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.     

Atypical presentation of distal renal tubular acidosis in two siblings

Primary distal renal tubular acidosis (dRTA) is an inherited disease characterized by the inability of the distal tubule to lower urine pH <5.50 during systemic acidosis. We report two male siblings who presented with severe hyperchloremic metabolic acidosis, high urinary pH, nephrocalcinosis, growth retardation, sensorineural hearing loss, and hypokalemic paralysis. Laboratory investigations revealed proximal tubular dysfunction (low molecular weight proteinuria, generalized hyperaminoaciduria, hypophosphatemia with hyperphosphaturia, and hypouricemia with hyperuricosuria). There was significant hyperoxaluria and laboratory evidence for mild rhabdomyolysis. Under potassium and alkali therapy, proximal tubular abnormalities, muscular enzymes, and oxaluria normalized. A homozygous mutation in the ATP6V1B1 gene, which is responsible for dRTA with early hearing loss, was detected in both siblings. In conclusion, proximal tubular dysfunction and hyperoxaluria may be found in children with dRTA and are reversible under appropriate therapy.     

Distal renal tubular acidosis: the value of urinary pH,PCO2 and NH4 + measurements

Distal renal tubular acidosis (dRTA) is not a single disease. The experimental forms of the syndrome are unsatisfactory as models of the naturally occurring disease, not least because they are seldom complicated by nephrocalcinosis, which is present in the majority of patients with spontaneous disease and contributes to the renal tubular defects found in the syndrome. Impairment of minimal urine pH, reduced urine carbon dioxide tension (PCO₂) during passage of alkaline urine, and reduced urinary ammonium (NH₄ ⁺) excretion, have all been advocated as essential criteria for the diagnosis of dRTA. Minimal urine pH, measured during metabolic acidosis, sulphate infusion, or after oral frusemide, is the yardstick against which other criteria should be assessed. A reduced urinaryPCO₂ is commonly found in dRTA but is not specific for the syndrome and may be accounted for by tubular defects other than those involving reduced distal hydrogen ion secretion. NH₄ ⁺ excretion is reduced in most patients with renal acidosis whatever the nature of the underlying renal disease; this function is closely related to nephron mass, and is not specifically impaired in renal tubular disease.     

Alkali action on the urinary crystallization of calcium salts: contrasting responses to sodium citrate and potassium citrate

Alkali therapy is used commonly to prevent recurrent stone formation in patients with distal renal tubular acidosis. We compared the effects of potassium citrate to those of sodium citrate in 6 well defined cases of incomplete distal renal tubular acidosis. The patients were studied during a control phase, during potassium citrate treatment (80 mEq. per day) and during sodium citrate treatment (80 mEq. per day) chosen in random order. Potassium citrate caused a decrease in urinary calcium and a significant increase in urinary citrate that resulted in a significant decrease in the urinary saturation of calcium oxalate. It did not alter the saturation of brushite and sodium urate. However, while sodium citrate also was able to increase the urinary citrate level, there was no decrease in the urinary calcium (owing to the increased sodium load). Thus, the urinary saturation of calcium oxalate did not decrease as much as with potassium citrate and the saturation of brushite increased significantly. Moreover, the urinary saturation of sodium urate increased significantly owing to the enhanced sodium excretion. The results suggest that potassium citrate therapy may retard the crystallization of calcium oxalate and may not cause calcium phosphate crystallization. In contrast, sodium citrate may have no effect or it sometimes may accentuate the crystallization of calcium salts. Thus, our study supports the potential clinical advantage of potassium citrate therapy over sodium alkali treatment in patients with incomplete distal renal tubular acidosis and recurrent calcium nephrolithiasis.     

Treatment-related changes in urinary excretion of high and low molecular weight proteins in patients with idiopathic membranous nephropathy and renal insufficiency.

BACKGROUND: In patients with idiopathic membranous nephropathy, an increased urinary excretion of high (IgG) and low [beta(2)-microglobulin (beta(2)M), alpha(1)-microglobulin (alpha(1)M)] molecular weight proteins predicts prognosis and precedes renal insufficiency. We have studied the changes in the urinary excretion of these proteins in patients with idiopathic membranous nephropathy and renal insufficiency during and after treatment with cyclophosphamide and steroids, and investigated their value in predicting long-term outcome. METHODS: Standardized measurements of urinary IgG, albumin, beta(2)M and alpha(1)M were performed at 0, 2, 6 and 12 months in 11 patients, at 12 months in 25 patients and in 17 of these last patients after 2-5 years. RESULTS: We observed a rapid improvement of glomerular permselectivity and tubular protein reabsorption within 2 months after the start of therapy. Despite a partial remission of proteinuria within 12 months in most patients, evidence of tubulo-interstitial injury remained apparent. Neither absolute levels of urinary IgG, beta(2)M or alpha(1)M at baseline or at 12 months nor the percentage reduction between baseline and 12 months clearly predicted the occurrence of a remission or a relapse to nephrotic range proteinuria. In the case of a persistent stable remission, we observed a gradual decrease of urinary beta(2)M towards normal values. CONCLUSIONS: In patients with idiopathic membranous nephropathy and renal insufficiency, treatment with cyclophosphamide and steroids resulted in an improvement of glomerular permeability and tubular proteinuria. Tubular proteinuria remained present for many years, even in patients with stable remission of proteinuria. Measurements of urinary proteins at 12 months after treatment start lacked predictive accuracy.     

The clinical significance of asymptomatic low molecular weight proteinuria detected on routine screening of children in Japan: a survey of 53 patients.

A nationwide questionnaire survey uncovered 53 patients with asymptomatic low molecular weight (LMW) proteinuria, 52 males and one female, aged 3 to 32 years. There was a slight tendency toward shortening stature with increasing age. Mild proteinuria was present in all of them, and microscopic hematuria was occasionally noted in one-fourth, while glucosuria or aminoaciduria was rare. The share of their urinary LMW proteins was increased as evidenced by an increase in the alpha-globulin fraction on cellulose-acetate membrane electrophoresis (27 patients) and/or by an increase in the LMW proteins on sodium dodecylsulfate-polyacrylamide gel electrophoresis (17 patients). Urinary beta 2-microglobulin, one of the LMW proteins, was measured and proved to be increased but electrophoretic analyses were not performed in 25 patients. Urinary N-acetyl-beta-D-glucosaminidase activity, an indicator of renal proximal tubular damage, was elevated in 31 of 38 patients studied: Histological studies of renal biopsies revealed focal changes: focal global sclerosis in seven and tubular atrophy and/or tubular casts in nine out of 32 patients studied.     

Pathophysiology of proteinuria

Proteinuria is consequence of two mechanisms: the abnormal transglomerular passage of proteins due to increased permeability of glomerular capillary wall and their subsequent impaired reabsorption by the epithelial cells of the proximal tubuli. In the various glomerular diseases, the severity of disruption of the structural integrity of the glomerular capillary wall correlates with the area of the glomerular barrier being permeated by "large" pores, permitting the passage in the tubular lumen of high-molecular-weight (HMW) proteins, to which the barrier is normally impermeable. The increased load of such proteins in the tubular lumen leads to the saturation of the reabsorptive mechanism by the tubular cells, and, in the most severe or chronic conditions, to their toxic damage, that favors the increased urinary excretion of all proteins, including low-molecular-weight (LMW) proteins, which are completely reabsorbed in physiologic conditions. Recent clinical studies showed that in patients with glomerular diseases the urinary excretion of some HMW proteins [immunoglobulins G and M (IgG and IgM)] and of some LMW proteins, alpha1-microglobulin, beta2-microglobulin, correlates with the severity of the histologic lesions, and may predict, better than the quantity of proteinuria, the natural course, the outcome, and the response to treatment. It is suggested that some patients have already, at the time of clinical presentation, a structural damage of the glomerular capillary wall (injury of podocytes) and of the tubulointerstitium, the severity and scarce reversibility of which are reliably indicated by an elevated urinary excretion of HMW and LMW proteins.     

Blunted renal dopaminergic system activity in puromycin aminonucleoside-induced nephrotic syndrome.

BACKGROUND: A primary tubular sodium handling abnormality has been implicated in the edema formation of nephrotic syndrome. Dopamine synthesized by renal proximal tubules behaves as an endogenous natriuretic hormone by activating D(1)-like receptors as a paracrine/autocrine substance. METHODS: We examined the time courses of the urinary excretion of sodium, protein and dopamine in puromycin aminonucleoside (PAN)-treated and control rats. The rats were sacrificed during greatest sodium retention (day 7) as well as during negative sodium balance (day 14) for the evaluation of renal aromatic l-amino acid decarboxylase (AADC) activity, the enzyme responsible for the synthesis of renal dopamine. Also, the influence of volume expansion (VE) and the effects of the D(1)-like agonist fenoldopam (10 microg/kg bw/min) on natriuresis and on proximal tubular Na(+),K(+)-ATPase activity were examined on day 7. RESULTS: The daily urinary excretion of dopamine was decreased in PAN-treated rats, from day 5 and beyond. This was accompanied by a marked decrease in the renal AADC activity, on days 7 and 14. During VE, the fenoldopam-induced decrease in proximal tubular Na(+),K(+)-ATPase activity was more pronounced in PAN-treated rats than in controls. However, the urinary sodium excretion during fenoldopam infusion was markedly increased in control rats but was not altered in PAN-treated animals. CONCLUSION: PAN nephrosis is associated with a blunted renal dopaminergic system activity which may contribute to enhance the proximal tubular Na(+),K(+)-ATPase activity. However, the lack of renal dopamine appears not to be related with the overall renal sodium retention in a state of proteinuria.     

Fanconi syndrome following honeybee stings

A 32-year-old gentleman was attacked by honey bees about 8 months and immediately afterwards his eyelids, cheeks and pinnae became swollen, red, and tender. However, the patient did not develop any renal or serum sickness symptoms and his physical examination and laboratory investigations were normal. He recovered completely. A week later, while working on his farm, he experienced a sudden loss of muscular tone in all four limbs without losing his consciousness. The medical examination subsequently revealed flaccid quadriparesis associated with a serum potassium of 2.1 mEq/L. He was also found to have hyperchloremic metabolic acidosis with normal anion gap and preserved ability to acidify urine to a pH of 5.5. These findings were suggestive of proximal renal tubular acidosis (Fanconi syndrome). Other abnormalities like hypophosphataemia, hypouricemia, renal glucosuria and high urinary excretion of calcium, phosphorus and uric acid further supported the diagnosis of proximal tubular dysfunction. The renal biopsy revealed dense lymphocytic interstitial infiltrate, a feature often seen in Sjogren’s syndrome, in which at least 50% of patients fail to acidify urine. In our patient, thorough search for other causes of proximal renal tubular acidosis was negative.     

Acid and mineral balances and bone in familial proximal renal tubular acidosis

BACKGROUND: Metabolic acidosis caused by increased rates of fixed acid production is associated with increased urinary excretion of Ca and negative Ca balances. Metabolic acidosis caused by a reduced capacity of the kidneys to excrete acid contributes to the development of bone disease in the course of chronic renal failure and may be associated with bone disease among some patients with renal tubular acidosis. METHODS: To assess the effects of life-long metabolic acidosis alone in the absence of other physiological disturbances, we measured the net balances of fixed acid and minerals in two brothers in a Costa Rican family with hereditary proximal renal tubular acidosis. Bone radiographs were assessed, and radial bone densities were measured. On a subsequent occasion, transiliac bone biopsies, following double-tetracycline labeling, were obtained from these two patients and an unaffected brother. RESULTS: During the balance studies, serum [HCO3-] concentrations of the two affected patients were stable at 12.5 +/- 0.9 and 19.2 +/- 0.7 mmol/L, respectively. Their rates of net fixed acid production were normal and appropriate for their body weights, averaging 0.90 and 1.02 mEq/kg/day. Because their distal renal tubular function was normal, they were capable of acidifying their urine maximally, allowing sufficient urinary excretion of titratable acid and ammonium to maintain net acid excretion at a level that matched acid production. Thus, their acid balances were near zero, as observed among healthy subjects, at -1.9 +/- 2.3 and -2.2 +/- 2.2 mEq/day, respectively. Their rates of urinary Ca excretion were normal at 1.6 +/- 0.3 and 2.7 +/- 2.4 mmol/day, and the their balances of Ca and other minerals were close to zero so that ongoing bone loss was not occurring despite the acidosis. Nevertheless, their heights, relative to their ages, were shorter than the heights of their unaffected relatives. Their radial bone densities were lower than normal for their age and sex, and their iliac cortices were thinner than that of their unaffected brother. However, they had no histomorphometric evidence of osteomalacia or osteitis fibrosa, and their rates of bone mineralization were normal. CONCLUSIONS: The results indicate that this chronic metabolic acidosis reduces growth, including that of bone. We speculate, without direct supporting evidence, that bone stores of HCO3-/CO3= are reduced, as has been observed in patients with the metabolic acidosis of chronic renal failure and in experimental metabolic acidosis in animals.     

Effects of the adenosine A1 receptor inhibitor FK 838 on proximal tubular fluid output in rats.

BACKGROUND: Adenosine A(1) receptor blockade has been suggested as a treatment in conditions with sodium and fluid retention because it increases urinary Na(+) excretion and increases proximal tubular fluid output. In the present study, we examine the time course for the renal responses to adenosine A(1) receptor blockade in order to investigate whether the effects may be prolonged and not just temporary. METHODS: The acute effects of the adenosine A(1) receptor inhibitor FK 838 on segmental tubular Na(+) handling were examined by a renal clearance technique in conscious chronically instrumented rats. Lithium clearance (C(Li)) was used as a clearance marker of proximal tubular fluid output. RESULTS: Acute adenosine A(1) receptor inhibition did not affect the glomerular filtration rate (GFR) significantly. In contrast, the inhibition led to significant increases in C(Li) (from 290+/-28 to 431+/-28 microl/min/100 g), fractional Li(+) excretion (FE(Li)) (from 33+/-2 to 47+/-3%) and fractional Na(+) excretion (FE(Na)) (from 0.44+/-0.07 to 2.03+/-0.42%). Sodium excretion, expressed as a fraction of proximal tubular fluid output (C(Na)/C(Li)), rose from 1.3+/-0.2 to 4.2+/-0.4%, suggesting that the natriuretic effect was supported by inhibition of distal nephron Na(+) reabsorption. All values returned to baseline values during the clearance study and thereby indicated that neither proximal tubular fluid output nor urinary sodium excretion remained elevated for a prolonged time. CONCLUSION: It is concluded that in conscious unstressed rats, acute adenosine A(1) receptor inhibition by FK 838 led to a significant natriuresis that was caused by inhibition of proximal tubular Na(+) reabsorption, possibly with a contribution from inhibition of distal nephron Na(+) reabsorption. The increased proximal tubular fluid output and the increased urinary Na(+) excretion returned to baseline values during the clearance study, indicating that none of these effects of adenosine A(1) blockade were long lasting.     

Transient neonatal distal renal tubular acidosis with secondary hyperparathyroidism

We describe a neonate with distal renal tubular acidosis with secondary hyperparathyroidism manifesting as hyperchloraemia, hypercalcaemia, elevated serum parathyroid hormone (PTH) and life-threatening metabolic acidosis. He exhibited general weakness, tachypnoea, dry skin and weight loss. Urinary excretion of titratable acid and ammonium was decreased. Daily alkali (2.5 mEq/kg body weight) was required to maintain a normal plasma bicarbonate (HCO₃–). With alkali therapy, the fractional excretion of HCO₃– was below 5%. Serum calcium and PTH were restored to normal promptly on initiation of alkali therapy. After 5 months of alkali therapy, normal growth and urine acidifying ability were restored and alkali therapy was discontinued. The acidification defect in this patient was transient. We consider this patient to be consistent with Lightwood's syndrome of transient infantile renal tubular acidosis.     

Alkalizitrate in der Urologie

Alkaline citrates have been used as an efficient therapy in hypocitraturic calcium nephrolithiasis, uric acid lithiasis, cystinuria, and renal tubular acidosis. Furthermore, alkaline citrates are very effective in treating and preventing hyperchloremic metabolic acidosis in patients with urinary diversion. The main physiological effects during urolithiasis therapy have been significant increases in urinary pH, in citrate and potassium, and a decrease in calcium excretion. This paper reviews current indications, therapy modalities, and metaphylactic use reported in the literature and/or recommended by the Deutsche Gesellschaft für Urologie (DGU) and the European Association of Urology (EAU). It is intended to give useful advice for the urologist's daily practice.     

Increased urinary excretion of N-acetylglucosaminidase in subjects with impaired glucose tolerance

N-acetylglucosaminidase (NAG) is a lysosomal enzyme produced by renal proximal tubular cells and has been widely used as a marker, which indicates a degree of renal tubular damage. An increase in urinary NAG excretion is though to result from the renal tubular damage. The aim of this study was to evaluate whether even mild hyperglycemia causes an increase in urinary excretion of NAG, which is a renal tubular protein. We examined urinary NAG excretion in overnight urine in 22 Japanese men with impaired glucose tolerance (IGT) for more than two years (IGT group) and 41 healthy control subjects matched in age, gender, BMI and blood pressure (control group). Urinary NAG excretion levels of IGT group and control group were 2.89 (1.23-7.97) and 2.22 (0.60-4.93) U/g creatinine, median (range), respectively. The IGT group showed significantly higher urinary excretion of NAG compared to the control group (p < 0.01). Several studies have indicated that plasma proteins filtered through the glomerular capillary may have intrinsic renal toxicity. Recently, we have reported that urinary excretion of plasma proteins (ceruloplasmin, IgG4 and IgG) with molecular radii of approximately 45-55 A is increased in subjects with IGT compared to healthy control subjects with normal glucose tolerance. Considering the present result together with our recent finding, we suggest that increased urinary excretion of NAG in the mildly hyperglycemic subjects may be due to the adverse effects of the plasma proteins highly filtered through the glomerular capillary on tubular cells.     

Renal acidification in hypothyroid man.

The role of thyroid hormone in renal hydrogen ion secretion remains largely unknown, and there is only limited information on renal acidification in hypothyroid patients. In the present study two of five adult male patients with untreated primary hypothyroidism and without clinical evidence of systemic autoimmune disease were unable to lower their urine pH appropriately after short duration acid-loading. Since, prior to acid-loading, their arterial blood gas values were within the normal range and urinary bicarbonate excretion was trival, the findings are consistent with the incomplete syndrome of distal renal tubular acidosis. Although the mechanism of this abnormality remains unknown, thyroxine deficiency per se may in part be responsible.     

Persistent isolated proximal renal tubular acidosis — a systemic disease with a distinct clinical entity

We describe a 16-year-old female with persistent isolated proximal renal tubular acidosis, cerebral calcification, mental retardation, band keratopathy, cataracts, glaucoma and short stature. Severe metabolic acidosis and hypokalaemia were linked to an abnormally low renal threshold for bicarbonate reabsorption (8 mmol/l). Maximal rates of urinary excretion of titratable acid and ammonium were normal; erythrocyte carbonic anhydrase II was normal. This rare case represents a systemic disease with a distinct clincal entity which may be transmitted by autosomal recessive inheritance.     

Might distal renal tubular acidosis be a proximal tubular cell disorder?

Incomplete renal tubular acidosis (RTA) and overt distal RTA may be different stages of the same underlying pathophysiology in certain individuals. The rationale that draws these conditions together is the relatively alkaline pH of the urine, hypocitraturia, and a possible familial association. The rate of excretion of ammonium (NH4+), on the other hand, suggests that these conditions stem from fundamentally different lesions. To explain this difference, we suggest that two possible disorders may result in the evolution from incomplete RTA to overt distal RTA. One subgroup could have gradient-limited distal RTA, while the other subgroup may have a lower pH of the intracellular fluid of the proximal convoluted tubular epithelium. Indices of proximal intracellular pH (rates of excretion of NH4+, NH3, and citrate) were culled from the literature spanning the years 1959 to 1991 on patients with incomplete RTA and overt distal RTA. Three points emerge: (1) the rate of excretion of NH4+ was lower in patients with overt distal RTA than in normals following an acute acid load (23 +/- 1 v 49 +/- 3 mumol/min); (2) the concentration of NH3 in the urine was almost 25-fold higher in incomplete RTA than in normals (69 +/- 14 v 3 +/- 0.4 nmol/min); and (3) in incomplete RTA, the pH of the urine fell to very low values (4.9 +/- 0.1) when high urine flows were induced with furosemide. The low pH of the urine would therefore suggest that many of these patients do not gradient-limited distal RTA, but more likely have proximal renal epithelial cell acidosis. We hypothesize that this high rate of excretion of NH4+ and low rate of excretion of citrate in the absence of acidosis or hypokalemia is consistent with proximal cell acidosis. To explain a transition from incomplete RTA to overt distal RTA, we speculate that toxicity of high concentrations of NH3 in the medullary interstitium as well as nephrolithiasis and nephrocalcinosis due to low urinary citrate and possibly an alkaline medullary interstitium may lead to damage of structures in this region.     

Urinary excretion of alpha1-microglobulin and albumin in acute myocardial infarction. Correlation with plasma concentrations of troponin I and C-reactive protein

OBJECTIVES: Microalbuminuria associated with myocardial infarction (MI) is normally ascribed to glomerular factors, but could just as well involve pathophysiological processes located in other parts of the nephron, e.g. proximal tubules where plasma albumin normally filtered through the glomerulus is almost completely reabsorbed. The aims of this study were to establish whether impaired tubular reabsorption of filtered albumin contributes to microalbuminuria during MI, and whether the urinary excretion of protein relates to plasma levels of C-reactive protein (CRP) and troponin I. MATERIAL AND METHODS: We monitored plasma CRP and troponin I as well as the urinary excretion of albumin and alpha1-microglobulin, a low-molecular-weight plasma protein and marker of tubular proteinuria, in 18 patients with MI. RESULTS AND CONCLUSIONS: The urinary excretion of alpha1-microglobulin and albumin was significantly elevated in nine patients, and the urinary excretion of the two proteins correlated significantly. A decrease in tubular reabsorption of albumin may thus be at least one of the causative factors underlying microalbuminuria during MI. The plasma levels of CRP and troponin I were also significantly higher in this group of nine patients, and correlated with urinary protein excretion, suggesting an interrelationship between inflammatory response and tubular dysfunction. Extrarenal inflammatory processes seem to affect renal tubular function, thereby contributing to microalbuminuria during MI.     

Endothelin excretion during ketoacidosis does not correlate with tubular dysfunction

Urinary excretion of endothelin was measured by radioimmunoassay in children with diabetes mellitus during severe ketoacidosis and 12 days later when blood pH and blood glucose concentrations were normal. Metabolically stable diabetic children served as controls. Results from apparently healthy children without diabetes mellitus were used as normal values. Renal tubular injury was evaluated by the urinary excretion of the proximal tubular marker ₁-microglobulin and the distal tubular marker Tamm-Horsfall protein (THP). During ketoacidosis we detected a decreased glomerular filtration rate associated with highly significant changes in the excretion of ₁-microglobulin, indicating proximal tubular damage, and THP, suggesting disturbance of cells of the ascending loop of Henle. The daily excretion of endothelin was unaltered but the ratio of endothelin/creatinine or endothelin excretion/creatinine clearance were significantly enhanced. In conclusion, we could demonstrate that, despite a proximal and distal tubular cell dysfunction, endothelin excretion when related to creatinine clearance may be a consequence of disturbed proximal tubular function or dysfunction of the renal medulla.     

What is the underlying defect in patients with isolated, proximal renal tubular acidosis?

Our aim in this article is to propose a new hypothesis concerning the etiology of renal tubular acidosis (RTA) in that subgroup of patients who have the isolated, primary type of proximal RTA. We suggest that their underlying disorder is a more alkaline intracellular pH of the proximal convoluted tubule. Increased alkalinity of proximal tubular cells would explain the low rate of bicarbonate reabsorption per liter glomerular filtration and the decreased rate of ammonium excretion despite a low urine pH and the presence of chronic metabolic acidosis. Additional diagnostic tests to evaluate this hypothesis in this specific subgroup of patients with proximal RTA are also outlined.