Myogenic constriction in renal failure : cause and therapy

In bloeddruk regulerende vaten, de zogenaamde weerstandsvaten, wordt myogene constrictie geactiveerd door verhoogde transmurale druk. De verhoogde transmurale druk zorgt voor contractie van het arteriële gladde spierweefsel, met vernauwing van het lumen en daardoor verminderde bloeddoorstroming naar de organen als gevolg. Myogene constrictie is een belangrijk autoregulatoir mechanisme van vaten: het draagt bij aan een constante doorbloeding van organen, ondanks variaties in systemische bloeddruk. In de nier is een toename van de intraglomerulaire druk een belangrijke factor in de ontwikkeling van nierschade. Vele factoren dragen bij aan de verslechtering van myogene constrictie, zoals hypertensie en diabetes mellitus. Ook de myogene constrictie in perifere arteriën verslechtert door nierfalen. Onze belangrijkste waarnemingen waren: hogere myogene constrictie van renale preglomerulaire vaten, is geassocieerd met een verminderde kwetsbaarheid voor nierschade in drie ratmodellen van chronische nierziekten: de 5/6 nefrectomie; de diabetische Zucker Diabetic Fatty rat; en een genetisch model voor hypertensie en nierschade: de Fawn Hooded rat. Verder hebben we in deze modellen de myogene constrictie onderzocht in mesenterische vaten, als maat voor de perifere vasculaire autoregulatie. Hierin lieten we zien dat de ontwikkeling van hypertensie, maar niet die van chronische nierziekten, geassocieerd is met verminderde myogene constrictie in deze arteriën. Tenslotte hebben we laten zien dat verschillende behandelingen myogene constrictie in zowel renale als perifere vaten van ratten met chronische nierziekten kan verbeteren. De studies tonen aan dat een goede werking van de vasculaire gladde spiercontractie in kleine nierslagaders cruciaal is in het beperken van nierschade en de progressie van nierziekte. In resistance arteries, myogenic constriction (MC) is activated by elevated transmural pressure, which causes contraction of arterial smooth muscle leading to reduction of vessel lumen thereby reducing blood flow in target organs. Myogenic constriction, as a vascular autoregulatory mechanism, helps to maintain stable blood flow over a wide systemic pressure range. Failure of MC in preglomerular arteries causes increased glomerular pressure resulting in chronic kidney disease (CKD). Many factors may contribute to impairment of MC e.g. hypertension or diabetes mellitus. Peripheral arteries MC is however, affected as well. Our key observations were: Higher MC of preglomerular vessels is associated with lower vulnerability of kidneys to damage in several rat models: reduced renal mass/hypertension – 5/6Nx, type 2 diabetes mellitus – ZDF rat, and in ageing induced hypertension with predisposition to kidney damage – FH rat. Furthermore, we examined MC of mesenteric artery, as a representative of the peripheral vasculature, in these models and demonstrate that development of hypertension - but not CKD - is associated with decreased MC in this artery. Than we identifyed in vivo glomerular vascular contractility to Angiotensin II can predict individual susceptibility to CKD in the adriamycine model and in 5/6Nx model. Finally we showed that several types of treatment improve MC in both the renal and peripheral vascular bed of rats with CKD with and without hypertension. The studies presented in this thesis therefore demonstrate that the patency of vascular smooth muscle contraction in small renal arteries is pivotal in limiting renal damage and limiting progression of renal disease.

Case Report:Enhanced Diazepam Elimination With the Molecular Adsorbents Recirculating System (MARS) in Severe Autointoxication: A Survival Case Report

Objective: Due to the extensive use of diazepam worldwide, self-induced intoxication is very common, yet rarely fatal. Nevertheless, the management of intoxication caused by extremely high doses of diazepam is not known, as well as the effectiveness of flumazenil, a specific benzodiazepine (BDZ) antagonist. Here we present the first report on the enhanced elimination (clearance) of diazepam using the Molecular Adsorbents Recirculating System (MARS) following autointoxication with an extremely high dose as part of a suicide attempt. Case: A 44-year-old male patient was admitted to the ICU because of impaired consciousness following the ingestion of 20 g of diazepam. Blood and urine samples revealed high benzodiazepine levels. Repeated doses of flumazenil were without effect on consciousness. Following deterioration of the patient's clinical condition, including unconsciousness, hypoventilation, and decreased SpO2 (88%), the patient was intubated and mechanically ventilated. On the fourth day after admission, the patient was unresponsive, with no attempt to breath spontaneously. The plasma level of benzodiazepines was 1,772 mu g/l. The elimination of benzodiazepines by MARS was attempted, continuing for 5 days, with one session per day. Five sessions of MARS effectively enhanced benzodiazepine elimination. After the first MARS treatment, the plasma level of benzodiazepines dropped from 1,772 to 780 mu g/l. After the final MARS treatment on the eighth day, the patient was weaned from mechanical ventilation and extubated. Two days later, the patient was discharged to the internal medicine department and subsequently to the psychiatry department. Conclusions: To the best of our knowledge, this is the first case reporting successful treatment of diazepam intoxication using MARS. In severe cases of diazepam intoxication, with prolonged unconsciousness and the necessity of mechanical ventilation, we suggest considering the use of MARS elimination therapy together with the monitoring of the BDZ plasma level

The protective effect of 1-methyltryptophan isomers in renal ischemia-reperfusion injury is not exclusively dependent on indolamine 2,3-dioxygenase inhibition

BACKGROUND AND PURPOSE: Indolamine 2,3-dioxygenase (IDO), an enzyme that catalyses the metabolism of tryptophan, may play a detrimental role in ischemia-reperfusion injury (IRI). IDO can be inhibited by 1-methyl-tryptophan, which exists in a D (D-MT) or L (L-MT) isomer. These forms show different pharmacological effects besides IDO inhibition. Therefore, we sought to investigate whether these isomers can play a protective role in renal IRI, either IDO-dependent or independent. EXPERIMENTAL APPROACH: We studied the effect of both isomers in a rat renal IRI model with a focus on IDO-dependent and independent effects. KEY RESULTS: Both MT isomers reduced creatinine and BUN levels, with D-MT having a faster onset of action but shorter duration and L-MT a slower onset but longer duration (24 h and 48 h vs 48 h and 96 h reperfusion time). Interestingly, this effect was not exclusively dependent on IDO inhibition, but rather from decreased TLR4 signalling, mimicking changes in renal function. Additionally, L-MT increased the overall survival of rats. Moreover, both MT isomers interfered with TGF-β signalling and epithelial-mesenchymal transition. In order to study the effect of isomers in all mechanisms involved in IRI, a series of in vitro experiments was performed. The isomers affected signalling pathways in NK cells and tubular epithelial cells, as well as in dendritic cells and T cells. CONCLUSION AND IMPLICATIONS: This study shows that both MT isomers have a renoprotective effect after ischemia-reperfusion injury, mostly independent of IDO inhibition, involving mutually different mechanisms. We bring novel findings in the pharmacological properties and mechanism of action of MT isomers, which could become a novel therapeutic target of renal IRI

A case of severe chlorite poisoning successfully treated with early administration of methylene blue, renal replacement therapy, and red blood cell transfusion:case report

The case of a 55-year-old man who attempted suicide by ingesting <100 mL of 28% sodium chlorite solution is presented. On arrival in the intensive care unit, the patient appeared cyanotic with lowered consciousness and displayed anuria and chocolate brown serum.Initial laboratory tests revealed 40% of methemoglobin. The formation of methemoglobin was effectively treated with methylene blue (10% after 29 hours).To remove the toxin, and because of the anuric acute renal failure, the patient received renal replacement therapy. Despite these therapeutic measures, the patient developed hemolytic anemia and disseminated intravascular coagulation, which were treated with red blood cell transfusion and intermittent hemodialysis. These interventions led to the improvement of his condition and the patient eventually fully recovered. Patient gave written informed consent.This is the third known case of chlorite poisoning that has been reported. Based upon this case, we suggest the management of sodium chlorite poisoning to comprise the early administration of methylene blue, in addition to renal replacement therapy and transfusion of red blood cells

Gastrointestinal tuberculosis following renal transplantation accompanied with septic shock and acute respiratory distress syndrome:A survival case presentation

Background: Post-transplant tuberculosis (PTTB) is a serious opportunistic infection in renal graft recipients with a 30-70 fold higher incidence compared to the general population. PTTB occurs most frequently within the first years after transplantation, manifesting as pulmonary or disseminated TB. Gastrointestinal TB (GITB) is a rare and potentially lethal manifestation of PTTB and may show delayed onset in renal transplant recipients due to the use of lower doses of immunosuppressants. Further, non-specificity of symptoms and the common occurrence of GI disorders in transplant recipients may delay diagnosis of GITB. Case presentation: Here we report a rare survival case of isolated GITB in a renal transplant recipient, occurring seven years after transplantation. The patient's condition was complicated by severe sepsis with positive blood culture Staphylococcus haemolyticus, septic shock, multiple organ failure including acute respiratory distress syndrome (ARDS) and acute renal failure, requiring mechanical ventilation, vasopressor circulatory support and intermittent hemodialysis. Furthermore, nosocomial infections such as invasive aspergillosis and Pseudomonas aeruginosa occurred during hospitalization. Antituberculosis therapy (rifampicin, isoniazid, ethambutol and pyrazinamide) was initiated upon Mycobacterium confirmation. Moreover, treatment with voriconazole due to the Aspergillus flavus and meropenem due to the Pseudomonas aeruginosa was initiated, the former necessitating discontinuation of rifampicin. After 34 days, the patient was weaned from mechanical ventilation and was discharged to the pulmonary ward, followed by complete recovery. Conclusion: This case offers a guideline for the clinical management towards survival of GITB in transplant patients, complicated by septic shock and multiple organ failure, including acute renal injury and ARDS

Renal endothelial function is associated with the anti-proteinuric effect of ACE inhibition in 5/6 nephrectomized rats

In healthy rats, the physiological variation of baseline endothelial function of intrarenal arteries correlates with the severity of renal damage in response to a subsequent specific renal injury. However, whether such a variation in endothelial function may also condition or predict the variable response to angiotensin-converting enzyme-inhibiting treatment in these individuals has not been addressed before. To study this, 5/ 6 nephrectomy was performed to induce renal injury and chronic kidney disease in a group of healthy Wistar rats. At the time of nephrectomy, interlobar arteries were obtained from the extirpated right kidney and studied in vitro for endothelium-dependent relaxation to acetylcholine. Six weeks thereafter, treatment with lisinopril was started (n = 11) and continued for 9 wk. Proteinuria (metabolic cages) and systolic blood pressure (SBP; tail cuff) were evaluated weekly, and these were analyzed in relation to renal endothelial function at baseline. 5/ 6 Nephrectomy induced an increase in SBP and progressive proteinuria. Treatment with lisinopril reduced SBP and slowed proteinuria, albeit to a variable degree among individuals. The acetylcholine-induced renal artery dilation at baseline negatively correlated with lisinopril-induced reduction of proteinuria (r(2) = 0.648, P = 0.003) and with the decrease in SBP (r(2) = 0.592, P = 0.006). Our data suggest that angiotensin-converting enzyme-inhibitor attenuates the progression of renal damage the most in those individuals with decreased basal renal endothelial-mediated vasodilation

Losartan protects mesenteric arteries from ROS-associated decrease in myogenic constriction following 5/6 nephrectomy

Background: Chronic renal failure (CRF) is associated with hypertension, proteinuria, loss of myogenic constriction (MC) of mesenteric arteries and increased production of reactive oxygen species (ROS) under experimental conditions. Previous results showed that ACE (angiotensin-converting enzyme activity) inhibitor therapy is effective in slowing down the progression of disease. Therefore, we wanted to study whether the inverse AT(1) (angiotensin II type 1) receptor agonist, losartan (LOS) was effective in preventing loss of MC in a rat model of CRF and whether acute ROS scavengers could improve MC. Methods: Rats underwent 5/6 nephrectomy (5/6 Nx) and were treated with vehicle or LOS (20 mg/kg/day; 5/6 Nx + LOS) for 12 weeks. Thereafter, the MC of the mesenteric arteries were measured in the presence and/or absence of tempol and catalase. Systolic blood pressure and proteinuria were measured weekly. Results: Systolic blood pressure and proteinuria in the 5/6 Nx + LOS group were significantly lower than in the 5/6 Nx group. Moreover, the MC of 5/6 Nx + LOS arteries was significantly increased compared with the untreated 5/6 Nx group (maximum MC, 32.3 +/- 6.9 vs 8.9 +/- 3.8% (p <0.01)). Tempol + catalase significantly increased the MC in the 5/6 Nx group, but not in the 5/6 Nx + LOS group (increase in MC, 59.7 +/- 13.0 (p <0.05) vs. 17.0 +/- 15.1%). Conclusion: These results support the roles of the RAAS (renin-angiotensin-aldosterone system) and ROS in the vascular dysfunction of systemic vessels in CRF

Extracellular DNA concentrations in various aetiologies of acute kidney injury

Extracellular DNA (ecDNA) in plasma is a non-specific biomarker of tissue damage. Urinary ecDNA, especially of mitochondrial origin, is a potential non-invasive biomarker of kidney damage. Despite prominent tissue damage, ecDNA has not yet been comprehensively analysed in acute kidney injury (AKI). We analysed different fractions of ecDNA, i.e. total, nuclear and mitochondrial, in plasma and urine of children, and different animal models of AKI. We also analysed the activity of the deoxyribonuclease (DNase), which is contributes to the degradation of ecDNA. Patients with AKI had higher total and nuclear ecDNA in both, plasma and urine (sixfold and 12-fold in plasma, and 800-fold in urine, respectively), with no difference in mitochondrial ecDNA. This was mainly found for patients with AKI due to tubulointerstitial nephritis and atypical haemolytic uremic syndrome. Increased plasma ecDNA was also found in animal models of AKI, including adenine nephropathy (fivefold), haemolytic uremic syndrome (fourfold), and ischemia–reperfusion injury (1.5-fold). Total urinary ecDNA was higher in adenine nephropathy and ischemia–reperfusion injury (1300-fold and twofold, respectively). DNase activity in urine was significantly lower in all animal models of AKI in comparison to controls. In conclusion, plasma total and nuclear ecDNA and urinary total ecDNA is increased in patients and animals with particular entities of AKI, suggesting a mechanism-dependent release of ecDNA during AKI. Further studies should focus on the dynamics of ecDNA and its potential role in the pathogenesis of AKI.publishedVersio