Glue-sniffing and distal renal tubular acidosis: sticking to the facts

An index case is presented to introduce the subject of the acid-base and electrolyte abnormalities resulting from toluene abuse. These include metabolic acidosis associated with a normal anion gap and excessive loss of sodium and potassium in the urine. The major question addressed is, what is the basis for the metabolic acidosis? Overproduction of hippuric acid resulting from the metabolism of toluene plays a more important role in the genesis of the metabolic acidosis than was previously believed. This conclusion is supported by the observation that the rate of excretion of ammonium was not low during metabolic acidosis in six of eight patients, suggesting that distal renal tubular acidosis was not an important acid-base abnormality in most cases where ammonium was measured. The excretion of hippurate in the urine unmatched by ammonium also mandates an enhanced rate of excretion of the cations, sodium and potassium. The loss of sodium causes extracellular fluid volume contraction and a fall in the glomerular filtration rate, which may transform the normal anion gap type of metabolic acidosis into one with a high anion gap (accumulation of hippurate and other anions). Continuing loss of potassium in the urine leads to hypokalemia. An understanding of the metabolism of toluene provides the basis for the unusual biochemical abnormalities seen with abuse of this solvent.     

Filtered bicarbonate and plasma pH as determinants of renal bicarbonate reabsorption

To examine if bicarbonate reabsorption varies with filtered bicarbonate and plasma pH, we infused anesthetized dogs i.v. with sodium chloride and sodium bicarbonate to alter plasma bicarbonate concentration (PHCO3) without changing hematocrit. Examinations in five dogs over a wide range of glomerular filtration rates (GFR) during ethacrynic acid infusion showed that bicarbonate reabsorption at equal filtered load and equal plasma pH of 7.5 was not significantly changed by increasing PHCO3 from 30.2 +/- 0.4 to 55.2 +/- 0.6 mM and PCO2 from 33.8 +/- 0.7 to 74.1 +/- 2.1 mm Hg. Examinations during respiratory and metabolic alkalosis in five dogs at plasma pH of 7.8 showed that bicarbonate reabsorption at equal filtered load was not significantly different at a PCO2 of 20.2 +/- 0.8 and 36.8 +/- 0.8 mm Hg. Finally, in five dogs that did not receive ethacrynic acid, plasma pH was lowered by inducing respiratory acidosis at a PHCO3 of 30 mM and raised during progressive respiratory and metabolic alkalosis, Bicarbonate reabsorption was linearly related to plasma pH within the range 7.1 to 7.85 (r = 0.92). By altering plasma pH by 0.1 unit, bicarbonate reabsorption was altered by 10 +/- 1%. Thus, filtered bicarbonate rather than GFR and plasma pH rather than PCO2 are important acute regulators of bicarbonate reabsorption. This regulation may be achieved by determining pH and bicarbonate concentration in the luminal fluid along the proximal tubules.     

Permeability defect with bicarbonate leak as a mechanism of immune-related distal renal tubular acidosis

We present a 15-year-old girl with distal renal tubular acidosis (dRTA) appearing in what is probably a very early stage of primary Sj?gren's syndrome. On the basis of tests evaluating renal handling of H+, we attempt to explain the mechanism of the urine acidification disorder. The inability to decrease urinary pH during systemic acidosis, together with the normal increase of urinary carbon dioxide partial pressure (pCO2) values after sodium bicarbonate and neutral phosphate loading, suggest a gradient-type dRTA. The inability to lower urinary pH in response to furosemide, accompanied by markedly increased urinary excretion of NH4, HCO3, Na, and K, points to a collecting tubule permeability disorder with bicarbonate leak to the tubular lumen. This patient had never been exposed to amphotericin B. To our knowledge, immune-related dRTA as a result of a gradient defect with bicarbonate leak into the tubular lumen has not been described.     

Proximal renal tubular dysfunction in primary distal renal tubular acidosis

Low-molecular-weight (LMW) proteinuria has been described in patients with primary distal renal tubular acidosis (dRTA). However, other proximal renal tubular dysfunctions have rarely been reported. In this report we describe reversible and multiple proximal renal tubular cell dysfunctions in a patient with dRTA. A 4-year-old girl was admitted to our hospital for investigation of short stature and proteinuria. Laboratory studies revealed a hyperchloremic metabolic acidosis without aciduria, hypokalemia, hypouricemia with uricosuria, hypercalciuria, LMW proteinuria, phosphaturia, and generalized aminoaciduria. The patient was diagnosed as having dRTA with multiple proximal renal tubular dysfunctions. All proximal renal tubular dysfunction subsided 1.5 years after starting alkali therapy. The precise pathogenic mechanisms underlying the development of multiple proximal renal tubular dysfunctions in dRTA remained unclear. However, proximal renal tubular endosomal dysfunction resulting from a profound intracellular acidosis caused by vacuolar H⁺-ATPase dysfunction or hypokalemic nephropathy might contribute to the development of proximal renal tubular dysfunctions in patients with dRTA.     

Experimental models of distal renal tubular acidosis

A number of potential defects may impair acidification either directly or indirectly in the CCT, the OMCT, the IMCD, or in all segments. These defects are summarized in Table 1. Findings from studies in animal models of DRTA have enhanced out understanding of the pathophysiological basis of these disorders. Nevertheless, considerable effort needs to be directed in the future toward defining the cellular basis of these defects, especially in the inherited forms of classical hypokalemic DRTA, for which an adequate experimental model does not yet exist.     

远端肾小管酸中毒的诊断和治疗

报告远端肾小管酸中毒１６例，其中完全型２例，不完全型１４例。完全型有高氯低钾性酸中毒，不完全型无酸中毒，但氯化铵负荷试验阳性。在口服枸橼酸钾期间，两型均观察到尿钙明显降低，尿ｐＨ和枸橼酸显著升高，完全型代谢性酸中毒得到纠正。对远端肾小管酸中毒的诊断和治疗进行了讨论。     

Renal histology and immunopathology in distal renal tubular acidosis.

Renal biospy studies are reported from 10 patients with distal renal tubular acidosis (DRTA). On the biopsies from 6 patients who had associated immunological abnormalities immunofluorescent studies for immunoglobulins, complement, and fibrin were performed. Interstitial cellular infiltration and fibrosis were common findings in patients with and without immunological abnormalities, and were usually associated with nephrocalcinosis and/or recurrent urinary infection. No immune deposits were demonstrated in association with the renal tubules. This study shows that DRTA in immunologically abnormal patients is not caused by tubular deposition of antibody or immune complexes. The possibility of cell mediated immune damage is discussed.     

Screening renal stone formers for distal renal tubular acidosis

A group of 110 consecutive renal stone formers were screened for distal renal tubular acidosis (RTA) using morning fasting urinary pH (mfUpH) levels followed by a short ammonium chloride loading test in patients with levels above 6.0. In 14 patients (12.7%) a renal acidification defect was noted; 13 had incomplete and 1 had complete distal RTA. Distal RTA was found particularly in recurrent stone formers (17%), and especially in those with bilateral stone disease, where a distal renal tubular acidification defect was found in 50%. We have been unable to differentiate primary from secondary RTA in renal stone formers. Regardless of whether the acidification defect is primary or secondary to stone formation, however, all renal stone formers with distal RTA can expect to benefit from prophylactic alkaline therapy and it is recommended that the screening procedure, which is easy to use in daily clinical practice, is applied to all stone formers and not restricted to patients with recurrent stone disease.     

Incomplete distal renal tubular acidosis affects growth in children.

BACKGROUND: Incomplete distal renal tubular acidosis (idRTA) is recognized as an underlying aetiology in recurrent nephrolithiasis. Until the recently reported high prevalence of idRTA in adults with osteoporosis, the effect of idRTA on skeletal parameters was not known. We hypothesize that idRTA has a potential to affect height in the paediatric population. METHODS: In a cross-sectional study, the children with posterior urethral valves (PUV), with normal estimated glomerular filtration rates, were evaluated for idRTA and complete dRTA. The idRTA evaluation was done by short ammonium chloride acidification test. The height standard deviation scores (SDS) in the idRTA group were compared with PUV children without dRTA, with complete dRTA, and to age and gender matched controls with no renal issue (n = 50). RESULTS: The idRTA group (n = 17) manifested a significantly lower mean height SDS (-1.94 +/- 0.41 vs -0.46 +/- 0.28; P < 0.001) and a higher short stature prevalence (height SDS below 2) (18% vs 0; P = 0.06) as compared with those without dRTA (n = 23). The matched controls showed a significantly higher height SDS as compared with the idRTA group (-0.39 +/- 0.25 vs -1.94 +/- 0.41; P < 0.001). As compared with the complete dRTA group (n = 9), the children with idRTA did have significantly higher height SDS (-1.94 +/- 0.41 vs -5.31 +/- 1.95; P = 0.002), and a lower short stature prevalence (18% vs 78%; P = 0.001). On multivariate analysis, dRTA was significantly associated with the height SDS (= -0.88; P < 0.001). CONCLUSIONS: Incomplete dRTA affects height in children. This observation needs validation in longitudinal studies.     

Secondary erythrocytosis associated with distal renal tubular acidosis

AIMS: Diagnosis and classification of renal tubular acidosis (RTA) have traditionally been made on the basis of functional studies. Despite recent expanding knowledge about the molecular abnormalities involved in renal bicarbonate (HCO3-) and H+ transport, the pathophysiology of secondary erythrocytosis in association with distal RTA remains obscure. CASE HISTORY: A 2-month-old boy with severe hyperchloremic metabolic acidosis with positive urine anion gap was diagnosed with distal RTA. Replacement therapy with sodium bicarbonate and potassium citrate succeeded in improving his metabolic acidosis and growth. His renal function remained normal. He had persistent erythrocytosis. CONCLUSION: Secondary erythrocytosis is a rarely reported association of distal RTA. It may increase the risk of thromboembolism.     

Light-chain-induced renal tubular acidosis: effect of sodium bicarbonate on sodium-proton exchange

We measured sodium-proton (Na⁺/H⁺) exchange in lymphocytes andplatelets of a 46-year-old woman with the adult Fanconi syndromebefore, during, and after treatment with NaHCO₃. Kappa lightchains in her urine and unique but rarely observed crystallinestructures confirmed the presence of light-chain nephropathy.Her glomerular filtration rate was only moderately impairedat 72 ml/min. NaHCO₃ at 1, 3, and 5 mmol/kg/day for 5 days increasedher serum HCO₃ and pH from 17 to 21 mmol/l and 7.28 to 7.39respectively. Plasma renin and aldosterone values were decreasedby NaHCO₃. Na⁺/H⁺ exchange (H_i/min) was measured with the fluorescentmarker BCECF after acidification of lymphocytes and plateletswith sodium propionate at five (10–50mM) doses. Na⁺/H⁺exchange was accelerated in this patient compared to normalcontrols. NaHCO₃ treatment significantly decreased Na⁺/H⁺ exchangein lymphocytes, but not in platelets. These findings suggestthat Na⁺/H⁺ exchange can be influenced by NaHCO₃ ingestion atdoses that only modestly affect systemic pH. Since Na⁺/H⁺ exchangeis involved in stimulus response coupling, cell growth regulation,cell differentiation, and perhaps the progression of nephrosclerosis,these observations may have clinical relevance.     

Biochemical and genetic advances in distal renal tubular acidosis

Distal renal tubular acidosis is a constellation of syndromes arising from different derangements of tubular acid transport. Recent advances in the biology of urinary acidification have allowed us to discern various molecular mechanisms responsible for these syndromes. This article relates clinical disorders of distal acidification to the underlying defective mechanisms responsible for them. A clinical classification of these disorders is presented which integrates each disorder with the prevailing serum potassium concentration. That distal renal tubular acidosis can be associated with low, normal, or high serum potassium concentration is now explainable by identifying the specific defect in transport causing each syndrome.