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| Year : 2011 | Volume
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| Issue : 2 | Page : 261-267 |
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| Clinical profile of distal renal tubular acidosis |
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Ratan Jha1, J Muthukrishnan2, Shekhar Shiradhonkar1, Kiran Patro1, KVS Harikumar2, KD Modi1
1 Department of Nephrology, Medwin Hospital, Hyderabad, India
2 Department of Endocrinology, Medwin Hospital, Hyderabad, India
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| Date of Web Publication | 18-Mar-2011 |
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 Abstract | | |
To determine the clinical profile and progression of renal dysfunction in distal renal tubular acidosis (dRTA), we retrospectively studied 96 consecutive cases of dRTA diagnosed at our center. Patients with unexplained metabolic bone disease, short stature, hypokalemia, recurrent renal stones, chronic obstructive uropathy or any primary autoimmune condition known to cause dRTA were screened. Distal RTA was diagnosed on the basis of systemic metabolic acidosis with urine pH >5.5 and positive urine anion gap. In those patients who had fasting urine pH >5.5 with normal baseline systemic pH and bicarbonate levels (incomplete RTA), acid load test with ammonium chloride was done. A cause of dRTA could be established in 53 (54%) patients. Urological defect in children (22/44) and autoimmune disease in adults (11/52) were the commonest causes. Hypokalemic paralysis, proximal muscle weakness and voiding difficulty were the common modes of presentation. Doubling of serum creatinine during the study period was noted in 13 out of 27 patients who had GFR <60 mL/min at presentation whereas in only one of the 70 with initial GFR >60 mL/min (P <0.005). In conclusion, urological disorders were the commonest cause of dRTA in children while autoimmune disorders were the commonest association in adults. Worse baseline renal function, longer duration of disease and greater frequency of nephrolithiasis/nephrocalcinosis and urological disorders were noted in those who had worsening of renal dysfunction during the study period.
How to cite this article:
Jha R, Muthukrishnan J, Shiradhonkar S, Patro K, Harikumar K, Modi K D. Clinical profile of distal renal tubular acidosis. Saudi J Kidney Dis Transpl 2011;22:261-7 |
How to cite this URL:
Jha R, Muthukrishnan J, Shiradhonkar S, Patro K, Harikumar K, Modi K D. Clinical profile of distal renal tubular acidosis. Saudi J Kidney Dis Transpl [serial online] 2011 [cited 2021 Sep 28];22:261-7. Available from: https://www.sjkdt.org/text.asp?2011/22/2/261/77601 |
| Introduction | |  |
Distal renal tubular acidosis (dRTA) is characterized by a heterogenous clinical profile and systemic manifestations with a wide spectrum of biochemical abnormalities depending on the degree of acidification defect and the presence of vitamin D deficiency or renal insufficiency. Age at presentation, duration of disease, nature of underlying primary etiology, and baseline renal function may have an impact on clinical presentation, biochemical profile and eventual outcome. [1],[2],[3] There are few large studies addressing this subject. [3],[4]
We aim in this study to characterize the dRTA (complete/incomplete) at our center based on the age at diagnosis and clinical and biochemical parameters. In addition, we studied the progression of renal dysfunction and factors contributing to it.
| Subjects and Methods | | |
This study was conducted in a tertiary care teaching hospital. Consecutive cases of dRTA treated at our center from 1994 to July 2008 were retrospectively analyzed. A total of 96 cases (48 males and 48 females, age range 3 months to 75 years, mean 22.9 yrs) were studied. Patients were divided based on age into two groups: children <18yrs and adults ≥18yrs. The mean age for the 44 children was 10.6 years (range 3 months to 17 years).
Duration of disease was noted from the onset of initial symptoms that resulted in the diagnosis of dRTA. Bone pains were considered as significant if they restricted activity and/or required analgesics. Proximal myopathy or quadriparesis was diagnosed in patients with difficulty in climbing stairs, getting up from squatting position or weakness of all four limbs. Rickets was diagnosed based on widening, cupping and fraying of metaphyseal ends of long bones. Osteomalacia was diagnosed based on presence of looser's zones (pseudofractures) on X-rays; correlation with raised alkaline phosphatase was made in both conditions. Short stature was diagnosed in children with height <5th percentile for age and gender based on growth charts approved for the study population. [5],[6] Nephrocalcinosis and nephrolithiasis were diagnosed by using plain abdominal radiographs [Figure 1] and ultrasound evaluation. Obstructive uropathy was diagnosed in patients with voiding difficulty using a micturating cystourethrogram and uroflowmetric studies. | Figure 1: Plain radiograph of the abdomen in a case of bilateral nephrocalcinosis
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Patients with unexplained rickets, osteomalacia, short stature, recurrent renal stones and underlying conditions known to cause dRTA (obstructive uropathy, autoimmune conditions) were screened using fasting urine pH by pH meter. Patients with fasting urine pH >5.5 were subjected to arterial blood gas (ABG) analysis. Serum and urine electrolytes (24 hrs collection) for anion gap calculation were done. Persistent fasting urine pH >5.5 with spontaneous or induced metabolic acidosis (pH <7.3, HCO3 <15) were considered to qualify for dRTA.
Metabolic acidosis with dRTA was either a) absent, b) classical normal anion gap, c) wide anion gap and negative Δ gap with reduced estimated GFR (eGFR). Patients with normal plasma anion gap (Na + -Cl - -HCO3 - , normal 12 ± 2) metabolic acidosis with positive urine anion gap (Na + K-HCO3) were diagnosed to have classical complete dRTA. Incomplete dRTA was diagnosed in the absence of systemic acidosis (pH and HCO 3 normal) with positive ammonium chloride loading test in appropriate clinical setting. Patients with reduced eGFR with wide anion gap metabolic acidosis and high urine pH (>5.5) were also included if the Δ change of bicarbonate exceeded Δ change of anion gap (negative Δ gap acidosis as it corroborates to distal acidification defect).
Patients with serum HCO3 >15 mmol/L were subjected to acid loading with ammonium chloride (0.1 g/kg body weight, in gelatin capsule PO) followed by hourly urine pH for six hours. [7],[8] Plasma pH and bicarbonate was done at two hours to document induced metabolic acidosis (pH <7.3, HCO3 <15). Persistent urine pH >5.5 during the test despite induced metabolic acidosis (change of serum bicarbonate by 3 mmol and blood pH <7.3) was taken as positive for dRTA.
Those with baseline wide anion gap metabolic acidosis and negative Δ gap associated with renal dysfunction (GFR 30-60 mL/min), where underlying dRTA was suspected, were subjected to furosemide test with oral furosemide 2 mg/kg body weight with or without fludrocortisone 1 mg, followed by hourly urine pH for six hours. Failure to acidify urine pH to less than 5.5 was taken as positive for dRTA.
Ammonium chloride loading test was done in 36 (16 adults and 20 children). Furosemide test was done in 13 cases (5 adults and 8 children) and two of them with fludrocortisone. The remaining 47 patients (31 adults and 16 children) with normal AG metabolic acidosis with HCO3 less than 15 mEq/L were not subjected to ammonium chloride or furosemide test.
Urinary calcium and creatinine were calculated on a second voided morning urine sample on a regular diet with no calcium or vitamin D supplementation. Calcium:Creatinine ratio > 0.2 or 24hr urinary calcium > 4 mg/kg body weight was considered as hypercalciuria. Parathyroid hormone (PTH) levels in 31 and vitamin D levels in 12 patients were available. Primary hyperparathyroidism was diagnosed on the basis of raised corrected serum calcium and simultaneous intact PTH, low-normal phosphorus with hypercalciuria. Secondary hyperparathyroidism was suspected in patients with raised PTH in presence of low-normal calcium, low to high phosphorus and elevated alkaline phosphatase (ALP) in an appropriate setting (vitamin D deficiency or low eGFR). Fall in PTH and ALP levels with vitamin D replacement was confirmatory of secondary hyperparathyroidism due to vitamin D deficiency. Vitamin D deficiency was diagnosed in patients with serum 25-OH vitamin D levels less than 30 ng/mL.
Diagnosis of fluorosis was based on residence in endemic region, dental fluorosis, osteosclerosis and interosseous membrane calcification [Figure 2]. Glomerular filtration rate (GFR) was estimated by Cockroft and Gault equation in adults (corrected to body surface area) and Schwartz formula in children. [9],[10] In patients with hyperkalemia, transtubular potassium gradient (TTKG) was calculated (Urinary K + × Serum Creatinine /Serum K + × Urinary Creatinine ). TTKG less than 4 was suggestive of renal cause of hyperkalemia. | Figure 2: Radiograph of forearm showing calcified interosseus ligament in a case of fluorosis
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Cases with urinary tract infection, diarrhea, respiratory alkalosis, renal transplant and GFR less than 30 mL/min were excluded.
| Statistical Analysis | | |
Paired T test for mean and Fisher's exact test for frequencies were used P< 0.05 was taken as significant.
| Results | | |
The causes of dRTA were urological in 26 (28%) patients, autoimmune disease in 11 (12%), toxin related in 6, primary hyperparathyroidism in 4 and medullary sponge kidney (MSK) in 3; dRTA was diagnosed as a congenital disorder in 2 cases. The distribution of the causes per age group is shown in [Table 1]. The mean duration of the presenting symptoms of dRTA was 6.5 yrs (SD ± 3.83 yrs) in adults and 4 yrs (SD ± 3.5 yrs) in children. Hyperkalemia was observed in 7 and hypokalemia in 45 cases. All patients with hyperkalemia had TTKG less than 4 suggestive of renal retention as a cause of hyperkalemia.
Twelve cases (7 adults and 5 children) had nephrolithiasis and nine (5 adults and 4 children) had nephrocalcinosis. Hypercalciuria was documented in all of them. Skeletal and dental fluorosis was diagnosed in 5 cases. Vitamin D deficiency was detected in 10 out of 12 patients in whom serum 25-OH vitamin D was done. All of them had bone pains, myopathy and secondary hyperparathyroidism, which responded to vitamin D replacement. The presence of dRTA was reconfirmed in these patients after adequate vitamin D replacement to rule out renal tubular dysfunction due to vitamin D deficiency. [11]
Incomplete dRTA was diagnosed in 4 adults and two children. Bone pains were the prominent symptom in these patients. Osteopenia was documented in these adult patients by DEXA scan (T-score-1.0 to-2.4). All these children were documented to have short stature (height < -2SD for age and gender). At initial diagnosis, GFR was greater than 60 mL/min in 70 and less than 60 mL/min in 26 patients. During the study period, Serum Creatinine doubled in one patient in the former group and in 14 in the latter group (P< 0.005).
All patients responded well to treatment with potassium citrate, vitamin D therapy and sodium bicarbonate except those with fluorosis. Details of clinical and biochemical parameters are presented in [Table 2] and [Table 3] respectively.
| Discussion | | |
We noted autoimmune diseases as the most frequent underlying cause of secondary dRTA in adults, which is similar to other studies in literature. [12] Associated fluorosis was diagnosed in adult subgroup. Role of fluorosis in renal tubular dysfunction in endemic regions has been documented in an earlier study. [15] Chronic urological defects are known to cause dRTA; [13] 50% of the children in our studyhad underlying urologic abnormality.
Proximal muscle weakness and hypokalemic paralysis were the dominant presentations in adults; more frequent hypokalemia and osteomalacia in the adult subgroup possibly contributed to greater prevalence of proximal myopathy in them. Voiding difficulty and short stature were the predominant presentation in children. Severity of metabolic acidosis, disturbances of potassium blood levels, nephrocalcinosis and nephrolithiasis were similar in both age groups. Progressive renal dysfunction in patients with longer disease duration, worse baseline renal function and lack of reversibility after delayed diagnosis in secondary dRTA underlines the need for early diagnosis.
In contrast with the reports from the western literature of symptomatic nephrolithiasis and nephrocalcinosis (77% of the cases) and electrolyte disturbances or metabolic myopathy (25% of cases), we have noted greater frequency of hypokalemic paralysis, metabolic myopathy (43%) and bone disease (33%). [4] Nephrocalcinosis and nephrolithiasis were seen in only 23% of our cases. Previous studies on hypokalemic paralysis too have noted greater frequency of dRTA as an underlying etiology. [16] High prevalence of proximal myopathy and symptomatic bone disease in addition to less prevalence of renal stone disease in our patients may be related to the frequently associated vitamin D deficiency.
PTH levels were available for 31 out of 58 patients with symptomatic metabolic bone disease and myopathy. Primary hyperparathyroidism in 4 patients (3 adults and 1 child) and secondary hyperparathyroidism in 10 (2 adults and 8 children) were diagnosed. The primary hyperparathyroidism patients presented with severe bone pains, proximal myopathy and solitary parathyroid adenoma on parathyroid scintigraphy. Distal RTA in 3 out of these 4 cases completely reverted to normal after surgical cure of primary hyperparathyroidism while lack of recovery in the fourth patient with renal stones was probably due to irreversible tubular damage. [14] Hypercalciuria or high PTH per se mediates renal tubular dysfunction in these patients. High frequency of secondary hyperparathyroidism in children correlated with the more frequent finding of symptomatic metabolic bone disease in them. All patients with secondary hyperparathyroidism had associated vitamin D deficiency as well and responded symptomatically to vitamin D (cholecalciferol) replacement.
All the patients were treated with potassium citrate with or without spironolactone in case of hypokalemia and sodium bicarbonate in case of hyperkalemia. Surgical treatment of the urological abnormalities and primary hyperparathyroidism were performed. All patients received oral vitamin D (400 IU) and calcium (500-1000 mg) supplementation. Those with documented vitamin D deficiency were treated with therapeutic doses of vitamin D. Treatment of autoimmune conditions followed the existing guidelines. Symptomatic improvement of neuromuscular symptoms, bone pain (in adults) and improved growth velocity (in children) were noted in the majority of these cases. Two children received growth hormone therapy with significant growth benefit. [17]
Our study is limited by its retrospective nature and resultant lack of details regarding urinary calcium and citrate excretion, serum vitamin D and PTH status in all patients and a high proportion of cases having developed renal dysfunction consequent to underlying primary urological disorder.
We understand that a purist's definition of dRTA would mean complete RTA with normal GFR and not with a variant preceding it (incomplete RTA) or succeeding it (with mild renal dysfunction superimposed). However, these demarcations are blurred in a clinical practice setting where the guiding principles of treatment are similar. Herein lies the strength of study, which has included a spectrum of cases which qualify as dRTA rather than excluding them based on a mere low GFR or incomplete dRTA. Inclusion of children with dRTA is strength of our study as most of the adult cases of dRTA have their onset in childhood.
Our study shows a high frequency of metabolic myopathy, paralysis, and metabolic bone disease in adults and children with dRTA. We noted that even incomplete dRTA was associated with significant skeletal effects and short stature; this has been documented in earlier studies. [18] Incomplete RTA is to be suspected or considered in the setting of family history of RTA, unexplained osteoporosis or history of calcium stone disease where urine pH is persistently above 5.5 in the absence of systemic acidosis. [19] The role of fluorosis and primary hyperparathyroidism in the cause and effect association with dRTA was noted. The patients with longer disease duration had more frequent baseline renal dysfunction. Progressive renal dysfunction was observed more frequently with a worse baseline renal function and primary urological defects. Poor response to therapy of dRTA was observed in patients with fluorosis. Effects of disease duration and treatment of underlying primary disease on the recovery from dRTA needs further follow-up studies. Fluorosis needs to be considered as an important risk factor for dRTA in endemic area though its association needs further study.
| Acknowledgement | | |
The authors wish to acknowledge the secretarial help rendered by Ms. Mrunalini Reddy and Ms. Y. Pushpalatha in preparation of this manuscript.
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Correspondence Address:
J Muthukrishnan
Department of Endocrinology, Medwin Hospital, Hyderabad - 500001
India
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PMID: 21422623 
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3] |
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