Secondary distal renal tubular acidosis and sclerotic metabolic bone disease in seronegative spondyloarthropathy

Abstract

Adults with distal renal tubular acidosis (dRTA) commonly present with hypokalaemia (with/without paralysis), nephrolithiasis/nephrocalcinosis and vague musculoskeletal symptoms. All adults with dRTA should be thoroughly evaluated for systemic diseases, certain medications and toxins. The leading cause of acquired or secondary dRTA in adults is primary Sjögren syndrome (SS); however, other collagen vascular diseases (CVDs) including seronegative spondyloarthropathy (SSpA) may at times give rise to secondary dRTA. Metabolic bone disease is often encountered in adults with dRTA, and the list includes osteomalacia and secondary osteoporosis; sclerotic metabolic bone disease is an extremely rare manifestation of dRTA. Coexistence of dRTA and sclerotic bone disease is seen in primary dRTA due to mutation in CA2 gene and acquired dRTA secondary to systemic fluorosis. Primary SS and SSpA, rarely if ever, may also lead to both secondary dRTA and osteosclerosis. Circulating autoantibodies against carbonic anhydrase II and possibly calcium sensing receptor may explain both these features in patients with CVD.

Background

Distal renal tubular acidosis (dRTA), arising out of impaired acid-secreting ability of the α-intercalated cells, is broadly classified into two types: inherited (primary) and acquired (secondary).¹ Primary dRTA is usually encountered in children, and mutations of ATP6V1B1, ATP6V0A4, SLC4A1 and CA2, which encode for B1 and A4 subunits of the hydrogen ATPase pump, chloride bicarbonate or anion exchanger 1 (AE1) and carbonic anhydrase (CA) II, respectively, are contemplated in the pathogenesis. In addition, mutations in FOXI1, WDR72 and ATP6V1C2 genes have recently been identified in patients with primary dRTA. On the other hand, acquired dRTA develops secondary to a variety of systemic diseases like autoimmune conditions (Sjögren syndrome (SS), systemic lupus erythematosus, chronic active hepatitis, primary biliary cirrhosis), metabolic disorders (Wilson’s disease, hypercalciuria), medications (amphotericin B, foscarnet, lithium) and environmental toxins. Secondary dRTA, though may manifest at any age, is frequently encountered in adults. The biochemical hallmark of dRTA is hyperchloremic normal anion gap metabolic acidosis and urine pH of more than 5.5 during systemic acidosis. In addition, majority of such patients have hypokalaemia (with/without muscle weakness), nephrolithiasis and/or nephrocalcinosis, and metabolic bone disease. With rare exceptions, nephrolithiasis and/or nephrocalcinosis typically discriminates dRTA from proximal renal tubular acidosis (pRTA). Metabolic bone disease in dRTA is primarily an effect of chronic systemic acidosis. Alterations in bone mineral metabolism, commonly encountered in dRTA, include skeletal resorption and resultant mobilisation of calcium and phosphate, hypercalciuria, hypophosphataemia and defective mineralisation of the osteoid matrix. Consequently, osteomalacia (and rickets in children) and osteoporosis are often seen in these patients; osteosclerosis possibly is an extremely rare manifestation of dRTA.² Osteosclerosis typically is seen in primary dRTA due to mutation in CA2, where cerebral calcification (basal ganglia, thalamus, grey-white matter junction), mental retardation and possibly isolated pRTA (without Fanconi syndrome) coexist.³ Sclerotic bone disease and secondary dRTA have rarely been encountered in fluorosis and primary SS, but never been reported in seronegative spondyloarthropathy (SSpA) to date.^{4 5}

Case presentation

A farmer in his early 40s presented to us with a history of recurrent episodes of hypokalaemic flaccid quadriparesis for the preceding 5 years. Most of the times the weakness involved both his proximal and distal group of muscles making him bedbound. He used to get hospitalised for intravenous potassium supplementation; however, weakness improved spontaneously on few occasions. He was also diagnosed to have bilateral renal stones, twice in the last 5 years, which was managed conservatively. The patient also reported low back pain (LBP) for the preceding 3 years that was insidious in onset, used to get worse during later half of night and early morning, and often improved after 1–2 hours of physical activity or with administration of non-steroidal anti-inflammatory drugs (NSAIDs). He was also being treated for left-sided de Quervain’s tenosynovitis with a single intralesional corticosteroid injection. On further enquiry, he admitted to have generalised aches and pains, polydipsia and polyuria for about 4–5 years. He did not report dry eyes and mouth and denied chronic use of any medication. There was no history of peripheral joint pain or skeletal fractures, and his family history was unremarkable.

Clinical examination revealed the following: height: 160 cm; weight: 66 kg; body mass index: 25.8 kg/m² (overweight category); blood pressure: 120/70 mm Hg. Trousseau’s sign and Chvostek’s sign were negative. There was no spinal deformity and tenderness. Schober’s test was negative. Chest expansion measured on maximal inspiration after forced maximal expiration at the level of fourth intercostal space was 5 cm.

The rest of his systemic examination was unremarkable.

Investigations

Complete blood count, erythrocyte sedimentation rate (ESR) (11 mm at 1st hour) and high-sensitivity C reactive protein (CRP) (0.314 mg/dL) were normal. Arterial blood gas analysis documented metabolic acidosis (pH: 7.303, PCO₂: 27.7 mm Hg, bicarbonate: 13.7 mmol/L) with normal serum anion gap (13 mmol/L (reference range: 12±4)). Relevant investigations have been summarised in table 1. Enthesitis and pseudofractures were evident on X-rays (figures 1 and 2).

Table 1.

Summary of investigations

Blood parameters
	Patient’s value	Reference range
Fasting plasma glucose	88	<100 mg/dL
Serum albumin corrected calcium	8.71	8.4–10.2 mg/dL
Serum phosphorus	2.53	2.3–4.7 mg/dL
Serum potassium	3.12	3.5–5.1 mmol/L
Serum sodium	137	135–145 mmol/L
Serum chloride	110	95–105 mmol/L
Serum bicarbonate	14	18–28 mmol/L
Serum creatinine	1.1	0.72–1.25 mg/dL
Estimated glomerular filtration rate (eGFR) (Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation)	81.2 mL/min/1.73 m2
Serum 25 hydroxy vitamin D	16.8	>20 ng/mL
Plasma-intact parathyroid hormone (iPTH)	17	14–72 pg/mL
Serum alkaline phosphatase	86	40–130 units/L
Urine parameters
Spot urine sodium	79 mmol/L	Not established
Spot urine potassium	11 mmol/L	Not established
Spot urine chloride	72 mmol/L	Not established
Urine pH during arterial pH of 7.3	6.8	<5.5
Urine anion gap ((Na++K+)−Cl−)	18 mmol/L (positive)	Negative
Spot urine phosphorus	21.2 mg/dL	Not established
Spot urine creatinine	46.85 mg/dL	Not established
Tubular reabsorption of phosphate	76.4	85%–95%
Tubular maximum reabsorption of phosphate/GFR	1.93	2.2–3.4 mg/dL
Spot urine β2-microglobulin	>20 000	0–300 ng/mL
24-hour urine volume	103	>50 mL/kg/day is defined as polyuria
24-hour urine creatinine	19.8	≥15 mg/kg/day suggests adequate collection
24-hour urine calcium	5	>4 mg/kg/day suggests hypercalciuria
24-hour urine potassium during serum potassium of 3.12 mmol/L	41	<15 mmol/day
Imaging
Skeletal survey	Increased density of the vertebral bones (figure 3) Widened and sclerotic margins of bilateral sacroiliac joints (figure 1) Pseudofracture over medial cortex of proximal left femur (figure 1) Pseudofracture over medial aspect of midshaft of right radius (figure 2) Interosseous membrane calcification of both forearms (figure 4)
Ultrasonography of the kidneys	Bilateral medullary nephrocalcinosis
Dual energy X-ray absorptiometry scan for bone mineral density (BMD)
	BMD (g/cm2)	T score	Z score
Left distal one-third radius	0.593	- 0.4	−0.4
Lumbar vertebrae (L1–L4)	1.877	+5.5	+5.9
Total right hip	1.297	+1.6	+2.2
Total left hip	1.098	+0.01	+0.07
CT scan of the brain	No evidence of intracranial calcification
MRI of sacroiliac joints (figure 2)	Margins show irregularity along with marrow signal changes suggesting bilateral sacroiliitis

Figure 1.

X-ray of the pelvis (anteroposterior view) showing irregular margin of the sacroiliac joints (right>left) and pseudofracture over left proximal femur (yellow arrow). Note calcification over the tendon insertions (white arrows) suggesting enthesitis.

Figure 2.

Pseudofracture over right radius (black arrow) and ossification of interosseus membranes (yellow arrows) in both forearms.

The patient was thoroughly evaluated for secondary causes of dRTA. Autoimmune markers for collagen vascular disease, autoimmune hepatitis and rheumatoid factor were negative. Schirmer’s test did not reveal any evidence of dry eyes. Histopathological examination of minor salivary gland specimen demonstrated focus score of less than 1, suggesting absence of focal lymphocytic sialoadenitis. Keeping in mind a high possibility of fluorosis, urine fluoride level was measured thrice in three different machines. Urine fluoride levels were 0.17 mg/L (reference: 0.1–1 mg/L), 0.76 mg/L (reference: 0.1–1 mg/L) and 0.34 ppm (reference: <1 ppm). Serum fluoride was undetectable (reference: 0.02–0.08 mg/L). Dental evaluation was unremarkable. Serum heavy metal screening was also normal. Whole exome sequencing for mutation of the known genes associated with primary dRTA including CA2 was negative.

Differential diagnosis

Urine pH of 6.8 and positive urinary anion gap (UAG) during simultaneous normal anion gap metabolic acidosis confirmed the diagnosis of dRTA. Medullary nephrocalcinosis and osteomalacia (pseudofractures) (figures 1 and 2) were consistent with dRTA, and coexistent proximal tubular dysfunction was evident in the form of raised urinary β₂-microglobulin and renal phosphate wasting as demonstrated by a low tubular reabsorption of phosphate and low tubular maximum reabsorption of phosphate (Tmp)/glomerular filtration rate (GFR) even with normal serum phosphate level. The age of the patient prompted us to look for secondary aetiologies of dRTA, SS in particular. Systemic fluorosis was an important differential diagnosis as the patient had increased bone density (figure 3) and calcification of interosseous membranes (figure 2). Mutation in CA2 gene was also considered in view of dRTA, proximal tubular dysfunction and osteosclerosis. However, deficiency of CA enzyme is associated with isolated pRTA, and not Fanconi syndrome.⁶ This patient had low molecular weight proteinuria and inappropriate phosphaturia, suggestive of more generalised proximal tubular dysfunction.

Figure 3.

X-ray of the lumbar spine showing increased density of the vertebrae.

Treatment

The patient was initially prescribed syrup potassium citrate, which delivers 2 mEq of K⁺ and 2 mEq of HCO3− in each millilitre, 30 mL per day in three divided dosages. Following normalisation of serum potassium, he was switched to tablet sodium bicarbonate (500 mg), two tablets four times per day; 1000 mg of sodium bicarbonate tablet delivers 12 mEq of bicarbonate. He was also put on etoricoxib (90 mg two times per day) and physiotherapy for LBP. Etoricoxib at this dose was continued for initial 1 month and gradually reduced to two tablets a week.

Outcome and follow-up

The patient noticed significant improvement in his symptoms and his blood parameters (pH, potassium) got normalised with the supportive treatment.

Discussion

Hyperchloremic normal anion gap metabolic acidosis, failure to acidify urine (urine pH remained above 5.5) during systemic acidosis and positive UAG confirmed dRTA in this patient. A strong inverse correlation between UAG and urinary ammonium (NH_4⁺) excretion was reported in earlier studies. Though UAG has long been used as a surrogate marker of urinary NH_4⁺, which in turn reflects distal tubular H⁺ secretion, the utility of UAG as an indirect measure of urinary NH_4⁺ excretion has recently been questioned.⁷ However, we could not measure urinary NH_4⁺, and relied on UAG instead. Recurrent nephrolithiasis, past episodes of hypokalaemic quadriparesis and nephrocalcinosis were also consistent with the diagnosis of dRTA. Elevated urinary β₂-microglobulin, phosphaturia and absence of glycosuria likely reflected potentially reversible proximal tubular dysfunction secondary to hypokalaemia and metabolic acidosis of dRTA.^{8 9} A thorough search for the known aetiologies of secondary dRTA, however, was negative. However, he was suffering from SSpA.

Two unusual features, which we came across in this patient, were coexistent SSpA and sclerotic bone disease. SSpA is a group of diseases characterised by inflammation of axial (spondylitis) skeleton, appendicular (arthritis) joints and at times enthesis (enthesitis). According to the Assessment of Spondyloarthritis International Society (ASAS) criteria, inflammatory LBP persisting for more than 3 months and imaging confirmation of sacroiliitis with onset at a relatively younger age (<45 years), even in absence of raised ESR and CRP, confirm SSpA.¹⁰ Though inflammatory markers are often elevated in SSpA, ESR and CRP levels may be normal in the early phase of the disease.¹¹ Clinical (inflammatory LBP for 3 years and response with NSAID) and imaging features (sacroiliitis) (figure 4), thus, were suggestive of SSpA in our patient as per ASAS criteria. To the best of our knowledge, secondary dRTA has never been reported in SSpA so far. However, in a survey-based analysis, SSpA was found to be an independent risk factor for nephrolithiasis.¹² Patients enrolled in that study were not evaluated by the investigators, hence underlying dRTA, incomplete form in particular, as a possible aetiology of renal stones was not excluded in that cohort. In addition, inflammatory bowel disease is associated with SSpA, and dRTA has been reported in Crohn’s disease.¹³ Some medications used for treating SSpA, notably leflunomide and NSAIDs like ibuprofen, have rarely been reported to be causally associated with RTA, which is completely reversible on drug discontinuation.^{14 15} The latter, if used in very high dose, inhibits CA II enzyme and may precipitate dRTA. However, our patient used NSAID only infrequently and denied use of leflunomide in the past. In addition, though an overlap of various susceptibility genetic loci between ankylosing spondylitis and few immune-mediated inflammatory and autoimmune diseases has been demonstrated, similar association between primary dRTA and SSpA has not been reported.¹⁶ dRTA in our patient, thus, appeared to develop secondary to SSpA.

Figure 4.

MRI of pelvis demonstrating T2 hyperintensities around both sacroiliac joints, suggesting sacroiliitis. The changes are more pronounced on right side (white arrows) compared with left (yellow arrows).

The other perplexing feature was osteosclerosis coexisting with dRTA. A number of environmental toxins, heavy metals in particular, are associated with RTA and sclerotic bone disease. While cadmium, lead and mercury often lead to pRTA and hypophosphataemic osteomalacia, fluorosis is an established aetiology of secondary dRTA.^{4 17 18} Chronic exposure to cadmium is rarely associated with spinal hyperostosis in patients with pRTA.¹⁹ Toxic levels of lead, copper and bismuth may give rise to radio dense transverse metaphyseal bands. Manifestations of skeletal fluorosis range from osteomalacia to osteosclerosis.²⁰ A combination of osteomalacia (pseudofractures) and sclerotic vertebrae along with interosseous membrane ossification in this patient with adult-onset dRTA led to a strong possibility of underlying fluorosis. However, repeated estimations of urine and serum fluoride concentrations were normal.

Elevated bone density at the lumbar spine, both with increased and decreased bone mass at the femoral neck, has been reported in patients with SSpA and hypophosphataemia due to renal phosphate wasting.^{21 22} However, underlying RTA, as a possible aetiology of hypophosphataemia, was not searched for in those patients. Hypophosphataemia per se can also give rise to enthesitis and sacroiliitis mimicking SSpA.¹⁹ However, despite inappropriate renal loss of phosphate, serum phosphate was normal in this patient, ruling out any possible aetiological role of hypophosphataemia in sacroiliitis or sclerotic bone disease.

Increased density of axial skeleton has been seen in rare patients with ankylosing spondylitis, a variety of SSpA.²³

Bone resorption as well as new bone formation occur either simultaneously or sequentially in close proximity to the affected skeletal sites in SSpA.²⁴ Bone morphogenic protein and Wnt signalling pathways are involved in pathogenesis of such aberrant bone formation, and possible roles of noggin and sclerostin have recently been suggested in such neo-ossification in SSpA. The sclerotic bone disease we came across in this patient with SSpA might be due to the above mechanisms, but it fails to reach a unifying diagnosis.

Very recently, sclerotic bone disease has been reported in a middle-aged woman with primary SS and dRTA, probably the first one in medical literature.⁵ Undetected anti-SSA and anti-SSB antibodies and negative labial gland biopsy refuted the diagnosis of primary SS as a cause of osteosclerosis and dRTA in our patient. However, we noticed a number of biochemical similarities between these two cases notably in low normal serum calcium (8.8 mg/dL and 8.7 mg/dL), low TmP/GFR, hypercalciuria and β₂-microglobulinuria. Serum intact parathyroid hormone (iPTH) was suppressed (9.43 pg/mL) in the former case, while our patient had low normal serum iPTH (17 pg/mL) despite vitamin D deficiency (25 hydroxy vitamin D (25OHD): 16.8 ng/mL). Though the authors of that particular paper did not discuss the possible underlying mechanism(s) of such association, we propose the following postulations to explain dRTA and osteosclerosis in both SS and SSpA.

Secondary dRTA in various autoimmune diseases is due to interfering autoantibody directed against one or more proteins (transporters, enzymes) involved in distal renal tubular acidification mechanisms. Antibody against CA II has also been suggested playing a role in pathogenesis of RTA in mouse model of SS.²⁵ In the absence of mutation in CA2 gene and use of exposure to drugs like topiramate and acetazolamide, which inhibit CA II, we postulate that autoantibody against CA II might have led to dRTA and increased bone density in both these patients.

Hypercalciuria in these patients results from increased mobilisation of calcium from bones, and decreased calcium reabsorption in renal tubules secondary to chronic metabolic acidosis. Metabolic acidosis upregulates claudin 14 expression via calcium sensing receptor (CaSR), which in turn inhibits claudin 16 and claudin 19 expression, the latter two are required for paracellular reabsorption of calcium in thick ascending limb of loop of Henle.²⁶ Patients with autosomal dominant hypocalcaemia with hypercalciuria due to activating mutation of CaSR frequently have high normal to elevated bone mineral density (BMD).²⁷ Circulating autoantibodies against CaSR have been found in autoimmune hypoparathyroidism and also in SS.^{28 29} Acquired Bartter’s syndrome due to circulating autoantibodies against one or more channels located in the thick ascending limb of loop of Henle is well established.^{30 31} Individuals with dRTA frequently demonstrate biochemical features of secondary hyperparathyroidism. These two patients might have stimulating autoantibodies against CaSR, which theoretically can explain low normal calcium, hypercalciuria, suppressed (in the former) or low normal iPTH (despite low 25OHD in the latter) and increased BMD. To conclude, our patient had SSpA as the primary disease. He probably developed circulatory autoantibody against CA II, which in turn led to secondary dRTA and osteosclerosis. In addition, he might also had activating autoantibody against CaSR, which contributed to increased bone density, hypercalciuria and low-normal iPTH despite vitamin D deficiency. This gives us a unifying diagnosis (Occam’s razor). Alternatively, the patient could have SSpA and coexistent acquired idiopathic dRTA: sclerotic bone disease was secondary to infrequently encountered neo-ossification related to SSpA, per se (Hickam’s dictum).

Learning points.

• All adults with distal renal tubular acidosis (dRTA) should be evaluated thoroughly for underlying systemic diseases and toxins. Collagen vascular disease, Sjögren syndrome in particular, is the leading cause of secondary dRTA. Patients with seronegative spondyloarthropathy may also have underlying secondary dRTA.

• Metabolic bone diseases, commonly encountered in dRTA, are osteomalacia, rickets and secondary osteoporosis. Sclerotic bone disease is rarely encountered in patients with dRTA.

• Metabolic bone disease in dRTA is multifactorial. Acidosis-mediated exaggerated osteoclastic bone resorption, hypercalciuria, secondary hyperparathyroidism, hypophosphataemia and abnormal mineralisation of the bone matrix contribute to the pathogenesis. Circulating autoantibodies against various renal tubular proteins (transporters, enzymes) possibly play an aetiological role in abnormal urine acidification and sclerotic bone disease in dRTA, secondary to autoimmune diseases.

• Patients with dRTA and coexistent sclerotic bone disease should be evaluated for genetic mutation of carbonic anhydrase enzyme, systemic fluorosis, primary Sjögren syndrome and seronegative spondyloarthropathy.

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