Oral Bicarbonate Research Articles

Oral Bicarbonate Slows Decline of Residual Renal Function in Peritoneal Dialysis Patients

Background/Aims: Metabolic acidosis is a common consequence of end-stage renal disease (ESRD) which may result in a substantial adverse outcome. The effect of oral bicarbonate on the preservation of residual renal function (RRF) in peritoneal dialysis (PD) patients has been rarely reported. Methods: We randomly assigned 40 continuous ambulatory peritoneal dialysis (CAPD) patients to the oral bicarbonate group or placebo group at a 1: 1 ratio. All enrollments were followed for a duration of 104 weeks. We took residual creatinine clearance (CCr), a measure of residual renal function (RRF), as the primary outcome. Residual CCr was calculated as the average of urea and creatinine clearance from a 24-hour urine collection. Results: Thirteen patients in the placebo group and 15 patients in the treatment group completed the 104 weeks of follow-up with a comparable dropout rate (placebo group: 35% vs treatment group: 25%). Compared with the placebo group, serum bicarbonate in treatment group was significantly increased at each time point, and oral bicarbonate resulted in a slower declining rate of residual CCr (F=5.113, p=0.031). Baseline residual CCr at enrollment also had a significant effect on residual CCr (F=168.779, P<0.001). Charlson Comorbidity Index which was adopted to calculate a comorbidity score had no significant effect on residual CCr loss (F=0.168, P=0.685). Conclusion: Oral bicarbonate may have a RRF preserving effect in CAPD patients, and a normal to high level of serum bicarbonate (≥24mmol/L) may be appropriate for RRF preservation.

The Relationship between Metabolic Acidosis and Nutritional Parameters in Patients on Hemodialysis.

The progressive loss of kidney function is accompanied by metabolic acidosis. The relationship between metabolic acidosis, nutritional status, and oral bicarbonate supplementation has not been assessed in the Indian chronic kidney disease (CKD) population who are on maintenance hemodialysis (MHD). This is a single-center prospective study conducted in the Western part of India. Thirty-five patients, who were receiving MHD were assessed for metabolic acidosis along with various nutritional parameters at the baseline and at the follow-up after 3 months, postcorrection of acidosis with oral sodium bicarbonate supplements. The relationship between the correction of metabolic acidosis with oral bicarbonate supplements and changes in dietary and various nutritional parameters were evaluated. Metabolic acidosis at the baseline evaluation was found in 62.86% cases of the cohort with a mean serum bicarbonate value of 20.18 ± 4.93 mmol/L. The correction of acidosis with increment in the mean dosage of oral sodium bicarbonate supplements from 0.69 ± 0.410 mmol/kg/day at baseline to 1.04 ± 0.612 mmol/kg/day, significantly reduced the prevalence of metabolic acidosis to 23.33% cases at the follow-up. Improvement in serum bicarbonate level showed significant dietary, anthropometric, and nutritional improvements in these patients. Hence, we conclude that correction of metabolic acidosis with optimal oral bicarbonate supplementation plays a pivotal role in the treatment of malnourished CKD patients on MHD.

Correction of metabolic acidosis improves insulin resistance in chronic kidney disease.

BackgroundCorrection of metabolic acidosis (MA) with nutritional therapy or bicarbonate administration is widely used in chronic kidney disease (CKD) patients. However, it is unknown whether these interventions reduce insulin resistance (IR) in diabetic patients with CKD. We sought to evaluate the effect of MA correction on endogenous insulin action in diabetic type 2 (DM2) CKD patients.MethodsA total of 145 CKD subjects (83 men e 62 women) with DM2 treated with oral antidiabetic drugs were included in the study and followed up to 1 year. All patients were randomly assigned 1:1 to either open-label (A) oral bicarbonate to achieve serum bicarbonate levels of 24–28 mmol/L (treatment group) or (B) no treatment (control group). The Homeostatic model assessment (HOMA) index was used to evaluate IR at study inception and conclusion. Parametric and non-parametric tests as well as linear regression were used.ResultsAt baseline no differences in demographic and clinical characteristics between the two groups was observed. Average dose of bicarbonate in the treatment group was 0.7 ± 0.2 mmol/kg. Treated patients showed a better metabolic control as confirmed by lower insulin levels (13.4 ± 5.2 vs 19.9 ± 6.3; for treated and control subjects respectively; p < 0.001), Homa-IR (5.9[5.0-7.0] vs 6.3[5.3–8.2]; p = 0.01) and need for oral antidiabetic drugs. The serum bicarbonate and HOMA-IR relationship was non-linear and the largest HOMA-IR reduction was noted for serum bicarbonate levels between 24 and 28 mmol/l. Adjustment for confounders, suggests that serum bicarbonate rather than treatment drives the effect on HOMA-IR.ConclusionsSerum bicarbonate is related to IR and the largest HOMA-IR reduction is noted for serum bicarbonate between 24 and 28 mmol/l. Treatment with bicarbonate influences IR. However, changes in serum bicarbonate explains the effect of treatment on HOMA index. Future efforts are required to validate these results in diabetic and non-diabetic CKD patients.Trial registrationThe trial was registered at www.clinicaltrial.gov (Use of Bicarbonate in Chronic Renal Insufficiency (UBI) study - NCT01640119)

Dysregulation of Pendrin and NBC‐e1 and Impaired HCO3− Secretion in the Kidneys of CFTR Knockout Mice: Role in the pathogenesis of metabolic alkalosis in cystic fibrosis

IntroductionPatients with cystic fibrosis (CF) are prone to the development of metabolic alkalosis, which is manifested by an elevation of arterial blood pH and bicarbonate concentration and produces a physiologic diminution of respiratory effort that is detrimental in CF patients. The pathogenesis of metabolic alkalosis in CF remains unknown.HypothesisInactivation of CFTR will impair the ability of the kidney to excrete excess bicarbonate via dysregulation of HCO3− transporters, therefore resulting in the elevation of arterial pH and bicarbonate concentration and subsequently, generation of metabolic alkalosis in mutant mice subjected to an oral bicarbonate load.MethodsCFTR knockout (CF) mice with the intestinal rescue (over‐expressing wild type CFTR transgene in their intestine‐Science 1994) were examined for the changes in arterial pH and bicarbonate concentration as well as the expression of pendrin and NBC‐e1. Animals were subjected to an oral bicarbonate load (140 mM/lit bicarbonate in the drinking water) and examined after 3 days.ResultsBaseline parameters, including acid‐base status and urine pH were comparable in CF and WT mice. Compared to WT animals, CF mice demonstrated a significant increase in blood HCO3− concentration (21.87 +/− 0.8 in wt vs. 26.83 +/− 0.9 mEq/l in CF mice, p&lt;0.004) and pH (7.33 +/− 0.01 in wt vs. 7.42 +/− 0.02 in CF mice, p&lt;0.003) and impaired kidney HCO3− excretion (urine pH 8.10 +/− 0.09 in wt vs. 7.35 +/− 0.09 in CF‐KO mice, p&lt;0.002) following a 3‐day oral bicarbonate load. Immunofluorescence labeling demonstrated profound reduction in the apical expression and increased cytoplasmic and basolateral localization of pendrin in the intercalated cells in CF mice (Fig. 1). Moreover, an unexpected aberrant induction of the Na+:HCO3− co‐transporter NBCe1 (kidney NBC1) was detected in principal cells of the cortical collecting duct in CF mice (Fig. 2).ConclusionWe propose that patients with cystic fibrosis are prone to the development of metabolic alkalosis secondary to the dysregulation of pendrin and NBC‐e1, specifically during volume depletion, which is a common occurrence in CF patients.Support or Funding InformationMerit Review Award from Veterans Administration

Oral dissolution therapy for radiolucent kidney stones. An old treatment revisited

Objective: We present our experience using oral bicarbonate as a dissolution therapy for radiolucent kidney stones in the pre-dual energy CT era. Methods: A retrospective analysis of dissolution therapy was undertaken over a four-year period. Stones were diagnosed as radiolucent on conventional KUB X-ray in combination with either ultrasound or CT KUB. Oral bicarbonate was given at a dose of 2 g tds orally, increased to 2 g five times daily according to urinary pH. Patients monitored their own urine dipstick daily to achieve a pH of at least seven. Results: Altogether 27 patients were identified with radiolucent stones. Stone size varied from 4–40 mm. Average length of therapy was nine weeks. Of the patients, 17 had renal U/S and six had CT KUB as end point imaging. We found that 39% had complete dissolution, 18% had a partial response and 43% showed no response. A high serum uric acid level correlated with a higher incidence of dissolution. Cost-benefit analysis shows bicarbonate therapy to be more cost-effective than lithotripsy, ureteroscopy or nephrolithotomy. Conclusions: Bicarbonate therapy remains an attractive option for the treatment of radiolucent kidney stones. The presence of hyperuricaemia or hyperuricosuria appears to influence the success rate. Further prospective randomised studies are needed to identify the most tolerable and effective treatment regime as well as the optimal duration of treatment. Dual-energy CT may hold the key to identifying patients most likely to benefit from treatment.

Absence of Band 3 in Severe Dyserythropoietic/Hemolytic Anemia with Complete Distal Renal Acidosis and a Novel Homozygous Exon 12 C.1430C>a (p.Ser477X) SLC4A1 Gene Mutation

The solute carrier 4A1 gene (SLC4A1) encodes theband 3 or bicarbonate anionic exchanger 1 (AE1). It is not only the major glycoprotein of the red blood cell (RBC) membrane but also expressed in acid secreting alpha-intercalated kidney cells. Functionally impairing SLC4A1 mutations reduce the expression and/or activity of AE1 thereby causing a unique combination of hemolytic anemia and distal renal tubular acidosis (dRTA). So far, only four such particular homozygote mutations have been documented in humans: an exon 11 p.400-408 deletion in Southeast Asian ovalocytosis (SAO) with transfusion-dependent dyserythropoietic anemia and dRTA (Picard et al, Blood 123:1963;2014), an exon 13 p.V488M mutation in transfusion-dependent hereditary spherocytosis (HS) and dRTA lacking band 3 (Ribeiro et al, Blood 96:1602;2000), an exon 16 p.S667F mutation in transfusion-dependent HS and incomplete dRTA (Toye et al, Blood 111:5380;2008), and finally an exon 19 p.Ala858Asp in a compensated hemolytic anemia with marked acanthocytosis, echinocytosis and dRTA (Fawaz et al, Europ J Haematol 88:350;2012). We report herein a novel homozygote variant in exon 12 in a patient with a transfusion-dependent dyserythropoietic/hemolytic anemia and complete dRTA.The now 4-years old Turkish boy was born after 32 weeks of gestation and presented with a severe hemolytic anemia (Hb 40 g/L) that required exchange transfusions and a complete dRTA that was treated with oral bicarbonate. He also suffered from delayed psychomotoric developmental with failure to thrive, trigonocephalus and strabismus convergens. Bone marrow smears showed marked dyserythropoiesis but normal myeloid and megakaryocytic lineages. Although necessary monthly transfusions impeded the patient's direct diagnostic work-up, a flow cytometric eosin-5-maleimide assay eventually revealed a reduced staining of his consanguine parents' and his two siblings' erythrocytes, who all had subclinical signs of spherocytosis despite normal RBC counts.Based on these findings, we analyzed the SLC4A1 gene and found two homozygous sequence variants in the patient, namely a novel disease-relevant exon 12 nonsense mutation c.1430C>A (p.Ser477X) and a disease-unrelated c.2312-48T>G (rs13306780). The ensuing stop codon of the former truncates the protein, prevents band 3 formation and reduces glycophorin A expression. Bright field imaging uncovered few phenotypic spherocytic band 3 null RBCs even in the peripheral blood.In accordance with the autosomal recessive inheritance pattern, both healthy parents as well as his healthy siblings were found to be heterozygous carriers. The band 3 protein was reduced to 50-60% in the parents' erythrocytes. An increased approximately 22 kDa-sized band was evident in Coomassie stained gels of the heterozygous mutation carriers' membrane preparations and classified by immunoblotting as peroxiredoxin 2 (PRDX2), which plays a major role in protecting RBCs from oxidative stress.Taken together, the provided data clearly confirm the relevance of this particular c.1430C>A (p.Ser477X) SLC4A1 mutation in the disease process. Of note, such a severe dyserythropoietic anemia and complete dRTA was also recently reported in a patient with Southeast Asian ovalocytosis and another form of homozygous SLC4A1 mutation (Picard et al, Blood 123:1963;2014). DisclosuresNo relevant conflicts of interest to declare.

Does oral sodium bicarbonate therapy improve function and quality of life in older patients with chronic kidney disease and low-grade acidosis (the BiCARB trial)? Study protocol for a randomized controlled trial.

BackgroundMetabolic acidosis is more common with advancing chronic kidney disease, and has been associated with impaired physical function, impaired bone health, accelerated decline in kidney function and increased vascular risk. Although oral sodium bicarbonate is widely used to correct metabolic acidosis, there exist potential risks of therapy including worsening hypertension and fluid overload. Little trial evidence exists to decide whether oral bicarbonate therapy is of net benefit in advanced chronic kidney disease, particularly in older people who are most commonly affected, and in whom physical function, quality of life and vascular health are at least as important outcomes as decline in renal function.Methods/DesignBiCARB is a multi-centre, double-blind, placebo controlled, randomised trial evaluating the clinical and cost-effectiveness of oral sodium bicarbonate in the management of older people with chronic kidney disease and severely reduced glomerular filtration rate (GFR) who have a mild degree of metabolic acidosis. The trial will recruit 380 patients from renal, Medicine for the Elderly, and primary care services across centres in the United Kingdom. Male and female patients aged 60 years and older with an estimated glomerular filtration rate of <30 mL/min/1.73 m2, not on dialysis, and with serum bicarbonate concentrations <22 mmol/L will be eligible for participation. The primary clinical outcome for the trial is the between-group difference in the Short Physical Performance Battery score at 12 months. Secondary outcomes include muscle strength, quality of life measured using the EQ-5D score and KDQoL tools, cost effectiveness, renal function, presence of albuminuria and blood pressure. Markers of bone turnover (25-hydroxyvitamin D, 1,25-hydroxyvitamin D, tartrate-resistant acid phosphatase-5b and bone-specific alkaline phosphatase) and vascular health (B-type natriuretic peptide) will be measured. Participants will receive a total of 24 months of either bicarbonate or placebo. The results will provide the first robust test of the overall clinical and cost-effectiveness of this commonly used therapy in older patients with severely reduced kidney function.Trial registrationwww.isrctn.com; ISRCTN09486651, registered 17 February 2012

Bicarbonate Therapy in End-Stage Renal Disease: Current Practice Trends and Implications.

Management of metabolic acidosis covers the entire spectrum from oral bicarbonate therapy and dietary modifications in chronic kidney disease to delivery of high doses of bicarbonate-based dialysate during maintenance haemodialysis (MHD). Due to the gradual depletion of the body's buffers and rapid repletion during MHD, many potential problems arise as a result of our current treatment paradigms. Several studies have given rise to conflicting data about the adverse effects of our current practice patterns in MHD. In this review, we will describe the pathophysiology and consequences of metabolic acidosis and its therapy in CKD and ESRD, and discuss current evidence supporting a more individualized approach for bicarbonate therapy in MHD.

Management of chronic metabolic acidosis in neobladder patients: survey among urologists regarding diagnosis and therapy

The guideline of the "Deutsche Gesellschaft für Urologie" recommends capillary blood gas analysis for neobladder patients every 3 months. In case of chronic metabolic acidosis (CMS), treatment with oral bicarbonate is recommended. However, it is unknown how these recommendations are implemented in daily practice. The aim of this study was to evaluate the current diagnosis, rating and therapy of CMA among neobladder patients by German urologists. A survey covering diagnosis, rating, and therapy of CMA was sent to 5,539 urologists in Germany in August 2013. All 350 (6.3%) completed surveys were analyzed. Nearly all respondents (98%) perform blood gas analysis (BGA) to diagnose CMA, usually following unspecific symptoms such as general discomfort and fatigue. In addition, about half of the urologists frequently check their neobladder patients for CMA, regardless of any symptoms. The incidence of CMA directly following neobladder construction was estimated to be 64%. Approximately 17% of all patients need permanent CMA treatment. Ninety nine percent of all respondents prefer to treat CMA with oral bicarbonate at a daily dose of 1000-3000 mg, mostly with enteric coated formulations. CMA is an important comorbidity after neobladder construction. Furthermore, the respondents of the survey expressed great interest in receiving medical education regarding the management of CMA in neobladder patients.

Treatment of metabolic acidosis in patients with stage 3 chronic kidney disease with fruits and vegetables or oral bicarbonate reduces urine angiotensinogen and preserves glomerular filtration rate

Alkali therapy of metabolic acidosis in patients with chronic kidney disease (CKD) with plasma total CO2 (TCO2) below 22 mmol/l per KDOQI guidelines appears to preserve estimated glomerular filtration rate (eGFR). Since angiotensin II mediates GFR decline in partial nephrectomy models of CKD and even mild metabolic acidosis increases kidney angiotensin II in animals, alkali treatment of CKD-related metabolic acidosis in patients with plasma TCO2 over 22 mmol/l might preserve GFR through reduced kidney angiotensin II. To test this, we randomized 108 patients with stage 3 CKD and plasma TCO2 22-24 mmol/l to Usual Care or interventions designed to reduce dietary acid by 50% using sodium bicarbonate or base-producing fruits and vegetables. All were treated to achieve a systolic blood pressure below 130 mm Hg with regimens including angiotensin converting enzyme inhibition and followed for 3 years. Plasma TCO2 decreased in Usual Care but increased with bicarbonate or fruits and vegetables. By contrast, urine excretion of angiotensinogen, an index of kidney angiotensin II, increased in Usual Care but decreased with bicarbonate or fruits and vegetables. Creatinine-calculated and cystatin C-calculated eGFR decreased in all groups, but loss was less at 3 years with bicarbonate or fruits and vegetables than Usual Care. Thus, dietary alkali treatment of metabolic acidosis in CKD that is less severe than that for which KDOQI recommends therapy reduces kidney angiotensin II activity and preserves eGFR.

Combined walking exercise and alkali therapy in patients with CKD4–5 regulates intramuscular free amino acid pools and ubiquitin E3 ligase expression

Muscle-wasting in chronic kidney disease (CKD) arises from several factors including sedentary behaviour and metabolic acidosis. Exercise is potentially beneficial but might worsen acidosis through exercise-induced lactic acidosis. We studied the chronic effects of exercise in CKD stage 4-5 patients (brisk walking, 30 min, 5 times/week), and non-exercising controls; each group receiving standard oral bicarbonate (STD), or additional bicarbonate (XS) (Total n = 26; Exercising + STD n = 9; Exercising +XS n = 6; Control + STD n = 8; Control + XS n = 3). Blood and vastus lateralis biopsies were drawn at baseline and 6 months. The rise in blood lactate in submaximal treadmill tests was suppressed in the Exercising + XS group. After 6 months, intramuscular free amino acids (including the branched chain amino acids) in the Exercising + STD group showed a striking chronic depletion. This did not occur in the Exercising + XS group. The effect in Exercising + XS patients was accompanied by reduced transcription of ubiquitin E3-ligase MuRF1 which activates proteolysis via the ubiquitin-proteasome pathway. Other anabolic indicators (Akt activation and suppression of the 14 kDa actin catabolic marker) were unaffected in Exercising + XS patients. Possibly because of this, overall suppression of myofibrillar proteolysis (3-methylhistidine output) was not observed. It is suggested that alkali effects in exercisers arose by countering exercise-induced acidosis. Whether further anabolic effects are attainable on combining alkali with enhanced exercise (e.g. resistance exercise) merits further investigation.

Alkaline Water–An Alternative to Oral Bicarbonate Supplementation in CKD?

Alkaline Water–An Alternative to Oral Bicarbonate Supplementation in CKD?

Alkaline Salts to Counteract Bone Resorption and Protein Wasting Induced by High Salt Intake: Results of a Randomized Controlled Trial

High sodium chloride (NaCl) intake can induce low-grade metabolic acidosis (LGMA) and may thus influence bone and protein metabolism. We hypothesized that oral potassium bicarbonate (KHCO(3)) supplementation may compensate for NaCl-induced, LGMA-associated bone resorption and protein losses. Eight healthy male subjects participated in a randomized trial with a crossover design. Each of two study campaigns consisted of 5 d of dietary and environmental adaptation followed by 10 d of intervention and 1.5 d of recovery. In one study campaign, 90 mmol KHCO(3)/d were supplemented to counteract NaCl-induced LGMA, whereas the other campaign served as a control with only high NaCl intake. When KHCO(3) was ingested during high NaCl intake, postprandial buffer capacity ([HCO(3)(-)]) increased (P = 0.002). Concomitantly, urinary excretion of free potentially bioactive glucocorticoids [urinary free cortisol (UFF) and urinary free cortisone (UFE)] was reduced by 14% [∑(UFF,UFE); P = 0.024]. Urinary excretion of calcium and bone resorption marker N-terminal telopeptide of type I collagen was reduced by 12 and 8%, respectively (calcium, P = 0.047; N-terminal bone collagen telopeptide, P = 0.044). There was a trend of declining net protein catabolism when high NaCl was combined with KHCO(3) (P = 0.052). We conclude that during high salt intake, the KHCO(3)-induced postprandial shift to a more alkaline state reduces metabolic stress. This leads to decreased bone resorption and protein degradation, which in turn might initiate an anticatabolic state for the musculoskeletal system in the long run.

Risk factors for nephrolithiasis in patients with ileal pouches

Background and aimsRestorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) has become a standard of care in patients with ulcerative colitis (UC). Nephrolithiasis is common in patients with inflammatory bowel disease (IBD), but has never been studied as a complication of IPAA. We aimed to assess the risk factors for nephrolithiasis in patients with IPAA. MethodsUsing an IRB-approved, prospectively maintained pouch registry, we identified 1221 patients between 2000 and 2010. Those with post-IPAA nephrolithiasis served as the study group whereas IPAA patients without nephrolithiasis served as the controls. Demographic and clinical variables were analyzed using multivariable logistic regression to identify risk factors. ResultsThere were a total of 218 IPAA patients: 81 with nephrolithiasis (37%) and 137 without (63%). Of the 81 patients in the study group, 17 were excluded due to limited clinical data. Three risk factors were found to be associated with nephrolithiasis: the presence of extra-intestinal manifestations (odd's ratio [OR]=2.9, 95% confidence interval [CI]: 1.4, 5.8, p=0.003), no use of antibiotics (OR=3.2, 95% CI: 1.5, 6.5, p=0.002) and low serum bicarbonate level (OR=0.87, 95% CI: 0.77, 0.99, p=0.038). ConclusionNephrolithiasis was a common finding in our patients with IPAA. As pouch patients with nephrolithiasis can develop adverse clinical complications, those with at least one of the risk factors we identified may need to be monitored more closely and possibly receive prophylactic treatment with oral bicarbonate.

A mitochondrial DNA deletion presenting with corneal clouding and severe Fanconi syndrome

Mitochondrial cytopathies are a diverse group of disorders characterized by impaired mitochondrial energy production. Disease manifestations are protean and may include seemingly disparate findings. Here we report a 5-year-old girl with the uncommon pairing of bilateral corneal dystrophy requiring corneal transplantation and severe Fanconi syndrome recalcitrant to oral bicarbonate therapy necessitating intravenous supplementation. Etiological work-up included qualitative urine organic acid testing, which demonstrated abnormalities in lactate, pyruvate, and ketoacids suggestive of a mitochondrial etiology. Confirmatory genetic testing in blood leukocytes revealed a large, novel, heteroplasmic, de novo mitochondrial DNA deletion at nt 8648-16072. The finding of Fanconi syndrome with disease processes in other, seemingly unrelated, organ systems should raise clinical suspicion for mitochondrial disease. Early assessment of urine organic acids in the etiological work-up of Fanconi syndrome may assist in the identification of respiratory chain disorders.

Reduced time for urinary alkalinization before high-dose methotrexate with preadmission oral bicarbonate

Hydration and urinary alkalinization are essential for reducing renal dysfunction with high dose methotrexate (HDMTX). This report presents an analysis of institutional methods used to achieve adequate urinary alkalinization and output for patients receiving single agent HDMTX. Renal and metabolic parameters of tolerance were examined. Medical records of adult patients receiving HDMTX during the calendar years of 2008-2009 were retrospectively reviewed to determine the time to achieve urine pH > 7. Number of hospital days, bicarbonate dose, ordered hydration rate, urine output, and urine pH were assessed. A survival analysis model was run for time to urine pH > 7 using preadmission oral bicarbonate as a predictor variable and including a frailty term. Observational statistics were performed for other parameters. The analysis included 79 encounters for ten patients. Urine pH > 7 was achieved more rapidly in patients receiving preadmission oral bicarbonate (P = 0.012). The number of patients receiving HDMTX on the same day as admission was greater for those receiving preadmission oral bicarbonate (47%) in comparison to those who did not (2%), and they spent less time in the hospital. A standard regimen for hydration and urinary alkalinization based on this project is reported. The nature and frequency of adverse events were as expected for this treatment. At our institution, the time to achieve urinary alkalinization was reduced for patients receiving preadmission oral bicarbonate which facilitated chemotherapy infusion on the same day as admission and decreased the number of calendar days that patients stayed in the hospital.

Deletion of the Cl-/HCO3- exchanger pendrin downregulates calcium-absorbing proteins in the kidney and causes calcium wasting

The epithelial calcium channel (ECaC) (TRPV5) and the Cl-/HCO3- exchanger pendrin (SLC26A4) are expressed on the apical membrane of tubular cells in the distal nephron and play essential roles in calcium re-absorption and bicarbonate secretion, respectively, in the kidney. A combination of functional and molecular biology techniques were employed to examine the role of pendrin deletion in calcium excretion. Here, we demonstrate that deletion of pendrin causes acidic urine [urine pH 4.9 in knockout (KO) versus 5.9 in wild-type (WT) mice, P<0.03)] and downregulates the calcium-absorbing molecules ECaC and Na/Ca exchanger in the kidney, as shown by northern hybridization, immunoblot analysis and/or immunofluorescent labeling. These changes were associated with a ∼100% increase in 24-h urine calcium excretion in pendrin null mice. Subjecting the pendrin WT and KO mice to oral bicarbonate loading for 12 days increased the urine pH to ∼8 in both genotypes, normalized the expression of ECaC and Na/Ca exchanger and reduced the urine calcium excretion in pendrin-null mice to levels comparable to WT mice. We suggest that pendrin dysfunction should be suspected and investigated in humans with an otherwise unexplained acidic urine and hypercalciuria.

Bicarbonate and dichloroacetate: Evaluating pH altering therapies in a mouse model for metastatic breast cancer

BackgroundThe glycolytic nature of malignant tumors contributes to high levels of extracellular acidity in the tumor microenvironment. Tumor acidity is a driving force in invasion and metastases. Recently, it has been shown that buffering of extracellular acidity through systemic administration of oral bicarbonate can inhibit the spread of metastases in a mouse model for metastatic breast cancer. While these findings are compelling, recent assessments into the use of oral bicarbonate as a cancer intervention reveal limitations.MethodsWe posited that safety and efficacy of bicarbonate could be enhanced by dichloroacetate (DCA), a drug that selectively targets tumor cells and reduces extracellular acidity through inhibition of glycolysis. Using our mouse model for metastatic breast cancer (MDA-MB-231), we designed an interventional survival study where tumor bearing mice received bicarbonate, DCA, or DCA-bicarbonate (DB) therapies chronically.ResultsDichloroacetate alone or in combination with bicarbonate did not increase systemic alkalosis in mice. Survival was longest in mice administered bicarbonate-based therapies. Primary tumor re-occurrence after surgeries is associated with survival rates. Although DB therapy did not significantly enhance oral bicarbonate, we did observe reduced pulmonary lesion diameters in this cohort. The DCA monotherapy was not effective in reducing tumor size or metastases or improving survival time. We provide in vitro evidence to suggest this outcome may be a function of hypoxia in the tumor microenvironment.ConclusionsDB combination therapy did not appear to enhance the effect of chronic oral bicarbonate. The anti-tumor effect of DCA may be dependent on the cancer model. Our studies suggest DCA efficacy is unpredictable as a cancer therapy and further studies are necessary to determine the role of this agent in the tumor microenvironment.

Green urine, but no infection

In September, 2007, an unconscious 88-year-old woman was brought to the emergency room. She had undergone a hysterectomy and radiotherapy because of carcinoma of the cervix 30 years previously; 10 years later she had developed neurogenic bladder dysfunction, requiring intermittent self-catheterisation. She had had mild renal insuffi ciency (creatinine 100 μmol/L) and mild hydronephrosis unilaterally, because of ureteric obstruction following the irradiation. Her medical history also included bilateral femoral artery angioplasty, a transient ischaemic attack, and group B streptococcal endocarditis with remaining mild mitral valve insuffi ciency. Medications included an ACE-inhibitor, aspirin, and dipyridamole for the past 4 years. On presentation she was unresponsive and hyperventilating (20 breaths per min) with a body temperature of 33·0°C, an irregular pulse (110 beats per min), and a blood pressure of 110/60 mm Hg. Auscultation showed no new cardiac abnormalities, and neurological evaluation was unremarkable. The electrocardiogram showed atrial fi brillation (110 beats per min). Blood gas analysis on supplemental oxygen, corrected for hypothermia, showed a pH of 7·08, pCO2 1·85 kPa, bicarbonate 3·6 mmol/L, and pO2 18·5 kPa, indicative of metabolic acidosis with incomplete respiratory compensation. 1300 mL of green purulent urine was emptied from the bladder on catheterisation. Urosepsis was suspected, blood samples were taken, and she was rehydrated with saline and treated with ceftriaxone and 8·4% NaHCO3. 1 h later laboratory test results showed a normal anion gap hyperchloraemic acidosis (anion gap 16, sodium 147 mmol/L, and chloride 127 mmol/L). Lactate (1 mmol/L), potassium (4·3 mmol/L), albumin (34 g/L), and glucose (7·9 mmol/L) were normal. Until this point she had received 1250 mL 0·9% NaCl (saline) and 200 mL of 8·4% NaHCO3. Repeat analysis showed sodium 159 mmol/L, chloride 131 mmol/L, potassium 3·4 mmol/L, and bicarbonate 7·0 mmol/L. Although the saline was replaced by 5% glucose solution, 1·5 L/day, with 4 mmol potassium added, plasma sodium and chloride concentrations inceased to 170 mmol/L and 143 mmol/L, respectively, over the next 2 days. Urine cultures were negative. Hyperchloraemia and hypernatraemia because of endogenous reuptake of urinary chloride in the bowel was suspected. Cystoscopy showed a large bladder wall defect with a vesicojejunal fi stula on CT (fi gure). Our patient refused additional procedures and was discharged to a nursing home with oral bicarbonate supplementation. She passed away 2 months later. Our patient had a hyperchloraemic metabolic acidosis because of a fi stula between bladder and jejunum caused by previous radiotherapy; it is possible that the fi stula caused the group B streptococcal endocarditis 3 years before presentation. The ileal and colonic mucous membrane harbours a Cl/HCO3 transporter that exchanges intraluminal chloride (in our patient, a large amount via the communication to the bladder) for bicarbonate; sodium is actively reabsorbed, leading to potassium excretion. This explains the hyperchloraemic acidosis that can be seen in patients following ureter implantation into the sigmoid commonly presenting with hypokalaemia. However, in our patient, renal insuffi ciency and ACE-inhibitor use induced normokalaemia, and correction of the acid-base status provoked hypokalaemia. Saline infusion and bicarbonate supplementation during initial resuscitation resulted in additional sodium re-uptake and worsening of hyperchloraemia and hypernatraemia. Several other factors may have contributed to the observed acidosis, for example elevated bladder pressure between the selfcatheterisations promoting fl uid movement through the fi stula. In addition, the proximal localisation of the fi stula could have extended ileal and colonic transit time, augmenting intestinal chloride uptake. Enterovesical fi stula can occur years after pelvic radiotherapy; the importance of taking into account the patient’s history cannot be emphasised enough.

Modified ureterosigmoidostomy for management of malignant and non-malignant conditions

To investigate the outcome of Mainz Pouch II urinary diversion for both malignant and non-malignant diseases. A retrospective analysis. Kilimanjaro Christian Medical Centre, Institute of Urology, Moshi, Tanzania from April 1995 to May 2007. Mainz Pouch II was created in 83 patients of which, 38 were females and 45 were males (M:F 1.2:1). Early complications were seen in 11 (13.2%) patients, as follows: one (1.2%) prolonged ileus, 1(1.2%) wound dehiscence, two (2.4%) perioperative deaths among the malignant group, seven (8.4%) superficial wound sepsis. Long term complications were seen in 14 (16.9%) patients, as follows: one (1.2%) patient developed an incision hernia, one (1.2%) patient developed unilateral pyelonephritis, one (1.2%) patient developed unilateral ureteral stenosis, two (2.4%) patients had deterioration of renal function, three (3.6%) patients developed mild to moderate unilateral hydronephrosis, three (3.6%) patients developed mucoceles. Among the 83 patients in this series, three (3.6%) patients developed metabolic acidosis, two (2.4%) of which, required oral bicarbonate supplementation. All (100%) patients had daytime continence while three (3.6%) patients had occasional night time incontinence. Overall total continence was achieved in 80 (96.4%) of the patients. The Mainz Pouch II is a safe and reproducible method of urinary diversion and serves as a satisfying method of continent urinary diversion in all age groups. This reconstructive surgery enabled the afflicted to achieve personal goals, hopes and aspirations, positively influencing their quality of life. The follow up show low complication rate with good results in terms of continence and quality of life, however, long term results remain to be evaluated.