Relationship between rickets and incomplete distal renal tubular acidosis in children

Rickets a disease of deficiency is still a common finding in the developing countries amongst the under 5 children. Consequent to report from studies on rickets in children from the developing countries it was accepted that calcium deficiency and very occasionally vitamin D deficiency was the main basis for its development[1–8]. Although rickets peak age of presentation is between the age 1- 3 years [1–3], there has been a disturbing observation of rickets in children 5 years and older. It is being contemplated that the basis of rickets in these older children may be through another mechanism or the calcium deficiency which was also observed was not purely a nutritional deficiency [1–8].

Renal tubular acidosis has been known to be associated with rickets and the recent reporting of high prevalence of incomplete distal renal tubular acidosis (idRTA) in adults with osteoporosis [9], has brought into focus the effect of idRTA on skeletal parameters and the possibility of a similar effect in children.

Incomplete distal renal tubular acidosis (idRTA) is a type of primary distal renal tubular acidosis type 1, in which the individual is unable to acidify urine. The impaired distal acidification is characterized by an inability to lower urinary pH maximally (< 5.5) under the stimulus of systemic acidemia but because of due to a compensatory high rate NH₄⁺ excretion for the limited amount of titrable acid there is no associated severe metabolic acidosis[10, 11].

Even though, unlike typical primary distal ubular acidosis, the metabolic acidosis in idRTA is mild, its chronic nature and the high urine pH initiate loss of calcium to into urine. This loss of calcium in the urine invariably leads to compensatory mechanisms in, which the bone is dissolved to release calcium though at a slower rate than in the typical RTA into the body system. Unfortunately the released calcium is lost through the kidneys into the highly alkaline urine perpetuating the hypocalcaemia, more leeching of the bone, further softening of the bone and subsequent rickets in a growing child. Other issues such as an associated abnormal vitamin D metabolism at the renal tubular level or calcium nutritional deficiency may accentuate the effect of the idRTA. A secondary hyperparathyroidism state usually arises from a combination of these events. Hyperparathyroidism has a direct effect on the tubules by increasing the rate of excretion of bicarbonate and invariably increasing the loss of mineral salt into the urine [10–12].

Diagnosis of Incomplete renal distal tubular acidosis is made when there is a demonstrable inability to lower urine pH below 5.5, either after NH₄Cl loading or after furosemide administration. To correct this chronic alkalinization of the urine buffering solution such as Shohl's solution is given. After ingestion it is metabolized into bicarbonates. The bicarbonates released increases the urinary pH by increasing its excretion as free bicarbonate ions without producing systemic alkalosis. By this action it reverses the loss of calcium into urine into reabsorbing thereby increasing blood calcium level.

However, the following condition must be ruled out before a diagnosis of incomplete renal acidosis is made: urinary tract infections, low potassium levels, and sodium retention. Urinary tract infections can raise the pH level of the urine. Low levels of potassium can cause increased ammonia production, which will then lead to increased urine pH since ammonia is an alkaline substance [10].

We are hypothesizing that incomplete renal tubular acidosis may be a causal mechanism for rickets amongst children seen with rickets and a cause for poor response to therapy.

The study design is a prospective observational study undertaken at the Lagos University Teaching Hospital which ran from April to December 20008 after institutional ethics review board committee approval.

Review of the three day recount food diary showed that at least 75% of the subjects had pap (corn meal) or tea with milk mixture every morning in combination with other foods. The amount of milk (powdered) used varied amongst the cohort from a teaspoonful to 2 tablespoons scoops of milk. Egg boiled or fried was seldom taken, either once or none per week. Fish (Tilapia or sardine or mackerel) was eaten daily but portion was small (a cultural belief that giving a bigger portion will egg on the child to steal encouraged this practice). Shrimps alone were not a common part of the diet usually a small portion may be added to vegetable soup. Liver was eaten by about 15% of cohort occasionally. A pat of margarine with bread was a common food item eaten by 60% of subjects. None took whole milk drink. Though the actual calcium intake could not be accurately assessed, it was obvious from the food portion size and frequency of intake that the daily calcium intake was not optimal.

19 (38.00%) of the subjects were unable to lower their urine pH below 5.5 after 8 hours of ingesting 0.1 mg/kg of ammonium chloride dissolved in water. They were considered to have incomplete distal Renal Tubular Acidosis (idRTA). The urine pH range was 5.7 to 7.50 with a mean of 6.40(0.09). 31(62.00%) could lower their urine pH below 5.5 and had a urine pH range of 4.62 to 5.48 with a mean of 5.10(0.07) There was a statistical difference p. <0.001 when the two groups urinary pH were compared. See table 2.

Of the 19 patients who were unable to lower their urine pH below 5.5, 13(68.42%) were aged between 3 to 6 years. Of these 13 subjects 8 (75%) were aged between 4 to 6 years. The mean urine 24 hour calcium was 0.12 mmol/kg/day for those able to lower their urine pH below 5.5, while those unable to lower their urine pH below 5.5, it was1.62 mmol/kg/day. See table 2. The 24 hour urine calcium value of 1.47-1.83 mmol/kg/day was observed for the three subjects with the highest urine pH value.

The preloading serum HCO3 observed for those whose pH were more than 5.5 was between 19 to 20 mmol/L while those whose pH were less than 5.5 had a serum HCO3 of 22-24 mmol/L. At 3 hours post loading with NH4CL, those whose urine pH was more than 5.5 had a reduction of serum HCO3 by 3-5 mmol/L to a new range of 14 to 16 mmol/L. see table 2. The lowest starting serum HCO3 of 19 mmol/L and highest reduction to 14 mmol/L at 3 hours post loading was observed in the two subjects with the highest urine pH of 7.01-7.50. For those whose pH was less than 5.5, 75% of them at three hours post loading maintained their initial serum HCO3 concentration. The remaining 25% had only a point reduction from their initial level of serum HCO3 concentration. Comparison of the two urine pH status was significant p < 0.001. The calculated anion gap for all the subjects who had mild acidosis was within normal range 8-12 mmol/L.

For the subjects in cohort B, (see table 3) improvements in all parameters were at par in both subsets of subjects despite the idRTA and by six months all parameters were at their normal ranges. Improvements of clinical features of rickets were also at par in both subset of cohort B.

Unfortunately about 3 of the subjects stopped their use of Shohls solution after healing of rickets was obtained. The solution was stopped by their parents unilaterally despite counseling and they were ultimately lost to follow up. Another four were using their solution but erratically after healing had been obtained.

Nutritional rickets has been associated with reduced calcium intake both in children and even adolescents [2–9]. The study done by Thacher et al [23] that looked analytically at the calcium intake of children with rickets found that dietary calcium intake was low amongst their Nigerian cohort. This observation and the constant finding of hypocalcaemia and not vitamin D deficiency amongst children from other studies [2–9], has given credence to the role of nutritional calcium deficiency in the aetiolgy of rickets. Disturbance of renal regulation of acid-base metabolism causing bicarbonate wasting, alkaline urine and mild acidosis has been observed amongst children with rickets from as far back as in the 1920 s by Burghess et al [24]. What was not stated categorically was if it was another aetiology of rickets in these children. Mankin et al [21] in his study of cohorts with rickets, osteomalacia and renal osteodystrophy observed amongst them bicarbonate wasting and found that unless alkalizing solution was added to therapy large doses of calciferol did not correct their rickets. The recently reported high prevalence of idRTA in adults with osteoporosis made Sharma et al [9] to check similar effect on the height of children. Although these children did not have rickets, they found that children with idRTA were shorter than those without and came to the conclusion that it may have a significant deleterious effect on their growth (height).

idRTA is an entity whose laboratory features is similar to what was observed by Burghess [24] amongst his cohort of children with rickets. Although presence of idRTA was not studied in these children the outcome if it had been done is better imagined. From the present study 38% can be assumed to have idRTA. Those who had the highest urine pH were those with the worst clinical features. They also had the highest urine calcium loss and the lowest serum calcium.

Hypocalcaemia due to nutrition deficiency has been accepted as the most common cause of rickets in the developing tropical country, as vitamin D deficiency rickets is seldom found amongst the children that had been studied [1–8]. More than 90% of the subjects had hypocalcaemia, this was expected taking into consideration their low dietary calcium intake Hypocalcaemia causes secondary hyperparathyroidism which promotes leaching of calcium from the bone and increase loss of calcium from the kidney. The minimal loss of calcium in the urine by the subjects without idRTA despite their calcium deficiency may due to this secondary parathyroid action on the tubule. This action of the parathyroid hormone in combination with the effect of idRTA may have led to the much lower serum calcium, hypercalciuria and subsequently more severe clinical features in the subjects with idRTA. The observation that at urine pH greater than 6.50 clinical features of severe rickets such as windswept deformity, chest deformity, loss of deciduous teeth and tetany became more commonly seen suggested that the degree of severity of idRTA is directly related to that of rickets. Relationship between idRTA and rickets can be further established by the observed response of the subject in cohort A with idRTA to addition of Shols solution to their initial modality 1 therapy. The good response of the subjects in cohort B with idRTA in comparison with those without also reinforced the association of idRTA and rickets. Mankin et al [21] also observed this amongst his cohort.

An important observation made, was the history of rickets amongst the family members of some of the patients in those with severe rickets and idRTA. The approved protocol did not include testing the family members therefore only few of the family members who were willing to perform the loading test did it. It was interesting to find two of the fathers had idRTA with mild bowing of their legs. This raised the possibility of a genetic component to this phenomenon which should be further studied to see if a familial tendency can be established.

The peak age for rickets is 1-3 years and rickets at an older age has been rare therefore its increasing occurrence needs more study. Oduwole et al from the preliminary report from their yet to be published work observed the presence of Vitamin D insufficiency amongst older children and adolescent. A child with vitamin D insufficiency, nutritional calcium deficiency and idRTA, will be more vulnerable to developing rickets. This is an association that requires further study.

The Ammonium chloride loading test is a test that is well tolerated and can be performed easily by a child. Although more studies is needed before idRTA can be associated with development of rickets an advocacy for the performance of this test in conjunction with other investigations performed to identify cause and type of rickets especially by older children with rickets is hereby advanced. Management of children with idRTA by Shol's solution is simple with minimal adverse effect. From the response of the patients, early addition to therapy in those with idRTA hastens improvement and healing. Unrecognized urinary infection is a common cause of morbidity amongst children it must always be tested for. A high urine pH may be secondary to urinary infection with urea-splitting organisms.

Rickets is still very much around and now unexpectedly, being seen in older children. It must be noted that the children with the worst clinical, biochemical and radiological features of rickets and the highest value of urine pH were the older children. Our Cohort showed that idRTA may exist amongst children with rickets and may be worth looking out for especially in older aged children, those with severe clinical features and poor response to therapy.

AOO is a Peadiatric endocrinologist at the College of Medicine, University of Lagos and Lagos University Teaching Hospital, Lagos. OSG is an Orthopaedic surgeon, at the College of Medicine, University of Lagos and Lagos University Teaching Hospital. Lagos. ARA is a Radiologist at College of Medicine, University of Lagos and Lagos University Teaching Hospital, Lagos