To the Editor: Brezina et al1.Brezina B. Qunibi W.Y. Nolan C.R. Acid loading during treatment with sevelamer hydrochloride: mechanisms and clinical implications.Kidney Int. 2004; 66: S39-S45Abstract Full Text Full Text PDF Scopus (65) Google Scholar ignore an important but neglected aspect of gastrointestinal physiology in attributing sevelamer-induced acidosis to replacement of intestinal phosphate, bicarbonate, and bile acid anions by chloride carried on the resin. These three anions are minor luminal constituents in the distal large intestine, where sevelamer reaches its final equilibrium with intestinal fluids before expulsion from the body. The predominant anions here are short-chain fatty acid anions (SCFAA)—acetate, propionate, and n-butyrate, with total concentrations of over 150 mmol/L, constituting over 70% of luminal anions2.Rubinstein R. Howard A.V. Wrong O.M. In vivo dialysis of faeces as a method of stool analysis: IV. The organic anion component.Clin Sci. 1969; 37: 549-564PubMed Google Scholar, 3.Bjork J.T. Soergel K.H. Wood C.M. The composition of "free" stool water.Gastroenterol. 1976; 70: 864Google Scholar, 4.Wrong O.M. Edmonds C.J. Chadwick V.S. The Large Intestine: Its Role in Mammalian Nutrition and Homeostasis. MTP Press, Lancaster1981Google Scholar. These SCFAA are derived from bacterial fermentation of food residues (mainly carbohydrate) and are bicarbonate precursors, normally being absorbed by the intestinal mucosa and incorporated into intermediary metabolism. Every mole of SCFAA removed from the body by sevelamer, and replaced by chloride from the resin, thus represents a loss of a mole of bicarbonate from the body and its replacement by chloride, equivalent to a gain by the body of a mole of hydrochloric acid; the amounts are far greater than would be generated by the resin's uptake of other anions from large bowel contents. This uptake of SCFAA by an anion-exchange resin passing through the gut was shown over 40 years ago, when normal subjects were fed four different anion-exchange resins5.Hurst P.E. Morrison R.B.I. Timoner J. et al.The effect of anion-exchange resins on faecal anions. Comparison with calcium salts and aluminium hydroxide.Clin Sci. 1963; 24: 189-200Google Scholar. Recovered from stool, the resins' anion-exchange capacity was 66% to 84% unaccounted for by chloride, sulphate, phosphate, bicarbonate, and carbonate, and must have been SCFAA, which we were then unable to measure.

We describe a familial form of renal Fanconi syndrome characterized by hypercalciuria, low-molecular-weight proteinuria, nephrocalcinosis and slowly progressive renal failure. Males are much more severely affected than females. The patients studied included 15 males and 10 females, and five families with up to three generations involved. Studies of the two largest families described here have already shown that their disease is inherited on the X-chromosome. The series contains the two unrelated patients originally described by Dent and Friedman in 1964 as ‘hypercalcuric rickets’.

An in vitro faecal incubation system was used to study the metabolism of complex carbohydrates by intestinal bacteria. Homogenates of human faeces were incubated anaerobically with added lactulose, pectin, the hemicellulose arabinogalactan, and cellulose, both before and after subjects had been pre-fed each carbohydrate. Fermentation of added substrate was assessed by the production of short-chain fatty acids (SCFA) and suppression of net ammonia generation over 48 h of incubation. Control faecal homogenates to which carbohydrate was not added yielded an average increment of SCFA of 43 mmol/l, equivalent to 172 mmol/kg in the original stool. The addition of lactulose, pectin and arabinogalactan each increased the yield of SCFA by a similar amount, averaging 6.5 mmol/g carbohydrate or 1.05 mol/mol hexose equivalent; organic acid yield was not increased by pre-feeding these substances for up to 2 weeks. Acetate was the major SCFA in all samples at all times and, after pre-feeding with extra carbohydrate, butyrate concentrations exceeded propionate in all samples. Faecal homogenates incubated with cellulose showed no greater SCFA production than controls over the first 48 h, but there was a slight increase when samples from two subjects pre-fed cellulose were incubated for 14 d. Net ammonia generation was markedly suppressed by addition of lactulose to faecal incubates with an initial period of net bacterial uptake of ammonia. Pectin and arabinogalactan also decreased ammonia generation, but the reductions were not significant unless subjects were pre-fed these materials; cellulose had no effect on ammonia generation.

A 74 year old woman had been unwell for three months with anorexia, nausea, upper abdominal pain, headache, low back pain, and 20 kg weight loss. She was born in Calcutta and at the age of 37 settled in London, remaining in Britain with the exception of a six month visit at the age of 54. She was lethargic, blood pressure was 100/60 mm Hg, and she had epigastric tenderness. Haematological concentrations were: blood urea 8-6 mmol/l (52 mg/100 ml), plasma creatinine 120 ,umol/l (14 mg/100 ml), sodium 129 mmol(mEq)/l, potassium 4-5 mmol(mEq)/l, albumin 27 g/l, and globulin 43 g/l. Alkaline phosphatase activity was 320 IU/l, aspartate transaminase activity 57 IU/l, haemoglobin concentration 17-2 g/dl, white cell count 3-9 x 10'/l (19% lymphocytes), and erythrocyte sedimentation rate <1 mm in first hour. The chest radiograph was normal and abdominal ultrasound showed an enlarged liver with increased echo pattern, compatible with metastases or cirrhosis. Ultrasound also detected a 5 cm retroperitoneal mass in the region of the splenic hilum, probably of pancreatic or lymph node origin. Endoscopy showed a hiatus hernia with oesophagitis; barium enema appearances were normal. Liver biopsy showed non-specific changes. One month after presentation she was confused and oedematous and her supine blood pressure was 80/60 mm Hg. Abdominal CT scan confirmed the hiatus hernia and showed fatty infiltration of the liver and large adrenal masses consistent with secondary deposits in both adrenal glands (fig 1). Blood urea concentration was 2-6 mmol/l (16 mg/100 ml), plasma sodium 132 mmol/l, potassium 2-7 mmol/l, albumin 19 g/l, globulin 46 g/l, and bilirubin 33 [tmol/l (1-9 mg/100 ml); serum enzyme activities were: alkaline phosphatase 741 IU/l, aspartate transaminase 76 IU/l, and y-glutamyltransferase 224 IU/I. Although random plasma cortisol concentrations were raised (770-810 nmol/l; 28-29 [ig/100 ml), progressive hypotension suggested adrenal failure and she was treated with parenteral dexamethasone, fludrocortisone, and saline. CT guided biopsy of an adrenal gland could not be performed because the blood pressure failed to improve and the prothrombin time was prolonged (ratio 1 5). Despite continued management of adrenal failure hypotension persisted and she died.

In a family exposed to metallic mercury vapour two patients had acrodynia, one had the nephrotic syndrome, and one person remained well. Recognition of the variable manifestations of the disease and prevention of further exposure were the most important aspects of management. Recovery appeared to be complete as blood mercury levels fell to normal. Urinary mercury levels were too variable to be reliable as indications of progress.

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1. Sodium tartrate labelled with 14 C was given orally and parenterally to man and rats, and by direct injection into the caecum in rats. From the differences in urinary excretion after oral and parenteral administration intestinal absorption of tartrate was calculated as 18% of the dose in man and 81% in rats. Urinary tartrate was equivalent to 14% of the dose in man and 70% in rats, the difference between absorption and urinary excretion representing metabolism in body tissues. 2. Both man and the rat excreted part of the 14 C as respiratory carbon dioxide. This occurred to a small extent after parenteral injection, suggesting metabolism of tartrate by body tissues, but was greater after oral or intracaecal administration, indicating that the main site of tartrate metabolism is the intestine. 3. Several genera of intestinal bacteria were shown to liberate [ 14 C]carbon dioxide from labelled tartrate, and in a faecal incubation system l-tartrate, the natural isomer, was metabolized five times as rapidly as d-tartrate. 4. Oral sodium l-tartrate, 1·5 mmol day —1 kg —1 , was given to two subjects and was shown to alkalinize the urine like sodium salts of other organic acids which are metabolized in the body. The reduction in renal hydrogen ion excretion showed that an average of 84% of the dose was metabolized. 5. Only 5% of labelled tartrate given by mouth appeared in faeces, and pharmacological doses of unlabelled l-tartrate had little or no aperient effect. 6. No evidence of toxicity of l-tartrate was encountered.

An in vitro fecal incubation system was used to demonstrate how lactulose influences ammonia metabolism in the colon. Lactulose and other fermentable substrates (glucose, mannitol, and sorbitol), pH and organic acid were varied independently so that their different effects could be determined. Fermentable substrate caused a fall in ammonia concentration during the period of fermentation. Acidification to pH 5.0 or less, with hydrochloric acid or a lactic-acetic acid mixture, significantly reduced ammonia generation, but unlike fermentable substrates, did not lower the existing ammonia concentration. The lactic-acetic acid mixture did not reduce ammonia generation significantly below that found with acidification by hydrochloric acid. The effect of lactulose in reducing ammonia concentration is attributed to its role as a bacterial substrate in either increasing bacterial assimilation of ammonia or reducing deamination of nitrogenous compounds. The effect of low pH in reducing generation of ammonia appears to be part of a general reduction in bacterial metabolism.

Conference Abstract| February 01 1976 Ammonia Generation by Incubated Faeces A. Vince; A. Vince 1Medical Unit, University College Hospital Medical School, London, and Department of Medicine, University of Dundee Search for other works by this author on: This Site PubMed Google Scholar P. F. Down; P. F. Down 1Medical Unit, University College Hospital Medical School, London, and Department of Medicine, University of Dundee Search for other works by this author on: This Site PubMed Google Scholar J. Murison; J. Murison 1Medical Unit, University College Hospital Medical School, London, and Department of Medicine, University of Dundee Search for other works by this author on: This Site PubMed Google Scholar F. J. Twigg; F. J. Twigg 1Medical Unit, University College Hospital Medical School, London, and Department of Medicine, University of Dundee Search for other works by this author on: This Site PubMed Google Scholar O. M. Wrong O. M. Wrong 1Medical Unit, University College Hospital Medical School, London, and Department of Medicine, University of Dundee Search for other works by this author on: This Site PubMed Google Scholar Author and article information Publisher: Portland Press Ltd © 1976 The Biochemical Society and the Medical Research Society1976 Clin Sci Mol Med (1976) 50 (2): 27P. https://doi.org/10.1042/cs050027Pa Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Cite Icon Cite Get Permissions Citation A. Vince, P. F. Down, J. Murison, F. J. Twigg, O. M. Wrong; Ammonia Generation by Incubated Faeces. Clin Sci Mol Med 1 February 1976; 50 (2): 27P. doi: https://doi.org/10.1042/cs050027Pa Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsClinical Science Search Advanced Search This content is only available as a PDF. © 1976 The Biochemical Society and the Medical Research Society1976 Article PDF first page preview Close Modal You do not currently have access to this content.

1. A 25% faecal suspension in sodium chloride solution, incubated anaerobically at 37 degrees C for 48 h, showed excellent survival of all the main groups of faecal bacteria. 2. All faecal incubation systems studied generated large amounts of ammonia, particularly those in which bacterial counts fell during incubation. As normal faeces contain negligible amounts of urea this ammonia must have been generated from sources other than urea. 3. Ammonia was also generated by faeces delivered by sodium chloride enema, and by ileostomy fluid, indicating that the phenomenon is not confined to distal colonic contents. 4. Ammonia generation by incubated faeces was inhibited by prior autoclaving of the sample, but not by sterilization with gamma-irradiation. 5. Generation of ammonia by incubated stool was accompanied by release of large amounts of organic anion and a fall in pH. 6. These observations are interpreted as evidence that ammonia generated within the colon in situ is not derived exclusively from urea, but also from bacterial deamination of amino acids, peptides and proteins. Simultaneously bacterial activity generates large amounts of organacid. The presence of living bacteria is not essential for ammonia generation, provided that bacterial enzymes are present. 7. Bacterial generation of organic solute in faeces which have left the body is sufficiently rapid to cast serious doubts on the validity of faecal centrifugation, or other time-consuming techniques involving lengthy handling of faeces, as methods of obtaining extracellular faecal fluid for measurements of organic constituents or ammonia.

1. Healthy subjects, given a long-acting preparation of vasopressin intramuscularly, excreted a significantly less concentrated urine than when subjected to fluid deprivation for 28 h. 2. When fludrocortisone, a potent mineralocorticoid, was given in addition to vasopressin the urine was not significantly less concentrated than after fluid deprivation. 3. Oral urea-loading also enhanced the urine-concentrating power of vasopressin but its effect was less marked than that of fludrocortisone. Oral urea did not increase further the urine concentration achieved by combined fludrocortisone and vasopressin. 4. Renal concentrating power was assessed in fourteen patients with renal disease and impaired concentrating ability. Fludrocortisone significantly enhanced the urine concentration achieved by vasopressin alone and the resultant urine was not significantly less concentrated than that achieved by fluid deprivation. 5. The action of fludrocortisone in enhancing the urine-concentrating effect of vasopressin is similar to that of aldosterone and is probably due to the increased sequestration of solute in the renal medulla, caused by increased reabsorption of sodium chloride in the ascending limb of the loop of Henle. 6. In the clinical assessment of renal concentrating power, the combined use of fludrocortisone and vasopressin has potential advantages over established methods.