Sarcoidosis is a multisystem disorder of unknown etiology characterized by the accumulation of lymphocytes, mononuclear phagocytes and non-caseating granuloma in involved tissues [
9]. Due to the frequency of pulmonary involvement bronchoscopy is an important diagnostic tool. Bronchoscopy enables the investigator to identify endobronchial lesions, which can be found in almost half of the cases [
10]. In our patient tissue biopsy did not show signs of sarcoidosis, but broncho-alveolar lavage rendered a lymphocytic alveolitis with a CD4/CD8-ratio (>3.5) which is highly consistent with sarcoidosis. The sensitivity of CD4/CD8-ratio ranges from 42 to 59% and specificity from 76–96% [
10]. Furthermore, it can be speculated if the tubulointerstitial nephritis was a sign of renal involvement and therefore responsible for graft failure. The true incidence of sarcoidosis kidney disease is hard to define. Notably granulomatous interstitial nephritis accounts only for 10–15% of renal involvement. Interstitial nephritis without granuloma has been described but seems much less common [
11]. In our case histology showed significant interstitial infiltration, moderate tubulitis and intimal arteriitis. Glomeruli had a normal morphology and no granulomata were found. Altogether, sarcoidosis cannot be ruled out, but sarcoid interstitial nephritis without granulomata is reported to be very rare, so that rejection seems to be more likely in our patient. However, the assumed epididymitis was probably a sarcoid lesion. In an autopsy series, 5% of cases had genital involvement (most frequently of the epididymis), with bilateral disease present in approximately one-third of them. It is often asymptomatic, but patients may also present with a scrotal mass or pain. Testicular granulomata are much less common [
12]. Finally it was only the synopsis of the clinical manifestations, the pathologic lab tests (hypercalcemia, ACE, IL-2-Receptor, lysozyme) and finally the response to treatment with steroids which allowed to confirm the diagnosis.
Our patient received an immunosuppressive treatment for a long time and retrospectively it is difficult to say whether sarcoidosis came up "de novo" after withdrawal of azathioprin and prednisone or if it was reactivated. IgA nephropathy was reason for end stage renal disease in our patient thirty years ago. The association of sarcoidosis and IgA glomerulonephritis is uncommon but has been reported [
13]. Unfortunately we had no possibility to re-examine the patient's initial renal biopsy to look for typical signs of sarcoidosis. Neither the patient's history offers any signs for sarcoidosis before, nor did a pulmonary CT scan three years earlier. Thus we assume that sarcoidosis developed "de novo" after reduction of the immunosuppressive regimen and was finally aggravated when the medication was stopped completely. There are only a few reports describing sarcoidosis in kidney graft recipients after withdrawal of immunosuppression (see Table
1). The spectrum of clinical presentation is highly various and reached from high fevers, neurologic symptoms, graft failure and lung involvement including pleural effusion [
3‐
7]. Distinct hypercalcemia was only reported in two patients. That should remind us, that many cases do not present with massive hypercalcemia. A calcium level in the upper normal range or slightly above that should also catch our attention. In patients with end stage renal disease tertiary hyperparathyreoidism, the use of vitamin D metabolites, calcium phosphate binders or high dialysate calcium are frequent causes of hypercalcemia and should be considered first. Further workup should follow a standardized regimen, like the one proposed by Carroll and colleagues [
14]. Noteworthy, all patients developed most likely a reactivation of sarcoidosis. In every case sarcoidosis occurred either after steroids have been tapered or in a patient receiving a steroid-free immunosuppressive regimen from beginning. This underlines the important role of steroids in the treatment of sarcoidosis. Hypercalcemia and the severity of clinical symptoms provoked us to initiate systemic treatment using prednisone immediately. Various theories of the pathogenesis (infection, hypersensitivity and autoimmunity) exist. Sarcoidosis may result from an exposure to an antigen in a genetically predisposed, susceptible host [
2,
11]. When therapy is required, corticosteroids are considered standard [
15]. Studies demonstrating their ability to modify the long-term outcome in this disease are still lacking. Often, the adverse side effects of corticosteroids necessitate the addition of other immunomodulating substances [
15]. Our patient remained on low-dose steroids without any clinical symptoms more that one year after diagnosis. This case demonstrates that withdrawal of immunosuppressive drugs sometimes unmasks sarcoidosis. It stresses the diagnostic difficulties of sarcoidosis due to its highly variable clinical presentation. Moreover, it reminds every nephrologist to consider sarcoidosis as a differential diagnosis even in hemodialysis patients, in whom other reasons for hypercalcemia are much more common.
Table 1
Cases reporting sarcoidosis after reduction of immunosuppression
Brown et al. Nephrol Dial Transplant. 1992;7(2):173. | Reactivation after transplantation (steroid-free immunosuppressive regimen) | [3] |
Herrero et al. Nephrol Dial Transplant. 1998 Dec;13(12):3280–1. | Reactivation in kidney graft after steroid withdrawal, Hypercalcemia | [4] |
Schmidt et al. Transplantation. 1999 Nov 15;68(9):1420–3 | Reactivation after steroid withdrawal (lung, pleura), Hypercalcemia | [6] |
Kukura et al. Nephrol Dial Transplant (2004) 19: 1640–1642 | Reactivation in graft after steroid withdrawal (during pregnancy) | [5] |