Salt-losing tubulopathy worsening the prognosis of renal sarcoidosis

We report the case of a 30-year-old north African male, the 7th child of consanguineous parents, initially treated in Algeria from 2006 to 2010. At the age of 14 years, he was admitted to hospital for fatigue, pallor and weight loss. Blood pressure was normal. Eye examination showed iridocyclitis. Blood tests confirmed hepatitis and acute kidney injury [AKI] with serum creatinine [Scr] of 11 mg/dl (Reference [ref] range 0.7–1.2 mg/dl) (Fig. 1). Considering a possible diagnosis of tubulointerstitial nephritis and uveitis (TINU) syndrome, high doses of local and i.v. methylprednisolone followed by oral doses were started, leading to a significant but transient improvement of kidney (Scr 1.7 mg/ dl) and liver parameters. One year later, the patient experienced recurrent iridocyclitis and AKI (Scr 11.4 mg/dl) accompanied by severe hypokalemia (2.9 mEq/l; ref. range 3.5–4.8), hyponatremia (132 mEq/l; ref. range 136–145), hypochloremia (80 mmol/l; ref. range 98–107) and metabolic alkalosis (36 mmol/l; ref. range 22–29), suggesting an acquired Bartter-like syndrome (Fig. 1B). Indomethacin administration and potassium supplementation were initiated. A first kidney biopsy showed noncaseating granulomas and tubulointerstitial infiltrates (Fig. 2A–C). Intravenous corticosteroids improved kidney function (nadir of Scr 1.3 mg/dl). The diagnosis of sarcoidosis had been suggested in 2009 on the basis of a very high level of angiotensin converting enzyme (193 U/L; ref. range 12–68). In 2010, the patient was admitted to our department. Indomethacin was discontinued due to hepatitis and renal failure. Hypokalemia, hypercalcemia and hyponatremia were treated by replacement of fluids and electrolytes. Pituitary disorders and primary hyperaldosteronism were ruled out by hormonal tests; autoimmune tests were negative. Oral corticosteroids (prednisolone 16 mg/day) and potassium supplements were maintained. A liver biopsy and a second kidney biopsy were performed. Extensive tubulointerstitial nephritis and a liver granuloma were detected, confirming the diagnosis of systemic sarcoidosis (Supplemental material). In 2017, a third episode of AKI (Scr increased to 5 mg/ dl) with hypercalcemia (2.93 mmol/l) and a very high level of 1.25 dihydroxy-vitamin D (268 ng/l) occurred, suggesting sarcoidosis relapse. No sign of nephrocalcinosis was detected at imaging. Over the last 10 years, seven intensive care unit (ICU) admissions for severe hyponatremia with life-threatening neurological complications, including seizures, confusion and behavior disorders, were required (Fig. 1B). Extensive neurological tests were performed, and neurosarcoidosis was ruled out. However, chronic kidney disease worsened, leading to hemodialysis initiation in September 2020. * Anis Abu Ayyach anis.abuayyach@chu-brugmann.be

A first kidney biopsy showed noncaseating granulomas and tubulointerstitial infiltrates ( Fig In 2010, the patient was admitted to our department. Indomethacin was discontinued due to hepatitis and renal failure. Hypokalemia, hypercalcemia and hyponatremia were treated by replacement of fluids and electrolytes. Pituitary disorders and primary hyperaldosteronism were ruled out by hormonal tests; autoimmune tests were negative. Oral corticosteroids (prednisolone 16 mg/day) and potassium supplements were maintained. A liver biopsy and a second kidney biopsy were performed. Extensive tubulointerstitial nephritis and a liver granuloma were detected, confirming the diagnosis of systemic sarcoidosis (Supplemental material).
In 2017, a third episode of AKI (Scr increased to 5 mg/ dl) with hypercalcemia (2.93 mmol/l) and a very high level of 1.25 dihydroxy-vitamin D (268 ng/l) occurred, suggesting sarcoidosis relapse. No sign of nephrocalcinosis was detected at imaging.
Over the last 10 years, seven intensive care unit (ICU) admissions for severe hyponatremia with life-threatening neurological complications, including seizures, confusion and behavior disorders, were required (Fig. 1B). Extensive neurological tests were performed, and neurosarcoidosis was ruled out.
However, chronic kidney disease worsened, leading to hemodialysis initiation in September 2020.

Lessons for the clinical nephrologist
Sarcoidosis is a multisystem granulomatous disease of unknown origin; it may be triggered by environmental factors (such as infection, drug toxicity) in individuals with a genetic predisposition [1,2]. Sarcoidosis may affect any organ, but mostly involves lungs and lymph nodes; besides the typical histological finding of noncaseating granulomatous interstitial nephritis, kidney manifestations are uncommon and may be underreported, and can include calcium homeostasis disorders, glomerular disease, tubular dysfunction, obstructive and vascular uropathy [1][2][3][4].
The present case illustrates how the diagnosis of systemic sarcoidosis with renal involvement is often delayed. The first diagnostic hypothesis was TINU syndrome because of ocular findings (granulomatous iridocyclitis) and interstitial nephritis at the first kidney biopsy. Differential diagnosis considered Sjögren's syndrome, tuberculosis, systemic lupus erythematosus, granulomatosis with polyangiitis and Behçet's syndrome.
Corticosteroids remain the cornerstone for the treatment of tubulointerstitial granulomatosis in renal sarcoidosis [1,8]. Our patient's clinical situation worsened in spite of longterm corticosteroid administration. Moreover, corticosteroid therapy was responsible for acquired Cushing syndrome, spinal deformations, and amyotrophy (Fig. 2b). In fact, severe osteoporosis was already present in 2010 (T-score − 4.9 at the level of the lumbar spine and − 2.9 at the level of the femoral neck), and had significantly worsened by 2018 (respective T-scores − 6.2 and − 3.2). In such a setting, other  (hypokalemia, hypocalcemia with hypercalciuria) and are associated with metabolic alkalosis, hyperreninemic hyperaldosteronism and normal blood pressure parameters [5]. In our case, blood pressure was normal. Blood tests revealed hypokalemia, hyponatremia, hypochloremia with metabolic alkalosis HCO3 at 33 mmol/l, confirmed on venous blood gas (pH 7.47). Blood magnesium was normal, however, severe hypercalcemia (11 mg/dl) was found and plasma renin and aldosterone levels were increased: renin 4600 ng/ ml (ref. range 0.84-2.5) and aldosterone 3903 pg/mL (ref. range 5.7-240), respectively. Potassium wasting was significant (298 mmol/l/24 h, ref. range 25-125) as was natriuresis wasting (479 mmol/l/24 h, ref. range 40-220). Hyper calciuria was absent upon admission and during our follow-up. Cases of pseudo Bartter/Bartter-like syndrome have been reported without association with hypercalciuria [9].
To our knowledge, this is the second reported case of acquired Bartter syndrome with renal involvement in systemic sarcoidosis.
Treatment with potassium supplementation, spironolactone and indomethacin was initiated early in our patient. Indomethacin (like other NSAIDs) is frequently given to treat Pseudo Barrter/Bartter-like syndrome [8]. Recurrent hepatitis and deleterious side effects of indomethacin on kidney function are however well known limiting factors for its long-term use [8].