Osteomalacia complicating renal tubular acidosis in association with Sjogren's syndrome

Zohra El Ati; Lilia Ben Fatma; Ghada Boulahya; Lamia Rais; Madiha Krid; Wided Smaoui; Hedi Ben Maiz; Soumaya Beji; Karim Zouaghi; Fatma Ben Moussa

doi:10.4103/1319-2442.139944

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CASE REPORT

Year : 2014 | Volume : 25 | Issue : 5 | Page : 1072-1077

Osteomalacia complicating renal tubular acidosis in association with Sjogren's syndrome

Zohra El Ati¹, Lilia Ben Fatma¹, Ghada Boulahya¹, Lamia Rais¹, Madiha Krid¹, Wided Smaoui¹, Hedi Ben Maiz², Soumaya Beji¹, Karim Zouaghi¹, Fatma Ben Moussa¹
¹ Nephrology Department, La Rabta Hospital, Tunis, Tunisia
² Laboratory of Renal Pathology, LR001SP, Tunisia

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Date of Web Publication

2-Sep-2014

Abstract

Renal involvement in Sjogren's syndrome (SS) is not uncommon and may precede other complaints. Tubulointerstitial nephritis is the most common renal disease in SS and may lead to renal tubular acidosis (RTA), which in turn may cause osteomalacia. Nevertheless, osteomalacia rarely occurs as the first manifestation of a renal tubule disorder due to SS. We herewith describe a 43-year-old woman who was admitted to our hospital for weakness, lumbago and inability to walk. X-ray of the long bones showed extensive demineralization of the bones. Laboratory investigations revealed chronic kidney disease with serum creatinine of 2.3 mg/dL and creatinine clearance of 40 mL/min, hypokalemia (3.2 mmol/L), hypophosphatemia (0.4 mmol/L), hypocalcemia (2.14 mmol/L) and hyperchloremic metabolic acidosis (chlorine: 114 mmol/L; alkaline reserve: 14 mmol/L). The serum alkaline phosphatase levels were elevated. The serum levels of 25-hydroxyvitamin D and 1,25-dihydroxy vitamin D were low and borderline low, respectively, and the parathyroid hormone level was 70 pg/L. Urinalysis showed inappropriate alkaline urine (urinary PH: 7), glycosuria with normal blood glucose, phosphaturia and uricosuria. These values indicated the presence of both distal and proximal RTA. Our patient reported dryness of the mouth and eyes and Schirmer's test showed xerophthalmia. An accessory salivary gland biopsy showed changes corresponding to stage IV of Chisholm and Masson score. Kidney biopsy showed diffuse and severe tubulo-interstitial nephritis with dense lymphoplasmocyte infiltrates. Sicca syndrome and renal interstitial infiltrates indicated SS as the underlying cause of the RTA and osteomalacia. The patient received alkalinization, vitamin D (Sterogyl ^®), calcium supplements and steroids in an initial dose of 1 mg/kg/day, tapered to 10 mg daily. The prognosis was favorable and the serum creatinine level was 1.7 mg/dL, calcium was 2.2 mmol/L and serum phosphate was 0.9 mmol/L.

How to cite this article:
El Ati Z, Fatma LB, Boulahya G, Rais L, Krid M, Smaoui W, Maiz HB, Beji S, Zouaghi K, Moussa FB. Osteomalacia complicating renal tubular acidosis in association with Sjogren's syndrome. Saudi J Kidney Dis Transpl 2014;25:1072-7

How to cite this URL:
El Ati Z, Fatma LB, Boulahya G, Rais L, Krid M, Smaoui W, Maiz HB, Beji S, Zouaghi K, Moussa FB. Osteomalacia complicating renal tubular acidosis in association with Sjogren's syndrome. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2020 Nov 28];25:1072-7. Available from: https://www.sjkdt.org/text.asp?2014/25/5/1072/139944

Introduction

Sjogren's syndrome (SS) is a chronic disorder of the exocrine glands with associated lymphocytic infiltrates of the affected glands. ^[1] The most common renal disease in SS is tubule interstitial nephritis, responsible for renal tubular acidosis (RTA) in 20% of the patients. ^[2]

Type-I distal RTA (RTA type-I) is characterized by non-anion gap hyperchloremic acidosis and hypokalemia. Type-II proximal RTA (RTA type-II) may occur secondary to generalized dysfunction of the proximal tubules and is associated with increased urinary excretion of glucose, uric acid, phosphate, amino acids and protein. ^[3] Osteomalacia rarely occurs as the first manifestation of renal tubule disorder due to SS. ^[4] Herein, we report a patient with RTA-induced osteomalacia caused primarily by SS.

Case Report

A 43-year-old woman presented with history of proximal muscle weakness, lumbago and inability to walk of one year's duration. Clinical examination revealed no fever and the blood pressure was 100/60 mmHg. She had no goiter or symptoms of thyroid dysfunction. She had a waddling gait and reported pain upon palpation of the bones. Neuromuscular function was normal. Urinary strip examination showed glycosuria without proteinuria or hematuria and inappropriate alkaline urine (urinary pH: 7, serum pH: 7.37). X-ray of the long bones showed bone demineralization [Figure 1]. Neither nephrocalcinosis nor nephrolithiasis was noted.

Figure 1: Bony demineralization in humerus (left and right).

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Laboratory investigations revealed serum sodium of 140 mEq/L (normal: 135-145 mEq/ L), potassium of 3.2 mEq/L (normal: 3.6-5.0 mEq/L), phosphate of 0.4 mmol/L (normal: 0.8-1.4 mmol/L), calcium of 2.14 mmol/L (normal: 2.2-2.6 mmol/L) and hyperchloremic metabolic acidosis [chlorine: 114 mEq/L (normal: 98-109 mEq/L); the alkaline reserve was 14 mEq/L (normal: 22-29 mEq/L)], anion gap was 13 mEq/L (normal: 8-16 mEq/L) and serum albumin was 40 g/dL (normal: 38-47 g/ dL). Arterial blood gas showed a pH of 7.37, partial pressure of carbon dioxide (pCO ₂ ) of 22 mm Hg, partial pressure of oxygen (pO ₂ ) of 100 mm Hg and bicarbonate (HCO ₃ ) of 14 mEq/L. The serum alkaline phosphatase levels were elevated at 270 IU/L (normal: 30-120 IU/L) with normal liver function tests. The serum levels of 25-hydroxy vitamin D was low at <7 μg/L (normal: 30-80) and serum 1-25 dihydroxy vitamin D was borderline at 25 μg/L (normal: 25-66) and the parathyroid hormone level was 70 pg/mL (normal: 7-65 pg/ mL). Serum-free T ₄ and TSH were, respectively, 0.83 ng/dL (normal: 0.7-1.5 ng/dL) and 1.88 μIU/mL (normal: 0.1-4.5 μIU/mL).

Urinalysis showed proteinuria of 0.42 g/day, phosphaturia of 693 mg/day (normal: 400-1300 mg/day), uricosuria of 444 mg/day (normal: 250-750 mg/day) and urinary calcium of 84 mg/day (normal: 93-248 mg/day). Glycosuria (1.83 g/L) was found on urinalysis with normal blood glucose. Urinary potassium excretion was relatively high (51 mEq/day) despite the presence of hypokalemia. These values indicated the presence of both distal and proximal RTA, and, based on the above data (radiologic and biologic investigations), the diagnosis of osteomalacia related to RTA was arrived at.

During evaluation, our patient also reported dryness of the mouth and eyes. Schirmer's test showed xerophthalmia. She had chronic kidney disease with serum creatinine of 2.3 mg/ dL and creatinine clearance of 40 mL/min using the Cockroft and Gault formula. On electrophoretic analysis, γ-globulin was elevated at 23 g/L. The sediment rate was 75 mm in the first minute.

Immunologic work-up showed positive anti-nuclear antibodies in a titer of 1/100 with a homogeneous fluorescence pattern, negative cryoglobulin and negative antibodies to SSA and SSB. Serology of hepatitis C and Latex Waaler Rose were negative. An accessory salivary gland biopsy showed changes corresponding to stage IV of Chisholm and Masson score. The kidney biopsy showed diffuse and severe tubulo-interstitial nephritis with dense lymphoplasmocyte infiltrates [Figure 2] and [Figure 3].

Figure 2: Kidney biopsy (optic microscopic HE stain ×30): Diffuse and severe tubulo-interstitial nephritis with dense lymphoplasmocyte infiltrates.

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Figure 3: Kidney biopsy (optic microscopic HE stain ×30): Intact glomerulus; -interstitium showing diffuse lymphoplasmocyte infiltration.

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Dryness of the mouth and eyes, the serological tests as well as biopsies of accessory salivary gland and kidney revealed that she had SS. Thus, our patient had both distal and proximal renal tubular disorder and osteomalacia, which may be attributed to diffuse tubulo-interstitial nephritis related to primary SS.

The patient received alkalinization, vitamin D (Sterogyl ^®), calcium supplements and steroids at 1 mg/kg/day, tapered to 10 mg daily. Her muscle weakness improved rapidly and the inability to walk disappeared gradually. After a 49-month follow-up period, no relapse of lumbago and pain of the bones was observed. The serum creatinine level was at 1.7 mg/dL, calcium was at 2.2 mmol/L, serum phosphate was at 0.9 mmol/L and alkaline reserve was at 22 mmol/L. Radiologic lesions were stable.

Discussion

Renal involvement is not rare in patients with SS, although rates of involvement vary widely across studies. Chronic tubulointerstitial nephritis is the usual pattern of kidney disease. Acquired RTA may be caused by lupus, hepatitis, treatment with amphotericin B, toluene toxicity and chronic pyelonephritis and SS. ^[5],[6],[7] In this case, the pathophysiological mechanisms remain unclear and cell apoptosis may play a part. ^[8] Studies have also suggested a key role for the Fas/Fas ligand system in the gland destruction that characterizes SS. ^[9] Overt or latent RTA, caused by the autoimmune tubulo-interstitial nephropathy, is a common extra-glandular manifestation occurring in 33% of SS patients. ^[10] The underlying mechanism is related to deficient H+-ATPase pump function. ^[11]

RTA is characterized by the presence of hyperchloremic metabolic acidosis with normal anion gap. The serum potassium may be normal, low or high, depending on the type of RTA. SS is most frequently associated with type-II RTA. Type-I RTA has been designated "distal RTA," as the establishment of a large pH gradient between urine and blood is a function of the distal nephron. Our patient had a normal anion gap, hyperchloremic acidosis, hypokalemia and alkaline urine in the presence of systemic acidosis, confirming a diagnosis of type-I RTA. Proximal RTA (type-II RTA) is caused by an inability to reabsorb bicarbonate in the proximal tubules. It may occur secondary to generalized dysfunction of the proximal tubules and can be associated with increased urinary excretion of glucose, uric acid, phosphate, amino-acid and protein, as shown in [Table 1]. ^[3],[5] In our case, although the urinary amino-acid excretion test was not performed, urinary excretion of phosphate with low levels of serum phosphate, urinary excretion of protein and glucosuria associated with normal glucose are suggestive of proximal tubular involvement. The proximal tubule dysfunction most often occurs in association with the Fanconi syndrome, light chain nephropathy, multiple myeloma or drug exposure.

Table 1: Distinguishing features of the different types of renal tubular acidosis.

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Osteomalacia is a metabolic bone disease characterized by an alteration of bone mineralization, frequently related to alterations in vitamin D or phosphate metabolism. Osteomalacia is still common, with the leading causes being nutritional deficiencies and intestinal diseases. The typical biochemical findings are low levels of serum calcium, low serum phosphate except in cases of renal osteodystrophy, low urinary calcium, low vitamin D concentration in blood and high alkaline phosphatase.

Radiological appearances include bone demineralization, pseudo-fractures and Looser's zones. However, osteomalacia caused by RTA rarely occurs as the presenting manifestation of SS. Furthermore, it is far more common with proximal than with distal RTA. ^[4] Our patient had a combined picture of distal and proximal tubular dysfunction. In proximal RTA, renal phosphate loss is the principal contributing factor to osteomalacia, while in distal RTA, a combination of acidosis and hypophosphatemia are implicated, and coexisting vitamin D deficiency may be an aggravating factor.

The radiological and analytical findings in osteomalacia vary, and may be confounded with other processes, especially osteoporosis. Indeed, osteoporosis is the most common skeletal disorder in the elderly, being characterized by impaired bone strength and increased risk of fracture. The levels of serum calcium or phosphate are unaffected and the osteoporosis is confirmed on the basis of densitometry criteria. ^{[12],[13],[14]}

The mechanisms leading to osteomalacia may include bone buffer release in response to metabolic acidosis and acidosis-induced dampening of osteoblast alkaline phosphatase activity. ^[15] Its diagnosis ultimately rests on the histologic finding of wide uncalcified osteoid seams in the bone. However,as in our case, the diagnosis can be inferred by finding characteristic radiological abnormalities and elevation of serum bone-specific alkaline phosphatase levels. ^[16] Furthermore, the pathogenesis of osteomalacia induced by RTA in SS is related to an autoimmune tubulo-interstitial nephropathy.

Over the years, several different criteria sets have been proposed for the classification of SS. In 2002, the American and European Consensus Group classification criteria (AECG-criteria) defined rules for classifying patients with primary or secondary SS. For patients without any potentially associated disease, primary SS may be defined in the presence of any four of the six items, which is indicative of primary SS, as long as either item IV (histo-pathology) or VI (serology) is positive or in the presence of any three of the four objective criteria items (i.e., items III, IV, V and VI) [Table 2]. ^[17],[18] In our case, the diagnosis of SS was made by the subjective ocular and oral symptoms (items I and II), positive Shirmer's test (item III) and focal sialoadenitis observed in accessory salivary gland biopsy (item V).

Table 2. American–European Consensus Group Criteria. Revised international classification criteria for Sjögren's syndrome.^[17]

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Glucocorticoid treatment has been used successfully in patients with osteomalacia related to RTA. ^{[8],[19],[20],[21]} However, correcting the acidosis by giving alkalinizing agents with supplemental vitamin D may be sufficient. ^[15],[22] Our case report is a valuable reminder that osteomalacia can reveal SS and that high-dose corticosteroid therapy may improve renal involvement by SS as well as osteomalacia-related clinical and biologic features.

Conclusion

Latent renal tubular disease is common is SS, but is rarely complicated by osteomalacia. Primary SS could be a differential diagnosis in women with acute weakness, mild hypokalemia and osteomalacia. In spite of the rarity of osteomalacia revealing SS, this complication should be taken into consideration in the diagnosis of SS with RTA.

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