Distal renal tubular acidosis (DRTA) is characterized by hyperchloremic metabolic acidosis with a normal anion gap and an inability of the kidneys to acidify urine below a pH of 5.3. In some cases, DRTA may present in an incomplete form, where patients remain asymptomatic and systemic acidosis is not immediately evident. This form of DRTA requires specific urinary acidification tests for diagnosis. The prevalence of DRTA in patients with autoimmune diseases, especially in its incomplete form, is not well established. Recent literature has reported several case studies linking DRTA to autoimmune conditions such as Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE), revealing key clinical and biochemical alterations associated with the condition (1). Additionally, understanding the underlying pathogenic mechanisms and exploring treatment options remain crucial for the management of DRTA in autoimmune diseases (2, 3).

Renal Tubular Acidosis (RTA) encompasses a group of disorders that impair the kidney's ability to regulate acid-base balance, resulting in metabolic acidosis and electrolyte disturbances. The condition is classified into four types: Type 1 (distal), Type 2 (proximal), Type 3 (mixed), and Type 4. Although determining the prevalence of RTA in autoimmune diseases is challenging, autoimmune conditions such as SS and SLE are frequently associated with RTA. Clinical manifestations of RTA in these patients are often nonspecific and include muscle weakness, fatigue, and electrolyte imbalances, which can complicate diagnosis. Notably, RTA tends to be more prevalent among females, reflecting the gender differences commonly observed in autoimmune disorders (1, 2, 3).

Objective

• To comprehensively analyse the demographic, clinical, and serological profiles, as well as treatment modalities, among patients presenting with renal tubular acidosis (RTA) associated with autoimmune disorders at a tertiary care centre in South India.

To systematically compare the identified profiles and treatment strategies in autoimmune-related RTA cases with those arising from non-autoimmune etiologies, thereby shedding light on the distinctive features and potential variations in the clinical management of RTA within this diverse patient population.

A retrospective study was undertaken at the Rheumatology Department of SRMC/SRIHER, Chennai, from March 2018 to March 2023.

Inclusion Criteria

• Screening of patients aged 18 years and above diagnosed with renal tubular acidosis (RTA).
• Identification of RTA patients involved the assessment of their arterial blood gas (ABG) profile, revealing the presence of normal anion gap metabolic acidosis along with urinary pH levels exceeding 5.5.
• Incomplete RTA patients were identified based on clinical features strongly suggestive of RTA, such as hypokalemia or nephrocalcinosis, and hyperchloremia without accompanying acidosis.

Other investigations included:

• Hematological parameters: Complete hemogram and urinary analysis with pH.
• Biochemical assessments: Renal function tests, liver function tests, and serum and urinary electrolytes.
• Immunological tests: ANA pattern (Immunofluorescence), LIA-immunoblot (Nephelometry), C3, C4, DCT, RF (Nephelometry), anti-CCP (ELISA), cryoglobulins (qualitative), ESR, and CRP.

Ophthalmic tests: Schirmer’s test, tear breakup time (TBUT), and minor salivary gland lip biopsy.

This retrospective study (March 2018–March 2023) included 52 patients with renal tubular acidosis (RTA), of which 27 had autoimmune-related RTA associated with Sjögren’s syndrome (SS), systemic lupus erythematosus (SLE), or overlap syndrome. The remaining 25 patients had non-autoimmune causes.

Potassium supplementation was the main treatment for all RTA patients, while DMARDs were administered in autoimmune cases with extra-glandular involvement.

Among non-autoimmune cases, diabetes insipidus, obstructive uropathy, and CKD were the most common causes. These findings underscore the importance of distinguishing autoimmune vs. non-autoimmune RTA in clinical practice.

Table 1: Demographic Profile of Autoimmune-Related RTA Patients (N=27)

All autoimmune-related RTA patients were female, highlighting a strong female predisposition, especially in Sjögren’s syndrome (SS). The median age at presentation was 40 years, indicating middle-aged adults are commonly affected.(Table 1)

Graph 1: Distribution of RTA Subtypes Among Autoimmune Patients (N=27)

Type 1 (Distal RTA) was the most prevalent form (96.3%) in autoimmune cases. This is consistent with its strong association with Sjögren’s syndrome (SS). Type 3 (Mixed RTA) was rare, with only one case (3.7%) reported. No cases of Type 2 (Proximal RTA) or Type 4 (Hyperkalemic RTA) were found in this cohort.(Graph 1)

Table 3: Clinical Features of Autoimmune-Related RTA Patients (N=27)

Fatigue (85.1%) was the most common clinical symptom, significantly affecting quality of life. Oral and ocular sicca symptoms (51.8% and 44.4%) were frequent, reinforcing the link between RTA and Sjögren’s syndrome (SS). Acute flaccid paralysis (48.1%) was a notable presentation, likely due to severe hypokalemia. Extra-renal manifestations like vasculitis (11.1%) and neuropathy (3.7%) were observed, but were less frequent.(Table 2)

Graph 2 : Serological and Laboratory Investigations of Autoimmune-Related RTA Patients (N=27)

All autoimmune RTA patients (100%) tested positive for SSA (Anti-Ro) antibodies, further supporting the strong association with Sjögren’s syndrome (SS). SSB (Anti-La) positivity was found in 81.4%, reinforcing an autoimmune basis. Schirmer test abnormalities (81.4%) confirmed significant ocular involvement. Low complement (C3: 11.1%, C4: 0%) was uncommon, indicating that complement activation is not a dominant feature in these patients.

Elevated ESR (33.3%) and CRP (18.5%) suggest mild inflammatory activity in some cases. Low vitamin D (62.9%) was frequently observed, which may contribute to bone mineralization issues in these patients.(Graph 2)

Renal tubular dysfunction is a known complication in various autoimmune diseases. In our study, the prevalence of renal tubular acidosis (RTA) in Sjögren’s syndrome (SS) was 11%. A study by Oana Ungureanu et al. reported a prevalence of SS ranging from 6.8% to 70%(1). Dr. Sandhya et al.’s Asian systemic review in 2022 showed a prevalence of 63.9%. In her 2014 study with a cohort of 380 SS patients, 25 (65.7%) had RTA. A Chinese cohort reported that 73.1% of SS patients developed RTA(3).

In our study, the commonly affected age group was between 20 to 60 years, with a median age of 40 years. The eldest patient was 60 years old. This median age was consistent with the study by Yuvying Zhang et al. Asian studies reported median ages of 37 and 32 years, respectively(2,4). A study from China reported early-onset SS with RTA(5). The median age in the study by Jain et al. was 34.9 years(6). This suggests that SS with RTA presents earlier than SS alone(8).

A significant observation in our study was the female predominance. Large cohort studies reported that all patients were female(4,3,6). Other studies showed male involvement, with 2 males in a cohort of 37 patients(1) and 4.5% male prevalence in another study(2). This reflects the well-documented 10:1 female-to-male ratio in SS. The small sample size in our study may also contribute to the female predominance. The association of RTA in SS in males and its severity remains an area for further research.

Distal RTA (95.2%) was the most common subtype in our study, followed by mixed RTA in one patient. None of the patients had type 2 or type 4 RTA. In contrast, an Asian survey reported three cases of mixed RTA(2). Other studies have shown a predominance of type 1 RTA (88.1%), followed by type 3 RTA (8.6%), type 2 RTA (1.8%), and type 4 RTA (0.6%)(2). Distal RTA is attributed to immune-mediated deposits, lymphocytic infiltration, chronic interstitial nephritis, and genetic factors that make the distal tubules particularly vulnerable.

In our study, one patient (47.1%) had a low estimated glomerular filtration rate (eGFR), suggestive of interstitial nephritis, though a biopsy was not performed. This is slightly higher than the 35% prevalence observed in the Asian population(2). This patient had risk factors, including antibody positivity and hypergammaglobulinemia, but lacked other risk factors such as long disease duration at presentation, which was a significant factor in the development of interstitial nephritis in the Vivino et al. study(9).

Fatigue (85.7%) was the most common symptom in our study, followed by oral sicca (52.3%). However, hypokalemic paralysis (47.6%) was the most common cause of hospital admission. Hypokalemic paralysis was not observed in non-autoimmune causes of RTA. Fatigue was reported by only 40% of patients in the Jain et al. study(6), highlighting the subjective nature of fatigue assessment and emphasizing the need for the ESSPRI scale in SS patients.

A higher rate of presentation with hypokalemic paralysis (64%) was reported in the Sandhya et al. study(4). Several studies have also identified hypokalemic paralysis as a presenting feature(1,2). Rao N et al. and Jain A et al. reported hypokalemic paralysis in 40% and 54.2% of cases, respectively(6,10). These findings underscore the necessity of screening for RTA secondary to autoimmune diseases.

Oral sicca (52.3%) was more common than ocular sicca (42.8%), with a Schirmer’s test positivity rate of 80.9% in our study. In an Asian study, oral sicca was present in 63.7%, with a higher ocular testing positivity rate (77.3%)(2). Objective ocular testing was essential for diagnosing more SS cases, whereas, in our study, most patients presented with oral sicca, and ocular testing aided in confirming symptoms.

Renal calculi were observed in 4.76% of patients with primary SS. In contrast, hypocalcemia and renal lithiasis were seen in 20 out of 37 patients in the study by Ungureanu et al.(1). In the Sandhya et al. study, pseudofractures were observed despite normal vitamin D3 levels, a finding not seen in our study(4).

Purpura was observed in two patients due to SS-associated vasculitis. Risk factors include hypergammaglobulinemia, cryoglobulinemia, low complement levels, rheumatoid factor positivity, lymphoma, and long disease duration. In our study, one patient had rheumatoid factor positivity and hypergammaglobulinemia, while the other had only hypergammaglobulinemia. Other risk factors were not present.

Bilateral painless parotidomegaly was seen in 23.8% of patients, except for one case of unilateral painful parotid enlargement. Painful parotidomegaly led to an earlier presentation and diagnosis of RTA in affected patients.

Only one patient in our study had interstitial lung disease (ILD) of the NSIP pattern along with RTA. There are no existing references specifically linking ILD with RTA in SS.

Neurological involvement was observed in one patient who presented with altered sensorium, and MRI revealed temporo-parietal infarcts. This neurological impairment was suspected to be secondary to SS vasculitis or vasculopathy in the background of herpes encephalitis. Another patient had peripheral neuropathy presenting as painful, bilateral, symmetrical length-dependent neuropathy. However, risk factors such as long disease duration, old age, cryoglobulin positivity, and hypergammaglobulinemia were not seen in this patient. Patients with vasculitis, neuropathy, and pulmonary involvement are more likely to develop RTA(13).

Immunologically, SSA+ > SSB+ antibodies were the most commonly detected, found in all patients, similar to the findings in the Sandhya et al. study(1,2,6). RO52 was positive in six cases in our study. C3 and C4 levels remained within normal limits, similar to the findings of Laing et al.(5). There was no association between C4 levels, cryoglobulinemia, and RTA in our study. Hepatitis C virus (HCV) testing was negative. Anti-dsDNA antibodies and direct Coombs test (DCT) positivity were observed in five patients. Elevated ESR was noted in nine patients, whereas only four exhibited raised CRP levels. Hypergammaglobulinemia was seen in four patients.

Low vitamin D levels (61.9%) were observed in our study, compared to 39% in another study(4). This highlights the need for treating vitamin D deficiency as a correctable cause of fatigue.

Non-autoimmune causes of RTA included diabetes insipidus (the most common), obstructive uropathy, and chronic kidney disease (CKD). This comparison highlights the importance of distinguishing autoimmune from non-autoimmune causes during diagnosis.

Among autoimmune RTA cases, our study included one case of systemic lupus erythematosus (SLE) with lupus nephritis and one case of overlap syndrome. Tubulointerstitial nephritis (TIN) followed by glomerulonephritis are common renal pathologies in SS with more severe extraglandular manifestations(14). However, none of our patients underwent renal biopsy. Renal biopsy is warranted to guide treatment, especially in cases with predominant interstitial nephritis requiring corticosteroids or immunosuppressants.

The mainstay of treatment for RTA patients was potassium supplementation. Disease-modifying antirheumatic drugs (DMARDs) were administered in cases with extraglandular involvement. Hydroxychloroquine was given to all SS patients with polyarthralgia.

Two patients with purpura (negative for cryoglobulins) received corticosteroids (0.5 mg/kg) followed by tapering doses and mycophenolate mofetil (MMF). Monthly cyclophosphamide for seven months was used in a patient with peripheral neuropathy and NSIP lung disease. Central nervous system involvement was treated with methylprednisolone pulse therapy (500 mg/day for five days), followed by oral steroids and MMF. This patient also received antiviral therapy for herpes simplex virus encephalitis. Peripheral nervous system involvement was observed in a patient with ILD.

Renal tubular acidosis (RTA) is a significant but underrecognized complication of Sjögren’s syndrome (SS), with a prevalence of 11% in our study. Distal RTA was the most common subtype, and hypokalemic paralysis was the leading cause of hospitalization. Female predominance was evident, aligning with global trends in SS. Fatigue, oral sicca, and parotidomegaly were frequently observed symptoms, while neurological and pulmonary involvement were less common. Immunological markers, particularly SSA and SSB positivity, were consistent with previous studies.

The findings highlight the importance of early screening for RTA in SS patients, especially those presenting with fatigue, sicca symptoms, and unexplained hypokalemic paralysis. Vitamin D deficiency was prevalent and should be addressed as a modifiable factor contributing to fatigue. While renal biopsy was not performed in our study, it remains a valuable tool for diagnosing and guiding treatment in cases of suspected tubulointerstitial nephritis.

Management primarily involved potassium supplementation, with immunosuppressive therapy reserved for cases with extraglandular involvement. The association of RTA with systemic manifestations such as vasculitis, neuropathy, and interstitial lung disease underscores the need for a multidisciplinary approach. Future studies with larger cohorts and renal histopathology correlations are needed to enhance our understanding of renal involvement in SS and refine treatment strategies.

Conflict of interest: Nil

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