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Background Uncovering the correct diagnosis of chronic hypokalemia with potassium (K+) wasting from the kidneys or gut can be fraught with challenges. We identified clinical and laboratory parameters helpful for differentiating the causes of chronic hypokalemia. Methods Normotensive patients referred to our tertiary academic medical center for the evaluation of chronic hypokalemia were prospectively enrolled over 5 years. Clinical features, laboratory examinations-including blood and spot urine electrolytes, acid-base status, biochemistries, and hormones-as well as genetic analysis, were determined. Results Ninety-nine patients with chronic normotensive hypokalemia (serum K+ 2.8 ± 0.4 mmol/L, duration 4.1 ± 0.9 years) were enrolled. Neuromuscular symptoms were the most common complaints. Although Gitelman syndrome (n = 33), Bartter syndrome (n = 10), and distal renal tubular acidosis (n = 12) were the predominant renal tubular disorders, 44 patients (44%) were diagnosed with anorexia/bulimia nervosa (n = 21), surreptitious use of laxatives (n = 11), or diuretics (n = 12). Patients with gastrointestinal causes and surreptitious diuretics use exhibited a female predominance, lower body mass index, and less K+ supplementation. High urine K+ excretion (transtubular potassium gradient >3, urine K+/Cr >2 mmol/mmol) was universally present in patients with renal tubular disorders, but also found in >50% patients with gastrointestinal causes. Of interest, while urine sodium (Na+) and chloride (Cl-) excretions were high and coupled (urine Na+/Cl- ratio ∼1) in renal tubular disorders and "on" diuretics use, skewed or uncoupled urine Na+ and Cl- excretions were found in anorexia/bulimia nervosa and laxatives abuse (urine Na+/Cl- ratio: 5.0 ± 2.2, 0.4 ± 0.2, respectively) and low urine Na+ and Cl- excretions with fixed Na+/Cl- ratios (0.9 ± 0.2) when "off" diuretics. Conclusion Besides body mass index, sex, and blood acid-base status, integrated interpretation of the urine Na+:Cl- excretion and their ratio is important to make an accurate diagnosis and treatment plan for patients with chronic normotensive hypokalemia.

Purpose To determine if kidney stone composition can predict the underlying medical diagnosis, and vice versa. Methods We studied 1392 patients with kidney stones who underwent a complete ambulatory evaluation and who submitted one or more stones for analysis. We ascertained the associations between medical diagnosis and stone composition. Results The most common kidney stones were composed of calcium oxalate (n = 1041 patients [74.8%]), mixed calcium oxalate–calcium apatite (n = 485 [34.8%]), and calcium apatite alone (n = 146 [10.5%]). The most common medical diagnoses were hypocitraturia (n = 616 patients [44.3%]), absorptive hypercalciuria (n = 511 [36.7%]), and hyperuricosuria (n = 395 [28.4%]). Calcium apatite and mixed calcium oxalate–calcium apatite stones were associated with the diagnoses of renal tubular acidosis and primary hyperparathyroidism (odds ratios ≥2), but not with chronic diarrheal syndromes. As the phosphate content of the stone increased from calcium oxalate to mixed calcium oxalate–calcium apatite, and finally to calcium apatite, the percentage of patients with renal tubular acidosis increased from 5% (57/1041) to 39% (57/146), and those with primary hyperparathyroidism increased from 2% (26/1041) to 10% (14/146). Calcium oxalate stones were associated with chronic diarrheal syndromes, but not with renal tubular acidosis. Pure and mixed uric acid stones were strongly associated with a gouty diathesis, and vice versa. Chronic diarrheal syndromes and uric acid stones were associated with one another, and brushite stones were associated with renal tubular acidosis. As expected, there was a very strong association between infection stones and infection, and between cystine stones and cystinuria. Conclusion Stone composition has some predictive value in diagnosing medical conditions, and vice versa, especially for noncalcareous stones.

Hypokalemic nonperiodic paralysis represents a group of heterogeneous disorders with a large potassium (K(+)) deficit. Rapid diagnosis of curable causes with appropriate treatment is challenging to avoid the sequelae of hypokalemia. We prospectively analyzed the etiologies and therapeutic characteristics of hypokalemic nonperiodic paralysis.Over an 8-year period, patients with hypokalemic nonperiodic paralysis were enrolled by excluding those with hypokalemic periodic paralysis due to acute shift of K(+) into cells. Blood and spot urine samples were collected for the measurements of electrolytes, pH, and biochemistries. Intravenous potassium chloride (KCl) at a rate of 10-20 mmol/h was administered until muscle strength recovered.We had identified 58 patients with hypokalemic nonperiodic paralysis from 208 consecutive patients with hypokalemic paralysis, and their average K(+) concentration was 1.8 ± 0.2 mmol/L. Among patients with low urinary K(+) excretion (n = 17), chronic alcoholism, remote diuretic use, and anorexia/bulimia nervosa were the most common causes. Among patients with high urinary K(+) excretion (n = 41) and metabolic acidosis, renal tubular acidosis and chronic toluene abuse were the main causes, while primary aldosteronism, Gitelman syndrome, and diuretics were the leading diagnoses with metabolic alkalosis. The average KCl dose needed to restore muscle strength was 3.8 ± 0.8 mmol/kg. Initial lower plasma K(+), volume depletion, and high urinary K(+) excretion were associated with higher recovery KCl dosage. During therapy, patients with paradoxical hypokalemia (n = 32) who required more KCl supplementation than patients without (4.1 ± 0.7 vs 3.4 ± 0.7 mmol/kg, P0.001) often exhibited significantly higher plasma renin activity and received a higher volume of normal saline before its appearance.Understanding the common etiologies of hypokalemic nonperiodic paralysis may aid in early diagnosis. Patients with initial lower plasma K(+), renal K(+) wasting, and hypovolemia required higher recovery K(+) dosage. Paradoxical hypokalemia is prone to develop in hypovolemic patients even during K(+) supplementation with volume repletion.

Fifty-four patients with Wilson's disease were studied with regard to renal stones. Seven of the 45 patients (16 per cent) who underwent roentgenographic procedures of the urinary tract had unequivocal evidence of renal stones. In four of the seven patients with Wilson's disease who had renal stones, the stones were discovered at the time or before the diagnosis of Wilson's disease was made. Of the several possible factors that may predispose patients with Wilson's disease to renal stone formation, the renal tubular acidosis pattern of abnormality in acid-base excretion is probably the most significant. In general, patients with renal stones and unexplained neurologic, bony or hepatic abnormalities should be screened for Wilson's disease by slit-lamp examination, determination of serum copper and ceruloplasmin concentrations, and urinary excretion of copper, particularly if they have relatively alkaline urine.

Discussed here is a 41 year old woman with galactorrhea associated with the empty sella syndrome and mild renal tubular acidosis. Basal serum prolactin (PRL) levels were normal, but a 24 hour serum PRL secretory profile demonstrated an increased mean PRL concentration. Serum PRL was appropriately suppressed by the administration of L-dopa; however, chlorpromazine stimulation resulted in a blunted serum PRL response. Pituitary luteinizing hormone, follicle stimulating hormone, ACTH and thyroid stimulating hormone levels were normal. Thus, galactorrhea associated with an enlarged sella does not establish the diagnosis of a pituitary tumor, and pneumoencephalography must be performed to exclude the empty sella syndrome.

A patient with paroxysmal nocturnal hemoglobinuria, who required many blood transfusions for hemolytic episodes, had a persistent hyperchloremic metabolic acidosis. Bicarbonate infusion demonstrated a large fractional excretion of bicarbonate (28.6 per cent at a plasma bicarbonate level of 23 meq/liter) which was consistent with proximal renal tubular acidosis. Generalized aminoaciduria and decreased tubular reabsorption of phosphate were also present. Marked deposition of iron in renal proximal tubules was associated with these functional abnormalities. We believe that, as systemic acidosis can promote hemolysis in patients with paroxysmal nocturnal hemoglobinuria, hemolysis can lead, by way of iron deposition in renal tubules, to further acidosis. This cycle should be interrupted with appropriate doses of bicarbonate.

The sine qua non for the diagnosis of distal renal tubular acidosis requires that the urinary pH cannot decrease maximally during systemic acidosis. A defect in distal acidification however, could also result from a decrease in the capacity (or rate) of distal hydrogen ion secretion. In this type of defect, the ability to lower the urinary pH during acidemia could be preserved as long as a certain capacity for hydrogen ion secretion remained. In this report, we describe four patients with deranged distal urinary acidification, in whom urinary pH was able to decrease (4.99 +/- 0.11) during acidemia. One of the patients had hyperchloremic metabolic acidosis whereas the remaining three were not spontaneously acidotic. In these patients, the defect for distal urinary acidification was disclosed by the inability of the urine-blood pCO2 gradient to increase normally (i.e., above 30 mm Hg) during bicarbonate loading. In contrast, a normal increase in the urine-blood pCO2 gradient was observed in each patient in response to neutral sodium phosphate infusion. The reabsorptive capacity of bicarbonate was not depressed in these patients, which indicated that the acidification process in the proximal nephron was intact. We propose that our four patients had a defect in distal urinary acidification caused by a reduction in the rate of distal hydrogen ion secretion rather than an inability to generate a steep pH gradient across the distal nephron. Our data also suggest that the inability to raise urinary pCO2 normally during sodium bicarbonate loading may be the most sensitive index of decreased distal urinary acidification available.

The mechanism of persistent hyperchloremic metabolic acidosis developing after kidney transplantation was investigated in six patients. In five patients in whom acidosis failed to lower the urine pH below 5.5, an infusion of sodium sulfate also failed to lower the urine pH. Neutral phosphate infusion failed to increase the urine minus blood (U-B) carbon dioxide tension (pCO2) difference normally in these patients. This abnormal response to both maneuvers indicates the presence of a tubular defect for distal hydrogen ion secretion. In the remaining patient, spontaneous acidosis lowered the urine pH below 5.5 and increased the U-B pCO2 normally with the administration of phosphate, demonstrating that this patient's distal capacity for hydrogen secretion was intact. The plasma aldosterone level was low in this patient, and thus he had the acidification defect characteristic of aldosterone deficiency. Hyperkalemia developed in two patients; both were aldosterone-deficient, and they had a low fractional potassium excretion ion response to stimulation with sodium sulfate or acetazolamide. In all but one patient, who lost his kidney to accelerated rejection, chronic rejection developed. Homogeneous deposition of complement (C3) along the tubular basement membrane was found in three patients. Our data suggest that a secretory type of distal renal tubular acidosis can be an early sign of the immunologic process that leads to chronic rejection.

A detailed study of the effects of amphotericin B on renal function in a patient receiving this drug revealed that inulin clearance (C IN ), p-aminohippurate clearance (C PAH ) and the maximal tubular secretory capacity for p-aminohippurate (Tm PAH ) decreased during therapy to about one third of their pretreatment values. Concentrating ability was impaired. Urinary potassium losses became excessive, with severe hypokalemia. Urinary calcium and magnesium excretion rates were depressed. Of special interest was the development of a syndrome of renal tubular acidosis. After twenty days of amphotericin B administration, the minimum urinary pH achieved in response to an ammonium chloride load was 6.7, and the excretion of titratable acid was severely impaired. This represents the second occasion on which a syndrome of renal tubular acidosis has been detected in patients receiving amphotericin B. Two months after amphotericin B therapy was stopped, acid excretion, concentrating ability and electrolyte excretion had returned to normal, and Tm PAH was 89 per cent of its pretreatment value, but C IN and C PAH were still moderately impaired. The findings of the study emphasize the severity of the renal damage and electrolyte changes that can be produced by amphotericin B therapy, and the need to assess renal function during and after the period of treatment. Prevention of dehydration and also of hypokalemia, by early oral administration of potassium supplements, are suggested as ways to help reduce the nephrotoxic effects of this drug. In view of the development of a renal tubular acidosis syndrome, concurrent alkali (citrate) therapy may be useful.

The responses of five adult patients with renal tubular acidosis to maneuvers designed to elucidate tubular function are compared to the responses of control subjects. After oral administration of ammonium chloride, a greater degree of acidosis developed in the patients with renal tubular acidosis than in the control subjects, they excreted less NH 4 + and HCO 3 − in the urine, and had a smaller drop in urine pH. The failure of HCO 3 − excretion to increase in three of these patients when their serum HCO 3 − levels were raised to normal indicates that diminished tubular HCO 3 − reabsorptive capacity is not the fundamental lesion in the disease. Urinary NH 4 + levels in renal tubular acidosis, although low in relation to the degree of systemic acidosis, proved to be higher than in the urines of equivalent pH of control subjects, suggesting that the capacity for tubular NH 4 + formation is not impaired in renal tubular acidosis. Inability to lower the pH of the urine appropriately is considered to be the primary disorder in renal tubular acidosis, continued HCO 3 − excretion and subnormal ammonia transfer into the urine being secondary phenomena. In spite of the relatively low urinary concentration of free hydrogen ion in renal tubular acidosis the total combined urinary hydrogen (titratable acidity) could be markedly increased by oral or intravenous phosphate loads. Orally administered neutral sodium phosphate (pH 7.4) corrected metabolic acidosis in one patient with renal tubular acidosis by increasing urinary titratable acidity without lowering pH. An adequate explanation for the inability of the patient with renal tubular acidosis to acidify the urine was not provided. Carbonic anhydrase deficiency seems an unlikely possibility because of the demonstrated ability of the patient with renal tubular acidosis to increase HCO 3 − reabsorbtion and titratable acidity.

A boy with idiopathic Fanconi's syndrome is described who exhibited, in addition to the usual features, an unusually large degree of urinary sodium chloride wastage accompanied by a metabolic alkalosis. No evidence of distal tubular abnormality was found and all urinary findings were explicable on the basis of proximal tubular malfunction. Investigations revealed that a combination of sodium, chloride and potassium depletion produced an alkalosis despite the presence of a low bicarbonate threshold commonly found in this syndrome. Detailed studies suggested that although potassium depletion may play a smaller role than sodium chloride wastage, its effects are real and in some degree mediated by an effect upon proximal tubular bicarbonate reabsorption.

A case of a young woman who had renal tubular acidosis with nephrocalcinosis, and in whom marked hypokalemia developed following hyperemesis gravidarum, is presented and discussed.

We have studied a family in which nine members present hyperchloremic acidosis with normal plasma creatinine and good ability to acidify urine. Renal functions, other than bicarbonate wasting, are normal, which identifies the condition as a pure form of proximal renal tubular acidosis. The acidosis persists into adult life and appears to be inherited as an autosomal dominant trait. All affected members are asymptomatic and the only peculiar finding is a decrease in stature. No hypercalciuria was detected, and no evidence of rickets or osteomalacia was found by x-ray studies. We consider these findings characteristic of a familial trait different from that in previously reported cases of renal tubular acidosis.

Selective hypoaldosteronism was demonstrated in a 60 year old black man with moderate renal insufficiency and hyperkalemic, hyperchloremic acidosis. Urine pH was appropriately low during acid loading demonstrating that the hydrogen ion gradient generating capability of the distal-most nephron was intact. In addition to impaired net acid excretion during acidosis, significant bicarbonaturia was present when serum bicarbonate concentration was normal. Desoxycorticosterone acetate (DOCA) administration improved renal potassium handling and corrected the hyperkalemia but not the acidosis or bicarbonaturia. It is concluded that the patient had idiopathic selective hypoaldosteronism and hyporeninemia and that the hyperkalemia was related to hypoaldosteronism. The patient's bicarbonaturia, however, did not appear to be related to mineralocorticoid deficiency and therefore should be attributed to other factors.

The proximal nephron is responsible for reabsorbing 80 to 99 percent of several filtered solutes, including amino acids, glucose and bicarbonate. Separate, high-affinity sodium co-transport mechanisms are used. Increasing luminal concentration of each of these solutes stimulates its active transcellular reabsorption until there is saturation. Slightly less than half of the filtered chloride is reabsorbed, partly by passive mechanisms that are linked to the reabsorption of organic solutes and bicarbonate, as well as by less well defined independent cellular and/or paracellular mechanisms that appear to be sensitive to transepithelial osmotic pressure gradients. Proximal tubule reabsorption is isosmotic and isonatric, and about 50 to 60 percent of the filtered sodium and water is reabsorbed. Disorders of proximal nephron function include conditions in which luminal, cellular and/or peritubular factors affecting reabsorption are altered. Clinical disorders caused by modification of the luminal reabsorptive determinants include conditions in which tubular flow rate is increased or luminal composition is altered, as when non-reabsorbable solutes (mannitol) are filtered or when reabsorbable solutes (glucose) are filtered in concentrations exceeding their tubular transport capacity. Other disorders occur due to loss of affinity or capacity of the cellular active transport systems for specific solutes, such as amino acids (renal aminoacidurias), glucose (renal glycosurias) and bicarbonate (proximal renal tubular acidosis), or for all solutes (Fanconi syndrome). Finally, disorders due to changes in the peritubular factors affecting reabsorption include states of altered peritubular Starling forces or pH, which modify sodium chloride or sodium bicarbonate reabsorption, respectively.

A 61 year old male patient was studied who manifested dehydration, azotemia, acidosis and hyperkalemia six weeks after exposure to methicillin. Thyroid and adrenal glucocorticoid and mineralocorticoid function were normal. The dehydration was found to be caused by a profound sodium-losing nephropathy; urinary sodium ranged from 78 to 101 meq/day during a salt restricted diet. A distal renal tubular acidosis and a quantitively impaired ability to excrete potassium were also found. These defects were relatively unresponsive to mineralocorticoid or prednisone therapy. A renal biopsy specimen showed an interstitial nephritis which selectively affected distal tubules and was thought to be secondary to methicillin. The data suggest functional impairment specific for the distal tubule, but with only a modest decrease in the glomerular filtration rate.

This report describes the occurrence of hyperkalemic hyperchloremic metabolic acidosis in six patients with sickle cell hemoglobinopathies. Three patients had sickle cell anemia, two had sickle cell trait and one had S-C disease. In all patients, decreased renal potassium excretion was demonstrated by the finding of a fractional potassium excretion lower than that of control subjects with comparable glomerular filtration rates. Two patterns of impaired urinary acidification were discerned. Four patients had a urinary pH above 5.5 in the presence of systemic acidosis and, thus, were classified as having distal renal tubular acidosis. The remaining two patients had very low rates of ammonium excretion despite intact capacity to lower urinary pH below 5.5 during systemic acidosis; this pattern was ascribed to selective aldosterone deficiency. Sickle cell hemoglobinopathies should be included in the differential diagnosis of hyperkalemic hyperchloremic metabolic acidosis.

Three adult sisters with osteopetrosis in infancy had spontaneous resolution of bone modeling defects and osteosclerosis. During adolescence, basal ganglia calcification developed in two. Renal tubular acidosis (type I) was diagnosed in each during early adulthood. The disorder was transmitted apparently as a recessive trait--the same mode of inheritance as for the "malignant" form of osteopetrosis which is usually fatal during childhood. Electron microscopy of bone suggested that osteoclasts failed to form "ruffled membranes" characteristic of active bone resorbing cells. Chronic systemic acidosis may have ameliorated the skeletal manifestations of this new syndrome.

Hypercalciuria was considered as a secondary condition when associated with familial renal tubular acidosis. Later studies suggested that hypercalciuria could lead to renal tubular acidosis and nephrocalcinosis. Selected members of a family spanning five generations were studied. Renal tubular acidosis was present in eight subjects in three consecutive generations. Increased 24-hour urinary calcium excretion was present in nine subjects in three consecutive generations, alone in the younger generation, and in combination with renal tubular acidosis and nephrocalcinosis in the older generation. Calcium loading tests showed the absorptive nature of hypercalciuria in nine of 18 subjects studied. This report suggests that in this family the absorptive hypercalciuria is an autosomal dominant genetic defect with complete penetrance and variable expressivity which leads to renal tubular acidosis and nephrocalcinosis.

A thirty-two year old woman with primary renal tubular acidosis, severe nephrocalcinosis and reduced glomerular function had bilateral, symmetric pathologic fractures of the femoral heads secondary to atypical osteitis fibrosa generalisata. There was no evidence of concomitant osteomalacia. The clinical, roentgenographic and pathologic features indicated that the hyperparathyroidism was secondary to the renal tubular acidosis. The course of the skeletal disease was monitored by serial metabolic balance measurements, radiocalcium turnover studies, x-ray examinations and bone biopsies. Almost complete reversal of the metabolic bone disease was achieved after subtotal parathyroidectomy and calcium lactate and vitamin D 2 therapy. Nevertheless, glomerular insufficiency progressed and caused death after a total course of between four and ten years. An awareness of atypical cases of renal tubular acidosis can facilitate early diagnosis and effective management, and improve the prognosis in this unusual condition.

A twenty-one year old man is described who has what appears to be a unique renal tubular defect in potassium excretion, associated with persistent hyperkalemia (up to 8.2 mEq. per L.), hypertension, systemic acidosis and slightly impaired renal excretion of acid. Renal failure was absent; glomerular filtration rate, maximal tubular secretion of p-aminohippurate, maximal urinary concentrating ability and urinary amino acid excretion pattern were all normal, as was the appearance of renal tissue at biopsy. Clearance of p-aminohippurate and phenolsulfonphthalein excretion were somewhat reduced. A balance study showed a positive potassium balance of 142 mEq. in four days, associated with low urinary potassium excretion and rising serum potassium levels; sodium balance was normal. Red cell electrolyte content was normal, as were salivary and sweat potassium concentrations. Sodium sulfate infusion combined with a carbonic anhydrase inhibitor, which markedly increased potassium excretion in control subjects, had little effect on the patient's potassium excretion, except when accentuated by prior salt depletion and 9α-fluorohydrocortisone administration. Adrenal insufficiency was excluded as a cause for hyperkalemia and there was no evidence of impaired tubular response to mineralocorticoids, since sodium metabolism was normal. The hypertension, associated with blood pressures up to 140 mm. Hg diastolic, responded well to treatment with sodium polystyrene sulfonate (Resonium ® A) and chlorothiazide, which also controlled the hyperkalemia. Diastolic blood pressures correlated significantly with serum potassium levels. Endocrine causes for hypertension were excluded. Presser responses to cold, smoking, norepinephrine and angiotensin were in the range reported in patients with hypertension of other causes. Chromosome studies were normal, but absent incisor teeth in the patient and in his brother, and a family history of mental illness raised the possibility of a genetic basis for his metabolic disorder.

Polyuria and polydipsia were the presenting symptoms in a young woman with Sjogren's syndrome. Tests for maximal reabsorption of water revealed a total inability of the renal tubules to abstract solute-free water during a sustained infusion of vasopressin. In addition to the renal concentrating defect, there were hyperchloremic acidosis with a defect in urinary acidification, increased clearance of phosphate and urate, and generalized aminoaciduria—a combination of findings compatible with the "adult Fanconi syndrome." The possible relationship of renal dysfunction in Sjogren's syndrome to an immunologic abnormality remains to be elucidated.

An eighteen year old girl with chronic active hepatitis and hyperimmunoglobulinemia manifested primarily by an increase in immunoglobulin M (IgM) and renal tubular acidosis is described, arid the literature on renal involvement in chronic active hepatitis is reviewed. The renal tubular disorder in this patient combines characteristics of both proximal and distal tubular defects. Treatment with prednisone and potassium supplement resulted in biochemical improvement but did not reverse the renal tubular dysfunction, and evidence of active hepatitis persists.

A metabolic case study of a four year old girl with renal tubular acidosis is presented. Renal function was normal except for inability to maintain a hydrogen gradient across the tubular epithelium. There was minimal limitation in total transfer of hydrogen ions into the urine, as expressed by titratable acidity, ammonia and reabsorbed bicarbonate. Histologic examination of a renal biopsy specimen disclosed dilatation of the tubules with some alteration in cellular surface. Enzyme assays for carbonic anhydrase and glutaminase activities were normal. Histochemical assay showed deficient staining for TPN diaphorase, but this was not corroborated by direct biochemical assay. No adequate explanation for the disorder was obtained, but it is suggested that a quantitative defect in energy production might have limited the renal secretion of free hydrogen ions.

Monocytic or myelomonocytic leukemia is associated with lysozymuria. These patients often also have hypokalemia. In order to determine whether or not there is an association between lysozymuria and hypokalemia, balance studies were performed in three patients with this disorder and hypokalemia. The results indicate that all three patients had marked lysozymuria and inappropriately high rates of renal potassium loss. There was also limitation in titratable acid excretion in one patient and glycosuria and hyperuricosuria in another. Ammonium excretion following the administration of an ammonium chloride load was above the expected values at a given urine pH in two patients. All subjects had osteoporosis and fractures developed spontaneously or following minor trauma.

This woman, who died of primary biliary cirrhosis at the age of forty-two, had twice the normal concentration of copper in her serum, the result of a fivefold increase in her nonceruloplasmin copper. She had general malaise and thirst for two years then an acute illness resembling infective hepatitis. This progressed to primary biliary cirrhosis culminating seven years later in portal hypertension and encephalopathy. She died of respiratory failure from profound muscle weakness. Besides the complications of primary biliary cirrhosis which included a duodenal ulcer, steatorrhea, nightblindness, osteomalacia and osteoporosis, she had ulcerative colitis, renal tubular dysfunction and congestive cardiac failure with a high metabolic rate and severe hypertrophic osteoarthropathy. We suggest that infective hepatitis disrupted the cholangioles and then the copper in the extravasated bile perpetuated the inflammatory process; and that when the biliary tract is obstructed the elimination of copper from the liver mainly depends on the production of ceruloplasmin. We attribute our patient's copper retention to inadequate ceruloplasmin production, and the defects in renal function to deposition of copper in the tubular epithelium. Penicillamine given to the patient six months before she died reduced the nonceruloplasmin copper in the serum and the urinary excretion of copper but did not help her. This treatment given earlier in primary biliary cirrhosis might retard its evolution.

Fraternal twins with the oculo-cerebral-renal syndrome of Lowe have been followed clinically for nine and a half years. Renal biopsies with electron microscopic study were performed at ages twenty-two months and nine years. There has been no evidence of significant deterioration in renal function, but morphologic renal disease has progressed. The initial biopsy specimens showed minimal or equivocal pathologic changes; the recent study revealed advancing glomerular disease with basement membrane thickening, podocyte fusion, increased glomerular cellularity and glomerular fibrosis, as well as scattered thickening of renal tubular basement membranes, multifocal tubular atrophy, the formation of casts, with extension of these casts into the interstitium, and interstitial fibrosis.

Clinical studies were conducted in four cases of Sjogren's syndrome complicated by renal tubular acidosis (group I) and in ten cases of Sjogren's syndrome without this complication (group II). No differences between the two groups were noted in respect to the ages of the patients or the duration of the disease. Hyperglobulinemia and an increase in serum IgG were observed in three of the four cases in group I, but no difference was found in the degree of increase when comparing the two groups. No differences were observed between the two groups when compared using various serologic tests. Marked lymphocytic infiltration was noted in the biopsy specimens of the lacrimal and parotid glands. In the kidney biopsy specimens in three cases of group I lymphocytic infiltration interspersed with plasma cells was conspicuous in the interstitial tissues. No lymphocytic infiltration was noted in one case without hyperglobulinemia but a marked interstitial fibrosis was seen. No remarkable changes were seen in the renal biopsy tissue in four cases of group II. Accordingly hyperglobulinemia of itself does not appear to be the primary cause of renal tubular acidosis in Sjogren's syndrome. Renal changes appear to represent one of several systemic changes occurring in Sjogren's syndrome. Therefore renal tubular acidosis is probably an inherent result of the disease process responsible for the development of Sjogren's syndrome.

A case of renal tubular acidosis is presented. Etiological, historical, clinical and biochemical data associated with this syndrome are described. A metabolic study in the patient presented established the presence of a potassium-losing diathesis, and probably of a less severe sodium-losing diathesis. The renal carbonic anhydrase system appeared to be intact. Features of note in the patient included an elevated erythrocyte sedimentation rate and serum globulin concentration and the presence of an abnormal histone in the urinary protein. A renal biopsy was performed, with equivocal findings. The significance of these points is discussed.