Primary Sjögren Syndrome (pSS) is a systemic autoimmune disease characterized by epithelitis most commonly affecting the exocrine glands. However, characteristic extraglandular features are associated with pSS and can even precede the occurrence of sicca symptoms. Electrolyte abnormalities in pSS are largely a consequence of renal involvement. Though in retrospective series the prevalence is around 5%, in prospective series where renal disease is specifically looked for higher prevalence has been reported. Tubulointerstitial nephritis (TIN) is the most commonly reported pathology and lymphocytic infiltration in tubular epithelium and interstitium is similar to the salivary gland pathology in pSS. The resulting tubular dysfunction results in disorders of electrolytes, acid-base imbalance and urine concentrating ability.
Salient features of tubular disorders causing electrolyte imbalances in pSS are depicted in Table 1. Nevertheless, other common causes of electrolyte abnormalities such as vomiting, diarrhea, diuretic use, chronic laxative abuse, toxin exposure and endocrine disorders must be looked for. Younger patients should also be evaluated for hereditary causes of tubular dysfunction. It should always be kept in mind that renal tubular disease and resulting electrolyte and acid-base imbalances can be the presenting manifestation of pSS. Therefore, it is essential to have dialogue with internal medicine/endocrinology/nephrology colleagues and prime them to screen all patients with renal tubular dysfunction for pSS even in the absence of sicca symptoms.
Table 1 Tubular Disorders causing electrolyte imbalance in Primary Sjögren Syndrome
Legends: *Prospective studies; $Fanconi ; N- normal ; **Only case reports ; GS-Gitelman syndrome;
RTA-Renal tubular acidosis; ABG- Arterial blood gas;
Bartter syndrome is rare in pSS. Clinical features are similar to Gitelman except for presence of hypercalciuria and absence of hypomagnesemia
Renal tubular disease in pSS can also be occult or present with such as life threatening hypokalemic paralysis, muscle weakness, cramps, renal stones and pseudo fractures. Timely detection can prevent complications. Hence, in every patient with pSS one needs to actively look for renal disease by doing a minimum of these tests - sodium, potassium, chloride, bicarbonate, creatinine, calcium, phosphate, urine pH and urinalysis. Even if these tests are normal, in case of suspicion, ultrasonography and arterial blood gas analysis needs to be performed. If renal tubular acidosis (RTA) is suspected for instance in a patient with renal stones but normal blood pH the possibility of incomplete RTA needs to be considered. The diagnosis can be established by giving an additional oral acid load (0.1 mg/kg of ammonium chloride or simultaneous furosemide(40mg) and fludrocortisone (1 mg) and monitoring urine pH hourly(8). Failure to acidify urine (urine pH<5.3) is diagnostic of distal RTA.
The following urinary testing is recommended in a patient with suspected tubular dysfunction in a patient with pSS - a 24h urinary volume, proteinuria, glycosuria, creatininuria, calciuria, phosphaturia, citraturia, urinary sediment and culture. Urinary tract infection with proteus species and other urea-splitting organisms should be excluded in those with high urine pH.
Hypokalemia is the most common electrolyte disturbance in the setting of pSS. Potassium replacement should follow standard guidelines for treating hypokalemia. Those with potassium <2.5mEq/L or presence of arrhythmias, marked muscle weakness, or rhabdomyolysis must be treated with intravenous potassium correction. Detailed history including drug history and possibility of gastrointestinal loss should be looked for. Routine blood tests, electrolytes including magnesium, uric acid, renal function tests, thyroid function tests and urine analysis must be done in all cases. First step in the evaluation is to determine the site of potassium loss (cellular shift, renal or gut) by measuring urinary potassium. An approach to hypokalemia resulting from urinary loss is depicted in Figure 1. Urinary loss can be estimated by measuring transtubular potassium gradient(TTKG), spot urine potassium:creatinine ratio or 24 hour urine potassium. Once renal potassium loss is established, the next important step is to check arterial blood gas analysis. Further investigations should be done to establish the different entities as given in Table 1.
Figure 1 Flow diagram shows approach to a patient with hypokalemia due to renal potassium loss
K+-Potassium; Cr-creatinine; Cl- Chloride; Mg-Magnesium; BP-Blood pressure; TTKG- Transtubular potassium gradient= Urine Potassium x Serum Osmolality/ Serum Potasium x Urine osmolality; AG-anion gap; NAG-Non-anion gap; ATN-Acute tubular necrosis;GS-Gitelman syndrome; BS- Bartter syndrome; dRTA- distal RTA; pRTA- proximal RTA.
Potassium supplementation must be done in severe hypokalemia prior to initiation of alkali supplementation. The goal of alkali therapy is to normalise serum bicarbonate levels (22 to 24 mEq/L). Correction of chronic acidemia prevents the deleterious effect on bone and muscle and decreases stone formation. This can be done by sodium bicarbonate or potassium citrate. Citrate may be more preferred due to less gastric adverse effects and potassium citrate is beneficial in those with stones and corrects hypokalemia as well (9). However sodium bicarbonate is cheaper. Higher alkali dosing is required in proximal as compared to distal RTA. Distal RTA generally requires alkali replacement of 1-3 mEq/kg/d, whereas 10-15 mEq/kg/d is required in proximal RTA. The total dose is split over 3-4 divided doses. The available preparations and dose equivalence for bicarbonate is as below.
1 g of sodium bicarbonate tablet is equal to 11.5 mEq of HCO3-
Potassium citrate solutions contain 1-2 mEq/mL of HCO3-
Shohl's solution contains sodium citrate-citric acid and contains 1 mEq/mL of HCO3-
Dose of alkali and potassium needs to be titrated based on weekly monitoring initially and less frequently once the levels are stabilised. In addition, phosphate and vitamin D supplementation may be required in those with bone disease.
There is no consensus on indication for renal biopsy in all pSS patients with abnormal electrolytes. Isolated mild electrolyte imbalance with normal eGFR and no proteinuria may be treated with correction of electrolytes alone and close monitoring of urinalysis and renal function tests (10). However, in all the below mentioned scenarios, renal biopsy must be considered (10).
In the absence of prospective/randomised trials, there are no clear recommendations on the management of kidney disease in pSS. TIN is the most common pathophysiology underlying tubular disorders. However it should be borne in mind that all TIN is not mild or benign. In most cases, features of chronicity such as interstitial fibrosis and tubular atrophy are seen. Insidious and silent progression of TIN can lead to CKD. Currently, it is unclear if there is a window of opportunity to identify and treat tubular dysfunction in pSS and reverse electrolyte imbalance and further prevent occurrence of complications. Data from retrospective studies suggest that short courses of steroids (≥0.5 mg/kg) are useful in case of TIN and could improve or stabilise eGFR even in presence of interstitial fibrosis in the renal biopsy (10,11). Immunosuppressive agents (azathioprine, mycophenolate, cyclophosphamide, rituximab) have been added upfront or if there is relapse on steroid tapering. However, addition of immunosuppressive agents including rituximab did not prove to have any added advantage in a large retrospective study (11). Unlike glomerulonephritis in lupus, the treatment effects are less dramatic and it is unlikely that proteinuria and renal dysfunction normalise completely due to chronicity that has set in by the time diagnosis is made.