Diagnosis Of Renal Tubular Acidosis Research Articles

In memoriam: Todd S. Ing, MD.

This special article describes the achievements and impact of Dr. Todd Siu-Toa Ing, MBBS, (1933-2023) on the field of nephrology as recounted by a colleague from Hong Kong, a U.S. nephrologist ex-trainee, and the daughter of an important mentor. Dr. Ing was a founding member of the International Society for Hemodialysis. He made important discoveries regarding the diagnosis of renal tubular acidosis and electrolyte transport in the gastrointestinal tract and published many innovative findings relating to peritoneal and hemodialysis. He was especially interested in nephrology and dialysis education and was co-editor of a Handbook of Dialysis that has been in publication in five editions since 1988 with translation into many foreign languages. Dr. Ing was very supportive of nephrology in China as well as Chinese nephrologists practicing in the United States, and was a founding member of the Chinese American Society of Nephrology.

Hypokalemic paralysis and renal tubular acidosis: Initial presentation of Sjogren’s syndrome

Sjogren’s syndrome is a rare autoimmune disease affecting multiple systems with varying clinical features.We report a case of 37 year old woman who presented with recurrent episodes of quadriparesis which was attributable to hypokalemia and initially labelled as hypokalemic periodic paralysis. Later on she was found to have metabolic acidosis rather than alkalosis which pointed towards the diagnosis of renal tubular acidosis (RTA) in the absence of apparent gastrointestinal tract loss. Once the diagnosis of RTA was established, an attempt to search the aetiology revealed that she was having primary Sjogren’s syndrome (pSS) though she did not have any symptom at the time of diagnosis. She was found positive for anti-SSA. Lip biopsy revealed lymphocytic infiltration in periductal as well as parenchymal region. Schirmer test confirmed presence of severe dry eye. A concomitant existence of autoimmune hypothyroidism was a noteworthy association. She responded well with potassium supplementation and symptomatic treatment. Presentation of this case reminds the importance of vigilance while managing a case of recurrent hypokalemia which might be a rare presenting feature of pSS.
 Bangladesh J Medicine July 2021; 32(2) : 145-148

WDR72 Mutations Associated with Amelogenesis Imperfecta and Acidosis

Dental enamel malformations, or amelogenesis imperfecta (AI), can be isolated or syndromic. To improve the prospects of making a successful diagnosis by genetic testing, it is important that the full range of genes and mutations that cause AI be determined. Defects in WDR72 (WD repeat-containing protein 72; OMIM *613214) cause AI, type IIA3 (OMIM #613211), which follows an autosomal recessive pattern of inheritance. The defective enamel is normal in thickness, severely hypomineralized, orange-brown stained, and susceptible to attrition. We identified 6 families with biallelic WDR72 mutations by whole exome sequence analyses that perfectly segregated with the enamel phenotype. The novel mutations included 3 stop-gains [NM_182758.2: c.377G>A/p.(Trp126*), c.1801C>T/p.(Arg601*), c.2350A>T/p.(Arg784*)], a missense mutation [c.1265G>T/p.(Gly422Val)], and a 62,138–base pair deletion (NG_017034.2: g.35441_97578del62138) that removed WDR72 coding exons 3 through 13. A previously reported WDR72 frameshift was also observed [c.1467_1468delAT/p.(Val491Aspfs*8)]. Three of the affected patients showed decreased serum pH, consistent with a diagnosis of renal tubular acidosis. Percentiles of stature and body weight varied among 8 affected individuals but did not show a consistent trend. These studies support that WDR72 mutations cause a syndromic form of AI and improve our ability to diagnose AI caused by WDR72 defects.

Renal tubular acidosis.

To facilitate the understanding and knowledge of renal tubular acidosis by providing a summarized information on the known clinical and biochemical characteristics of this group of diseases, by updating the genetic and molecular bases of the primary forms renal tubular acidosis and by examining some issues regarding the diagnosis of distal renal tubular acidosis (RTA) in the daily clinical practice. The manuscript presents recent findings on the potential of next-generation sequencing to disclose new pathogenic variants in patients with a clinical diagnosis of primary RTA and negative Sanger sequencing of known genes. The current review emphasizes the importance of measuring urinary ammonium for a correct clinical approach to the patients with metabolic acidosis and discusses the diagnosis of incomplete distal RTA. We briefly update the current information on RTA, put forward the need of additional studies in children to validate urinary indexes used in the diagnosis of RTA and offer a perspective on diagnostic genetic tests.

Evaluation of cases of rickets that presented to the outpatient clinic of rickets in the National Institute of Neuromotor System in Giza

Objectives The aim of this study was to assess clinical findings in different types of rickets, nutritional or resistant rickets. Background Rickets is a metabolic disease of growth plate mineralization and ossification commonly occurring in children and adolescents. Vitamin D deficiency may result in bone diseases, such as rickets in children and osteomalacia and osteoporosis in adults. Patients and methods This study included 100 cases that presented with rickets in the rickets outpatient clinic of the National Institute of Neuromotor System. The initial search presented 100 cases of rickets aged from 4 months to adolescence. Cases less than 4 months of age or those above 18 years of age or with other bone diseases such as osteogenesis imperfecta, and hyperparathyroidism cases were excluded from the study. Comparisons were made by means of structured review with the results tabulated. Results Of the 100 cases, 85% of cases were nutritional, whereas refractory rickets represented 15% of our cases. The incidence of refractory rickets was as follows: 26.7% hypophosphatemic rickets, 20% vitamin D-dependent type II, 20% vitamin D-dependent type I, 6.7% renal osteodystrophy, 13.3% renal tubular acidosis, 6.7% Fanconi syndrome, and 6.7% hypophosphatasia. Conclusion We found that the most common nonnutritional form of rickets was hypophosphatemic rickets. These results indicate the necessity to look for the diagnosis of renal tubular acidosis and hypophosphatemic rickets among children with rickets, especially in older-aged children, those with severe clinical features and poor response to therapy.

Renal tubular acidosis

Renal tubular acidosis (RTA) refers to a group of disorders of multiple etiology characterised by a hyperchloremic, normal anion-gap metabolic acidosis caused by different defects affecting several mechanisms of urinary acidification: an impaired secretion of protons by collecting duct in distal hypokalemic RTA (type 1), impaired resorption of bicarbonate in proximal RTA (type 2), a mixed proximal and distal defect in RTA type 3 and an impaired ammoniagenesis due to an absolute or functional hypoaldosteronism in distal hyperkalemic RTA (type 4). Etiology is heterogeneous and ranges from primitive genetic forms to secondary RTA within a multi-system disorder such as autoimmune disease, paraproteinemia and calcium-phosphate disorders. Drug-induced RTA has been increasingly reported over the last decade due to widespread use of some molecules (e.g. antiviral and oncologic agents, inhibitors of renin-angiotensin system). The diagnosis of RTA is based on assessment of serum and urine anion-gap, whereas differe...

A case report of recurrent hypokalaemic periodic paralysis in a young male patient

A 21-year-old normotensive male patient presented with acute-onset flaccid paralysis with the history of a similar episode a few months back. Clinical and laboratory evaluation revealed lower motor neuron type of flaccid quadriparesis with hypokalaemia, normal anion gap metabolic acidosis, bicarbonaturia and transtubular potassium concentration gradient more than 7. Subsequently, urine acidification test (by ammonium chloride challenge test) was performed and diagnosis of renal tubular acidosis was established. The patient ultrasound did not show nephrocalcinosis, and history of recurrent diarrhoea preceding the attack revealed that the patient also had coeliac disease. The patient responded to conservative management (Sohl’s solution) and gluten-free diet.

Clinical and laboratory approaches in the diagnosis of renal tubular acidosis.

In the absence of a gastrointestinal origin, a maintained hyperchloremic metabolic acidosis must raise the diagnostic suspicion of renal tubular acidosis (RTA). Unlike adults, in whom RTA is usually secondary to acquired causes, children most often have primary forms of RTA resulting from an inherited genetic defect in the tubular proteins involved in the renal regulation of acid-base homeostasis. According to their pathophysiological basis, four types of RTA are distinguished. Distal type 1 RTA, proximal type 2 RTA, mixed-type 3 RTA, and type 4 RTA can be differentiated based on the family history, the presenting manifestations, the biochemical profile, and the radiological findings. Functional tests to explore the proximal wasting of bicarbonate and the urinary acidification capacity are also useful diagnostic tools. Although currently the molecular basis of the disease can frequently be discovered by gene analysis, patients with RTA must undergo a detailed clinical study and laboratory work-up in order to understand the pathophysiology of the disease and to warrant a correct and accurate diagnosis.

Bilateral Kidney Calcifications

This 37-year-old man was given a diagnosis of renal tubular acidosis at 9 years of age but had no medical follow-up or treatment for 22 years.

Renal Fanconi syndrome with ultrastructural defects in lysinuric protein intolerance

Renal Fanconi syndrome developed rapidly in a 3-year-old Moroccan girl with established lysinuric protein intolerance. She was hospitalized because of lowered consciousness, uncoordinated movements and hepatosplenomegaly after a febrile period. Laboratory investigations revealed plasma ammonia 270 micromol/L (normal <70 micromol/L), ferritin 159 micromol/L (normal 2-59 micromol/L), LDH 1180 U/L (normal 26-534 U/L). LPI was diagnosed based on the findings of reduced plasma ornithine, arginine and lysine, and an increased level of glutamine. Urinary orotic acid (645 micromol/mmol creatinine; normal <3.6) was strongly increased. A defect in the SLC7A7 amino acid transporter was established (homozygous c.726G > A mutation). Detailed renal function tests including an acid challenge test, bicarbonate loading, and tubular maximal reabsorption of glucose showed complex tubular dysfunction. No evidence of respiratory chain defects was found in muscle or kidney tissue. No morphological abnormalities were demonstrated in the mitochondria. Ultrastructural analysis of proximal tubular cells showed vacuolization and sloughing of the apical brush border (Fig. 1). Renal involvement in LPI has only been described in a few reports; however, no detailed studies of the renal acidification mechanism were performed. Our patient had evidence of a full-blown Fanconi syndrome. Surprisingly, a metabolic acidosis was found with a moderately increased serum anion gap combined with repeatedly normal plasma organic acid values. This finding is in contrast with the diagnosis of renal tubular acidosis. Patients with hyperlysinaemia have a similar heavy load on the renal tubules; they never develop a renal Fanconi syndrome. Therefore, we consider the intratubular accumulation of lysine an unlikely candidate for the development of the renal Fanconi syndrome.

Acute Flaccid Quadruparesis In A Young Male: A Case Report

A 28year old normotensive euthyroid male presented with recurrent lower motor neuron type of weakness without any sensory or autonomic involvement, with preserved reflexes. Systemic examination was significant for a mild hepatosplenomegaly. Investigations revealed persistent hypokalemic, hyperchloremic, normal anion gap metabolic acidosis with deranged liver functions. Urine pH was 6.0 even after an oral ammonium-chloride loading test. A case of Type I Renal Tubular Acidosis (RTA) was diagnosed. A search for the etiology revealed bilateral Kayser-Fleischer (KF) ring, with low serum ceruloplasmin levels and high urinary copper , confirming it to be Wilson's Disease (WD). A 28 year-old male farmer was admitted with weakness of all the four limbs. To start with, the weakness involved the lower limbs and then progressed rapidly to involve the upper limbs making the patient bed–bound within the next day. The weakness involved both proximal and distal group of muscles and was associated with significant flaccidity but without fasciculations, sensory abnormalities or diurnal variation. There was no history suggestive of alteration of higher functions, cranial nerve or sphincter involvement and of radicular pain or girdle sensation. Weakness was not preceded by vaccination, respiratory tract infection or diarrhoea and was not associated with food intake, exercise or change of temperature. He denied unexplained sweating, tremors, heat intolerance, prolonged vomiting, diabetes, hypertension or any drug intake over a prolonged period of time. The patient had 2 such similar attacks in the past, but those were milder, subsided spontaneously and didn't require hospitalization. His personal and family history was noncontributory. The patient had a normal higher function, and normal vitals with blood pressure of 110/80mm Hg. The neurological examination revealed marked hypotonia and weakness in all four limbs, the power being 1/5 in the lower and 2/5 in the upper limbs. There was no cranial nerve involvement, sensory impairment and no abnormality in any of the superficial or deep reflexes. Plantar reflexes were bilaterally flexor and coordination could not be tested. Both the lobes of liver were palpable 3c.m below the costal margin with firm consistency. He had a mild splenomegaly without any venous prominence and clinical evidence of free fluid in the abdomen. The complete blood count, serum urea and creatinine were normal but the fasting plasma glucose was 182mg/dl and the post-challenge plasma glucose was 214mg/dl. The liver function test revealed the following: Bilirubin-0.9mg/dl, AST-168U/L, ALT-58U/L, Albumin-2.2gm/dl and Globulin-4.1gm/dl. The serum sodium, potassium, chloride and bicarbonate were 140mEq/L, 2.8mEq/L,108.1mEq/L and 20.4mEq/L respectively. The arterial blood gas analysis suggested mild metabolic acidosis with normal anion gap. A provisional diagnosis of hypokalemic paralysis was considered and the electrolyte deficit was corrected with oral and intravenous potassium supplementation. The patient improved completely but a repeat estimation after 4 days showed a persistent hypokalemia (K=2.7meq/L) and metabolic acidosis. Measured calcium (9.1mg/dl) and magnesium (1.9mg/dl) were within normal limits. He had a normal thyroid profile. Serum HIV serology, Serum electrophoresis , Creatine Kinase, Aldolase, Porphobilinogen, Cerebrospinal fluid study and Electrophysiological studies were all normal. 24 hours urinary potassium excretion was 242.76mEq. Acute Flaccid Quadruparesis In A Young Male: A Case Report 2 of 4 Plasma and urinary osmolality were 296.76mosm/kg and 482.2mosm/kg respectively. Estimated transtubular potassium gradient(TTKG) came out to be 15.25. To proceed with the diagnosis of a case of hypokalemia, we followed the algorithm given in Figure 1(1). A potassium excretion >15mmol/day and a TTKG of more than 4 narrowed our possibilities further. A diagnosis of renal tubular acidosis (RTA) was made and oral NH4Cl test (0.1gm/kg) revealed worsening of acidosis(7.377 to 7.289) with a urinary pH of 6.

D -lactic acidosis 23 years after jejuno-ileal bypass

Accumulation of d -lactate after gastrointestinal surgery, particularly jejuno-ileal bypass, is an uncommon and often misdiagnosed clinical disturbance. The syndrome may be complicated by dizziness, ataxia, confusion, headache, memory loss, and aggressive behavior. Serum chemistries are often deceptive because the anion gap is frequently normal in spite of severe metabolic acidosis. Moreover, the urine anion gap may be positive, incorrectly suggesting a defect in renal net acid excretion. Indeed, the combination of a normal anion gap metabolic acidosis and positive urine anion gap may erroneously suggest a diagnosis of renal tubular acidosis. Importantly, all reported cases of d -lactic acidosis secondary to bypass surgery have been encountered within 5 to 10 years following the surgery. Here we present an unusual case of d -lactic acidosis (complicated by encephalopathy) presenting 23 years after a jejuno-ileal bypass procedure. The patient was initially diagnosed with a drug intoxication secondary to benzodiazepines. Ultimately, the diagnosis of d -lactate encephalopathy was established after challenging the patient with a carbohydrate load. Thus, administration of 40 kcal/kg over 16 hours reproduced the clinical syndrome and was accompanied by a marked increment in serum and urine d -lactate concentration. The patient had sustained resolution of her symptoms after treatment with oral vancomycin.

Renal Tubular Acidosis

The pathophysiology of renal tubular acidosis is slowly being unraveled, which has implications for the traditional classification of the condition. Nonetheless, the diagnosis of renal tubular acidosis is still easy to establish, and identification of the specific pathophysiological subtype is relatively straightforward. The diagnostic information required usually includes only urinary pH and sodium, potassium, and chloride concentrations and serum potassium level. The urinary pH is not a diagnostic test for renal tubular acidosis, but it serves to distinguish between the various subtypes.

Renal tubular acidosis in the Silver-Russell syndrome.

Several patients with the Silver-Russell syndrome (SRS) attending our Genetics Clinic were diagnosed as having persistent metabolic acidosis. Since this abnormality has not been reported previously in the SRS, we reexamined 33 SRS patients to evaluate the frequency and type of metabolic acidosis, the clinical and laboratory findings, and the growth pattern in SRS patients with and without metabolic acidosis. Among them, 14 had a consistent decrease in HCO3- levels. Renal studies in acidotic patients showed urine pH of 5.8 and 24 h urine calcium of < 2.4 mg/kg/24 h; serum creatinine, excretion of glucose, and amino acids were normal, as were renal ultrasound and excretory urography findings. These data supported the diagnosis of renal tubular acidosis, probably type II; the patients were treated with oral bicarbonate and acidosis was corrected successfully. Clinical manifestations were similar in acidotic and non-acidotic patients. The nutritional indices at diagnosis and at last evaluation (at least 8 months after diagnosis) were abnormally low in all patients; however, acidotic patients, treated with bicarbonate, showed an improvement of nutritional status particularly in the weight/height index, although the difference between groups after follow-up did not reach statistical significance. We suggest that metabolic acidosis due to renal tubular acidosis, probably type II, may occur in children with the SRS and should be looked for and treated in all patients.

Renal Tubular Acidosis in Children Treated With Trimethoprim-Sulfamethoxazole During Therapy for Acute Lymphoid Leukemia

The antibiotics trimethoprim (TMP) and sulfamethoxazole (SMZ), when used in combination, can cause metabolic acidosis, renal bicarbonate wasting, and growth failure. Retrospective review of repeated random serum chemistries from 10 children receiving TMP-SMZ and maintenance chemotherapy for acute lymphoid leukemia revealed low serum bicarbonate (P = .0002) and elevated serum chloride (P less than .0005) concentrations. These values normalized after all medications were discontinued. Prospective study of 8 children receiving TMP-SMZ and chemotherapy for acute lymphoid leukemia revealed lower serum bicarbonate concentrations and higher urine pH following a dose of TMP-SMZ than paired values obtained more than 3 days after a dose. Four children (50%) met serum bicarbonate and urinary pH criteria for the diagnosis of renal tubular acidosis soon after a dose of TMP-SMZ. The occurrence of TMP-SMZ-induced renal tubular acidosis has implications for the acid-base balance of children receiving TMP-SMZ on a long-term basis.

Renal tubular acidosis

The term renal tubular acidosis (RTA) is applied to a group of transport defects in the reabsorption of bicarbonate (HCO3-), the excretion of hydrogen ions, or both. On clinical and pathophysiological grounds, RTA can be separated into three main types: distal RTA (type 1), proximal RTA (type 2) and hyperkalaemic RTA (type 4). Some patients present combined types of proximal and distal RTA or of hyperkalaemic and distal RTA. Diagnosis of RTA should be suspected when a patient presents a normal plasma anion gap, and hyperchloraemic metabolic acidosis. A normal plasma anion gap (Na(+)-[Cl- + HCO3-] = 8-16 mEq/l) reflects loss of HCO3- from the extracellular fluid via the gastro-intestinal tract or the kidney, dilution of extracellular buffer or administration of hydrochloric acid (HCl) or its precursors. Distinction of RTA from other disorders is greatly facilitated by the study of the urine anion gap (Na+ + K+ - Cl-). This index estimates the urinary concentration of ammonium in a patient with hyperchloraemic metabolic acidosis. A negative urine anion gap (Cl- much greater than Na+ + K+) suggests the presence of gastro-intestinal or renal loss of HCO3-, while a positive urine anion gap (Cl- less than Na+ + K+) is indicative of a distal acidification defect. Determination of plasma potassium, of urine pH at low plasma HCO3- concentration, and of urine PCO2 and fractional excretion of HCO3- at normal plasma HCO3- concentration permits the differentiation between the various types of RTA.

Suspected renal tubular acidosis in two dogs

Clinical signs of hyperventilation, muscle weakness and lethargy were recognised in a one-year-old female Bichon Frise and a three-year-old male Poodle. One dog was also hyperexcitable and pyrexic. The diagnosis of renal tubular acidosis was confirmed by demonstrating the tendency to an elevated urine pH, a low blood pH and low blood bicarbonate level, and by eliminating other causes of metabolic acidosis. Both dogs were treated with oral sodium bicarbonate resulting in improvement in their clinical condition and a return to near normal blood pH and bicarbonate levels.

Absence Seizures Associated With Bicarbonate Therapy and Normal Serum pH

To the Editor.— Renal tubular acidosis is known to cause failure to thrive. 1,2 We found that treating children with this condition by oral administration of sodium bicarbonate is both beneficial and benign. Report of a Case.— A 2 1/2-year-old girl with failure to thrive and weight and height below the third percentile for her age was referred to our department. Extensive investigation revealed metabolic acidosis (pH, 7.3 to 7.33), with hypocarbonemia of 16 to 18 mEq/L and hyperchloremia of 116 to 117 mmol/L. After excluding other causes, a presumptive diagnosis of renal tubular acidosis was made and oral therapy with 4 mEq/kg per day of sodium bicarbonate was instituted. This raised her blood pH level to 7.41 to 7.43 and enabled the child to attain the 10th percentile of weight and height for her age. A month later, the child experienced four episodes of absencelike seizures. There was no

The renal excretion of hydrogen ion in renal tubular acidosis: I. Quantitative assessment of the response to ammonium chloride as an acid load

In order to establish criteria for the quantitative assessment of the renal excretion of hydrogen ion in patients suspected of having renal tubular acidosis, or in their relatives who might have a genetically determined latent impairment of this function, a standard three day and five day ammonium chloride test was performed twenty times in eighteen normal adults. The results were analyzed and compared with similar data from five adult patients with the clinical diagnosis of renal tubular acidosis. The results show that: 1. 1. Increment indices, in which the change in hydrogen ion excretion is compared with the increment in chloride excretion or in acid load, do not always separate the patients from the normal subjects. 2. 2. A clearance index in which the absolute excretion rate of hydrogen ion is related to the total hydrogen content of the extracellular buffer systems (quantitated as the reciprocal of the serum carbon dioxide level) does separate the patients from the normal subjects under circumstances of an increased total hydrogen load. 3. 3. In these adult patients with renal tubular acidosis the primary impairment of hydrogen ion excretion appears to involve the excretion of titratable acid; the excretion of ammonium ion is somewhat less deficient relative to the degree of systemic acidosis and normal or high relative to the pH of the urine. 4. 4. Two of the patients with RTA were primarily limited in their ability to excrete acid by the amount of phosphate available in the tubular urine to accept hydrogen ions, and the other three patients with RTA were primarily limited by the capacity of the tubular cells to reabsorb bicarbonate and to transfer hydrogen ions against a concentration gradient. Thus more than one mechanism of acid excretion apparently is disturbed in renal tubular acidosis if all patients are included who have actual or potential acidosis due to “non-contractive” disease of the kidney. It is concluded that the test and data here presented provide a tool for the investigation of the pathogenesis and etiology of latent as well as overt disturbances in this renal function.