the association between AKI and stroke, but showed no association during the 3-year follow-up. These findings are in contrast to those found in Taiwan by Wu and colleagues [15], where in a matched case-controlled study AKI patients had a higher risk and higher severity of stroke than non-AKI patients. An important difference with the cohort of Gammelager and colleagues was that the study cohort included only severe AKI treated with renal replacement therapy and was not limited to ICU patients. Severity of AKI may therefore play a role in risk for stroke.Another important lesson that can be learned from these long-term outcome data is that AKI survivors should have long-term follow-up. We were already aware that follow-up of kidney function is important, but these data also highlight the importance of cardiovascular follow-up. As other types of ICU survivors also have specific long-term morbidity issues, this highlights the need for specific and multidisciplinary follow-up programs for ICU survivors.     

Successful treatment of Fusarium keratitis with cornea transplantation and topical and systemic voriconazole

A case of invasive Fusarium keratitis in a previously healthy male patient was treated successfully with cornea transplantation and systemic and topical voriconazole after treatment failure with topical amphotericin B and systemic itraconazole. Topical voriconazole was well tolerated, and, in conjunction with the oral administration, it resulted in a high level of the drug in the anterior chamber of the eye (which was 160% of the plasma drug level).     

Physiologic regulation and tissue localization of renal erythropoietin messenger RNA

Although erythropoietin (Epo) is produced primarily by the kidneys in response to hypoxia, the precise cell type(s) and mechanisms by which these cells regulate production are poorly understood. In the experiments we report, the kinetics of renal Epo production in response to acute hypoxia and the intrarenal localization of cellular Epo synthesis were studied at the level of Epo mRNA. Erythropoietin mRNA expression was determined by Northern blot analysis of rat kidney RNAs using a probe derived from the mouse Epo gene. Renal Epo mRNA content increased as early as 1 hour after initiation of hypoxia and continued to accumulate during 4 hours of stimulation. Discontinuation of the hypoxic stimulus resulted in rapid decay of mRNA levels. Kidney and plasma Epo levels measured by radioimmunoassay paralleled, with respective lag times, the changes in renal Epo mRNA content, suggesting that Epo production in response to acute hypoxia represents de novo synthesis and is regulated by changes in Epo mRNA. Northern blot analysis of RNAs extracted from separated glomerular and tubular tissue fractions revealed Epo mRNA in the tubular fraction, whereas glomerular tissue did not contain Epo mRNA. Thus, the site of cellular Epo synthesis is located in the renal tubule or its interstitium and not in the glomerular tuft.     

Protein C, an antithrombotic protein, is reduced in hospitalized patients with intravascular coagulation

Activated protein C is a potent anticoagulant and profibrinolytic enzyme that can be derived from the vitamin-K-dependent serine protease zymogen, protein C, by the action of thrombin. Protein C antigen concentration was determined in plasmas from normals (n = 40) and from 38 patients with intravascular coagulation as evidenced by positive FDP (greater than micrograms/ml). Plasma protein C was 4 micrograms/ml in normals and was significantly depressed (less than 2 SD below the mean of normals) in 19 of the 38 patients. Of 15 patients with suspected intravascular coagulation but normal FDP, protein C was decreased in 5 individuals; 3 of these 5 patients had liver disease. Based on these results, we suggest that extensive activation of the coagulation system in vivo causes a significant consumption of protein C, presumably due to its activation by thrombin and subsequent clearance.     

Granulocyte-macrophage colony-stimulating factor, interleukin-3 (IL-3), and IL-5 greatly enhance the interaction of human eosinophils with opsonized particles by changing the affinity of complement receptor type 3

Eosinophil functions can be modulated by several cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin- 3 (IL-3), and IL-5. We have investigated the modulatory role of these cytokines on the interaction of human eosinophils with opsonized particles (serum-treated zymosan [STZ]). Addition of STZ to eosinophils isolated from the peripheral blood of normal human donors resulted in an interaction of the STZ particles with only 15% to 25% of the cells. Treatment of the eosinophils with GM-CSF, IL-3, or IL-5 strongly enhanced both the rate of particle binding and the percentage of eosinophils binding STZ. The effect of the cytokines is most likely mediated by a change in affinity of the complement receptor type 3 (CR3) on the eosinophils for the complement fragment iC3b on the STZ particles. This is indicated by the observation that (1) the effect of the cytokines on STZ binding was prevented by a monoclonal antibody against the iC3b-binding site on CR3 and (2) the enhanced binding was already apparent before upregulation of CR3 on the cell surface was observed. In a previous study, similar results were obtained with platelet-activating factor (PAF)-primed eosinophils. Because we found that the cytokines strongly enhanced the STZ-induced PAF synthesis, we investigated the role of both released PAF and cell-associated PAF in the priming phenomenon by the cytokines. Cytokine priming appeared to be largely independent of the synthesis of PAF.     

Electrical neuromodulation for disabling angina pectoris related to isolated stenoses of small epicardial coronary arteries

Patients with symptomatic small vessel coronary artery disease may be inadequate candidates for revascularization procedures. They may suffer from refractory angina, which does not respond to maximal anti-anginal drug therapy. In addition to patients with end stage coronary artery disease and syndrome X, this newly defined group of subjects with an isolated stenosis of a small coronary artery may benefit from electrical neurostimulation. We describe two patients with intractable angina caused by a significant narrowing of a diagonal branch. This treatment modality should be considered as an alternative method for unsatisfactory revascularization procedures.