Hyperchloremic Acidosis Research Articles

A New Insight into Hyperchloremic Metabolic Acidosis in Kidney Transplant Recipients: Increased Postglomerular Blood Flow Is a Key Condition for Calcineurin Inhibitor-Induced Renal Tubular Acidosis

A New Insight into Hyperchloremic Metabolic Acidosis in Kidney Transplant Recipients: Increased Postglomerular Blood Flow Is a Key Condition for Calcineurin Inhibitor-Induced Renal Tubular Acidosis

Hyperchloremic acidosis develops at the stage G4 and shifts to high anion gap acidosis at the stage G5 in chronic kidney disease.

Amelioration of hyperchloremic acidosis (Cl-Ac), a common complication in chronic kidney disease (CKD), could preserve renal function in chronic kidney disease (CKD). However, the development of Cl-Ac in CKD has not been clarified yet. The degree of Cl-Ac, which is indicated as the bicarbonate concentration decrease with serum chloride concentration increase (∆[HCO3-]Cl), was compared with the estimated glomerular filtration rate (eGFR) by using CKD patient records. In 307 records with metabolic acidosis, a spline curve obtained from the plot comparing ∆[HCO3-]Cl with eGFR showed that ∆[HCO3-]Cl did not change, increased, and decreased during eGFR decrease until 27, from 27 to 17.5, and from 17.5mL/min/1.73m2, respectively. By CKD progression, Cl-Ac progressed and regressed at the CKD stages G4 and G5, respectively. The regression would have reflected the shift of Cl-Ac to high anion gap acidosis.

Renal Tubular Acidosis.

Renal tubular acidosis (RTA) comprises a group of disorders characterized by low capacity for net acid excretion and persistent hyperchloremic metabolic acidosis, despite preserved glomerular filtration rate. RTA are classified into chiefly three types (1, 2 and 4) based on pathophysiology and clinical and laboratory characteristics. Most patients have primary RTA that presents in infancy with polyuria, growth retardation, rickets and/or hypotonia. Diagnosis requires careful evaluation, including exclusion of other entities that can cause acidosis. A variety of tests, administered stepwise, are useful for the diagnosis and characterization of RTA. A genetic or acquired basis can be determined in majority of patients through focused evaluation. Management involves correction of acidosis and dyselectrolytemia; patients with proximal RTA with Fanconi syndrome and rickets require additional supplements of phosphate and vitamin D.

Plasma-Lyte 148 and Plasma-Lyte 148 + 5% glucose compatibility with commonly used critical care drugs

PurposePlasma-Lyte is a balanced, crystalloid intravenous fluid which has been shown to avoid the hyperchloremic metabolic acidosis associated with 0.9% sodium chloride. Data on physical, pH and chemical compatibility with other medicines are essential.MethodsThe compatibility of adrenaline, dobutamine, dopamine, furosemide, midazolam, morphine and milrinone with Plasma-Lyte 148 (PLA) and Plasma-Lyte 148 with 5% glucose (PLA-G) was investigated. Control solutions were 0.9% sodium chloride and 5% glucose. Chemical stability was defined as < 5% concentration change with high-performance liquid chromatography (HPLC). Physical compatibility was assessed by checking for colour changes and precipitate formation. The pH of the admixtures was considered acceptable if between 5 and 9 at all time points. Six repeats were carried out for HPLC, 2 for physical compatibility checks and pH measurements, with all admixtures being tested at 0, 2 and 24 h after mixing.ResultsAll combinations were found to be chemically stable at 0, 2 and 24 h apart from furosemide with PLA-G at 24 h and midazolam with PLA or PLA-G at both 2 and 24 h. Only midazolam was physically incompatible when mixed with both Plasma-Lyte solutions. The pH remained stable in all admixtures, although not all pH values recorded were within the range of 5–9.ConclusionAll drugs excluding furosemide and midazolam were shown to be chemically, physically and pH stable at the tested concentrations when diluted with PLA and PLA-G.

P0601SAFETY AND EFFICACY OF INTRAVENOUS ADMINISTRATION OF RINGER'S LACTATE VERSUS NORMAL SALINE 0.9% SOLUTION IN PATIENTS WITH ACUTE KIDNEY INJURY AND ESTABLISHED CHRONIC KIDNEY DISEASE

Abstract Background and Aims Crystalline solutions, such as normal saline 0.9% (N/S 0.9%) and Ringer's Lactate (L/R), are readily administered for increasing plasma volume. Despite the utility of administering N/S 0.9% to hypovolemic patients, the dose of 154 mmol of sodium (Na) contained in 1 L exceeds the recommended daily dose increasing the risk of sodium overload and hyperchloremic metabolic acidosis. In contrast, L/R solution has the advantage of lower Na content, significantly less chlorine and contains lactates which may be advantageous in patients with significant acidemia such as patients with acute kidney injury (AKI) and chronic kidney disease (CKD). The aim of the present study is to investigate the safety and efficacy of administration of L/R versus N/S 0.9% in patients with prerenal AKI and established CKD. Method The study included adult patients with known CKD stage II to V without need for dialysis, with prerenal AKI (AKIN Stage I to III Criteria). Patients with other forms of AKI as well as hypervolemia, heart congestion or hyperkalemia (serum K&amp;gt;5.5 meq/l) were excluded from the study. Patients were randomized in 1:1 ratio to receive intravenously either N/S 0.9% or L/R solution at a dose of 20 ml/kg body weight/day. We studied kidney function (eGFR: CKD-EPI) and response to treatment at discharge and at 30 days after discharge, duration of hospitalization, improvement in serum bicarbonate levels (HCO3), acid-base balance, serum potassium levels and the need for dialysis. Results The study included 26 patients (17 males) with a mean age of 59.1 ± 16.1 years. Thirteen patients received treatment with N/S 0.9% and the rest with L/R solution. Baseline demographic and clinical characteristics at hospital admission and historical data did not show any significant differences in both groups of patients. Renal function at the onset of AKI did not show significant differences between the two groups (16.4 ± 5.8 vs 16.9 ± 5.7 ml/min/1.73 m2, p=ns, treatment with N/S and L/R respectively). The mean volume of solutions received by the two groups (N/S 0.9% 1119 ± 374 vs L/R 1338 ± 364 ml/day, p=ns) as well as the mean total volume of liquids received per day, did not differ significantly (2888 ± 821 vs 3069 ± 728 ml/d, p=ns). Patients treated with L/R were discharged 1 day earlier than patients treated with N/S (5.2 ± 3.2 vs 6.2 ± 4.9 days of hospitalization, p=ns). Renal function improvement during hospitalization and 30 days after discharge did not differ significantly between the two groups. Patients that received L/R showed a higher increase in plasma HCO3 (ΔHCO3) concentration at discharge than those that received N/S 0.9% (4.9 ± 4.1 vs 2.46 ± 3.7 meq/l, p=ns) and pH increase (ΔpH) was slightly higher in those that received L/R solution (0.052 ± 0.066 vs 0.023 ± 0.071, p=ns). Patients treated with N/S 0.9% showed a greater decrease in serum potassium (ΔK) at discharge compared to those treated with L/R (-0.39 ± 1.03 vs -0.17 ± 0.43 meq/l, p=ns, respectively). No patient received acute dialysis treatment. Conclusion Administration of L/R solution as a hydration treatment to patients with prerenal AKI and established CKD is not inferior concerning safety and efficacy to N/S 0.9% solution. In addition, L/R administration seems to marginally improve acid-base balance in this specific group of patients.

P0058THE ROLE OF GENETICS IN INCOMPLETE DISTAL RENAL TUBULAR ACIDOSIS IN NEPHROLITHIASIS

Abstract Background and Aims Distal renal tubular acidosis (dRTA) is characterized by an impairment of urinary acidification resulting in a hyperchloremic non-anion gap metabolic acidosis, hypokalemia and inappropriately elevated urine pH. If not treated, this chronic condition eventually leads to nephrocalcinosis and recurrent nephrolithiasis, impaired renal function and bone demineralization due to reabsorption of bicarbonate and phosphate complexed with calcium from the bone as a buffer for metabolic acidosis. Distal RTA is therefore a well-defined entity that can be diagnosed by genetic testing of five genes known to be disease-causative (ATPV1B1 and ATPV0A4, FOXi1, SLC4A1 and WDR72). Incomplete distal renal tubular acidosis (idRTA) is defined as impaired urinary acidification that does not lead to overt metabolic acidosis and therefore can be diagnosed if patients fail to adequately acidify urine after an ammonium chloride (NH4Cl) challenge or other acid load tests. It is observed in 10-20% of calcium stone formers. It is still uncertain whether idRTA represents a distinct entity or it is part of the dRTA spectrum and whether it is caused by mutations in the same genes of overt dRTA. Heterozygous ATP6V1B1 pathogenic variants have been linked to idRTA, as well as mutations in SLC4A1. Method In this cross-sectional study we investigated a group of 23 stone formers whose clinical features were suspicious of idRTA: a history of nephrolithiasis or nephrocalcinosis with morning urinary pH &amp;gt; 5.8 in the absence of overt metabolic acidosis. They therefore underwent a simplified NH4Cl challenge and were found to have impaired urinary acidification ability. These patients were then analyzed by genetic testing with sequencing of 4 genes: SLC4A1, ATP6V1B1, ATP6V0A4 and FOXi1. Results Two unrelated individuals were found to have mutations in SLC4A1: 2 different variants in heterozygosis that had never been described before. The first patient was a 47-year old man, recurrent stone former (mainly apatite, but also some calcium oxalate), with hypercalciuria but normal bone mineral density (BMD). His family history revealed 1 uncle with kidney stones. The second patient was a 56-year old woman with a diagnosis of osteogenesis imperfecta, a history of reduced BMD and severe restrictive ventilation disorder and passed 1 stone (35% apatite, 65% CaOx). She was found to have bilateral nephrocalcinosis and hypocitraturia. Her family history revealed a sister with kidney stones. Conversely, 21 patients did not show any mutations for the genes sequenced, leading to a prevalence of genetic mutations of 8.7%. This is a much lower figure compared with overt dRTA, in which only 30% of patients with a clinical diagnosis of hereditary dRTA have no identified causative mutations in the currently known genes. Conclusion This suggests the involvement of other genes (WDR72 or others) or non-genetic tubular dysfunction in the pathogenesis of idRTA in stone formers.

P0003ADHERENCE BENEFITS OF ADV7103, AN INNOVATIVE PROLONGED-RELEASE ORAL COMBINATION PRODUCT, IN PATIENTS WITH DISTAL RENAL TUBULAR ACIDOSIS

Abstract Background and Aims Distal renal tubular acidosis (dRTA) is a rare disorder leading to impaired net acid excretion by the kidney inducing hyperchloremic metabolic acidosis and hypokalemia. The therapeutic effect of the standard of care is of short duration and requires multiple day and night administrations; it is also often accompanied by gastrointestinal discomfort and poor palatability impacting medication adherence. ADV7103, the first advanced therapy for dRTA, consists of a combination of prolonged-release potassium citrate and prolonged-release potassium bicarbonate granules providing round-the-clock alkali and potassium coverage with twice daily administration. Long-term adherence with ADV7103 is reported, along with acceptability of the product. Method B22CS is a multicentre, open-label long-term extension study, evaluating safety, tolerability, acceptability and efficacy of ADV7103 in adult and paediatric patients with dRTA. Adherence was assessed at each study visit up to 24 months, based on accountability of study drug retrieval, laboratory results, and interview of the patients in a diary and expressed as the proportion of patients that presented adherence lower than 50%, between 50% and 74%, between 75 and 90%, and higher than to 90%. Treatment acceptability as well as quality of life of the patients and their parents were assessed using a 100-mm visual analogue scales (VAS). Results Table 1 shows the evolution of compliance between Month 6 and Month 24. Overall, of the 29 patients remaining in the study after 24 months, 18 (62%) had adherence rates &amp;gt;90%, 5 (17%) had adherence rates of 75-90%, 6 (21%) had adherence rates of 50-74%, and there were no patients with adherence &amp;lt;50%. Adherence was good in all age groups, with rates of ≥75% in 100% of adults, 63% of adolescents 85% of children, and 67% of infants and toddlers. Compared to the alkalising treatments they had before the study, more than 80% of the patients perceived both the improvement of the formulation and of the number of daily doses at scores ≥ 75 mm. The overall improvement of quality of life reported by the patients was of 89 ± 19 mm and that reported by their parents was of 90 ± 14 mm after 24 months of treatment. Conclusion Adherence to treatment was maintained at a high level throughout the 24 months of the study confirming the good acceptance of ADV7103 therapy.

Parenteral Fluid Therapy in Children

Parenteral fluids are commonly administered in the hospital setting. For decades, clinicians have used a standardized approach for the prescription of maintenance IV fluids. Such an approach, however, has led to concerns regarding the development of hyponatremia using hypotonic fluids, especially in settings of heightened ADH release such as hypovolemia. Compared to balanced solutions for IV fluid administration, normal saline use has led to separate concerns regarding the development of hyperchloremic metabolic acidosis and acute kidney injury. A number of randomized controlled trials have shown lower rates of hyponatremia using isotonic fluids when compared to hypotonic fluids. Clinical practice guidelines from the United Kingdom and United States have both recommended isotonic IV fluids for the otherwise healthy child in need of maintenance fluid administration, while those with alterations in water or solute balance require more individualized approaches. Large studies in adults have shown lower rates of acute kidney injury with balanced solutions compared to normal saline although similar data in children is lacking. Retrospective pediatric data has not shown a consistent difference between these interventions. Isotonic fluids should be first line therapy for otherwise healthy children in need of maintenance IV fluids. Evidence for the standard use of balanced solutions in children remains more limited, until large randomized trials can be performed.

Adenocarcinoma at Ureterosigmoidostomy Site

Ureterosigmoidostomy is a method for total diversion of the urinary stream into the sigmoid colon, away from the urinary bladder and lower urinary tract, and the anus providing the continence mechanism for urine as well as for feces. However, this type of urinary diversion has multiple serious mid- and long-term complications, including cancer at the anastomotic site, ascending urinary infection, hyperchloremic metabolic acidosis, electrolyte imbalance, incontinence, and urinary stone. We present here a case of adenocarcinoma at the ureterosigmoidostomy site, performed for ectopia vesicae, 47 years ago.

SAT-LB309 Amphotericin B Induced Hypocalcemia in a Patient With Severe Hypercalcemia Due to Acute T-Cell Leukemia/Lymphoma

SAT-LB309 Amphotericin B Induced Hypocalcemia in a Patient With Severe Hypercalcemia Due to Acute T-Cell Leukemia/Lymphoma

Perioperative Infusion Therapy in Children

The composition and type of intravenous fluids during paediatric anaesthesia have been subjects of debates for decades. Errors in perioperative infusion therapy in children may lead to serious complications and a negative outcome. Therefore, in this review historical and recent developments and recommendations for perioperative fluid management in children are presented, based on physiology and focused on safety and efficacy. Recent studies showed that optimized preoperative fasting times and liberal clear fluid intake until 1 h improve patient comfort and metabolic and haemodynamic condition after induction of anaesthesia. Physiologically composed balanced isotonic electrolyte solutions are safer than hypotonic electrolyte solutions or saline 0.9% to protect young children against the risks of hyponatraemia and hyperchloremic acidosis. For intraoperative maintenance infusion, addition of 1 - 2% glucose is sufficient to avoid hypoglycaemia, lipolysis or hyperglycaemia. Modified fluid gelatine or hydroxyethyl starch in balanced electrolyte solution can safely be used to quickly normalize blood volume in case of perioperative circulatory instability and blood loss. In conclusion, physiologically composed infusion solutions are beneficial for maintaining homeostasis, shifting the status more towards the normal range in children with pre-existing imbalances and have a wide safety margin in case of accidental hyperinfusion.

Spironolactone-furosemide combination therapy and acid-base disorders in liver cirrhosis patients .

Respiratory alkalosis (RA) and dilutional hyperchloremic acidosis (DHA) are the most common acid-base balance (ABB) disorders in patients with liver cirrhosis. The aims of this study were to clarify whether RA develops in relation to DHA via respiratory compensation of metabolic acidosis and whether spironolactone in combination with low-dose furosemide - diuretics known to ameliorate DHA - positively affects RA in liver cirrhosis patients. 59 patients with advanced cirrhosis were divided into two groups. Group D consisted of individuals (urine sodium concentration (UNa+) > 20 mmol/L) who responded to combination therapy consisting of spironolactone and low-dose furosemide. The non-D group consisted of individuals (UNa+ ≤ 20 mmol/L) who either did not respond to the treatment or who were not administered it. In both groups, we examined serum and urine concentrations of electrolytes and ABB parameters, including SNa+-SCl- and SNa+/SCl- values. In group D, we found a statistically significant relationship between pCO2 and SHCO3-: r = 0.756 (p < 0.001) and between pCO2 and SNa+-SCl-: r = 0.522 (p = 0.001). Neither Salb nor the corrected anion gap were associated with changes in SHCO3- or pCO2 values. Although SHCO3- values were normal, abnormal pCO2 values were observed in one third of group D patients. Based on multivariable analysis, SHCO3- proved to be a statistically significant influencing factor on pCO2 values. DHA contributes to the development of RA in individuals with liver cirrhosis. Reducing DHA by means of effective diuretic therapy comprising spironolactone and furosemide has a beneficial effect on RA in such patients.

Association between perioperative normal saline and delayed graft function in deceased-donor kidney transplantation: a retrospective observational study.

Isotonic 0.9% sodium chloride (normal saline; NS) solution use is common, but its high chloride content has been shown to contribute to acid-base disturbances and acute kidney injury (AKI). As kidney transplant recipients are at high risk of postoperative AKI and renal replacement therapy, we aimed to evaluate the impact of perioperative NS administration on graft function after kidney transplantation. All adult patients undergoing deceased-donor kidney transplantation between January 2010 and December 2014 at the Rennes University Hospital were included. Logistic regression models were constructed to evaluate the association of hyperchloremia and hyperchloremic acidosis on delayed graft function (DGF), defined as the need for renal replacement therapy within the first week after transplantation. Three hundred and fifty-nine patients were included, 20% developed DGF. The mean (standard deviation) volume of NS infused in the operating room and in the standard postoperative intensive care unit stay was 4,832 (2,242) mL. In the first 24 postoperative hours, 11% of patients developed hyperchloremia and 11% developed hyperchloremic acidosis. These outcomes were not associated with significantly higher total volumes of NS administration or with DGF. In contrast, multivariable analysis showed that cold ischemia time, donor terminal creatinine, and perioperative NS volume were all independent predictors of DGF. Perioperative NS infusion volume was associated with DGF in deceased-donor kidney transplant recipients. Conversely, postoperative hyperchloremia and hyperchloremic acidosis were not associated with an increased risk of DGF, suggesting other mechanisms than a chloride effect.

Clinical features, genetic background, and outcome in infants with urinary tract infection and type IV renal tubular acidosis.

Type IV renal tubular acidosis (RTA) is a severe complication of urinary tract infection (UTI) in infants. A detailed clinical and molecular analysis is still lacking. Infants with UTI who exhibited features of type IV RTA were prospectively enrolled. Clinical, laboratory, and image characteristics and sequencing of genes responsible for phenotype were determined with follow-up. The study cohort included 12 infants (9 males, age 1-8 months). All exhibited typical type IV RTA such as hyperkalemia with low transtubular potassium gradient, hyperchloremic metabolic acidosis with positive urine anion gap, hypovolemic hyponatremia with renal salt wasting, and high plasma renin and aldosterone levels. Seven had hyperkalemia-related arrhythmia and two of them developed life-threatening ventricular tachycardia. With prompt therapy, all clinical and biochemical abnormalities resolved within 1 week. Five had normal urinary tract anatomy, and three of them carried genetic variants on NR3C2. Three variants, c.1645T>G (S549A), c.538G>A (V180I), and c.1-2C>G, on NR3C2 were identified in four patients. During follow-up, none of them had recurrent type IV RTA, but four developed renal scaring. Genetic mutation on NR3C2 may contribute to the development of type IV RTA as a complication of UTI in infants without identifiable risk factors, such as urinary tract anomalies.

Assessment of Acute Kidney Injury in Neurologically Injured Patients Receiving Hypertonic Sodium Chloride: Does Chloride Load Matter?

Background: Increasing evidence suggests that large-volume infusions of 0.9% sodium chloride (NaCl) for resuscitation are associated with hyperchloremic metabolic acidosis, renal vasoconstriction, and increased risk of acute kidney injury (AKI). Patients with neurological injury may require hypertonic NaCl for therapeutic hypernatremia, treatment of cerebral salt wasting, hyponatremia, or elevated intracranial pressure. Consequently, this increased exposure to chloride may result in an increased risk for development of AKI. Objective: The primary aim of this study was to describe the risk for development of AKI in neurologically injured patients receiving large volumes of intravenous hypertonic NaCl. Methods: This single-center, retrospective study looked at neurologically injured patients who received hypertonic NaCl and sodium acetate. Data were collected to assess renal function, hyperchloremia, and acidemia. Receiver operating characteristic (ROC) curve analysis was used to determine the predictive association between the amount of daily and overall chloride exposure and development of AKI. Results: A total of 301 patients were screened, and of those, 142 were included. Of the 142 patients included, 13% developed AKI, and 38% developed hyperchloremia. Additionally, 32% of patients were switched from NaCl to sodium acetate after an average of 3.4 ± 1.5 days of NaCl therapy. The ROC curve demonstrated that if patients received greater than 2055 mEq of chloride over 7 days, they were more likely to develop AKI (sensitivity 72%, specificity 70%; P = 0.002; area under the curve = 0.7). Conclusion and Relevance: Neurologically injured patients receiving hypertonic sodium therapy with a high chloride load are at risk of developing hyperchloremia and AKI.

Treatment of refractory and superrefractory status epilepticus with topiramate: A cohort study of 106 patients and a review of the literature.

Novel treatments are needed to control treatment-resistant status epilepticus (SE). We present a summary of clinical cases where oral topiramate (TPM) was used in refractory SE (RSE) and superrefractory SE (SRSE). A review of medical records was carried out to detect TPM administration in SE patients treated in Frankfurt and Marburg between 2011 and 2016. The primary outcome question concerned SE resolution after TPM initiation. In total, TPM was used in 106 of 854 patients having a mean age of 67.4±18.1years, 61 of whom were female (57.5%). The median latency from SE onset to TPM initiation was 8.5days. Patients with SE had previously failed a median of five other antiepileptic drugs. The median initial TPM dose was 100mg/d, which was uptitrated to a median maintenance dose of 400mg/d. Treatment with TPM was continued for a median time of 12days. TPM was the last drug provided to 42 of 106 (39.6%) patients, with a resultant response attributed to TPM observed in 29 of 106 (27.4%) patients. A response was attributed to TPM in 21 (31.8%) of 66 RSE cases and eight (20%) of 40 SRSE cases. Treatment-emergent adverse events were attributed to TPM usage in two patients, one each with pancreatitis and hyperchloremic acidosis, and in 38 patients (35.8%), hyperammonemia was seen. Thirty-four of these patients received a combination of TPM and valproate and/or phenobarbital. The intrahospital mortality rate was 22.6% (n=24). The rate of SE cessation attributed to TPM treatment (27.4%) represents a relevant response given the late treatment position of TPM and the treatment latency of more than8 days. Based on these results and in line with the findings of other case series, TPM can be considered an alternative option for treating RSE and SRSE.

Defective bicarbonate reabsorption in Kir4.2 potassium channel deficient mice impairs acid-base balance and ammonia excretion

The kidneys excrete the daily acid load mainly by generating and excreting ammonia but the underlying molecular mechanisms are not fully understood. Here we evaluated the role of the inwardly rectifying potassium channel subunit Kir4.2 (Kcnj15 gene product) in this process. In mice, Kir4.2 was present exclusively at the basolateral membrane of proximal tubular cells and disruption of Kcnj15 caused a hyperchloremic metabolic acidosis associated with a reduced threshold for bicarbonate in the absence of a generalized proximal tubule dysfunction. Urinary ammonium excretion rates in Kcnj15- deleted mice were inappropriate to acidosis under basal and acid-loading conditions, and not related to a failure to acidify urine or a reduced expression of ammonia transporters in the collecting duct. In contrast, the expression of key proteins involved in ammonia metabolism and secretion by proximal cells, namely the glutamine transporter SNAT3, the phosphate-dependent glutaminase and phosphoenolpyruvate carboxykinase enzymes, and the sodium-proton exchanger NHE-3 was inappropriate in Kcnj15-deleted mice. Additionally, Kcnj15 deletion depolarized the proximal cell membrane by decreasing the barium-sensitive component of the potassium conductance and caused an intracellular alkalinization. Thus, the Kir4.2 potassium channel subunit is a newly recognized regulator of proximal ammonia metabolism. The kidney consequences of its loss of function in mice support the proposal for KCNJ15 as a molecular basis for human isolated proximal renal tubular acidosis.

Whole exome sequencing identified ATP6V1C2 as a novel candidate gene for recessive distal renal tubular acidosis

Distal renal tubular acidosis is a rare renal tubular disorder characterized by hyperchloremic metabolic acidosis and impaired urinary acidification. Mutations in three genes (ATP6V0A4, ATP6V1B1 and SLC4A1) constitute a monogenic causation in 58-70% of familial cases of distal renal tubular acidosis. Recently, mutations in FOXI1 have been identified as an additional cause. Therefore, we hypothesized that further monogenic causes of distal renal tubular acidosis remain to be discovered. Panel sequencing and/or whole exome sequencing was performed in a cohort of 17 families with 19 affected individuals with pediatric onset distal renal tubular acidosis. A causative mutation was detected in one of the three "classical" known distal renal tubular acidosis genes in 10 of 17 families. The seven unsolved families were then subjected to candidate whole exome sequencing analysis. Potential disease causing mutations in three genes were detected: ATP6V1C2, which encodes another kidney specific subunit of the V-type proton ATPase (1 family); WDR72 (2 families), previously implicated in V-ATPase trafficking in cells; and SLC4A2 (1 family), a paralog of the known distal renal tubular acidosis gene SLC4A1. Two of these mutations were assessed for deleteriousness through functional studies. Yeast growth assays for ATP6V1C2 revealed loss-of-function for the patient mutation, strongly supporting ATP6V1C2 as a novel distal renal tubular acidosis gene. Thus, we provided a molecular diagnosis in a known distal renal tubular acidosis gene in 10 of 17 families (59%) with this disease, identified mutations in ATP6V1C2 as a novel human candidate gene, and provided further evidence for phenotypic expansion in WDR72 mutations from amelogenesis imperfecta to distal renal tubular acidosis.

Urinary undiversion from a sigma-rectum pouch to a cutaneous urinary stoma as a treatment for severe metabolic disorders post-radical cystectomy: A case report.

A total of six male patients, who had undergone radical cystectomy and sigma-rectum pouch surgery due to bladder cancer (2–5 years previously), developed hyperchloremic metabolic acidosis, hypokalemia and renal dysfunction. The patients underwent urinary undiversion surgery (the pouch was isolated from the intestinal tract, abdominal ostomy was performed, and the sigmoid colon and rectum were reconnected) and blood gas and electrolyte analysis and renal function were compared pre- and post-surgery. Blood hydrocarbonate levels significantly improved 3 months post-surgery compared with the preoperative levels (17.90±4.12 vs. 7.57±4.25; P=0.026). At 6 months post-surgery, blood pH (7.36±0.04 vs. 7.16±0.08; P=0.028) and potassium levels (3.95±0.38 vs. 3.12±0.21; P=0.032) were found to have improved significantly compared with the pre-surgery levels, and remained normal. Serum creatinine levels decreased significantly from the preoperative levels at 6 months post-surgery (213.00±44.85 vs. 304.67±55.58; P=0.028). Serum chlorine (99.17±2.75 vs. 110.90±4.38; P=0.038) significantly improved until 3 years post-surgery. The results of this case report indicated that urinary undiversion from a sigma-rectum pouch to a cutaneous urinary stoma that separates the pouch and intestine may be a beneficial treatment for post-sigma-rectum pouch surgery acidosis and electrolyte disturbances.

Outcome and complications in horses administered sterile or non-sterile fluids intravenously.

BackgroundObtaining commercial fluids for intravenous administration (IVF) was challenging during a recent shortage. This necessitated use of custom‐made non‐sterile fluids for intravenous administration (JUGs) in some hospitals. There are no studies comparing outcome of horses treated with JUG versus IVF and limited information is available about adverse effects of JUGs.Hypothesis/ObjectivesTo evaluate death, complications, blood pH, and plasma electrolyte concentrations of horses that received JUG versus IVFs.AnimalsOne hundred eighty‐six horses that received IVFs and 37 that received JUGs.MethodsA retrospective review of medical records was performed to identify horses that received IVFs or JUGs during hospitalization. Information including survival to discharge, complications (fever [>38.5°C], jugular vein phlebitis/thrombosis, arrhythmia, or laminitis), blood pH, and plasma electrolyte concentrations were obtained.ResultsThere was no difference (P = .67) in survival to discharge for horses that received JUGs (78%) compared to horses that received IVFs (87%). Horses that received JUGs were more likely to develop a jugular vein complication (3 of 37 versus 1 of 186, odds ratio 17.2 [95% CI 1.9‐389.8], P = .04). Horses that received JUGs were more likely to have electrolyte abnormalities consistent with hyperchloremic metabolic acidosis.Conclusion and Clinical ImportanceVeterinarians using JUGs should obtain informed client consent because of a potential increased risk of jugular vein complications. Chloride content of JUGs should be considered to limit development of hyperchloremic metabolic acidosis.