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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2021  |  Volume : 32  |  Issue : 5  |  Page : 1470-1474
Distal renal tubular acidosis and nephrocalcinosis as initial manifestation of primary sjögren's syndrome

1 Department of Nephrology, Hippokration General Hospital, Athens, Greece
2 2nd Department of Medicine, Joint Rheumatology Program, School of Medicine - Clinical Immunology - Rheumatology Unit, National and Kapodistrian University of Athens, Athens, Greece

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Date of Web Publication4-May-2022


There is a well-established association between primary Sjögren’s syndrome and distal renal tubular acidosis (dRTA). dRTA is a relatively infrequent manifestation of primary Sjögren’s syndrome which can present with life-threatening electrolyte abnormalities while, in some patients, it could be the first manifestation of the syndrome. We report the case of a 35-year-old woman who presented with unexplained episodes of generalized weakness, severe hypokalemia, nephrocalcinosis, and normal anion gap metabolic acidosis. Subsequent evaluation revealed primary Sjögren’s syndrome as her underlying condition. The patient responded well to potassium supplementation, sodium bicarbonate, and oral prednisolone. After four years of follow-up, there were no other extraglandular manifestations, the renal function remained stable and the acidosis was partially improved without the need for oral bicarbonate. This case demonstrates that dRTA could be the initial manifestation of primary Sjögren’s syndrome and highlights the necessity for increased vigilance for patients presenting with persistent hypokalemia or nephrocalcinosis so that an early diagnosis can be made allowing for better control and prevention of disease progression.

How to cite this article:
Chalkia A, Giannou1 P, Thomas K, Vassilopoulos D, Petras D. Distal renal tubular acidosis and nephrocalcinosis as initial manifestation of primary sjögren's syndrome. Saudi J Kidney Dis Transpl 2021;32:1470-4

How to cite this URL:
Chalkia A, Giannou1 P, Thomas K, Vassilopoulos D, Petras D. Distal renal tubular acidosis and nephrocalcinosis as initial manifestation of primary sjögren's syndrome. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 May 25];32:1470-4. Available from: https://www.sjkdt.org/text.asp?2021/32/5/1470/344770

   Introduction Top

Sjögren’s syndrome is a common autoimmune disease, in which the reported prevalence of renal involvement varies widely, ranging between 2% and 67%.[1],[2] There are two distinct types of kidney involvement one involving the tubulointerstitial space [tubulointerstitial inflammation (TIN)] and the other the glomeruli (glomerulopathy).[3],[4] The manifestations of TIN (the most common lesion) include mild elevation of creatinine, tubular abnormalities such as the Fanconi syndrome, distal renal tubular acidosis (dRTA) (5%–70%), nephrogenic diabetes insipidus, and hypokalemia.[3],[4]

   Case Report Top

A 35-year-old Caucasian woman presented to the emergency department with severe weakness. Her medical history included nephrolithiasis and multiple visits to the emergency department complaining of muscle weakness. An examination of her nervous system revealed that there was proximal muscle weakness (MRC scale 4/5) and that her reflexes were flaccid. There was no evident muscle tenderness or sensory deficit.

Laboratory tests revealed severe hypokalemia [serum potassium (K+) = 2 mmol/L], normochromic and normocytic anemia (hemoglobin = 10 g/dL), serum creatinine = 1.5 mg/dL, estimated glomerular filtration rate = 42 mL/min/1.73 m2 per the Chronic Kidney Disease Epidemiology Collaboration equation, hypophosphatemia (serum phosphate =1.2 mg/dL) and hyperchloremia (serum chloride = 121 mmol/L). The patient had a normal anion gap metabolic acidosis (pH =7.2, HCO3- = 7 mEq/L, AG = 5 mEq/L) with a high urine pH of 7 and the urine anion gap was +34.9 mEq/L (positive value), suggesting dRTA. Plain films of the abdomen showed severe nephroncalcinosis [Figure 1].
Figure 1: Nephrocalcinosis.

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An acidification test with furosemide which showed that the patient failed to reach urine pH <5.3 confirmed the diagnosis of dRTA. A hereditary form of dRTA seemed unlikely due to the delayed appearance and lack of family history. On further questioning, the patient complained for dry eye and dry mouth (sicca symptoms) which was confirmed by an objective test (Schirmer test <2 mm/5 min in each eye).

Other laboratory tests revealed hypergamma-globulinemia (IgG = 2260 mg/dL, normal 700–1600) with normal serum IgG4, positive rheumatoid factor (RF = 54.3 IU/mL, normal <15 IU/mL), antinuclear antibody (ANA = 1:640), anti-Ro/SSA and anti-La/SSB antibodies. Urine sediment was normal, while serum cryoglobulins and immunofixation were negative. Serology for hepatitis B virus, hepatitis C virus, and human immunodeficiency virus viruses were negative. Thyroid, parathyroid function, and Vitamin D levels were within the normal limits. There was no hypercalciuria. A kidney biopsy was not performed due to the potential risk associated with her severe nephrocalcinosis.

The patient underwent a lip biopsy which showed a focal lymphocytic sialadenitis (lymphocytic focus score = 4 foci/4 mm2 of glandular tissue) [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d. The presence of sicca symptoms, the positive anti-SSA antibodies and Schirmer test confirmed the diagnosis of primary Sjögren’s syndrome (total score = 7/9), according to the most recent ACR/EULAR Classification Criteria.[5]
Figure 2: (a-d) Labial salivary gland biopsy showed focal lymphocytic sialadenitis with four lymphocytic aggregates present and no acinar destruction (grade 4, Daniel's scoring system).

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The patient was managed initially with intravenous potassium, bicarbonates, and normal saline. Her condition improved and her weakness receded (MRC scale 5/5). She was also given a short course of glucocorticoids (oral methylprednisolone × 6 months), hydroxychloroquine (200 mg/day), oral sodium bicarbonate (120 mEq/day), and potassium citrate. After six months, she was only on potassium citrate. Four years later, she remains on potassium citrate (partial improvement in acidosis) without any other extra-glandular manifestations or new episodes of nephrolithiasis and normal renal function [Table 1].
Table 1: Initial and posttreatment laboratory findings.

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The authors obtained all appropriate consent forms from the patient for the publication of this case report.

   Discussion Top

dRTA is an uncommon extraglandular manifestation of primary Sjogren’s syndrome. It is most likely due to an immune-mediated injury of the H+-ATPase pump in the intercalated cells of the collecting tubules (responsible for distal proton secretion) that leads to loss of H+-ATPase activity. dRTA can be classified as complete or incomplete; the former is characterized by metabolic acidosis with morning urine pH >5.5 and a positive urinary anion gap. The incomplete form presents with normal serum bicarbonate levels, but urinary pH fails to fall to <5.3 after ammonium chloride loading. The incomplete form is the most frequent.

Increased urinary K+ wasting leading to hypokalemia is the most common electrolyte abnormality in dRTA. Severe undiagnosed hypokalemia may cause muscle weakness or even paralysis[6] that may precede sicca symptoms for months or even years before the final diagnosis of primary Sjogren’s syndrome, as in our case.[7] Most of these patients were women in their 50s and a diagnosis was not made until significant renal dysfunction had occurred. Other dRTA manifestations include nephrolithiasis or osteomalacia (leading to bone fractures). Our patient presented with severe nephrocalcinosis, which is quite a rare manifestation of renal tubular acidosis, especially when associated with primary Sjogren’s syndrome.

Renal biopsy is not mandatory in these patients,[8] but when it is performed may help to rule out other causes of renal dysfunction and assess renal prognosis. IgG-4-related disease is often confused with Sjögren’s syndrome and the differentiation is made largely based on serological and histopathological findings. In 12 patients with TIN secondary to primary Sjogren’s syndrome, Evans et al observed CD4+ T-cell predominance in biopsies, similar to those seen in lip salivary glands and similar lymphocytic infiltrate around renal tubules.[9]

As far as treatment is concerned, glucocorticoids are the cornerstone of treatment for primary Sjogren’s syndrome-associated TIN to prevent interstitial fibrosis and tubular atrophy and improve renal dysfunction based on very few studies.[9],[10] Evans et al[9] included 12 patients treated with a course of prednisone associated with mycophenolate mofetil (11 of 12) or azathioprine (1 of 12) with a median duration of treatment 24 months (interquartile range 24). Interestingly, patients presented a significant response evidenced in their serum creatinine levels (P = 0.02) and estimated glomerular filtration rate. Maripuri et al[10] included 24 patients and demonstrated that a mixed population including patients with primary Sjogren’s syndrome and glomerulopathy effectively responded to prednisone with hydroxychloroquine, cyclophosphamide, or rituximab. Although 14/16 of the patients presented improvement or stabilization of renal function at follow-up, however in the seven patients with dRTA there appeared to be the minimal improvement in acidosis despite immunosuppressive therapy and all of these patients were maintained on oral bicarbonate supplementation.

In our case, renal tubular acidosis was improved partially with the immunosuppressive treatment and the patient released by oral bicarbonate. After four years of follow-up, the patient remains only on potassium citrate. To our knowledge, long-term follow-up in these patients is lacking from the literature on renal function, acidemia, and implications such as episodes of nephrolithiasis. Tubulointerstitial injuries in Sjogren’s syndrome can have minimal response to standard immunomodulatory therapy and these patients usually remain on oral bicarbonate.

In conclusion, as our case illustrates, in patients (especially women in their 50s) presenting with unexplained episodes of hypokalemia, muscle weakness, and nephrolithiasis or nephrocalcinosis the possibility of primary Sjogren’s syndrome-associated dRTA should be explored further by appropriate medical history, physical examination, and laboratory testing. Diagnostic delays may lead to severe consequences for patient’s health.

   Acknowledgments Top

We would like to thank Eleftheria Lakiotaki, MD, PhD, Pathologist, Academic Scholar and Scientific Collaborator, National and Kapodistrian University of Athens First Department of Pathology for providing the histological pictures.

Conflict of interest: None declared.

   References Top

Mariette X, Criswell LA. Primary Sjögren’s syndrome. N Engl J Med 2018;379:97.  Back to cited text no. 1
Bossini N, Savoldi S, Franceschini F, et al. Clinical and morphological features of kidney involvement in primary Sjögren’s syndrome. Nephrol Dial Transplant 2001;16:2328-36.  Back to cited text no. 2
Ren H, Wang WM, Chen XN, et al. Renal involvement and follow up of 130 patients with primary Sjögren’s syndrome. J Rheumatol 2008;35:278-84.  Back to cited text no. 3
Goules A, Masouridi S, Tzioufas AG, Ioannidis JP, Skopouli FN, Moutsopoulos HM. Clinically significant and biopsy-documented renal involvement in primary Sjögren syndrome. Medicine (Baltimore) 2000;79:241-9.  Back to cited text no. 4
Shiboski CH, Shiboski SC, Seror R, et al. 2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary Sjögren’s Syndrome: A consensus and data-driven methodology involving three international patient cohorts. Arthritis Rheumatol 2017;69:35-45.  Back to cited text no. 5
Yılmaz H, Kaya M, Özbek M, ÜUreten K, Safa Yildirim İ. Hypokalemic periodic paralysis in Sjogren’s syndrome secondary to distal renal tubular acidosis. Rheumatol Int 2013;33:1879-82.  Back to cited text no. 6
Pun KK, Wong CK, Tsui EY, Tam SC, Kung AW, Wang CC. Hypokalemic periodic paralysis due to the Sjögren syndrome in Chinese patients. Ann Intern Med 1989;110: 405-6.  Back to cited text no. 7
Ramos-Casals M, Brito-Zerón P, Seror R, et al. Characterization of systemic disease in primary Sjögren’s syndrome: EULAR-SS Task Force recommendations for articular, cutaneous, pulmonary and renal involvements. Rheumatology (Oxford) 2015;54:2230-8.  Back to cited text no. 8
Evans RD, Laing CM, Ciurtin C, Walsh SB. Tubulointerstitial nephritis in primary Sjögren syndrome: Clinical manifestations and response to treatment. BMC Musculoskelet Disord 2016;17:2.  Back to cited text no. 9
Maripuri S, Grande JP, Osborn TG, et al. Renal involvement in primary Sjögren’s syndrome: A clinicopathologic study. Clin J Am Soc Nephrol 2009;4:1423-31.  Back to cited text no. 10

Correspondence Address:
Aglaia Chalkia
Department of Nephrology, Hippokration General Hospital, Athens
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1319-2442.344770

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