Citrate metabolism and its complications in non-massive blood transfusions: association with decompensated metabolic alkalosis+respiratory acidosis and serum electrolyte levels.

BACKGROUND AND OBJECTIVES: Metabolic alkalosis, which is a non-massive blood transfusion complication, is not reported in the literature although metabolic alkalosis dependent on citrate metabolism is reported to be a massive blood transfusion complication. The aim of this study was to investigate the effect of elevated carbon dioxide production due to citrate metabolism and serum electrolyte imbalance in patients who received frequent non-massive blood transfusions. MATERIALS AND METHODS: Fifteen inpatients who were diagnosed with different conditions and who received frequent blood transfusions (10-30 ml/kg/day) were prospectively evaluated. Patients who had initial metabolic alkalosis (bicarbonate>26 mmol/l), who needed at least one intensive blood transfusion in one-to-three days for a period of at least 15 days, and whose total transfusion amount did not fit the massive blood transfusion definition (<80 ml/kg) were included in the study. RESULTS: The estimated mean total citrate administered via blood and blood products was calculated as 43.2 ± 34.19 mg/kg/day (a total of 647.70 mg/kg in 15 days). Decompensated metabolic alkalosis+respiratory acidosis developed as a result of citrate metabolism. There was a positive correlation between cumulative amount of citrate and the use of fresh frozen plasma, venous blood pH, ionized calcium, serum-blood gas sodium and mortality, whereas there was a negative correlation between cumulative amount of citrate and serum calcium levels, serum phosphorus levels and amount of urine chloride. CONCLUSION: In non-massive, but frequent blood transfusions, elevated carbon dioxide production due to citrate metabolism causes intracellular acidosis. As a result of intracellular acidosis compensation, decompensated metabolic alkalosis+respiratory acidosis and electrolyte imbalance may develop. This situation may contribute to the increase in mortality. In conclusion, it should be noted that non-massive, but frequent blood transfusions may result in certain complications.

[Two cases of encrusted cystitis].

Encrusted cystitis is a type of severe cystitis, which progresses chronically and is characterized by excessively alkaline urine and calcifications within the bladder wall. We report two cases of encrusted cystitis. Both cases were high aged and had severe anemia with chronic cystitis. They complained of gross hematuria, voiding frequency and pain upon urination. Urine pH was 8-9, and urine cytology was negative. Urine culture contained Corynebacterium Group D2. Abdominal computed tomography and transurethral resection revealed wall bladder wall calcification and inflammatory change. We diagnosed it as encrusted cystitis. The patients underwent excision of plaques of calcified encrustation, adapted antibiotic therapy and acidification of urine. It is essential to diagnose encrusted cystitis early and to provide adequate treatment promptly.

Primary Sjögren's syndrome associated with Gitelman's syndrome presenting with muscular paralysis.

A 38-year-old woman presented with muscle cramping of 4 extremities and paralysis for months. Laboratory results showed an elevated antinuclear antibody titer; antibodies to the ribonucleoprotein antigen Ro; hypokalemia; hypomagnesemia with hyperreninemia, but abnormally high urine potassium and magnesium levels and low urine calcium levels; and a blunted diuretic effect to thiazide, but not furosemide, which met the criteria for Gitelman's syndrome (GS) and led to the diagnosis of primary Sjögren's syndrome (pSS). She received medical treatment, including a potassium supplement and aldosterone antagonist. GS as a presentation of pSS has never been reported in the literature. The features of renal diseases related to SS are reviewed. SS is the underlying cause of GS, which may precede the onset of the well-known sicca complex.

Identification of fifteen novel mutations in the SLC12A3 gene encoding the Na-Cl Co-transporter in Italian patients with Gitelman syndrome.

The SLC12A3 gene encodes the thiazide-sensitive Na-Cl co-transporter (NCCT) expressed in the apical membrane of the distal convoluted tubule of the kidney. Inactivating mutations of this gene are responsible for Gitelman syndrome (GS), a disorder inherited as an autosomal recessive trait. We searched for SLC12A3 gene mutations in 21 Italian patients with the clinical and biochemical features of GS (hypokalemia, hypomagnesemia, metabolic alkalosis, hypocalciuria, and the absence of nephrocalcinosis). All coding regions with their intron-exon boundaries were analyzed using PCR and SSCP techniques followed by sequencing analysis. We identified 21 different mutations evenly distributed throughout the gene without any mutation hot-spot. Fifteen are novel variants, including 12 missense mutations, one deletion, one deletion-insertion and one splice site mutation: R158Q, T163M, W172R, G316V, G374V, G463E, A464T, S615W, V677M, R852S, R958G, C985Y, 2114-2120delACCAAGT, 2144-2158delGCCTTCTACTCGGATinsTG, and 531-2A>G.

Renal responses of trout to chronic respiratory and metabolic acidoses and metabolic alkalosis.

Exposure to hyperoxia (500-600 torr) or low pH (4.5) for 72 h or NaHCO(3) infusion for 48 h were used to create chronic respiratory (RA) or metabolic acidosis (MA) or metabolic alkalosis in freshwater rainbow trout. During alkalosis, urine pH increased, and [titratable acidity (TA) - HCO(-)(3)] and net H(+) excretion became negative (net base excretion) with unchanged NH(+)(4) efflux. During RA, urine pH did not change, but net H(+) excretion increased as a result of a modest rise in NH(+)(4) and substantial elevation in [TA - HCO(-)(3)] efflux accompanied by a large increase in inorganic phosphate excretion. However, during MA, urine pH fell, and net H(+) excretion was 3.3-fold greater than during RA, reflecting a similar increase in [TA - HCO(-)(3)] and a smaller elevation in phosphate but a sevenfold greater increase in NH(+)(4) efflux. In urine samples of the same pH, [TA - HCO(-)(3)] was greater during RA (reflecting phosphate secretion), and [NH(+)(4)] was greater during MA (reflecting renal ammoniagenesis). Renal activities of potential ammoniagenic enzymes (phosphate-dependent glutaminase, glutamate dehydrogenase, alpha-ketoglutarate dehydrogenase, alanine aminotransferase, phosphoenolpyruvate carboxykinase) and plasma levels of cortisol, phosphate, ammonia, and most amino acids (including glutamine and alanine) increased during MA but not during RA, when only alanine aminotransferase increased. The differential responses to RA vs. MA parallel those in mammals; in fish they may be keyed to activation of phosphate secretion by RA and cortisol mobilization by MA.

Concomitant occurrence of Gitelman and Bartter syndromes in the same family?

The molecular defects responsible for the two most-common forms of inherited normotensive hypokalemic metabolic alkalosis have recently been defined. Most patients with Bartter syndrome have defects in transporters in the thick ascending limb of the loop of Henle, such as the Na-K-2Cl cotransporter, NKCC2, or the ATP-sensitive potassium channel, ROMK. Patients with Gitelman syndrome usually have mutations in the thiazide-sensitive Na-Cl cotransporter in the distal convoluted tubule. The location of the affected transporters correlates well with the typical presentation of these syndromes. Patients with Bartter syndrome typically present with normal or increased calcium excretion. Hypomagnesemia is present in only one-third of affected individuals. In contrast, hypomagnesemia and hypocalciuria are considered hallmarks of Gitelman syndrome. This report describes siblings presenting as young adults with mild symptoms associated with normotensive hypokalemic metabolic alkalosis. One sibling has hypocalciuria and hypomagnesemia, consistent with Gitelman syndrome. Surprisingly, the other sibling has normal serum magnesium and urinary calcium excretion. These siblings demonstrate the biochemical heterogeneity that can exist in patients with normotensive hypokalemic metabolic alkalosis. This report indicates that hypocalciuria does not always distinguish Gitelman and Bartter syndromes.

Effect of metabolic alkalosis and metabolic acidosis on urinary kallikrein excretion of anaesthetized rats: evidence for a role of blood pH as regulator of renal kallikrein secretion.

The effect of altering the acid-base status on urinary kallikrein excretion of barbiturate-anaesthetized rats was investigated. Alkalosis was induced in a group of rats by intravenous (i.v.) infusion of NaOH at 0.45 mmol x h(-1) for 30 min. Acidosis was induced in two groups of rats by i.v. infusion of HCl at 1.5 mmol x h(-1) for 30 min (uncompensated acidosis) or 0.15 mmol x h(-1) for 3 h (compensated acidosis), respectively. Time controls received 0.45 mmol x h(-1) NaCl. Rats with alkalosis excreted less kallikrein than their controls (P < 0.05). Rats with uncompensated acidosis excreted more active kallikrein (P < 0.05), whereas rats with compensated acidosis excreted similar amounts when compared with their respective controls. In rats with uncompensated acid-base derangements, the urinary kallikrein excreted per millilitre of glomerular filtrate was correlated with blood H+ activity (r = 0.99, P < 0.01). Arterial blood pressure, haematocrit, glomerular filtration rate, urine flow rate and Na+ and K+ excretions of experimental and control animals did not differ. Thus, renal kallikrein secretion into the tubular fluid appears to be regulated by blood proton activity. This, along with our previous demonstration that kallikrein inhibits HCO3- secretion into the tubular lumen (Renal Physiol 17:301-306, 1994; J Physiol (Lond) 488:163-170, 1995), indicates that this enzyme is part of a feedback loop regulating acid-base balance.

Urinary chloride excretion distinguishes between renal and extrarenal metabolic alkalosis.

UNLABELLED: The aetiology of normotensive hypokalaemic metabolic alkalosis is sometimes not obtainable from the history. Observations in adults indicate that the urinary chloride excretion is low in metabolic alkalosis of extrarenal origin. The chloride/creatinine ratio in random urines was therefore compared in 283 healthy children and in eight paediatric patients with metabolic alkalosis. The urinary chloride/creatinine ratio was reduced in four patients with metabolic alkalosis of extrarenal origin and within reference values or above in four patients with metabolic alkalosis of renal origin. CONCLUSION: The study confirms that urinary chloride/creatinine ratio discriminates between extrarenal and renal forms of metabolic alkalosis.

Neutral phosphate administration generates and maintains renal metabolic alkalosis and hyperparathyroidism.

We examined the effects of chronic intravenous neutral phosphate administration on systemic acid-base equilibrium and parathyroid function in six normal, NaCl-replete male human subjects under metabolic balance conditions. The subjects received 4.35 mmol of neutral sodium phosphate.kg body wt-1.day-1 intravenously and continuously for 7 days and the same amount of sodium as NaCl during control and recovery. Blood pH increased from 7.388 to 7.411 (P < 0.001) and plasma bicarbonate from 23.5 to 26.0 mmol/l (P < 0.001). Urinary pH increased from 6.58 to 6.79 (P < 0.001). Net acid excretion increased from 59 to 100 mmol/24 h (P < 0.001). Plasma ionized calcium concentration decreased and plasma phosphate concentration increased transiently. Serum intact parathyroid hormone increased from 24 to 62 pg/ml (P < 0.001). Chronic phosphate administration also resulted in a significant increase in renal phosphate clearance (35 to 229 ml/min) and decrease in the fractional excretion of calcium (1.8 to 0.9%). Thus chronic intravenous phosphate administration generates and maintains renal metabolic alkalosis in salt-replete humans and induces hyperparathyroidism. The severity of metabolic alkalosis is mitigated by an apparent increase in effective endogenous acid production as evidenced by the significant increase in steady-state net acid excretion.

Combined K+ and Cl- repletion corrects augmented H+ secretion by distal tubules in chronic alkalosis.

NaCl administration enhances HCO3 secretion in the distal tubule of animals with chronic metabolic alkalosis but does not correct the augmented H+ secretion characteristic of this disorder. The present studies used in vivo microperfusion micropuncture to investigate whether combined repletion of K+ and Cl- corrected the augmented H+ secretion in the distal tubule of rats with chronic furosemide-induced metabolic alkalosis. Correction of alkalosis was induced in one group of animals with NaCl and in another group with a similar amount of Cl- as NaCl + KCl for 24 h; each group was compared with animals with maintained alkalosis. Total 24-h urine HCO3 excretion by each Cl(-)-repleted group comprised > or = 70% of the calculated HCO3 loss necessary to induce the respective decrease in plasma total CO2. Alkalotic animals given NaCl+KCl had significantly lower H+ secretion in the distal tubule compared with animals with maintained alkalosis (15.5 +/- 1.2 vs. 34.6 +/- 1.8 pmol.mm-1.min-1, P < 0.01) but those given only NaCl did not (28.3 +/- 1.5 pmol.mm-1.min-1, P = 0.14). H+ secretion was not different among control animals given similar amounts of Na+, K+, and Cl-. These studies demonstrate that Cl- repletion corrects chronic furosemide-induced metabolic alkalosis predominantly by a renal mechanism and that combined administration of K+ and Cl-, but not of Cl- alone, corrects the augmented H+ secretion in the distal tubule in this model of chronic alkalosis.

Hypercalciuria and nephrocalcinosis in children.

Hypercalciuria has become a significant clinical focus both for pediatricians and for pediatric nephrologists after it was found that increased urinary calcium excretion is the most common abnormality in children with nonglomerular hematuria and with nephrolithiasis. The question of long-term implications of hypercalciuria in growing children, regardless of the underlying cause, remains unanswered. Whether dietary or pharmacologic therapy is warranted in children with hypercalciuria is controversial. One of the proposed consequences of hypercalciuria is nephrocalcinosis. With the availability of increasingly sensitive, noninvasive imaging techniques, nephrocalcinosis is being recognized more frequently. In some instances, concern about the risk and progression of nephrocalcinosis is provoking reevaluation of well-established metabolic therapies. New urinary inhibitors of crystal formation and aggregation have recently been identified. As the basic pathogenesis of nephrocalcinosis becomes clearer, clinical therapies will become more specific and effective.

Charge-dependent renal uptake of beta 2-microglobulin in conscious rats.

The influence of molecular charge on the tubular reabsorption of proteins was studied in conscious rats injected intravenously with beta 2-microglobulins of different isoelectric points (pI). Native human beta 2-microglobulin (pI 5.8), two anionized (pI 4.85 and 5.55) and three cationized derivatives (pI 7.2, 8.35 and 8.7) were used. The six forms of beta 2-microglobulin had a molecular radius between 15.7 and 15.9 A. The renal uptake was estimated by measuring the amount excreted in urine with a sensitive immunoassay. The ability of rat kidney to reabsorb beta 2-microglobulin was clearly related to the net charge of the protein. Increasing the pI of the protein significantly reduced the urinary excretion, whereas lowering it had the opposite effect. Anionization was particularly effective in reducing the beta 2-microglobulin uptake, since a decrease of the pI of one unit enhanced the urinary output by two orders of magnitude. This charge-dependency persisted when the tubular reabsorption of proteins was partly inhibited by lysozyme. By contrast, it was practically abolished by lysine, probably because the inhibitory effect of this amino acid on protein tubular reabsorption is not competitive. The administration of ammonium chloride in rats produced an immediate and transient elevation of rat beta 2-microglobulinuria. This phenomenon, which was partly inhibited by the subsequent administration of sodium bicarbonate, presumably results from a competition between the NH4+ ion and beta 2-microglobulin for tubular binding sites. These data support the hypothesis that proteins bind to the luminal membrane of tubular cells mainly via positively charged amino groups.

Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis: Bartter and Gitelman syndromes.

Clinical or biochemical findings were reevaluated in 34 pediatric patients with primary renal tubular hypokalemic metabolic alkalosis. The patients were subdivided into two groups. Bartter syndrome (primary renal tubular hypokalemic metabolic alkalosis with normocalciuria or hypercalciuria) was diagnosed in 18 patients with molar urinary calcium/creatinine ratios greater than 0.20, and Gitelman syndrome (primary renal tubular hypokalemic metabolic alkalosis with magnesium deficiency and hypocalciuria) was diagnosed in 16 patients with molar urinary calcium/creatinine ratios less than or equal to 0.20 and plasma magnesium levels less than 0.75 mmol/L. Some clinically important differences between the groups were observed. Patients with Bartter syndrome were often born after pregnancies complicated by polyhydramnios (8/18) or premature delivery (7/18) and had short stature (11/18) or polyuria, polydipsia, and a tendency to dehydration (16/18) during infancy (12/18) or before school age (18/18). Patients with Gitelman syndrome had tetanic episodes (12/16) or short stature (3/16) at school age (14/16). We conclude that the Bartter and Gitelman syndromes represent two distinct variants of primary renal tubular hypokalemic metabolic alkalosis and are easily distinguished on the basis of urinary calcium levels.

Chronic metabolic alkalosis in an infant with cystic fibrosis.

A 6-month-old infant suffering from cystic fibrosis is reported. In spite of an apparently appropriate treatment and in absence of respiratory infection, the patient showed progressive anorexia, intermittent vomiting and weight loss. These non-specific signs and symptoms could all be explained by metabolic alkalosis and disappeared immediately after oral supplementation with sodium and potassium chloride. This unusual metabolic complication should be searched for in every cystic fibrosis infant with unexplained anorexia and failure to thrive.

Decrease in N-ethylmaleimide-sensitive ATPase activity in collecting duct by metabolic alkalosis.

Changes in systemic acid-base balance are known to influence acidification in the collecting duct. The H+ secretion in the collecting duct has been shown to be an electrogenic process and it has been suggested that an H-ATPase sensitive to inhibition by N-ethylmaleimide (NEM) is responsible for H+ secretion. This study was designed to determine the effect of metabolic alkalosis on NEM-sensitive ATPase activity in the microdissected segments of the distal nephron. Metabolic alkalosis was produced by giving NaHCO3 to normal rats for 7 days. The plasma total CO2 concentration in the experimental group was 31.5 +/- 1.8 mM compared with 23.4 +/- 1.0 mM in the control group. NEM-sensitive ATPase activity was significantly lower in the cortical collecting duct and in the outer and inner medullary collecting ducts of alkali-loaded rats than those of control rats. There was no significant difference in the enzyme activity between the two groups of animals in the other nephron segments examined. Our results suggest that NEM-sensitive H-APTase activity in all three segments of the collecting duct is modulated by the acid-base status of the animal.