**5. Glomerular diseases associated with sarcoidosis**

Glomerular involvement in sarcoidosis is not very common. The spectrum of commonly reported glomerular diseases include focal segmental sclerosis, membranous glomerulonephritis (GN), mesangioproliferative glomerulonephritis, mesangiocapillary glomerulonephritis, IgA nephropathy and crescentric glomerulonephritis. (Sheffield 1997) The exact mechanisms of glomerular disease in sarcoidosis are not known. Due to the absence of a consistent glomerular pathology and a well described etiological pathway, most cases are believed to be coincidental associations. Broadly speaking, abnormalities in both the humoral and cellular immune system in sarcoidosis contribute to the development of immune complex –type glomerulonephritis which also explains why immunoglobulin and complement deposition are commonly observed in renal biopsies in sarcoidosis. (Gobel et al 2001).

### **5.1 Membranous glomerulonephritis**

Overall, membranous glomerulonephritis (MGN) is the most commonly reported glomerular pathology. Amongst 39 cases of glomerular diseases reported in sarcoidosis, Vanhille et al found that 13 were MGN, largely occurring late in the course of overt disease. (Vanhille et al 1986) Khan et al. described a 56-yr-old woman with pulmonary sarcoidosis who developed heavy proteinuria. A renal biopsy revealed both interstitial granulomas and membranous glomerulonephritis. (Khan et al 1999) Rarely patients may be diagnosed to have sarcoidosis during the work up for secondary causes of nephrotic syndrome. Dimitriades et al. described a 13-yr-old girl who presented with the nephrotic syndrome and renal biopsy showed membranous nephropathy. (Dimitriades 1999) Typical subepithelial deposits were found with electron microscopy. Bilateral hilar adenopathy was present, which suggested sarcoidosis. The diagnosis was confirmed by a bone marrow biopsy, which disclosed noncaseating granulomas. The patient was treated with corticosteroids and cyclophosphamide, and her condition stabilized. In an experimental study, Maruyama et al, induced subepithelial deposits in pigs injected with heterologous antibodies to angiotensin converting enzyme (ACE). Confocal microscopy showed co localization of the granular deposits of ACE and anti ACE goat IgG on the outer aspect of glomerular basement. The authors conjectured that a similar autoimmune process may cause membranous GN in sarcoidosis. While traditionally idiopathic MGN is steroid resistant, most cases of MGN associated with sarcoidosis seem to respond to high dose steroid therapy especially if there is coexistent granulomatous interstitial nephritis (GIN) (Khan et al 1999). Others used pulse methylprednisolone plus oral cyclophosphamide to show remission of the nephrotic state. (Dimitriades et al 1999) See Figure 2. for histology of membranous nephropathy in sarcoidosis.

Sarcoidosis and Kidney Disease 93

to high dose steroids or cyclophosphamide. (Parry et al 1997) The patient had to be started on cyclosporine which was given for a year and a sustained remission was attained. Spontaneous occurrence and remission of heavy proteinuria coinciding with the relapse of the disease is also well described. (Mery 2005) The authors postulated that there is a functional and transient increase of glomerular permeability to proteins secondary to release

Crescent Glomerulonephrits (GN) has also been frequently reported in patients with sarcoidosis and co-existing ANCA associated vasculitis. ANCA are autoantibodies found in some autoimmune diseases, recognized by their reactivity with cytoplasmic antigens in neutrophils; two groups are recognized: c-ANCA, reacting with proteinase 3, is found in polyangiitis and Churg-Strauss syndrome; p-ANCA, reacting with myeloperoxidase is found in Wegener granulomatosis. Auinger et al described a patient with rapidly progressive glomerulonephritis and hepatosplenomegaly with no prior diagnosis of sarcoidosis whose renal biopsy showed crescentic GN. (Auinger et al 1997) Diagnosis of sarcoidosis was made with raised angiotensin converting enzyme (ACE) levels and both liver and kidney biopsies showing interstitial noncaseating granulomas. Patient was started on high dose steroids with which renal function improved. Subsequently, the patient developed anti- myeloperoxidase (MPO) antibodies. In contrast, Ahuja et al reported a patient with crescentic GN in the setting of Wegener's granulomatosis (WG). (Ahuja et al 1996). Patient responded well to long term oral cyclophosphamide treatment. Subsequently, the patient developed biopsy-confirmed pulmonary sarcoidosis months later. Given such close associations, it is believed that these sarcoidosis and granulomatous vasculitis like WG

Rare associations of sarcoidosis with post-infectious GN have also been noted. Michaels et al. described two patients with sarcoidosis : one with recent history of pneumonia and other with elevated antistreptolysin O titres who developed acute renal failure with active urinary sediments and nephrotic range proteinuria (Michaels et al 2000). Biopsies disclosed diffuse endocapillary proliferative GN with hump-like epithelial deposits. Both patients responded well to corticosteroids with resolution of proteinuria and azotemia. Similarly IgA nephropathy (IgAN), coexisting with sarcoidosis is not unusual given the wide prevalence of IgAN. Taylor and Nishiki described a case of IgAN in sarcoidosis typically presenting as nephritic syndrome that responded well to steroids. (Taylor at el 1996 and Nishiki et al 2010) Renal amyloidosis (AA type) has also noted in patients with long standing sarcoidosis with the classical presentation of steroid resistant nephrotic syndrome with slow progression to end stage renal disease. (Tchenio et al. 1996 and

After excluding abnormalities affecting calcium homeostasis, tubulointerstitial diseases are the most commonly encountered renal abnormalities in sarcoidosis. They are

of vascular permeability factor like lymphokines by activated T cells.

**5.3 Crescentic glomerulonephritis** 

may have some common mechanisms. See Figure 3.

**5.4 Other glomerular diseases** 

Rainfray et al 1988).

**6. Tubulointerstitial diseases** 

Fig. 2. (A) Immunofluorescence shows granular IgG deposits along the glomerular basement membrane consistent with membranous glomerulonephritis. (B) Left forearm biopsy with epithelioid granulomas. A star-shaped asteroid body is visible within a giant cell. Magnifications: x800 in A (IgG); x500 in B (hematoxylin and eosin). Gobel U et al. JASN 2001;12:616-623

#### **5.2 Minimal change disease**

Nephrotic syndrome due to minimal change disease (MCD) also has been described in patients with sarcoidosis. Mundlein et al, described a patient with Grave's disease with steroid dependent MCD who achieved complete remission with cyclophosphamide. (Mundlein et al 1996) Patient was subsequently diagnosed to have typical chest findings of pulmonary sarcoidosis. In contrast, Parry and Falk described a case of longstanding pulmonary sarcoidosis that later went on to develop steroid resistant MCD not responding

Fig. 2. (A) Immunofluorescence shows granular IgG deposits along the glomerular basement membrane consistent with membranous glomerulonephritis. (B) Left forearm biopsy with

Nephrotic syndrome due to minimal change disease (MCD) also has been described in patients with sarcoidosis. Mundlein et al, described a patient with Grave's disease with steroid dependent MCD who achieved complete remission with cyclophosphamide. (Mundlein et al 1996) Patient was subsequently diagnosed to have typical chest findings of pulmonary sarcoidosis. In contrast, Parry and Falk described a case of longstanding pulmonary sarcoidosis that later went on to develop steroid resistant MCD not responding

epithelioid granulomas. A star-shaped asteroid body is visible within a giant cell. Magnifications: x800 in A (IgG); x500 in B (hematoxylin and eosin). Gobel U et al. JASN

2001;12:616-623

**5.2 Minimal change disease** 

of vascular permeability factor like lymphokines by activated T cells.
