Metabolic Pathways Affected in Patients Undergoing Hemodialysis and Their Relationship with Inflammation.

Worldwide, 3.9 million individuals rely on kidney replacement therapy. They experience heightened susceptibility to cardiovascular diseases and mortality, alongside an increased risk of infections and malignancies, with inflammation being key to explaining this intensified risk. This study utilized semi-targeted metabolomics to explore novel metabolic pathways related to inflammation in this population. We collected pre- and post-session blood samples of patients who had already undergone one year of chronic hemodialysis and used liquid chromatography and high-resolution mass spectrometry to perform a metabolomic analysis. Afterwards, we employed both univariate (Mann-Whitney test) and multivariate (logistic regression with LASSO regularization) to identify metabolites associated with inflammation. In the univariate analysis, indole-3-acetaldehyde, 2-ketobutyric acid, and urocanic acid showed statistically significant decreases in median concentrations in the presence of inflammation. In the multivariate analysis, metabolites positively associated with inflammation included allantoin, taurodeoxycholic acid, norepinephrine, pyroglutamic acid, and L-hydroorotic acid. Conversely, metabolites showing negative associations with inflammation included benzoic acid, indole-3-acetaldehyde, methionine, citrulline, alphaketoglutarate, n-acetyl-ornithine, and 3-4-dihydroxibenzeneacetic acid. Non-inflamed patients exhibit preserved autophagy and reduced mitochondrial dysfunction. Understanding inflammation in this group hinges on the metabolism of arginine and the urea cycle. Additionally, the microbiota, particularly uricase-producing bacteria and those metabolizing tryptophan, play critical roles.

X-Linked hypophosphatemia. Data from a Spanish adult population cohort.

BACKGROUND: X-linked hypophosphatemia (XLH) represents the most prevalent cause of hereditary hypophosphatemia. X-linked hypophosphatemia causes an elevation of fibroblast growth factor 23 (FGF23), a hormone responsible for inducing hyperphosphaturia, and reduced active vitamin D synthesis. Challenges in diagnosis and the absence of well-defined clinical guidelines have resulted in higher rates of late diagnoses. While numerous reports focus on pediatric X-linked hypophosphatemia patients, studies in adults are limited. METHODS: Multicenter, cross-sectional, observational study of a cohort of adult patients diagnosed with X-linked hypophosphatemia. The study identified demographic, clinical, genetic, laboratory variables, treatments used, comorbidities, and complications. RESULTS: Twenty patients diagnosed with X-linked hypophosphatemia were collected. The median age at diagnosis was 11 (1-56) years and at data collection was 44 (21-68) years. Fifty percent of cases were diagnosed in adulthood. Main clinical manifestation was osteoarticular pain, in 75% of cases, and no relation to age at diagnosis, height, phosphorus, or parathyroid hormone (PTH) levels was observed (p > 0.05). Lower limb deformities were associated with reduced stature and earlier diagnosis (p < 0.05). Sixty percent of patients reported pain requiring chronic medication and no significant correlation was found with other variables. Anxiety and depression were found in an important number of patients. FGF23 levels were not related to any of the clinical variables studied (p > 0.05). DISCUSSION: This is the largest study on adult patients with X-linked hypophosphatemia in southern Europe. It may offer valuable insights into the natural progression and course of the condition in adults, which can aid in better clinical management.

Uremic Toxins and Inflammation: Metabolic Pathways Affected in Non-Dialysis-Dependent Stage 5 Chronic Kidney Disease.

Chronic kidney disease (CKD) affects approximately 12% of the global population, posing a significant health threat. Inflammation plays a crucial role in the uremic phenotype of non-dialysis-dependent (NDD) stage 5 CKD, contributing to elevated cardiovascular and overall mortality in affected individuals. This study aimed to explore novel metabolic pathways in this population using semi-targeted metabolomics, which allowed us to quantify numerous metabolites with known identities before data acquisition through an in-house polar compound library. In a prospective observational design with 50 patients, blood samples collected before the initial hemodialysis session underwent liquid chromatography and high-resolution mass spectrometer analysis. Univariate (Mann-Whitney test) and multivariate (logistic regression with LASSO regularization) methods identified metabolomic variables associated with inflammation. Notably, adenosine-5'-phosphosulfate (APS), dimethylglycine, pyruvate, lactate, and 2-ketobutyric acid exhibited significant differences in the presence of inflammation. Cholic acid, homogentisic acid, and 2-phenylpropionic acid displayed opposing patterns. Multivariate analysis indicated increased inflammation risk with certain metabolites (N-Butyrylglycine, dimethylglycine, 2-Oxoisopentanoic acid, and pyruvate), while others (homogentisic acid, 2-Phenylpropionic acid, and 2-Methylglutaric acid) suggested decreased probability. These findings unveil potential inflammation-associated biomarkers related to defective mitochondrial fatty acid beta oxidation and branched-chain amino acid breakdown in NDD stage 5 CKD, shedding light on cellular energy production and offering insights for further clinical validation.

Metabolomics of Plasma in XLH Patients with Arterial Hypertension: New Insights into the Underlying Mechanisms.

X-linked hypophosphatemia (XLH) is a rare genetic disorder that increases fibroblast growth factor 23 (FGF23). XLH patients have an elevated risk of early-onset hypertension. The precise factors contributing to hypertension in XLH patients have yet to be identified. A multicenter cross-sectional study of adult patients diagnosed with XLH. Metabolomic analysis was performed using ultra-performance liquid chromatography (UPLC) coupled to a high-resolution mass spectrometer. Twenty subjects were included, of which nine (45%) had hypertension. The median age was 44 years. Out of the total, seven (35%) subjects had a family history of hypertension. No statistically significant differences were found between both groups for nephrocalcinosis or hyperparathyroidism. Those with hypertension exhibited significantly higher levels of creatinine (1.08 ± 0.31 mg/dL vs. 0.78 ± 0.19 mg/dL; p = 0.01) and LDL-C (133.33 ± 21.92 mg/dL vs. 107.27 ± 20.12 mg/dL, p = 0.01). A total of 106 metabolites were identified. Acetylcarnitine (p = 0.03), pyruvate p = (0.04), ethanolamine (p = 0.03), and butyric acid (p = 0.001) were significantly different between both groups. This study is the first to examine the metabolomics of hypertension in patients with XLH. We have identified significant changes in specific metabolites that shed new light on the potential mechanisms of hypertension in XLH patients. These findings could lead to new studies identifying associated biomarkers and developing new diagnostic approaches for XLH patients.

Acquired perforating dermatosis in patients on peritoneal dialysis: a report of 3 cases.

Background: Acquired perforating dermatosis (APD) is a heterogeneous group of unfrequented diseases (2.5 cases for 100,000 habitants) associated with multiple pathologies like end-stage renal disease and other concomitant conditions such as diabetes mellitus (DM). Case Description: We described 3 cases of APD in patients on peritoneal dialysis (PD), one of them with a giant variant of reactive perforating collagenosis (RPC). The first case is a 28-year-old man with chronic kidney disease on PD and a lousy control of disturbances of calcium and phosphorus metabolism that develops an APD. The second case is a 44-year-old man with DM, chronic kidney disease (CKD) on PD, and poor control of disturbances of calcium and phosphorus metabolism that develops an RPC. The third case is a 58-year-old man with DM, rheumatoid arthritis, hypothyroidism, CKD and bad control of calcium and phosphorus metabolism that develops a giant variant of RPC with poor evolution. Conclusions: CKD and concomitant conditions such as DM present an increased risk of developing APD. Poor control of calcium and phosphorus metabolism is frequently found in patients with CKD and seems to be related to the development of APD in our cases. With the description of these cases, we want to emphasize the importance of knowing this rare disease, in order to promptly refer to Dermatology and start treatment.

Role of the Nephrologist in Non-Kidney Solid Organ Transplant (NKSOT).

BACKGROUND: Chronic kidney disease (CKD) is a common complication of a non-kidney solid organ transplant (NKSOT). Identifying predisposing factors is crucial for an early approach and correct referral to nephrology. METHODS: This is a single-center retrospective observational study of a cohort of CKD patients under follow-up in the Nephrology Department between 2010 to 2020. Statistical analysis was performed between all the risk factors and four dependent variables: end-stage renal disease (ESKD); increased serum creatinine ≥50%; renal replacement therapy (RRT); and death in the pre-transplant, peri-transplant, and post-transplant periods. RESULTS: 74 patients were studied (7 heart transplants, 34 liver transplants, and 33 lung transplants). Patients who were not followed-up by a nephrologist in the pre-transplant (p < 0.027) or peri-transplant (p < 0.046) periods and those who had the longest time until an outpatient clinic follow-up (HR 1.032) were associated with a higher risk of creatinine increase ≥50%. Receiving a lung transplant conferred a higher risk than a liver or heart transplant for developing a creatinine increase ≥50% and ESKD. Peri-transplant mechanical ventilation, peri-transplant and post-transplant anticalcineurin overdose, nephrotoxicity, and the number of hospital admissions were significantly associated with a creatinine increase ≥50% and developing ESKD. CONCLUSIONS: Early and close follow-up by a nephrologist was associated with a decrease in the worsening of renal function.

The metabolomic differential plasma profile between dialysates. Pursuing to understand the mechanisms of citrate dialysate clinical benefits.

Background: Currently, bicarbonate-based dialysate needs a buffer to prevent precipitation of bicarbonate salts with the bivalent cations, and acetate at 3-4 mmol/L is the most used. However, citrate is being postulated as a preferred option because of its association with better clinical results by poorly understood mechanisms. In that sense, this hypothesis-generating study aims to identify potential metabolites that could biologically explain these improvements found in patients using citrate dialysate. Methods: A unicentric, cross-over, prospective untargeted metabolomics study was designed to analyze the differences between two dialysates only differing in their buffer, one containing 4 mmol/L of acetate (AD) and the other 1 mmol/L of citrate (CD). Blood samples were collected in four moments (i.e., pre-, mid-, post-, and 30-min-post-dialysis) and analyzed in an untargeted metabolomics approach based on UPLC-Q-ToF mass spectrometry. Results: The 31 most discriminant metabolomic variables from the plasma samples of the 21 participants screened by their potential clinical implications show that, after dialysis with CD, some uremic toxins appear to be better cleared, the lysine degradation pathway is affected, and branched-chain amino acids post-dialysis levels are 9-10 times higher than with AD; and, on its part, dialysis with AD affects acylcarnitine clearance. Conclusion: Although most metabolic changes seen in this study could be attributable to the dialysis treatment itself, this study successfully identifies some metabolic variables that differ between CD and AD, which raise new hypotheses that may unveil the mechanisms involved in the clinical improvements observed with citrate in future research.

Comparative Study of 2 Extended-Release Tacrolimus Formulations in Kidney Transplantation.

BACKGROUND: During the 1900s, tacrolimus became the mainstay immunosuppressive agent to prevent rejection after kidney transplant. Subsequently, an extended-release tacrolimus (ER-Tac) formulation was developed to improve adherence, and its generic version has been marketed over the last years. This study examines the differences in efficacy and safety between the generic ER-Tac (Conferoport) and the reference brand-name drug (Advagraf). METHODS: Prospective, randomized and parallel single-center study (May 2020 to June 2021) with 52 kidney transplant recipients who were randomly assigned to 1 of the following groups: study group (Conferoport, n = 31) and control group (Advagraf, n = 21). The variables of interest were collected and analyzed to compare tacrolimus efficacy and safety between them. Demographic characteristics of the patients and clinical donor data were homogeneous in both groups (P > .05). RESULTS: No statistically significant differences were found among treatments regarding dosage used, levels, creatinine, and proteinuria (P > .05), with these variables presenting a downward trend during follow-up and, consequently, the improvement of graft function. Analyses also revealed the absence of differences concerning the incidence of acute rejection and intrapatient variability (coefficient of variation) throughout the first year of evolution between both formulations (P > .05). A total of 5 graft losses occurred, 2 resulting from patient death. CONCLUSIONS: In our experience, we found no significant differences between the measured parameters in relation to the efficacy and safety profile of both drugs, with generic ER-Tac being an alternative comparable with the reference brand-name ER-Tac.

Impact of Acetate versus Citrate Dialysates on Intermediary Metabolism-A Targeted Metabolomics Approach.

Acetate is widely used as a dialysate buffer to avoid the precipitation of bicarbonate salts. However, even at low concentrations that wouldn't surpass the metabolic capacity of the Krebs tricarboxylic acid (TCA) cycle, other metabolic routes are activated, leading to undesirable clinical consequences by poorly understood mechanisms. This study aims to add information that could biologically explain the clinical improvements found in patients using citrate dialysate. A unicentric, cross-over, prospective targeted metabolomics study was designed to analyze the differences between two dialysates, one containing 4 mmol/L of acetate (AD) and the other 1 mmol/L of citrate (CD). Fifteen metabolites were studied to investigate changes induced in the TCA cycle, glycolysis, anaerobic metabolism, ketone bodies, and triglyceride and aminoacidic metabolism. Twenty-one patients completed the study. Citrate increased during the dialysis sessions when CD was used, without surpassing normal values. Other differences found in the next TCA cycle steps showed an increased substrate accumulation when using AD. While lactate decreased, pyruvate remained stable, and ketogenesis was boosted during dialysis. Acetylcarnitine and myo-inositol were reduced during dialysis, while glycerol remained constant. Lastly, glutamate and glutarate decreased due to the inhibition of amino acidic degradation. This study raises new hypotheses that need further investigation to understand better the biochemical processes that dialysis and the different dialysate buffers induce in the patient's metabolism.

Improvements in Inflammation and Calcium Balance of Citrate versus Acetate as Dialysate Buffer in Maintenance Hemodialysis: A Unicentric, Cross-Over, Prospective Study.

INTRODUCTION: The composition of the dialysate is a crucial feature in the dialysis treatment. Two of its most debated elements are the optimal calcium concentration and the use of acetate as a buffer. Moreover, among the different alternatives to achieve acetate-free dialysis, the use of citrate is postulated as the most suitable option. The objective of this study is to identify the potential beneficial effects of citrate when compared to acetate dialysate (AD) both in short-term effects (especially regarding intradialytic calcium balance and cardiac damage biomarkers) and in medium-term ones with CKD-mineral and bone disorder (CKD-MBD) and inflammatory biomarkers measured after twelve sessions performed with each dialysate. METHODS: This is a unicentric, cross-over, prospective study. Each patient underwent 24 dialysis sessions, 12 with each dialysate buffer. Blood samples were taken in 2 different sessions with each acidifier. They include CKD-MBD and inflammatory biomarkers. The calcium concentration of both dialysates was 1.5 mmol/L, while all other dialysis parameters and patients' treatment remained unchanged during the study period. RESULTS: When comparing AD and citrate dialysate (CD), there were no differences in pre-dialysis ionized calcium (iCa) (1.11 vs. 1.08 mmol/L) in both groups. However, there was a significant increase in iCa with the use of AD in immediate and 30-min post-dialysis blood samples. In contrast, iCa levels remained stable with the use of citrate. Inflammatory biomarkers were also reduced after the use of CD. CONCLUSIONS: The use of citrate provides interesting advantages when compared to acetate. It maintains iCa levels stable during dialysis sessions with a neutral or negative effect on calcium balance, and it improves the chronic inflammatory condition that comes with long-time hemodialysis treatment. These beneficial effects may lead to an improvement in clinical outcomes.

X-linked hypophosphatemic rickets: Diagnosis in adult and paucisymptomatic form. / Raquitismo hipofosfatémico ligado al cromosoma X: diagnóstico en la edad adulta y forma paucisintomática.

X-linked hypophosphataemic rickets (XLH) is the main form of hereditary rickets caused by mutation of the PHEX gene and occurs mainly in childhood. Clinically, it causes growth retardation and bone deformities; however, there are atypical forms of presentation that make diagnosis difficult. We present a case of XLH of late diagnosis and paucisymptomatic form with multiple fractures and greatly affecting quality of life, under treatment with traditional therapy for this disease.

Genetic Diagnosis of Rare Diseases: Past and Present.

Rare diseases are heterogeneous life-threatening or seriously debilitating conditions that affect < 1 in 2000 individuals, and most have a genetic component. The diagnostic process is usually based on classic clinical practices, such as physical examination, personal and family history (inheritance pattern), laboratory tests and image studies, but diagnosis can be delayed several years after the initiation of symptoms. The advances in molecular genetics that have taken place in recent years have led to an important shift in medical practice and in its approach to the diagnosis and treatment of many rare diseases. The objective of this review is to promote a better understanding of the mechanisms underlying genetic diseases in humans and the tools available for their diagnosis. A practical example of X-linked hypophosphataemic rickets is described.

Immune Complex Membranoproliferative Glomerulonephritis Associated with Transjugular Intrahepatic Portosystemic Shunts in Alcoholic Cirrhosis: Two Case Reports.

OBJECTIVE: To report on 2 patients with alcoholic cirrhosis who were treated with transjugular intrahepatic portosystemic shunt (TIPS) placement. CLINICAL PRESENTATION AND INTERVENTION: The 2 patients had a history of alcoholic cirrhosis, and TIPS surgery was performed on them. In both cases, 4 months after TIPS placement, proteinuria was observed along with histological alterations characteristic of immune complex membranoproliferative glomerulonephritis (MPGN). CONCLUSION: The TIPS in one patient was successful without immediate complications, while the other patient was referred for a combined liver-kidney transplant. In both cases, immune complex MPGN might have developed after TIPS placement probably due to a reduced immune complex clearance.

Membranous glomerulonephritis and cellular crescents induced by levamisole-adulterated cocaine abuse: a case report.

Levamisole is illicitly employed as a cocaine adulterant. The consumption of levamisole-adulterated cocaine can provoke anti-neutrophil cytoplasmic antibody (ANCA)-associated syndromes. Patients carrying an HLAB27 allele are known to be at higher risk of developing agranulocytosis when treated with levamisole. Likewise, patients with ANCA-associated vasculitis (AAV) and internal organ involvement have typically been exposed to offending agents for prolonged periods of time, often on the order of years. Here, we report an unusual case of a patient in which kidney biopsy showed membranous glomerulonephritis with cellular crescents associated with levamisole-contaminated cocaine use.

A randomized controlled study on the effects of acetate-free biofiltration on organic anions and acid-base balance in hemodialysis patients.

Metabolic acidosis correction is achieved by the transfer of bicarbonate and other buffer anions in dialysis. The aim of this study was to evaluate changes in the main anions of intermediary metabolism on standard hemodiafiltration (HDF) and on acetate-free biofiltration (AFB). A prospective, in-center, crossover study was carried out with 22 patients on maintenance dialysis. Patients were randomly assigned to start with 12 successive sessions of standard HDF with bicarbonate (34 mmol/L) and acetate dialysate (3 mmol/L) or 12 successive sessions of AFB without base in the dialysate. Acetate increased significantly during the standard HDF session from 0.078 ± 0.062 mmol/L to 0.156 ± 0.128 mmol/L (P < 0.05) and remained unchanged at 0.044 ± 0.034 mmol and 0.055 ± 0.028 mmol/L in AFB modality. Differences in the acetate levels were observed at two hours (P < 0.005), at the end (P < 0.005) and thirty minutes after the session between HDF and AFB (P < 0.05). There were significantly more patients above the normal range in HDF group than AFB group (68.1% vs 4.5% P < 0.005) postdialysis and 30 minutes later. Serum lactate and pyruvate concentrations decreased during the sessions without differences between modalities. Citrate decreased only in the AFB group (P < 0.05). Acetoacetate and betahydroxybutyrate increased in both modalities, but the highest betahydroxybutyrate values were detected in HDF (P < 0.05). The sum of postdialysis unusual measured organic anions (OA) were higher in HDF compared to AFB (P < 0.05). AFB achieves an optimal control of acid-base equilibrium through a bicarbonate substitution fluid. It also prevents hyperacetatemia and restores internal homeostasis with less production of intermediary metabolites.