Systematic review and case report: Systemic lupus erythematosus with renal tubular acidosis

Abstract Immune profile assessment—particularly for SLE—and subsequent specific therapy are beneficial in patients with persisting unexplained hyperkalemic or hypokalemic paralysis, especially in case of isolated RTA.


| INTRODUCTION
Although the glomerular involvement in systemic lupus erythematosus (SLE) is widely described in the literature, renal tubular acidosis (RTA) has been rarely reported. We aimed to report a case of RTA in the setting of SLE as well as systematically review all the previously reported cases.
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that predominantly affects females with an overall 8:1 female-to-male ratio; this ratio varies with age to be 7:1 and 15:1 in the elderly and adults, respectively. 1,2 SLE is a multiorgan disease with a characteristic renal involvement. While glomerular involvement has been widely reported, interstitial involvement (eg, in the form of renal tubular acidosis (RTA)) has been rarely reported; attributable to potassium imbalance in almost all cases. Interstitial diseases used to manifest either prior to or ensuing the diagnosis of SLE. Distal RTA (type 1) together with the inability to concentrate urine, hyporeninemic hypoaldosteronism, and reduced secretion of urinary acid have been observed. [3][4][5] Accordingly, the diagnosis of SLEis challenging since its criteria may not appear simultaneously. Moreover, RTA has a multitude of differential diagnoses ranging from autoimmune diseases (Sjogren syndrome and rheumatoid arthritis) 6 to other nonautoimmune etiologies like hypercalciuria and drug associations with ifosfamide, amphotericin B, and lithium carbonate. 7 RTA is characterized by serum potassium imbalance in the setting of normal serum anion gap metabolic acidosis and positive urinary anion gap. 8 When hypokalemia is the case, the condition may be complicated by weakness of the respiratory muscles up to respiratory arrest; the presentation of RTA is commonly misdiagnosed as hypokalemic periodic paralysis. 9 Nonetheless, the persistence of hypokalemia in line with the negative family history of hypokalemic periodic paralysis favors RTA diagnosis. 7 The reason why practices misdiagnose the autoimmune disorders presenting as RTA is that these cases may initially present as hypokalemic paralysis. Of note, the RTA is diagnosed via a combination of hyperchloremic metabolic acidosis and abnormally alkaline urine (PH > 5.5).
Herein, this article systemically depicts the previously reported RTA cases in the setting of SLE together with presenting a new similar case. Although the primary Sjögren's syndrome had been proved to be a common cause for RTA, we would investigate such relation in SLE patients. 10 In August 2018, an EMBASE, Web of Science, PubMed, and Scopus computerized systematic search was conducted encompassing the terms "systemic lupus erythematosus" and "tubular acidosis OR renal tubular acidosis." All human studies with relevant data on the association between SLE and RTA were included with no restriction on study design, age, or publication year. Two independent authors screened the yielded articles for inclusion/exclusion. Supplementing the electronic search, the reference lists of the relevant studies were surveyed for further relevance.

| CASE REPORT
In November 2017, an 18-year-old female patient presented to the neuropsychiatry department with a week history of progressive lower limb weakness. The patient reported a history of large joints (knee and elbow) arthralgia, for which she received occasional analgesics. There was no malar rash or oral ulcers by examination. She recalled no family history of a similar complaint and had a negative history of illicit drug use or alcohol consumption. Also, she reported a past history of splenectomy as a therapeutic measure for immune thrombocytopenia. The patient had vital signs within normal range. Laboratory evaluation revealed severe hypokalemia (1.5 mmol/L). Electrolyte assessment (serum Na, mg, ionized ca) and thyroid function tests (TSH = 1.18; FT4 = 2.1; FT3 = 1.34) were within normal. She had no history of vomiting or diarrhea. Moreover, electromyography (EMG) demystified mild acute inflammatory demyelinating polyradiculoneuropathy (AIDP). Eventually, the patient was diagnosed with hypokalemic periodic paralysis. Accordingly, she received potassium chloride (100 meq; IV infusion) and was eventually discharged after improvement.
Four months later, the patient was readmitted with a similar attack. Again, the blood workup revealed metabolic acidosis with a potassium level of 2.28 mEq/L and a normal serum anion gap (11 mEq/L). Causes of hypochloremic acidosis like severe diarrhea were excluded. Urine analysis showed alkaline urine (pH 7.5). The patient condition ameliorated after  receiving intravenous sodium bicarbonate and potassium infusion. The diagnosis of hypokalemia secondary to distal RTA was considered; then, she was discharged after being scheduled for follow-up in the general internal medicine clinic. In our patient, we did not perform urinary anion gap calculation since the patient was diagnosed with RTA based on normal serum anion gap, metabolic acidosis, exclusion of vomiting and diarrhea, high urinary potassium. Correction of metabolic acidosis was conducted by NaHco3 which confirmed that it is distal RTA not proximal one. Ultrasound revealed no nephrolithiasis in our patient. Throughout her follow-up, the patient was persistently hypokalemic (K level 2-3 mEq/L) with a mild metabolic acidosis (blood pH = 7.17, HCO 3 -=10.5 mmol/L) and urinary potassium level of 25.8 mEq/L/day. Serum aldosterone and diurnal variation of cortisol were normal. Complete blood count showed persistent leucopenia (TLC 2800-3500/cumm). Serum urea and creatinine were within normal. The 24-hour urinary protein was 1540 mg. The autoimmune workup revealed positive both Anti-double stranded DNA antibody (anti-dsDNA) (225 IU/mL) and antinuclear antibody (ANA) titer (1/300). Complement proteins C3 and C4 were markedly consumed: 55 mg/dL and 8 mg/dL, respectively. Renal biopsy revealed lupus nephritis, the mesangioproliferative type. The persistent hypokalemic weakness improved dramatically on administering a dose of 40 mg prednisolone daily. Also, the serum potassium level and acidosis normalized with administering sodium bicarbonate and potassium. This emphasized the diagnosis of secondary distal RTA due to systemic lupus erythematosus. A search of databases mentioned above revealed a total of 196 relevant articles. Of which, only 26 case reports fit our selection criteria. So, a total of 26 cases were included, including the presented case ( Figure 1).
Data from 26 case reports entailing 33 patients were extracted and analyzed. The mean age of the population in these reports was 28.7 years. The overall number of females was 30 (90.9%), and they presented with a multitude of manifestations. Twenty-six cases were eventually diagnosed with type-one/distal RTA whereas only six patients were diagnosed with type-four RTA; our case was type 1 as well. The symptoms at presentation varied greatly between isolated neurologic weakness of the lower limbs, as evident in our case, progressive weakness of both upper and lower limbs, generalized flaccid paralysis, or generalized weakness with massive weight loss. Also, the onset of diagnosis of SLE and RTA in relation to each other had a great variation: SLE has been diagnosed in 13 cases at a point varying from one week to 10 years before diagnosing RTA. Whereas eight cases were diagnosed with SLE at points ranging from one month to six years after diagnosing RTA. Simultaneous diagnosis of SLE and RTA was evident in 11 patients. Of note, our patient was diagnosed with SLE during the RTA follow-up (Table 1).
Most articles have reported PH-related and potassium values. Serum PH was within normal range (7.35-7.45  Histopathological exams revealed membranous glomerulonephritis in five patients and diffuse proliferative glomerulonephritis in other five patients. However, the result of kidney biopsy was not reported in 14 patients. Fifteen patients reported no complications, while hypokalemic paralysis and nephrocalcinosis detected in four and eight cases, respectively. Moreover, renal failure was noticed in four patients. Most of the patients received immunosuppressive drugs, steroids, and/ or electrolytes. Only one patient reported death complication while most of the patients (n = 24) improved or at least showed remission of symptoms then were discharged. The outcome was not clearly declared in seven cases ( Table 2).

| DISCUSSION
The literature has reported few cases of RTA in the context of SLE, especially the distal type (type 1) with fewer reports on the association with proximal RTA (type 2). The diversity of systematic manifestations of SLE, and the challenge in recognizing and approaching such manifestations prior to establishing SLE's diagnosis necessitate a thorough assessment to provoke clinical suspension in similar settings. In our review, we reported a rare case of type 1 RTA presenting with lower limb weakness prior to diagnosing SLE. While renal glomerular injury is the major finding in lupus nephritis, renal tubular injury has been rarely reported. 11 Each type of RTA is a separate entity with unique characteristics and therapeutic measures. Type 1 (distal RTA) is mostly associated with hypokalemia while (type 4) is associated with hyperkalemia. 12 Distal RTA is mostly a genetic disorder that presents in childhood; however, it occurs in adolescence secondary to other disorders like auto-immune dysfunctions. 13 RTA has a wide range of presentations either neurologic (isolated lower limb weakness, generalized weakness, quadriparesis, etc), nonspecific GI tract symptoms (epigastric pain, weight loss, joint pain, etc), or even the symptoms of the primary disorder (eg, discoid rash or proteinuria in case of SLE). Accordingly, the diagnosis of secondary RTA and its related primary etiology is troublesome. While RTA is mainly a biochemical diagnosis, the treatment is not restricted to correcting/balancing the biochemical values/electrolyte level, but rather it includes treatment of the cause, and is dependent on recognizing the type and pathology of the acidosis. For example, practices should consider early steroid use for SLE and most autoimmune diseases to curtail recurrences. Therefore, it is important to thoroughly investigate any renal symptoms or general symptoms that depict renal injury to avoid any delays in treatment or any misdiagnoses. In addition, it is vital to rule out any plausible causes of renal tubular acidosis prior to the initiation of any therapy.
Of the 36 reported SLE-RTA associations, our case, as well as 27 previous cases, had type 1 RTA. That is confirmed by the dramatic reversal of the serum potassium and acid levels to normal values with sodium bicarbonate and potassium administration. Similar to eight other reported cases, our patient was diagnosed with SLE following RTA diagnosis, which made it harder to initially consider SLE as the primary etiology. Based on our case, the diagnosis of SLE in a previously diagnosed RTA patient established on the ground of significant proteinuria that led to immunology workup (anti-double stranded DNA antibody, rheumatoid factor (RF), antinuclear antibody (ANA) titer, and complement proteins C3 and C4 levels).

| CONCLUSION
As the immune profile confers a considerable prebiopsy evaluation of the primary disorders, clinicians are recommended to consider assessing it in patients with persisting unexplained hyperkalemia or hypokalemic paralysis; moreover, we recommend an emphasis on autoimmune diseases, especially SLE, in patients with isolated RTA. Further studies are needed to investigate the strength of correlation and to better understand the underlying etiology of such association.