Impaired Excretion Research Articles

Interplay between the glymphatic system and neurotoxic proteins in Parkinson's disease and related disorders: current knowledge and future directions.

Parkinson's disease is a common neurodegenerative disorder that is associated with abnormal aggregation and accumulation of neurotoxic proteins, including α-synuclein, amyloid-β, and tau, in addition to the impaired elimination of these neurotoxic protein. Atypical parkinsonism, which has the same clinical presentation and neuropathology as Parkinson's disease, expands the disease landscape within the continuum of Parkinson's disease and related disorders. The glymphatic system is a waste clearance system in the brain, which is responsible for eliminating the neurotoxic proteins from the interstitial fluid. Impairment of the glymphatic system has been proposed as a significant contributor to the development and progression of neurodegenerative disease, as it exacerbates the aggregation of neurotoxic proteins and deteriorates neuronal damage. Therefore, impairment of the glymphatic system could be considered as the final common pathway to neurodegeneration. Previous evidence has provided initial insights into the potential effect of the impaired glymphatic system on Parkinson's disease and related disorders; however, many unanswered questions remain. This review aims to provide a comprehensive summary of the growing literature on the glymphatic system in Parkinson's disease and related disorders. The focus of this review is on identifying the manifestations and mechanisms of interplay between the glymphatic system and neurotoxic proteins, including loss of polarization of aquaporin-4 in astrocytic endfeet, sleep and circadian rhythms, neuroinflammation, astrogliosis, and gliosis. This review further delves into the underlying pathophysiology of the glymphatic system in Parkinson's disease and related disorders, and the potential implications of targeting the glymphatic system as a novel and promising therapeutic strategy.

Warburg-Effect Driven Lactic Acidosis Is Associated with Early Death in Patients with Lymphoma

Introduction: Lactic acidosis is a medical emergency and in most cases results from an imbalance between tissue oxygenation and oxygen demand (Type A). However, Type B lactic acidosis occurs in the absence of a recognizable impairment in systemic oxygen delivery, and is most commonly associated with drug or toxin ingestion, sepsis, severe nutritional deficits such as thiamine, and less commonly, malignancy. The capacity of shifting glucose metabolism to anaerobic pathway despite the presence of adequate oxygen, enhancing the rate of glucose uptake, accelerated glycolysis and hence producing more lactate, is a well-defined phenomenon in malignant cell metabolism, and is called the Warburg Effect (WE) or aerobic glycolysis. A systemic rise in lactate and lactic acidosis has been reported in hematologic malignancies and less commonly in solid tumors, and is thought to occur as a consequence of both increased production of lactate- reflecting high malignancy burden, and impaired lactate turnover or elimination by liver or kidney. Few case reports or series have demonstrated a possible correlation between early death and elevated lactate in patients with hematologic malignancy (Table 1). We aimed to characterize the incidence and clinical impact of Warburg-driven lactic acidosis on outcome including early death. Methods: A retrospective study of patients admitted to the haemato-oncology department in a large tertiary medical center between the years 2013- 2022, that presented with elevated lactate levels during the first week of admission. Patients with hematologic diseases other than lymphoma were excluded. Of 40 patients reviewed, 21 patients were excluded because of underlying hematological malignancy other than lymphoma. Medical records were retrieved and reviewed for a recognizable cause for elevated lactate, or non (assigned as the WE group). Early-death was defined as death of any cause within 4 weeks of admission. Results: Nineteen patients had lymphoma and elevated lactate levels within the first week of admission. Of these, 12 patients fulfilled the criteria for WE and 7 patients had their high lactate attributed to other causes such as hemorrhagic shock (n=1), sepsis (n=5) and concomitant metformin use (n=1). Median age among patients with WE was 72.5 years (range 66-86) with 41.6% (n=5) males. All but one had aggressive lymphoma. Diffuse Large B cell Lymphoma was the most frequent type (n=9) followed by T cell Lymphoma (n=2) and follicular lymphoma (n=1). Most patients had advanced disease (Stage III-IV in 75%) and the median International Prognostic Index (IPI) of the patients was 4 (range 3-5). The median lactate level was 31.5 mg/dL (range 25-64; with upper limit of normal value-20 mg/dL). Two patients received thiamin therapy once WE was recognized. Early-death rate was 75% (9 patients) among patients with WE. The established cause of death in this population was: sepsis (n=3), DIC (n=1), uremia and multi organ failure (n=2) and respiratory failure due to lung infiltration by lymphoma (n=3). Both steroid and chemotherapy were initiated earlier in surviving patients as compared to those who died early (within 4 weeks of admission); in surviving patients, chemotherapy was initiated at a median of 3 days before first elevated lactate was detected (range (-)7-1), and steroids at median of 3 days before first elevated lactate was detected, while in those who died early, chemotherapy was initiated at median of 5 days after first elevated lactate was detected (range (-)2-18) and steroids at median 1 day after first elevated lactate (p=0.29 and 0.05 for steroids and chemo, respectively). (Table 2). Conclusion: Warburg driven lactic acidosis is a marker of ‘acute cancer’ in lymphoma patients and is associated with a very high mortality rate. Early recognition of this very high-risk clinical scenario is of utmost importance and should prompt immediate anti-lymphoma therapy that may improve outcome.

Characteristics of acute kidney injury in patients with acute decompensation of heart failure

Introduction. Acute decompensation of heart failure (AHF) can cause acute kidney injury (AKI), hyponatremia, episodes of oliguria and polyuria in the treatment of furosemide. These complications lengthen the time of hospitalization, increase the economic costs of treatment and worsen the prognosis. Currently, the relationship of these manifestations in patients with CHF has not been studied.Objective. To evaluate the effect of AKI on the rate of diuresis and the level of plasma sodium during the complex therapy of AHF.Materials and methods. Kidney function was assessed in 125 patients receiving complex therapy for AHF. The glomerular filtration rate (GFR) was determined in two ways: by the level of creatinine and cystatin C in blood serum. The number of AKI, hyponatremia, episodes of oliguria and polyuria were studied. An analysis of the relationship between these events was carried out.Results. At the time of admission to the hospital, the study of GFR by the level of cystatin C showed 2.6 times more AKI than by the level of creatinine. In total, AKI was found in 22.4% of cases, hyponatremia in 24.8%, episodes of oliguria in 18.4%, episodes of polyuria in 24.8%. The analysis showed that there is a connection of violations of the rate of diuresis and hyponatremia with AKI.Conclusions. Сases of impaired urinary excretion and hyponatremia during AHF therapy are more common in patients with AKI.

Molecular mechanisms regulating uric acid metabolism in the human intestine, systematic literature review

This review presents recent data on direct and indirect pathogenetic relationships between metabolism of purine compounds and biochemical processes in cells of the digestive system. A comprehensive analysis of available modern publications for the period from 2000 to 2022 in the Scopus, PubMed, eLIIBRARY, and Google Scholar databases was performed. The hypothesis linking the pathogenesis of hyperuricemia to “renal overload” suggests that the disease may develop due to impaired renal excretion with insufficient excretion of uric acid (UA) via the intestine. Some of the UA transport systems work actively in hepatocytes and enterocytes, which determines their formation and excretion. UA transporter proteins are divided into two categories: urate reabsorption transporters and urate excretion transporters; their expression is regulated by transcription factors, hormones, and metabolites of the intestinal microflora. The influence of intestinal microbiota on UA metabolism is associated with its involvement in purine metabolism, degradation and excretion of UA together with metabolites of intestinal flora, and suppression of gout inflammation, and is evaluated as a new therapeutic potential for gout and hyperuricemia to prevent renal damage and urolithiasis.

Consequences of Disturbing Manganese Homeostasis.

Manganese (Mn) is an essential trace element with unique functions in the body; it acts as a cofactor for many enzymes involved in energy metabolism, the endogenous antioxidant enzyme systems, neurotransmitter production, and the regulation of reproductive hormones. However, overexposure to Mn is toxic, particularly to the central nervous system (CNS) due to it causing the progressive destruction of nerve cells. Exposure to manganese is widespread and occurs by inhalation, ingestion, or dermal contact. Associations have been observed between Mn accumulation and neurodegenerative diseases such as manganism, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. People with genetic diseases associated with a mutation in the gene associated with impaired Mn excretion, kidney disease, iron deficiency, or a vegetarian diet are at particular risk of excessive exposure to Mn. This review has collected data on the current knowledge of the source of Mn exposure, the experimental data supporting the dispersive accumulation of Mn in the brain, the controversies surrounding the reference values of biomarkers related to Mn status in different matrices, and the competitiveness of Mn with other metals, such as iron (Fe), magnesium (Mg), zinc (Zn), copper (Cu), lead (Pb), calcium (Ca). The disturbed homeostasis of Mn in the body has been connected with susceptibility to neurodegenerative diseases, fertility, and infectious diseases. The current evidence on the involvement of Mn in metabolic diseases, such as type 2 diabetes mellitus/insulin resistance, osteoporosis, obesity, atherosclerosis, and non-alcoholic fatty liver disease, was collected and discussed.

Neuropsychiatric disorders in Wilson’s disease: literature review

Wilson’s disease is a rare autosomal recessive disease due to the pathogenic mutations in the ATP7B gene that causes impaired copper excretion in the liver and its accumulation in tissues and organs. Clinically, the disorder of copper metabolism is manifested by various symptoms, usually changes in the liver function, neuropsychiatric symptoms, and Kayser-Fleischer rings in the cornea. Wilson’s disease can be manifested by various neuropsychiatric disorders: cognitive and executive function, sleep and mood disorders, personality changes, or psychosis. Diagnosis of the disease is often delayed, especially when psychiatric symptoms appear. The mechanism of these symptoms is not clear, and the data of the conducted studies are controversial. Copper chelators and zinc are prescribed for the treatment. In order to treat mental disorders, psychotropic drugs and psychotherapy can be used. It is important for healthcare professionals to understand the link of the symptoms of Wilson’s disease and neuropsychiatric disorders in order to achieve timely disease diagnosis and effective treatment. In this article, we review the latest literature on neuropsychiatric disorders in people with Wilson’s disease, their causes, diagnosis, and treatment recommendations.

THU268 Hyperuricemia In Insulin Resistance Is Associated With Increased Synthesis And Not Decreased Renal Excretion Of Uric Acid In Humans

Abstract Disclosure: R. Haykal: None. A. Kinzer: None. B. Abel: None. M. Lightbourne: None. M.S. Startzell: None. E. Cochran: None. R.J. Brown: None. Title: Hyperuricemia in insulin resistance is associated with increased synthesis and not decreased renal excretion of uric acid in humans. Background: In obesity and lipodystrophy (LD), insulin resistance (IR) is “selective”, with lack of insulin signaling causing hyperglycemia, but enhanced insulin signaling causing dyslipidemia. Rare human conditions exist in which there is extreme, non-selective IR impairing all insulin signaling pathways (e.g. mutations of the insulin receptor, INSR), resulting in hyperglycemia without dyslipidemia. We previously found that patients with non-selective IR do not have the hyperuricemia observed in selective IR. Potential mechanisms of hyperuricemia in selective IR include altered expression of renal uric acid transporters leading to impaired uric acid excretion, and increased activity of xanthine oxidoreductase (XOR), causing increased uric acid synthesis. We thus hypothesized that enhanced insulin signaling in selective IR would result in decreased fractional excretion of uric acid (FEUA) and/or increased biomarkers of XOR activity compared to non-selective IR. Method: We conducted 2 cross-sectional analyses of patients with severe IR that was either selective (due to LD) or non-selective (due to INSR mutation). Analysis 1 compared fasting insulin, fasting serum uric acid, and FEUA from 24-hr urine collection in 46 patients with LD and 13 with INSR. Analysis 2 compared products of purine nucleotide catabolism and salvage pathways by untargeted metabolomics in serum of 30 subjects each with LD and INSR. Results: In analysis 1, fasting insulin was lower in LD vs INSR (median 37.5 [25th-75th percentile 23.1-87.0] vs 88.7 [41.9-458.6] mcU/mL; P=0.0097). Serum uric acid was higher in LD vs INSR (5.3±1.6 vs 3.3±1.0 mg/dL; P=0.04). FEUA was comparable in the 2 groups (9.0±5 vs 8.5±3.5%; P=0.75). In analysis 2, uric acid was 1.6 fold higher (P<0.0001) in LD vs INSR. Xanthine, hypoxanthine, and xanthine to hypoxanthine ratio were comparable in both groups, but uric acid to xanthine ratio was 1.5 fold higher (P=0.01) and AMP was 0.8 fold lower in LD vs INSR (P=0.0029). Conclusion: Patients with selective IR due to LD had elevated serum uric acid, consistent with the hyperuricemia seen in selective IR due to obesity. By contrast, patients with non-selective IR due to INSR had lower serum uric acid despite higher fasting insulin. However, FEUA did not differ in these groups, thus hyperuricemia in non-selective IR might not be related to decreased renal excretion of uric acid. Elevated uric acid to xanthine ratio and lower AMP in selective IR suggest increased irreversible conversion of xanthine to uric acid by XOR, precluding salvage of purine nucleotides to AMP. Direct measurement of XOR activity in selective vs non-selective IR is needed to this potential mechanism by which insulin may lead to hyperuricemia. Presentation: Thursday, June 15, 2023

The role of glycosaminoglycans in blood pressure regulation.

Essential hypertension (HT) is the global health problem and is a major risk factor for the development of cardiovascular and kidney disease. High salt intake has been associated with HT and impaired kidney sodium excretion is considered to be a major mechanism for the development of HT. Although kidney has a very important role in regulation of BP, this traditional view of BP regulation was challenged by recent findings suggesting that nonosmotic tissue sodium deposition is very important for BP regulation. This new paradigm indicates that sodium can be stored and deposited nonosmotically in the interstitium without water retention and without increased BP. One of the major determinants of this deposition is glycosaminoglycans (GAGs). By binding to GAGs found in the endothelial surface layer (ESL) which contains glycocalyx, sodium is osmotically inactivated and not induce concurrent water retention. Thus, GAGs has important function for homeostatic BP and sodium regulation. In the current review, we summarized the role of GAGs in ESL and BP regulation.

A-126 Evaluation of NMR-based GFR Estimation in Dosing of High-dose Methotrexate

Abstract Background The cytotoxic agent methotrexate (MTX) is mainly used in oncology and rheumatology. MTX is 80%–90% excreted unchanged in the urine, thus, impaired renal excretion because of kidney disease leads to accumulation and prolonged exposure, with a consequent increased risk of myelosuppressive and other toxic adverse effects. Direct kidney damage from MTX crystal precipitation and tubular injury may also occur. Therefore, precise and accurate measurement of renal function prior to MTX administration is of paramount importance to determine accurate dosing and to minimize such adverse risks. Commonly used estimated glomerular filtration rate (eGFR) equations perform poorly in patients with cachexia and at later stages of life—the typical oncology patient. Here we evaluate the feasibility of applying the recently introduced nuclear magnetic resonance (NMR)-based GFR equation (GFRNMR) using creatinine, cystatin C, myo-inositol, and valine, in oncology patients receiving high-dose MTX. Methods A series of residual sera from patients scheduled to receive high-dose MTX infusion for oncological indications were collected from two sites: n = 52 sera from the University Hospital Regensburg (Regensburg, Germany), at four time points (t0h, t24h, t42h, and t48h), and n = 10 cross-sectionally from the Mayo Clinic (MN). Standard drug-monitoring trough levels were used as a reference. Serum was prepared and NMR-measured in five replicates for all samples. GFRNMR was compared with the current standard GFR equations: i) CKD-EPI2021Cr (creatinine) and ii) CKD-EPI2021CrCys (creatinine and cystatin-C). Coefficient of determination for linear regression, kappa coefficient for categorical regression and bootstrapped confidence intervals were calculated. Results MTX was shown not to increase the GFRNMR failure rate or affect the intra-assay precision of GFRNMR. When monitoring eGFR during high-dose MTX treatment, MTX affected GFR according to the RIFLE criteria for AKI in 13 cycles in 9 patients; 1/13 were classified as ‘risk’ (creatinine increased 1.5-fold) and 1/13 were classified as ‘injury’ (creatinine increased 2.0-fold). Using MTX clearance as a surrogate for measured GFR, GFRNMR was shown to reflect the MTX plasma clearance constant k more accurately (using a fitting function c = c0*e−kt) with r = 0.758 (95% CI 0.36–0.92, P = 0.004) compared to CKD-EPI2021Cr (r = 0.401, 95%CI −0.19–0.78, P = 0.176) and CKD-EPI2021CrCyc (r = 0.632, 95% CI 0.12–0.88). Conclusion The robustness of GFRNMR test results is not affected by HD-MTX treatment. Compared to standard eGFR equations, GFRNMR is more closely associated with MTX renal clearance rates and may therefore be a novel method to improve the accuracy of MTX dosing in the future.

A-108 Validation of Plasma Oxalate Measurement on the Roche Cobas c501

Abstract Background Measurement of plasma oxalate is important in patients with renal failure as oxalate may build up due to impaired excretion and lead to organ damage due to precipitation of calcium oxalate crystals. However, the measurement of plasma oxalate is challenging due to the low concentrations present in individuals with healthy kidney function and the pre-analytical steps needed to prevent erroneous oxalate results due to conversion from ascorbate. In order to provide improved turn-around-time for plasma oxalate testing, our objective was to develop and validate a method to measure plasma oxalate on the Roche cobas c501. Methods Samples used in the validation study included both fresh collections and residual plasma from specimens collected in lithium heparin, no-gel tubes. Samples from fresh collections were kept on ice prior to centrifugation, and then frozen if not analyzed immediately. Thawed plasma was acidified by addition of 12.1 M HCl to a pH between 2 and 3 and mixed thoroughly by vortexing. One milliliter of the acidified plasma was added to a Centrifree filter (Millipore). The samples were then centrifuged for 90 min at 1500 × g 20°C in a fixed angle rotor to remove plasma proteins. The resulting filtrate was assayed on the Roche cobas c501. The assay (Trinity Biotech) uses oxalate oxidase to produce an indamine dye through the production of hydrogen peroxide from oxalate in the sample, which is measured spectrophotometrically at 600 nm at a single time point. The analytical measuring range (AMR) was evaluated by performing serial dilutions of a high sample. Interferences from hemolysis, icterus, and lipemia were assessed at both low and high oxalate concentrations. Precision was evaluated using two QC concentrations, and patient samples with low and high concentrations of oxalate. Samples were tested ten times in a single day, or twice per day for ten days to estimate intra- and inter-precision, respectively. Spike recovery studies were used to assess method accuracy. Lastly, reference intervals were verified by assaying samples from twenty healthy volunteers. Total allowable error was ±30% or 2 µmol/L with a maximum 15%CV. Results The assay was validated to be linear across an AMR of 2 to 30 µmol/L, with an average recovery of 105% across five concentrations. The total assay imprecision was <15%. Initial spike recovery studies across the AMR showed an average recovery of 99.4% (n = 12), with a range of 76.6 to 132.4%. In a mixing study, hemolyzed and lipemic sample recovery was on average 82.1% and 76.1% respectively, which was low, but acceptable. Samples mixed with icteric specimens demonstrated unacceptably low recovery (average of 64.1%). The reference interval of <2 µmol/L was successfully verified as all twenty healthy volunteers had results <2 µmol/L. Conclusion Initial validation studies support the clinical utility of the newly developed method. Plasma oxalate methods are documented to have significant inter-method variability and variable recovery, which is hypothesized to be due to variation at the filtration step. This semi-automated assay will require less technologist time and will reduce the possibility for human error affecting the result.

Current Management of Hepatic Encephalopathy: A Review Article

Hepatic encephalopathy, a neuropsychiatric syndrome stemming from liver failure, manifests in acute and chronic cases. The prevailing cause behind its development involves the neurotoxicity resulting from elevated ammonia levels in the brain, which can occur due to increased ammonia production or impaired ammonia excretion. The main objective in treating hepatic encephalopathy is to decrease ammonia levels. The detoxification of ammonia in this condition is regulated by two enzymes: glutaminase and glutamine synthetase. Numerous drugs, such as lactulose, rifaximin, BCAA, LOLA, glycerol phenylbutyrate, and zinc, have been utilized to treat hepatic encephalopathy. In terms of future research, experimental treatment options like fecal microbiota transplant, probiotics, bromocriptine, minocycline, indomethacin, ibuprofen, and flumazenil warrant investigation. Furthermore, albumin infusions have been shown to enhance cognitive function and improve the psychosocial quality of life, possibly by alleviating endothelial dysfunction in patients with minimal hepatic encephalopathy or previous episodes of hepatic encephalopathy. This review article offers a comprehensive overview of the current management strategies for hepatic encephalopathy.

Metabolomics Point out the Effects of Carfilzomib on Aromatic Amino Acid Biosynthesis and Degradation.

(1) Carfilzomib (Cfz) is an antineoplastic agent indicated for the treatment of multiple myeloma. However, its beneficial action is attenuated by the occurrence of cardiotoxicity and nephrotoxicity as the most common adverse effects. Presently, there is well-established knowledge on the pathomechanisms related to these side effects; however, the research on the metabolic alterations provoked by the drug is limited. (2) An in vivo simulation of Cfz-induced toxicity was developed in (i) Cfz-treated and (ii) control mice. An RP-HRMS-based protocol and an advanced statistical treatment were used to investigate the impact of Cfz on the non-polar metabolome. (3) The differential analysis classified the Cfz-treated and control mice and resulted in a significant number of identified biomarkers with AUC > 0.9. The drug impaired the biosynthesis and degradation of aromatic amino acids (AAA) and led to alterations of uremic toxins in the renal and urine levels. Furthermore, the renal degradation of tryptophan was affected, inducing its degradation via the kynurenine pathway. (4) The renal levels of metabolites showed impaired excretion and degradation of AAAs. Cfz was, finally, correlated with the biosynthesis of renal dopamine, explaining the biochemical causes of water and ion retention and the increase in systolic pressure.

An Overview on Neonatal Jaundice

A significant proportion of term and preterm infants develop neonatal jaundice. Jaundice in a healthy term infant is the most common reason for readmission to hospital. Jaundice is caused by a significant increase in serum bilirubin levels, largely due to the breakdown of red blood cells. Bilirubin is transported in the blood as 'unconjugated' bilirubin, largely bound to albumin. The bilirubin is converted into a conjugated form by the liver, which is excreted in the bile. Very high levels of unconjugated bilirubin led to neurotoxicity. In most infants, severe hyperbilirubinemia is caused due to an increase in bilirubin production (e.g., due to haemolysis) and thus reducing bilirubin production is a rational approach for its management. The situation can become critical in infants with an associated impaired bilirubin elimination mechanism as a result of a genetic deficiency and polymorphism. The simplest way to reduce bilirubin levels is by phototherapy. Current management of jaundice in the UK is guided by the NICE guideline.1

Treatment of Cholestasis in Infants and Young Children.

Cholestasis is characterized by a conjugated hyperbilirubinemia secondary to impaired bile synthesis, transport, or excretion from the liver. It is always pathologic and can be indicative of an underlying hepatobiliary, genetic, or metabolic disorder, several of which require timely diagnosis to ensure proper management and optimal outcomes. This review provides an overview of the evaluation of cholestasis with a focus on current and emerging treatment strategies. Increased accessibility of next generation sequencing (NGS) allows for utilization of genetic testing early in the diagnostic process. This may alter the clinical algorithm for diagnosis of cholestatic disorders. An enhanced understanding of the underlying pathophysiology may help guide future development of targeted therapies, such as ileal bile acid transporter (IBAT) inhibitors. These were recently approved for treatment of cholestatic pruritus in patients with Alagille syndrome and Progressive Familial Intrahepatic Cholestasis. Current management of cholestasis is aimed at the biochemical consequences of impaired bile flow, including malnutrition, pruritus, and progressive fibrosis. NGS has led to an enhanced understanding of biliary pathology and may guide development of future treatment modalities based on specific gene mutations. Rapid discernment of the underlying etiology is essential as new treatment modalities emerge.

Excessive vincristine exposure in a child being treated for acute lymphoblastic leukaemia with underlying Dubin-Johnson syndrome: a case report.

Dubin-Johnson syndrome is a rare benign autosomal recessive condition that causes an isolated increase of conjugated bilirubin in the serum. Impaired biliary excretion is due to mutation in the multiple drug-resistance protein 2 gene (MRP2). We describe the case of a 4-year-old girl being treated for acute lymphoblastic leukaemia who had a history of conjugated hyperbilirubinaemia and persistently elevated bilirubin levels on initiation of chemotherapy. During treatment for leukaemia, she was diagnosed with Dubin-Johnson syndrome for the underlying condition. Following administration of vincristine at the recommended dose of 1.5mg/m2, an abnormally high vincristine exposure was observed (AUC > 200µg/L*h), approximately 3 times higher than previously reported exposures in a comparable clinical setting. Vincristine dose reductions were applied on subsequent cycles of treatment and resulted in markedly reduced drug exposures, within the normal target range. This case provided a rare opportunity to assess the impact of MRP2 mutations associated with Dubin-Johnson syndrome on the pharmacokinetics of vincristine and strongly indicates that a marked dose reduction should be recommended. Clinicians should be made aware of the potential for altered drug disposition for agents such as vincristine in patients with this rare genetic condition.

Salt Substitutes – Utility and Safety in Chronic Kidney Disease

In the shadow of the global sodium burden, chronic kidney disease (CKD) patients face a particularly precarious balancing act. While reducing sodium intake is essential for mitigating cardiovascular risks and slowing CKD progression, conventional salt substitutes containing potassium pose a looming threat of hyperkalemia due to impaired renal potassium excretion. Despite promising benefits like lowered blood pressure and reduced cardiovascular events observed in the general population, robust data on the efficacy and safety of these substitutes in CKD is scarce. Hence, the urgent need arises for targeted research to establish precise risks and benefits of various salt-substitution strategies tailored specifically for the CKD population. Ideally, the holy grail of this endeavor would be the discovery of a sodium-minimizing, potassium-free substitute that flawlessly mimics the sensory experience of salt, thus empowering CKD patients to navigate experience nutritional prudence and culinary delight. The path forward demands meticulous investigation and the development of personalized sodium-reduction strategies that hold the key to unlocking a healthier future for CKD patients.

Quality of life and depression in Wilson’s disease: a large prospective cross-sectional study

BackgroundWilson's disease (WD) is an autosomal recessive genetic disorder due to a mutation of the ATP7B gene, resulting in impaired hepatic copper excretion and accumulation in various tissues. Lifelong decoppering treatments are the keystone of the treatment. These treatments can prevent, stabilize, or reverse the symptoms making WD a chronic disease. Quality of life (QoL) is one of the best outcome measures of any therapeutic intervention in chronic diseases but has not been evaluated in large cohorts of WD patients.MethodTo better evaluate the QoL in WD and the correlation with different clinical or demographic factors we have performed a prospective cross-sectional study.ResultsTwo hundred fifty-seven patients (53.3% men, mean age of 39.3 years and median disease duration of 18.8 years) were included between 1st January 2021 and 31st December 2021. Hepatoneurological form of the disease and depression were significantly correlated with low QoL (p < 0.001 for both). However, the patients' quality of life was similar to that of the general population, and only 29 patients (11.3%) had moderate to severe depression.ConclusionsNeurological patients should be closely monitored to prevent and treat symptoms of depression that impact their quality of life.

Hyperuricemia: A key contributor to endothelial dysfunction in cardiovascular diseases.

As an end product of purine metabolism, uric acid (UA) is a major endogenous antioxidant in humans. However, impaired UA synthesis and excretion can lead to hyperuricemia (HUA), which may in turn induce endothelial dysfunction (ED) and contribute to the pathogenesis of cardiovascular diseases (CVDs; e.g., atherosclerosis and hypertension). In this review, we discuss recent advances and novel insights into the effects exerted by HUA conditions in ED and related underlying mechanisms focusing on impaired UA metabolism, reduction in the synthesis and bioavailability of nitric oxide, endothelial cell injury, the endothelial-to-mesenchymal transition, insulin resistance, procoagulant activity, and acquisition of an inflammatory phenotype. We additionally discuss intervention strategies for HUA-induced ED and the paradoxical roles of UA in endothelial function. We summarize major conclusions and perspectives: the deleterious effects of HUA contribute to the initiation and progression of CVD-related ED. However, the treatment strategies (in addition to urate-lowering therapy) for increasing endothelial function are limited because the majority of literature on pharmacological and pathophysiological mechanisms underlying HUA-induced ED solely describes in vitro models. Therefore, a better understanding of the mechanisms involved in HUA-induced ED is critical to the development of novel therapies for preventing and treating CVD-HUA comorbidities.

Differentiated disorders of the immune system in acute hematogenic and acute posttraumatic osteomyelitis in children

Osteomyelitis is an inflammation of bone and bone marrow caused by the spread of S. aureus from a local focus by the hematogenous route or from an open traumatic fracture; it is difficult to treat and remains a serious problem. The condition for spreading of the infectious process into bone is the effect of S. aureus and its impaired elimination due to immune system (IS) dysfunction. Controversial information on the immunopathogenetic mechanisms of acute osteomyelitis needs study, which would allow the development of sound immunotherapy. Purpose of the study: to specify the variants of antibacterial immune protection disorders in children with acute hematogenous and acute posttraumatic osteomyelitis. Materials and methods. Children 8-15 years old (n = 22) were studied: Study Group 1 (SG1, n = 12) – with acute hematogenous osteomyelitis (AHO); Study Group 2 (SG2, n = 10) – with acute post-traumatic osteomyelitis (APTO). The comparison group (CG) – 13 healthy children. Tested: Tlymphocytes (CD3+CD19- , CD3+CD4+, CD3+CD8+), B lymphocytes (CD3- CD19+), NK (CD3- CD16+CD56+) and TNK (CD3+CD16+CD56+) lymphocytes, neutrophil granulocytes (NG, CD16, CD32, CD64) (FC-500 Beckman Coulter, USA); the level of serum IgA, IgM, IgG (ELISA). Phagocytic function of NGs in relation to S. aureus was assessed: the number of actively phagocytizing NGs (%PhAN), capture processes (PhN, PhI) and killing activity (%D, DI). Results. In both groups was revealed a decrease of T lymphocytes, T helpers, TCTL and NK quantity (p1-4 &lt; 0.05). In AHO, the levels of IgA, IgM, IgG did not differ from that in GS, while in APTO the levels of IgA and IgG increased (p1, 2 &lt; 0.05). The density of CD64, CD16, CD32 receptor expression on NG in the studied groups has been a different equipping, predetermining an incompetence of the phagocytic function: in AHO associated with abnormalities in the function capture and killing, in APTO only with the S. aureus digestion. Conclusion. The revealed combined defects of IS functioning necessitate the development of new approaches in the treatment of AHO and APTO in children, pathogenetically substantiating the use of immunotherapy in the complex etiopathogenetic treatment. This approach will contribute to the restoration of mechanisms of anti-infective immunity, timely elimination of pathogens, improve the clinical course of the diseases, prevent the chronic inflammatory process.

The pathophysiology of distal renal tubular acidosis

The kidneys have a central role in the control of acid-base homeostasis owing to bicarbonate reabsorption and production of ammonia and ammonium in the proximal tubule and active acid secretion along the collecting duct. Impaired acid excretion by the collecting duct system causes distal renal tubular acidosis (dRTA), which is characterized by the failure to acidify urine below pH 5.5. This defect originates from reduced function of acid-secretory type A intercalated cells. Inherited forms of dRTA are caused by variants in SLC4A1, ATP6V1B1, ATP6V0A4, FOXI1, WDR72 and probably in other genes that are yet to be discovered. Inheritance of dRTA follows autosomal-dominant and -recessive patterns. Acquired forms of dRTA are caused by various types of autoimmune diseases or adverse effects of some drugs. Incomplete dRTA is frequently found in patients with and without kidney stone disease. These patients fail to appropriately acidify their urine when challenged, suggesting that incomplete dRTA may represent an intermediate state in the spectrum of the ability to excrete acids. Unrecognized or insufficiently treated dRTA can cause rickets and failure to thrive in children, osteomalacia in adults, nephrolithiasis and nephrocalcinosis. Electrolyte disorders are also often present and poorly controlled dRTA can increase the risk of developing chronic kidney disease.