**6. Tubulointerstitial diseases**

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

Sarcoidosis and Kidney Disease 95

Despite great clinical variability, the most common clinical syndrome associated with sarcoidosis and GIN is chronic kidney disease with decline in renal function usually over weeks to months (Jean-Philllipe 2005). Acute renal failure as an initial presentation is also well known (O'Riordan et al 2001). Renal dysfunction may progress at variable rates but can irreversibly progress to end stage renal disease despite high dose glucocorticoid treatment. (Tsiouris et al 1999) Consistent with a pattern of tubulointerstitial disease, proteinuria is either absent or mild. Urine analysis shows leucocytes and granular casts. Rarely, patient may present as frank hematuria lasting several weeks. (Mills et al 1994) Functional tubular abnormalities can occur in as much as 50% of cases of sarcoidosis when aggressively investigated which include renal glycosuria, urinary sodium and potassium wasting, Fanconi's Syndrome, decreased urinary concentration ability, proximal or distal tubular acidosis. (Muther et al 1981) It is uncertain whether the presence of interstitial lesions solely contributes to these abnormalities but hypercalcemia and hypergammaglobulinemia also

GIN is usually associated with enlarged kidneys mimicking polycystic kidney disease or renal carcinoma. (Mery, 2005) Renal sonogram shows bilateral renal masses which are either hyper- or hypoechoic in comparison to adjacent renal parenchyma. Computer tomogram shows the renal masses to be low intensity. A Gallium-76 citrate scan commonly reveals increased uptake suggesting active granulomatous inflammation. (Mery and Kenouch, 1988) Serum ACE concentration is a poor marker of active renal lesion and may even be normal in

In most cases, a diagnosis of GIN is made in the context of typical extra-renal manifestations of sarcoidosis and/or hyperkalemia. Rarely renal involvement may be isolated and preceding other sites of the disease for months to years. Some have even considered isolated GIN as a localized form of sarcoidosis. In such isolated cases, it is important to rule out drug induced interstitial nephritis which is far more easily treatable cause of GIN that sarcoidosis itself. (Muther et al 1981) Another syndrome commonly associated with Sjogren's Syndrome but also reported with sarcoidosis is the "TINU syndrome or the Dobrin Syndrome (Sinnamon et al 2008) which is characterized by acute interstitial nephritis, anterior uveitis and epitheliod granulomas in bone marrow and lymph nodes. The renal lesion consists of interstitial infiltrates mainly composed of mononuclear cells and few eosinophils. Although no interstitial granulomas are seen in TINU, the interstitial cell infiltrate is the same as a sarcoid granuloma. Therefore it is possible that some cases described as Dobrin syndrome

Analyzing all cases of GIN, Joss et al, noted that the background diagnosis of sarcoidosis was known in only 1 of 5 patients of GIN who eventually were categorized as sarcoid GIN. Mean age of presentation was 56. 8 years. ACE levels were elevated in a minority of patients (1 out of 5) and hypercalcemia was seen in only 2 patients. Pulmonary findings of hilar

Renal pathology of GIN consists of the typical non-caseating granuloma widely distributed throughout the cortex and the medulla, although the density of these lesions may differ from patient to patient. (Mery 2005) The sarcoid granuloma consists of lymphocytes, mononuclear, cells and plasma cells. The center of the granuloma consists of epitheliod and

lymphadenopathy was seen in only 1 patient and one had the TINU syndrome.

play a pathogenic role. (Mery, 2005)

may be atypical forms of sarcoidosis.

(Joss et al 2007)

active GIN with severe renal failure. (Hannedouche et al 1990)

Fig. 3. (A) Roentgenogram showing bilateral hilar adenopathy in a patient with sarcoidosis. (B) Extracapillary glomerulonephritis with crescent formation. Magnification, x500 (periodic acid-Schiff). Gobel U et al. JASN 2001; 12:616-623

histopathologically described as granulomatous interstitial nephritis (GIN). Approximately 20% of patients with sarcoidosis show granulomatous inflammation in the kidney (Sheffield 1997) although values range from 15 to 40% (Mery 2005) reflecting differences in the indication for renal biopsies. In many instances, patients may be clinically silent and GIN may present with concomitant findings with well known clinicopathological syndromes. The variability in incidence of GIN also reflects sampling error in detecting scarce granulomas especially in inadequate biopsy specimens.

Overall GIN is a rare histologic diagnosis seen in 0. 5 and 0. 9% of native renal biopsies and 0. 6% of renal transplant biopsies (Joss et al 2007). Possible etiologies include medications, infections, sarcoidosis, Sjogren's syndrome, crystal deposits, paraproteinemia, Wegener's granulomatosis and idiopathic causes. Drugs implicated include anticonvulsants, antibiotics, nonsteroidal anti-inflammatory drugs, allopurinol, and diuretics. Mycobacteria and fungi are the main infective causes and seem to be the main causative factor in cases in renal transplants or in countries with high prevalence of tuberculosis. In the largest collection of data so far on this disease, Joss et al noted 18 cases of GIN from of etiologies such as sarcoidosis (n=5), drug induced (n=2), idiopathic (n=9) and tubulointerstitial nephritis with uveitis (n=2). The most common presentation of GIN was advanced renal failure with minimal proteinuria. (Joss 2007)

Fig. 3. (A) Roentgenogram showing bilateral hilar adenopathy in a patient with sarcoidosis. (B) Extracapillary glomerulonephritis with crescent formation. Magnification, x500 (periodic

histopathologically described as granulomatous interstitial nephritis (GIN). Approximately 20% of patients with sarcoidosis show granulomatous inflammation in the kidney (Sheffield 1997) although values range from 15 to 40% (Mery 2005) reflecting differences in the indication for renal biopsies. In many instances, patients may be clinically silent and GIN may present with concomitant findings with well known clinicopathological syndromes. The variability in incidence of GIN also reflects sampling error in detecting scarce

Overall GIN is a rare histologic diagnosis seen in 0. 5 and 0. 9% of native renal biopsies and 0. 6% of renal transplant biopsies (Joss et al 2007). Possible etiologies include medications, infections, sarcoidosis, Sjogren's syndrome, crystal deposits, paraproteinemia, Wegener's granulomatosis and idiopathic causes. Drugs implicated include anticonvulsants, antibiotics, nonsteroidal anti-inflammatory drugs, allopurinol, and diuretics. Mycobacteria and fungi are the main infective causes and seem to be the main causative factor in cases in renal transplants or in countries with high prevalence of tuberculosis. In the largest collection of data so far on this disease, Joss et al noted 18 cases of GIN from of etiologies such as sarcoidosis (n=5), drug induced (n=2), idiopathic (n=9) and tubulointerstitial nephritis with uveitis (n=2). The most common presentation of GIN was advanced renal

acid-Schiff). Gobel U et al. JASN 2001; 12:616-623

granulomas especially in inadequate biopsy specimens.

failure with minimal proteinuria. (Joss 2007)

Despite great clinical variability, the most common clinical syndrome associated with sarcoidosis and GIN is chronic kidney disease with decline in renal function usually over weeks to months (Jean-Philllipe 2005). Acute renal failure as an initial presentation is also well known (O'Riordan et al 2001). Renal dysfunction may progress at variable rates but can irreversibly progress to end stage renal disease despite high dose glucocorticoid treatment. (Tsiouris et al 1999) Consistent with a pattern of tubulointerstitial disease, proteinuria is either absent or mild. Urine analysis shows leucocytes and granular casts. Rarely, patient may present as frank hematuria lasting several weeks. (Mills et al 1994) Functional tubular abnormalities can occur in as much as 50% of cases of sarcoidosis when aggressively investigated which include renal glycosuria, urinary sodium and potassium wasting, Fanconi's Syndrome, decreased urinary concentration ability, proximal or distal tubular acidosis. (Muther et al 1981) It is uncertain whether the presence of interstitial lesions solely contributes to these abnormalities but hypercalcemia and hypergammaglobulinemia also play a pathogenic role. (Mery, 2005)

GIN is usually associated with enlarged kidneys mimicking polycystic kidney disease or renal carcinoma. (Mery, 2005) Renal sonogram shows bilateral renal masses which are either hyper- or hypoechoic in comparison to adjacent renal parenchyma. Computer tomogram shows the renal masses to be low intensity. A Gallium-76 citrate scan commonly reveals increased uptake suggesting active granulomatous inflammation. (Mery and Kenouch, 1988) Serum ACE concentration is a poor marker of active renal lesion and may even be normal in active GIN with severe renal failure. (Hannedouche et al 1990)

In most cases, a diagnosis of GIN is made in the context of typical extra-renal manifestations of sarcoidosis and/or hyperkalemia. Rarely renal involvement may be isolated and preceding other sites of the disease for months to years. Some have even considered isolated GIN as a localized form of sarcoidosis. In such isolated cases, it is important to rule out drug induced interstitial nephritis which is far more easily treatable cause of GIN that sarcoidosis itself. (Muther et al 1981) Another syndrome commonly associated with Sjogren's Syndrome but also reported with sarcoidosis is the "TINU syndrome or the Dobrin Syndrome (Sinnamon et al 2008) which is characterized by acute interstitial nephritis, anterior uveitis and epitheliod granulomas in bone marrow and lymph nodes. The renal lesion consists of interstitial infiltrates mainly composed of mononuclear cells and few eosinophils. Although no interstitial granulomas are seen in TINU, the interstitial cell infiltrate is the same as a sarcoid granuloma. Therefore it is possible that some cases described as Dobrin syndrome may be atypical forms of sarcoidosis.

Analyzing all cases of GIN, Joss et al, noted that the background diagnosis of sarcoidosis was known in only 1 of 5 patients of GIN who eventually were categorized as sarcoid GIN. Mean age of presentation was 56. 8 years. ACE levels were elevated in a minority of patients (1 out of 5) and hypercalcemia was seen in only 2 patients. Pulmonary findings of hilar lymphadenopathy was seen in only 1 patient and one had the TINU syndrome.

#### (Joss et al 2007)

Renal pathology of GIN consists of the typical non-caseating granuloma widely distributed throughout the cortex and the medulla, although the density of these lesions may differ from patient to patient. (Mery 2005) The sarcoid granuloma consists of lymphocytes, mononuclear, cells and plasma cells. The center of the granuloma consists of epitheliod and

Sarcoidosis and Kidney Disease 97

In contrast to conventional pathological dogma, Joss et al showed that asteroid bodies and calcification were not common in sarcoid GIN. (Joss et al 2007) Interestingly, asteroid bodies were seen in 1 case of drug induced AIN. However, lymphocyte cuffing and giant cell infiltration were prominent in sarcoid granulomas in the kidney. Necrosis and eosinophil infiltration of the interstitum was more common in drug induced GIN as compared to sarcoidosis. It is now believed that idiopathic GIN, TINU and sarcoidosis represents a clinicopathological spectrum and that idiopathic GIN or TINU may subsequently develop

The mainstay of treatment of sarcoid GIN is glucocorticoids. Initial treatment requires a daily dose of prednisone or prednisolone preferably 1-1. 5 mg/kg. Response to treatment can often be dramatic in terms of improvement of renal insufficiency. The best response to glucocorticoids was noted in a study by Mahevas et al. in which 47 patients with renal sarcoid received prednisolone while 10 also received pulse methylprednisolone. (Mahevas et al 2009) The authors concluded that at 24 months, a complete and partial remission occurred in 30 and 5 patients respectively. But no response was noted in patients with severe interstitial fibrosis of greater than 50%. Underlying functional tubular dysfunction improves with progressive drop in serum creatinine. An important point to realize here is that steroid treatment has to be prolonged and must exceed at least 6 months as nephropathy relapses very frequently with short term therapy (Gene and Cheviot 1988). A commonly followed strategy is to give the initial dose for 2 months followed by progressive taper and switching to an alternate –day therapy. A maintenance therapy period for 1 year at least is recommended. Serial renal biopsies have shown a regression of granuloma in conjunction with improvement of renal function (Farge et al 1986) although given the variability in results (Gene and Cheviot 1988) routine biopsies after starting steroids is not recommended. Treatment in advanced disease is often associated with interstitial fibrosis along with focal segmental glomerulosclerosis and vascular lesions. However, vascular lesions are more common with long term corticosteroid therapy and are associated with delayed development of hypertension which is a major contributor to progression of renal

While analyzing outcomes of steroid treatment in a heterogeneous population of GIN, Joss et al, presented data of 16 patients of which 5 were labeled as sarcoidosis. Patients were treated with prednisolone (starting dose of 0. 55mg/kg) (Joss et al 2007) for a mean period of 25 months and then followed up for a period of 45 months. Overall, renal function stabilized or improved at the end of the study with mean GFR improving from 21 to 56 ml/min. One patient who was on dialysis at the beginning of therapy was able to discontinue dialysis within 3 months. Six patients relapsed on dose reduction of which 4 were sarcoid GIN who required azathioprine to break steroid dependence. Sarcoid patients required longer treatment (36 months) as compared to idiopathic or TINU patients. The greatest renal recovery occurred in the first year of treatment. There was no difference in renal outcome when analyzing the degree of interstitial fibrosis. Age less than 60 years was associated with a better outcome. Table 1 summarizes data on treatment of GIN in some important studies

Long term results with steroid therapy in sarcoid GIN have not been rigorously tested in randomized controlled trials. In a large case series of 39 patients with sarcoid renal disease,

typical extra-renal manifestations of sarcoidosis.

failure. (Mery and Kenouch 1988)

so far.

**6.1 Treatment** 

multinucleate giant cells both of which are derived from activated macrophages. Multinucleate giant cells are formed by the coalescence of epitheliod cells. Lymphocytes largely consist of T-helper cells (CD 4+) in the center and CD 8+ lymphocytes in the periphery. Some granulomas have small arteries in their center. Although granulomas may also form in drug induced interstitial nephritis it is less well formed than in sarcoidosis. Varying degrees of fibrosis may also be present. The severity of fibrosis correlates with tubular atrophy and degeneration. In the absence of any predominant glomerular pathology, the glomeruli are either normal or show mesangial hypertrophy and thickening of the basement membrane. Electron microscopy may show fusion of epithelial foot processes (Farge et al 1986). However, there are no significant immune deposits in either the glomeruli or tubules as seen by immunoflourescent microscopy. In a significant number of cases, immunoflourescence with anti-ACE serum showed localization in the sarcoid granuloma in addition to normal staining of the brush border of the proximal tubules. (Mery et al 1988) See Figure 4.

Fig. 4. Renal biopsy showed a granulomatous interstitial nephritis with a broadened interstitial, cellular infiltrates and granuloma with typical multinucleated giant cells (arrowheads). Kettritz R et al. Nephrol. Dial. Transplant. 2006; 21:2690-2694

In contrast to conventional pathological dogma, Joss et al showed that asteroid bodies and calcification were not common in sarcoid GIN. (Joss et al 2007) Interestingly, asteroid bodies were seen in 1 case of drug induced AIN. However, lymphocyte cuffing and giant cell infiltration were prominent in sarcoid granulomas in the kidney. Necrosis and eosinophil infiltration of the interstitum was more common in drug induced GIN as compared to sarcoidosis. It is now believed that idiopathic GIN, TINU and sarcoidosis represents a clinicopathological spectrum and that idiopathic GIN or TINU may subsequently develop typical extra-renal manifestations of sarcoidosis.
