Prevention of Kidney Stones Due to Paraffin Oil Induced Granuloma: A Prospective Interventional Study

Cosmetic treatments are becoming increasingly popular, now also encompassing injection of different sorts of fillers. One such approach is the injection of paraffin oil into muscular regions for the sole purpose of enhancing muscular size. During the last 4 years we have experienced that injections with paraffin oil are being more widely used than anticipated. Usage is mainly seen in the younger segment of the male Danish population, causing severe morbidity including hypercalcemia, kidney stones and renal failure in patients often in their thirties. Injected paraffin oil causes foreign body reactions, leading to inflammation and granuloma formation. Granulomas are rich in macrophages capable of producing large amount of activated vitamin D (1,25OH2D3) that may cause severe hypercalcemia. Although, the link between foreign body granuloma, and hypercalcemia has been known for more than 60 years sparse evidence-based treatments exist to control calcium and vitamin D balance in these patients. Physiologically, cutaneous produced or orally absorbed 25OH2D3 (cholecalciferol) needs activation before it can activate the vitamin D receptor (VDR) and exert its actions. This activation occurs through hydroxylation by CYP27B1 in the kidneys creating the active 1,25(OH)2D3 (calcitriol). CYP27B1 is the rate-limiting step in calcitriol synthesis and is tightly regulated under physiologic conditions. Control of high 1,25(OH)2D3 is achieved by a feedback system, where 1,25(OH)2D3 stimulates the enzyme CYP24A1, which in turn hy-droxylate 1,25(OH)2D3 to the inactive 1,24,25OH2D3. Several other players, e.g. parathy-roid hormone (PTH) and fibroblast growth factor 23 (FGF23) regulate calcium homeostasis. However, in macrophages, CYP27B1 is upregulated by interleukin 2, and the inhibiting enzyme CYP24A1 is not upregulated. Therefore, granulomas can produce large amounts of 1,25OH2D3, and this production is not counteracted by the otherwise tight regulatory and physiological mechanisms. Unimpeded 1,25OH2D3 in turn increase calcium absorption from the intestines, reabsorption from the kidneys and to some extent calcium release from bones, all leading to hypercalcemia. Hypercalcemia is a late feature of accelerated 25OH2D3 activation, as several counter regulatory mechanisms will attempt to maintain normocalcemia. As a result, these patients suffer from nephrolithiasis or progressive kidney disease due to nephrocalcinosis and/or nephrolithiasis, with some patients progressing to end stage renal dis-ease (ESRD).

SGLT2 inhibitors were developed for treatment of type 2 diabetes to lower blood glucose levels but they had a more pronounced effect in patients with heart or renal failure irrespective of diabetes status. SGLT2 inhibitors could prevent or reduce eGFR decline in patients with renal failure and it appeared in some trials that it could also lower the risk of nephrolithiasis. SGLT2 inhibitors have few adverse effects in non-diabetics and may be used to prevent progression of paraffin oil disease by protecting the kidney and reducing the risk of kidney stones in these patients. ACEi's and ARB's have also been shown to reduce progression of kidney disease. Although the data on prevention of kidney stones is less convincing for ACEi/ARB's the renoprotective effects make them a potential treatment option.

Data from our cohort of patients:

During our initial investigation of 88 patients, milder symptoms of hypercalcemia were often accompanied by hypercalcuria with increased risk of kidney stones and later nephrocalcinosis and ultimately progressive renal failure and vascular calcification as seen in patients with primary hyperparathyroidism or CKD. 3 deaths have been recorded in our cohort of young men, so paraffin disease leads to significant morbidity, but presumably also increased mortality. Currently, paraffin disease is still very sparsely described in the medical literature. The number of affected individuals is presumably large because early disease causes few symptoms and many of these men rarely seek medical attention. At the section of Endocrinology at Herlev-Gentofte Hospital, there is currently more than 310 young males who injected paraffin oil prior to referral. In the first published cohort of 88 males (32 ± 7 years (mean ± SD)) who injected paraffin oil 6 years prior to their first visit, the minority (42%) have managed to maintain an apparent normal calcium metabolism (normocalcemic and normoparathyoid), while the majority have developed an abnormal calcium metabolism ranging from normocalcemic and hypoparathyroid (24%) to hypercalcemic and hypoparathyroid (34%). Renal stone formers ranging from 22 % in patients with an apparent normal calcium homeostasis to a stunning 47-48% in those with abnormal calcium homeostasis (5-10% in back-ground population). Importantly, a significant number of patients (approx. 30%) had already developed mild to severe renal impairment with reduced eGFR. Most patients tended to have increased inflammatory markers (interleukine-2 receptor (IL-2R) and/or pepti-dyldipeptidase (ACE)) - even in those with apparent normal calcium metabolism. Surgical resection may improve both local reactions and pain. However, due to granuloma formation within muscle tissue and oilmigration, it is difficult to remove all the granuloma tissue. Currently, first line of treatment for paraffin disease is prednisolone, which has proven effective in lowering calcium levels in all our patients. However, patients require relatively large (15-75 mg daily) and long term (years) doses of prednisolone to achieve and maintain normal or near normal calcium levels with many possible adverse effects. Noteworthy, after 4 years observation we have not yet seen any decrease in inflammatory markers in any male suggesting that prednisolone monotherapy is not enough when you have large amount of granuloma tissue. Paraffin disease mimics sarcoidosis, both being granulomatous diseases with hypercalcemia due to macrophage mediated 25OH2D3 activation. Interestingly, RAAS activation has been shown to contribute to sarcoidosis granuloma formation in an ex vivo model, highlighting an additional potential role for treatment with ACEi/ARB's. However, paraffin disease appears to be much more progressive, not self-limiting and require more aggressive treatment probably because the volume of granulomatous tissue is so huge.

Since ACEi's, ARB's and SGLTi's are the only drug classes consistently shown to slow progression in CKD in a non-diabetic population, we hypothesize that these treatments will be effective in a cohort of patients with hypercalcemia due to paraffin oil induced granulomatous disease. Furthermore, we hypothesize that SGLTi will have a greater effect due to the potential decrease in incident nephrolithiasis. However, the ketosis associated with this treatment may not be beneficial, which clearly justifies the face-to-face comparison.