The Importance of Natural and Acquired Immunity to SARS-CoV-2 Infection in Patients on Peritoneal Dialysis.

The pandemic caused by the SARS-CoV-2 virus had a great impact on the population of patients treated with peritoneal dialysis (PD). This study demonstrates the impact of infection and vaccination in 66 patients treated with PD and their outcomes during a 6-month follow-up. This is the first research that has studied the dynamics of anti-SARS-CoV-2 IgG in serum and effluent. In our research, 57.6% of PD patients were vaccinated, predominantly with Sinopharm (81.6%), which was also the most frequently administered vaccine in the Republic of Serbia at the beginning of immunization. During the monitoring period, the level of anti-SARS-CoV-2 IgG antibodies in the PD patients had an increasing trend in serum. In the group of vaccinated patients with PD, anti-SARS-CoV-2 IgG antibodies had an increasing trend in both serum and effluent, in contrast to non-vaccinated patients, where they decreased in effluent regardless of the trend of increase in serum, but statistical significance was not reached. In contrast to vaccinated (immunized) patients who did not acquire infection, the patients who only underwent the COVID-19 infection, but were not immunized, were more prone to reinfection upon the outbreak of a new viral strain, yet without severe clinical presentation and with no need for hospital treatment.

Increased Peritoneal Protein Loss and Diabetes: Is There a Link?

Increased peritoneal protein loss has been associated with the fast transport of small molecules, diabetes mellitus (DM), and a reduced survival in patients on peritoneal dialysis (PD), although some studies did not confirm the association with survival. In this single-center retrospective study, we investigated the relationship of baseline peritoneal albumin and protein loss with transport status, comorbidities including DM, and survival in 106 incident PD patients during the period of July 2005-June 2014. Five-year survival rate was determined using Cox-regression analysis. There were not significant differences in D/Pcr or peritoneal protein and albumin loss between diabetics and non-diabetics. In the group of 66 non-diabetics, high and high-average transporters for creatinine had higher values for both peritoneal protein (11.85 ± 6.77 vs. 7.85 ± 4.36 g/day; p = 0.002) and albumin (5.03 ± 2.32 vs. 3.72 ± 1.54 g/day; p = 0.016) loss as compared to slow transporters. However, in the group of 40 diabetics, this association was not observed. Upon multivariable regression analysis, the independent association of D/PCr with peritoneal albumin (ß = 0.313; p = 0.008) and protein (ß = 0.441; p = 0.001) loss was found only in non-diabetics in whom ultrafiltration also appeared as a significant predictor of peritoneal protein loss (ß = 0.330; p = 0.000). A high comorbidity grade, older age, and low serum albumin were associated with mortality, but both peritoneal protein and albumin loss as well as D/Pcr were not determinants of survival. Baseline peritoneal protein and albumin loss was not associated with DM and did not predict survival. The clinical significance of the absence of association between fast peritoneal transport status and peritoneal protein flux in diabetics should be evaluated in a prospective study comprising a greater number of diabetics with evaluation of overhydration as a main inducing variable of protein leak.

Nonasthmatic Churg-Strauss syndrome superimposed on chronic pyelonephritis: a case report.

Churg-Strauss syndrome (CSS) is a granulomatous small-vessel vasculitis. Asthma is seen in the majority of patients with CSS, but atypical nonasthmatic forms of CSS are also being recognized. We herein describe a 67-year-old woman with a history of chronic pyelonephritis and drug allergy reactions who was admitted to our hospital because of worsening renal function preceded by fever, purpura, sinusitis, and a positive urine culture that confirmed a urinary infection. She was initially treated with pipemidic acid for 7 days, followed by clarithromycin for sinusitis. Laboratory tests on admission showed an absolute eosinophil count of 1750 cells/µL and serum creatinine concentration of 4.72 mg/dL. Urine and blood cultures showed no growth. Kidney biopsy revealed crescent formations with diffuse interstitial fibrosis and foci of eosinophil infiltration. An atypical form of CSS was diagnosed based on tissue eosinophilia, peripheral eosinophilia, and sinusitis. Intravenous methylprednisolone and cyclophosphamide pulse therapy together with hemodialysis treatment improved the patient's clinical condition but did not resolve the kidney damage. The onset of an atypical form of CSS in our patient manifested as symptoms and signs mimicking those of chronic pyelonephritis and drug allergy reactions. The patient's chronic kidney disease finally progressed to dialysis dependence.

mTOR Inhibitor Therapy and Metabolic Consequences: Where Do We Stand?

mTOR (mechanistic target of rapamycin) protein kinase acts as a central integrator of nutrient signaling pathways. Besides the immunosuppressive role after solid organ transplantations or in the treatment of some cancers, another promising role of mTOR inhibitor as an antiaging therapeutic has emerged in the recent years. Acute or intermittent rapamycin treatment has some resemblance to calorie restriction in metabolic effects such as an increased insulin sensitivity. However, the chronic inhibition of mTOR by macrolide rapamycin or other rapalogs has been associated with glucose intolerance and insulin resistance and may even provoke type II diabetes. These metabolic adverse effects limit the use of mTOR inhibitors. Metformin is a widely used drug for the treatment of type 2 diabetes which activates AMP-activated protein kinase (AMPK), acting as calorie restriction mimetic. In addition to the glucose-lowering effect resulting from the decreased hepatic glucose production and increased glucose utilization, metformin induces fatty acid oxidations. Here, we review the recent advances in our understanding of the metabolic consequences regarding glucose metabolism induced by mTOR inhibitors and compare them to the metabolic profile provoked by metformin use. We further suggest metformin use concurrent with rapalogs in order to pharmacologically address the impaired glucose metabolism and prevent the development of new-onset diabetes mellitus after solid organ transplantations induced by the chronic rapalog treatment.

Comparison of accepted and unaccepted living kidney donors: one-center experience.

BACKGROUND: Kidney transplantation from living donors (LD) has stagnated in many countries. This study aimed to check whether correction of LD selection practice could increase the number of kidney transplantations. METHODS: From January 2003 to December 2012, 241 potential adult LD were evaluated in our hospital. Outcome (mortality and end-stage renal disease-ESRD) of accepted LD (182) was compared with unaccepted (59) donors. RESULTS: Mortality of LD was comparable with that for the standardized Serbian population (SMR = 1.104; 95% CI (0.730-1.606). Among evaluated potential LD, almost every fourth had been unaccepted, but reasons were modifiable in 42.4% of them. In pre-donation period unaccepted donors were significantly older, measured glomerular filtration rate was lower, with higher 15-year and lifelong projected ESRD risks than accepted donors. Despite this, ten years outcome of both groups LD was similar: none of LD developed ESRD, 9.8% of accepted and 11.8% of unaccepted LD died (p = .803). CONCLUSIONS: During an average of 101 months of follow-up mortality of accepted LD did not differ significantly as compared to the age standardized Serbian population and none of them developed ESRD. In examination of potential LD, the use of accurate and precise methods for kidney function estimation and the evaluation of risk for ESRD and mortality as well as treatment of modifiable contraindications for kidney donation are necessary.

The Role of Quinidine in the Pharmacological Therapy of Ventricular Arrhythmias 'Quinidine'.

Historically, quinidine was the first medicine used in the therapy of heart arrhythmias. Studies in the early 20th century identified quinidine, a diastereomer of the antimalarial quinine, as the most potent of the antiarrhythmic substances extracted from the cinchona plant. Quinidine is used by the 1920s, as an antiarrhythmic agent to maintain sinus rhythm after the conversion from atrial flutter or atrial fibrillation and to prevent recurrence of ventricular tachycardia or ventricular fibrillation. Its value in chronic prophylaxis of relapse of ventricular arrhythmia was brought under suspicion after publishing of meta analysis that showed that the application of quinidine increases mortality. Due to numerous proofs of increased risk for the appearance of ventricular arrhythmia and sudden death, as well as a number of other adverse effects and drug interactions, quinidine was withdrawn from use and in the recent years has become unavailable in many countries. On the other hand, recent studies have demonstrated that quinidine is the only oral medication that has consistently shown efficacy in preventing arrhythmias and terminating storms due to recurrent ventricular fibrillation, in patients with Brugada syndrome, idiopathic ventricular fibrillation and early repolarization syndrome. Quinidine is also the only antiarrhythmic drug that normalized the QT interval in patients with the congenital short QT syndrome. The aim of this review is to provide good insight into pro and contra arguments for quinidine use in ventricular arrhythmias evidence based on recently published literature.

Innate Immune Response in Kidney Ischemia/Reperfusion Injury: Potential Target for Therapy.

Acute kidney injury caused by ischemia and subsequent reperfusion is associated with a high rate of mortality and morbidity. Ischemia/reperfusion injury in kidney transplantation causes delayed graft function and is associated with more frequent episodes of acute rejection and progression to chronic allograft nephropathy. Alloantigen-independent inflammation is an important process, participating in pathogenesis of injurious response, caused by ischemia and reperfusion. This innate immune response is characterized by the activity of classical cells belonging to the immune system, such as neutrophils, macrophages, dendritic cells, lymphocytes, and also tubular epithelial cells and endothelial cells. These immune cells not only participate in inflammation after ischemia exerting detrimental influence but also play a protective role in the healing response from ischemia/reperfusion injury. Delineating of complex mechanisms of their actions could be fruitful in future prevention and treatment of ischemia/reperfusion injury. Among numerous so far conducted experiments, observed immunomodulatory role of adenosine and adenosine receptor agonists in complex interactions of dendritic cells, natural killer T cells, and T regulatory cells is emphasized as promising in the treatment of kidney ischemia/reperfusion injury. Potential pharmacological approaches which decrease NF-κB activity and antagonize mechanisms downstream of activated Toll-like receptors are discussed.

Mitochondria-Targeted Antioxidants: Future Perspectives in Kidney Ischemia Reperfusion Injury.

Kidney ischemia/reperfusion injury emerges in various clinical settings as a great problem complicating the course and outcome. Ischemia/reperfusion injury is still an unsolved puzzle with a great diversity of investigational approaches, putting the focus on oxidative stress and mitochondria. Mitochondria are both sources and targets of ROS. They participate in initiation and progression of kidney ischemia/reperfusion injury linking oxidative stress, inflammation, and cell death. The dependence of kidney proximal tubule cells on oxidative mitochondrial metabolism makes them particularly prone to harmful effects of mitochondrial damage. The administration of antioxidants has been used as a way to prevent and treat kidney ischemia/reperfusion injury for a long time. Recently a new method based on mitochondria-targeted antioxidants has become the focus of interest. Here we review the current status of results achieved in numerous studies investigating these novel compounds in ischemia/reperfusion injury which specifically target mitochondria such as MitoQ, Szeto-Schiller (SS) peptides (Bendavia), SkQ1 and SkQR1, and superoxide dismutase mimics. Based on the favorable results obtained in the studies that have examined myocardial ischemia/reperfusion injury, ongoing clinical trials investigate the efficacy of some novel therapeutics in preventing myocardial infarct. This also implies future strategies in preventing kidney ischemia/reperfusion injury.

Effects of everolimus on oxidative stress in kidney model of ischemia/reperfusion injury.

BACKGROUND/AIMS: Reactive oxygen species play an important role in the pathogenesis of kidney ischemia/reperfusion injury (IRI) which may be influenced by immunosuppressive therapy. Pertinent to this, we investigated the effects of the mTOR inhibitor everolimus on redox settings and the activity of the anti-oxidative system in kidneys exposed to IRI. METHODS: C57BL/6 mice were subjected to IRI by clamping both renal pedicles for 45 min. Everolimus was applied in daily, subcutaneous doses (0.25 mg/kg body weight), starting 1 day before IRI induction. Both everolimus-treated and non-treated mice were sacrificed at several time points, starting 30 min and finishing 7 days after IRI induction. Markers of oxidation such as glutathione and NADPH levels and anti-oxidative enzyme activities were determined in the kidneys. RESULTS: In comparison to both sham and non-treated animals, the treatment with everolimus resulted in an increased level of markers of oxidation, including a lower level of glutathione, increased level of oxidized glutathione and reduced level of NADPH. The activity of superoxide dismutase was reduced in both experimental groups, but the effects were less pronounced in everolimus-treated animals. In the early phase of reperfusion, everolimus-treated animals showed higher activity of glutathione reductase in comparison to non-treated animals, whereas the activities of glutathione peroxidase and catalase were generally similar. The treatment with everolimus significantly reduced heme oxygenase-1 expression and increased iNOS mRNA expression when compared to non-treated animals. CONCLUSION: Our data imply that everolimus treatment may decrease cytoprotective capacity in kidneys exposed to IRI due to promoted oxidative/nitrosative stress.

[Influence of blood pressure control on maintenance of residual function in patients treated by haemodialysis].

INTRODUCTION: Residual renal function (RRF) in the patients treated by haemodialysis (HD) is associated not only with better volume and blood pressure control but also with better metabolic control.The condition of the cardiovascular system significantly affects RRF. OBJECTIVE: The aim of the study was to find if there was any association between blood pressure regulation and the achieved HD ultrafiltration in the first year of haemodialysis treatment and the maintenance of RRF. METHODS: In this retrospective study, 53 patients were analyzed in the period 1994-2002. Residual clearance of urea (RCU) was measured for the first time at the beginning of HD treatment, and for the second time one year later. Laboratory data and values of blood pressure as well as the achieved HD ultrafiltration were taken from the electronic database of the Nephrology Hospital. RESULTS: The value of RCU less than 1 ml/min was considered as the loss of RRF and, at the beginning of HD treatment, 14 patients (26.4%) had that result. The rise of mean arterial pressure (MAP) was associated in linear regression analysis with a drop of residual diuresis volume (beta = -0.28; p = 0.04), but there was no association with RCU. The patients with MAP > 105 mm Hg had RKU less than the patients with MAP < 105 mm Hg (t = 2.23; p = 0.03). The rise of the HD ultrafiiltration significantly affected the loss of RRF obtained by the linear regression analysis (beta = -0.44; p = 0.0001). CONCLUSION: The greater HD ultrafiltration is related to a drop of RCU values. Only prospective randomised trials with the use of multiple regression analysis could define a more precise association between hypertension and RKU.

[Multiorgan dysfunction in a gravid woman with placental abruption and disseminated intravascular coagulation].

The most frequent obstetrical cause of coagulation disorders as disseminated intravascular coagulation is placental abruption, which can be found in women without any apparent clinical disturbances or in the state of established preeclampsia. Hypertension occurs in 5-8% of all pregnancies and may be complicated by preeclampsia. Preeclampsia is a complex clinical syndrome with insufficiently clear pathophysiology based on the damage of the vascular endothelium. As a result of this, generalized endothelial disruption in preeclampsia, a multiorgan dysfunction, can develop, most frequently reflected in the clinical presentation with haematological and renal disturbances and with a disordered function of the liver and central nervous system. We are presenting a case of a gravid woman with poorly regulated hypertension that resulted from development of preeclampsia, later complicated by placental abruption and disseminated intravascular coagulation (DIC) with multi-organ dysfunction. The importance of rapid recognition of coagulation disorder and the attempt at surgical treatment aiming at removal of the triggering mechanisms of DIC was shown, suggesting all the symptomatic therapeutic measures would be ineffective. Although our patient was surgically treated in the phase of generalised disorder characterised by development of coma, acute respiratory distress syndrome and renal insufficiency when mortality was 70%, the recovery of functions of all involved organs was achieved, except for the renal function that required chronic haemodialysis treatment.

[Hepatorenal syndrome].

Hepatorenal syndrome is complication of the advanced cirrhosis characterized by functional renal failure and changes of systemic blood pressure due to increased activity of endogenous vasoactive systems. Functional renal failure is due to severe renal cortical ischemia and reduction of glomerular filtration rate (GFR) developing in the late stages of cirrhosis. The pathogenesis of hepatorenal syndrome is the result of an extreme underfilling of the arterial circulation secondary to arterial vasodilatation located in the splanchnic circulation. Reduced effective arterial blood volume triggers a compensatory response with activation of systemic and renal vasoconstrictor systems. At the same time, the ascites becomes refractory in some patients, as it is no longer responsive to diuretic treatment. These changes result from combination of deteriorating liver function and increasing portal pressure, further splanchnic vasodilatation, increase of circulating vasoconstrictors, and decrease of renal blood flow and GFR. Hepatorenal syndrome can be precipitated by shock, infection, nephrotoxic drugs, bleeding, surgery or large volume paracentesis. Renal failure may be rapidly progressive (type I HRS) or may develop more slowly (type II HRS), which is usually associated with refractory ascites. The diagnosis of HRS is based on established diagnostic criteria aimed at excluding the nonfunctional causes of renal failure. The prognosis of patients with HRS is very poor. Liver transplantation remains the only curative treatment for the time being. Pharmacological therapies based on the use of vasoconstrictor drugs may serve as a bridge to liver transplantation. Prevention of HRS by albumin infusion is recommended in patients with spontaneous bacterial peritonitis and by pentoxifylline in patients with the acute alcoholic hepatitis.