**6.1 Treatment**

96 Chronic Kidney Disease

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

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

et al 1988) See Figure 4.

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 failure. (Mery and Kenouch 1988)

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 so far.

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,

Sarcoidosis and Kidney Disease 99

be attributed to steroids which included acute psychosis and type 2 diabetes. Long term use of corticosteroids, especially in adolescents, can cause substantial side effects including diabetes, growth retardation and cataract. Alternative agents that have been attempted in treating sarcoid GIN include mycophenolate (Moudgil 2002) and mizoribine (Rajakariar et al 2006 and Ito et al 2009) which are limited to case reports and have been primarily used in pediatric patients to break steroid dependence or ameliorate significant side effects. Other agents which have been tried in systemic extra-renal sarcoidosis include mycophenolate mofetil, methotrexate, azathioprine, antimalarials, and phosphodiesterase inhibitors such as pentoxifylline and thalidomide although no data on treating renal sarcoidosis exists. (Baughman 2003) There has been great interest in the use of TNF-antagonists as another modality to treat sarcoid GIN in order to avoid use of steroids. TNF-alpha, which is expressed by monocytes, is critical in the development of these noncaseating granulomas. TNF-alpha receptor antagonists have also been shown to prevent the initiation and perpetuation of inflammation and subsequent interstitial fibrosis. Etanercept is a soluble TNF-alpha receptor fusion protein that binds TNF-alpha. Infliximab and adalimumab are monoclonal antibodies that bind specifically to and neutralize TNF-alpha. While etanercept is an ineffective agent in the treatment of systemic sarcoidosis, (Ulz et al 2003) infliximab has been shown to be effective in a case of renal sarcoid. Thumfart et al, described the case of a boy presenting with severe arterial hypertension and acute renal failure caused by an isolated sarcoid granulomatous interstitial nephritis. Renal function improved initially with prednisone treatment but later, the patient showed signs of severe steroid toxicity and progressive renal failure. Monthly treatment with infliximab was initiated resulting in a steady improvement in renal function and resolution of renal granulomata, as well as reduction in antihypertensive medication. (Thumfart 2005) Ahmed et al presented a patient with acute renal failure due to isolated granulomatous infiltration of the renal parenchyma. (Ahmed et al 2007) Renal biopsy showed granulomatous interstitial nephritis with noncaseating granulomas. There was no evidence of extrarenal sarcoid involvement. Prednisone 60mg daily resulted in significant improvement in renal function. Due to recurrent flares while tapering the prednisone and steroid toxicity, treatment with infliximab was instituted and resulted in stabilization of renal function. This case demonstrated that steroid-dependant or refractory renal sarcoidosis cases may respond to infliximab. We recently reported the case of a 46-year-old woman with multi-organ sarcoidosis, type 2 diabetes, subnephrotic-range proteinuria, hypertension and recurrent episodes of hypercalcemia-induced acute kidney injury who was referred for evaluation of worsening renal function and nephrotic range proteinuria. (Gupta et al 2008) A kidney biopsy showed sarcoid GIN with moderate-to-severe chronic tubulointerstitial disease, hypertensive vasculopathy, and diabetic glomerulosclerosis. Because steroids had caused multiple side effects including diabetes, hypertension and obesity and attempts to wean steroids had caused hypercalcemia and acute renal failure, Adalimumab (HumiraTM) 40 mg/0. 8 cc weekly for 6 months was initiated. After 6 months of treatment with adalimumab, serum creatinine improved from 345 μmol/L (3. 9 mg/dL) to 1. 8 mg/dl (her baseline for years) and proteinuria improved from 10 g/day to 3. 5 g in 24 hours respectively. A repeat biopsy showed persistent diabetic glomerulosclerosis, moderate chronic tubulointerstitial inflammation with complete resolution of interstitial epitheliod granulomas. Although adalimumab and infliximab are generally safe, some side effects


1 Data excluding the two cases of drug-induced GIN.

Table 1. Comparison on treatment of GIN in literature.

17 patients with biopsy-proven tubulo-interstitial nephritis with significant renal impairment were analyzed over a one year period of corticosteroid therapy. (Robson et al 2003). All patients were initially started on prednisolone at 0. 5 mg/kg body weight at a daily dose of 30–60 mg which was tapered by 5 mg each week once the renal function has improved and/or stabilized. Thereafter, patients were maintained on 5–7. 5 mg daily indefinitely. Mean duration of study was 84 months. Estimated glomerular filtration rate (eGFR) at baseline was 26. 814 ml/min which improved to 49. 65. 2 ml/min (P<0. 01) at 1 year, and 47. 96. 8 ml/min (P<0. 05) at last review. Interestingly, the response to treatment was similar regardless of the degree of renal impairment at baseline, race and the degree of tubulo-interstitial scarring on renal biopsy. Three patients developed side effects that could

*n* 18 161 7 5 6 5

Age (yr) 55 56 69 48 to 71 62 61 Male gender (%) 61 56 71 60 50 60

(ml/min) 21 24 14 6 NA NA

Hypercalcemia 3/18 3/16 2/7 0/5 2/6 1/5

ACE 4/17 4/15 3/7 1/5 4/4 1/5

function 17/18 15/16 5/7 4/5 6/6 5/5 Long-term RRT 0/18 0/16 2/7 0/5 0/6 0/5 Prednisolone (%) 89 88 100 100 100 100

(mo) 45 48 25 35 75 NA

end of therapy 56 53 22 20 NA NA

17 patients with biopsy-proven tubulo-interstitial nephritis with significant renal impairment were analyzed over a one year period of corticosteroid therapy. (Robson et al 2003). All patients were initially started on prednisolone at 0. 5 mg/kg body weight at a daily dose of 30–60 mg which was tapered by 5 mg each week once the renal function has improved and/or stabilized. Thereafter, patients were maintained on 5–7. 5 mg daily indefinitely. Mean duration of study was 84 months. Estimated glomerular filtration rate (eGFR) at baseline was 26. 814 ml/min which improved to 49. 65. 2 ml/min (P<0. 01) at 1 year, and 47. 96. 8 ml/min (P<0. 05) at last review. Interestingly, the response to treatment was similar regardless of the degree of renal impairment at baseline, race and the degree of tubulo-interstitial scarring on renal biopsy. Three patients developed side effects that could

373 357 420 NA 566 396

159 159 296 NA 192 225

TINU/sarcoid Idiopathic Isolated

*et al.* 

Hannedouche

sarcoid Sarcoid Sarcoid

Brause *et al.* 

*et al.* 

Parameter Joss et al Robson *et al.* O'Riordan

Cause Mixed Idiopathic/

Renal function at

baseline BaselineCC

Baseline creatinine (μmol/L)

Raised serum

Improved renal

Mean follow-up

Renal function at

ECC (ml/min) at

1 Data excluding the two cases of drug-induced GIN.

Table 1. Comparison on treatment of GIN in literature.

last visit

Creatinine (μmol/L) at end of study

be attributed to steroids which included acute psychosis and type 2 diabetes. Long term use of corticosteroids, especially in adolescents, can cause substantial side effects including diabetes, growth retardation and cataract. Alternative agents that have been attempted in treating sarcoid GIN include mycophenolate (Moudgil 2002) and mizoribine (Rajakariar et al 2006 and Ito et al 2009) which are limited to case reports and have been primarily used in pediatric patients to break steroid dependence or ameliorate significant side effects. Other agents which have been tried in systemic extra-renal sarcoidosis include mycophenolate mofetil, methotrexate, azathioprine, antimalarials, and phosphodiesterase inhibitors such as pentoxifylline and thalidomide although no data on treating renal sarcoidosis exists. (Baughman 2003) There has been great interest in the use of TNF-antagonists as another modality to treat sarcoid GIN in order to avoid use of steroids. TNF-alpha, which is expressed by monocytes, is critical in the development of these noncaseating granulomas. TNF-alpha receptor antagonists have also been shown to prevent the initiation and perpetuation of inflammation and subsequent interstitial fibrosis. Etanercept is a soluble TNF-alpha receptor fusion protein that binds TNF-alpha. Infliximab and adalimumab are monoclonal antibodies that bind specifically to and neutralize TNF-alpha. While etanercept is an ineffective agent in the treatment of systemic sarcoidosis, (Ulz et al 2003) infliximab has been shown to be effective in a case of renal sarcoid. Thumfart et al, described the case of a boy presenting with severe arterial hypertension and acute renal failure caused by an isolated sarcoid granulomatous interstitial nephritis. Renal function improved initially with prednisone treatment but later, the patient showed signs of severe steroid toxicity and progressive renal failure. Monthly treatment with infliximab was initiated resulting in a steady improvement in renal function and resolution of renal granulomata, as well as reduction in antihypertensive medication. (Thumfart 2005) Ahmed et al presented a patient with acute renal failure due to isolated granulomatous infiltration of the renal parenchyma. (Ahmed et al 2007) Renal biopsy showed granulomatous interstitial nephritis with noncaseating granulomas. There was no evidence of extrarenal sarcoid involvement. Prednisone 60mg daily resulted in significant improvement in renal function. Due to recurrent flares while tapering the prednisone and steroid toxicity, treatment with infliximab was instituted and resulted in stabilization of renal function. This case demonstrated that steroid-dependant or refractory renal sarcoidosis cases may respond to infliximab. We recently reported the case of a 46-year-old woman with multi-organ sarcoidosis, type 2 diabetes, subnephrotic-range proteinuria, hypertension and recurrent episodes of hypercalcemia-induced acute kidney injury who was referred for evaluation of worsening renal function and nephrotic range proteinuria. (Gupta et al 2008) A kidney biopsy showed sarcoid GIN with moderate-to-severe chronic tubulointerstitial disease, hypertensive vasculopathy, and diabetic glomerulosclerosis. Because steroids had caused multiple side effects including diabetes, hypertension and obesity and attempts to wean steroids had caused hypercalcemia and acute renal failure, Adalimumab (HumiraTM) 40 mg/0. 8 cc weekly for 6 months was initiated. After 6 months of treatment with adalimumab, serum creatinine improved from 345 μmol/L (3. 9 mg/dL) to 1. 8 mg/dl (her baseline for years) and proteinuria improved from 10 g/day to 3. 5 g in 24 hours respectively. A repeat biopsy showed persistent diabetic glomerulosclerosis, moderate chronic tubulointerstitial inflammation with complete resolution of interstitial epitheliod granulomas. Although adalimumab and infliximab are generally safe, some side effects

Sarcoidosis and Kidney Disease 101

The usual cause of end stage renal disease in sarcoidosis requiring renal replacement therapy is usually due to hypercalcemic nephropathy rather than granulomatous interstitial nephritis or a glomerular disease. The outcome in renal transplantation in patients with sarcoidosis has been described in the literature. The first recurrence of sarcoid GIN in renal allograft was diagnosed 6 years after deceased donor kidney transplantation in a patient

aimed to describe a multicenter experience with kidney transplantation in patients with sarcoidosis. (Aouizerate et al 2010) In this study, the authors retrospectively identified 18 patients who underwent renal transplantation. Patient medical charts, demographics were reviewed. The median time between the last sarcoidosis episode and renal transplantation was 78 (8 to 900) months. Only 3 out of 18 patients had been on immunosuppression prior to transplantation. Vast majority of the patients had in the past received steroids and other immunosuppression for their sarcoid before transplantation. Renal disease was attributable to biopsy proven renal sarcoid in 10 out of the 18 patients and was attributed to other causes in 8 patients. Mean age of transplantation was 43. 5 +/- 11 years. 17 out of 18 patients had a deceased donor transplant. Mean donor age was 36. 5 +/ 15 years. Mean cold ischemia time was 16. 6 +/- 8 hours. 11 patients received induction therapy with anti-thymocyte globulin or Il-2 receptor antagonists. Maintenance immunosuppression included calcineurin inhibitor (CNI) for all patients, mycophenolate mofetil or azathiporine, sirolimus and corticosteroids for 16 out of the 18 patients. At the end of the 42 month follow up period, patient and death censored graft survival was 94. 4% and mean GFR was 60 cc/min per 1. 73 m2. Recurrence of sarcoidosis after renal transplantation was observed in 5 (27%) of patients. The median period between renal transplantation and recurrence was 13 months and four of five patients exhibited recurrence in the first 18 months after renal transplantation. Recurrences involved in the same organ in four of five patients and included renal involvement in three patients and lung and liver involvement in one patient. Mean GFR at end of follow-up was significantly lower in the three patients with recurrence than that for the entire cohort. (31 versus 60 cc/min per 1. 73 m2). Analysis of the recurrences showed that they occur in the first 18 months after transplantation. Primary disease related to sarcoidosis was strongly associated with recurrence (40% in the group with renal sarcoidosis versus 12. 5% in a group with a primary nephropathy, and median period between last episode of sarcoidosis and renal transplantation was shorter in the case of sarcoidosis recurrence (42 versus 78 months respectively). This study showed that patients with initial renal involvement display sensitivity to disease recurrence in allograft. The incidence of recurrence was significant as all patients were maintained on triple immunosuppressive therapy including steroids and mycophenolate mofetil. This study showed that renal transplant can be conducted safely in transplant patients with sarcoidosis, but recurrences do occur and affect overall graft

Kukura reported a case of recurrence of sarcoidosis in the renal allograft during pregnancy. (Kukura et al 2004) This was a 27 yr old female diagnosed with sarcoidosis at age 14 by lacrimal and parotid gland biopsy. 4 years after presentation, she developed hypertension and renal insufficiency. Kidney biopsy showed interstitial nephritis and nephrosclerosis, but no granulomas. Patient was eventually started in hemodialysis and underwent kidney

Shen et al 1986). A recent French study

**8. Kidney transplantation in patients with sarcoidosis**

that was diagnosed with GIN before transplantation (

outcome.

include risk of lymphoma and reactivation of latent tuberculosis (Denys et al 2007). These agents may hold promise for the future once large scale randomized studies are available to show consistent benefits with minimal side effects.

#### **7. Renovascular diseases associated with sarcoidosis**

Renovascular diseases secondary to sarcoidosis are distinctly rare and attributed to a form of secondary vasculitides. Systemic vasculitis associated with sarcoidosis has been reported as an isolated entity in the literature after excluding other common causes of vasculitis. It is predominantly large vessel vasculitis although few instances of small vessel vasculitis have been reported. In a large case series and review of literature on sarcoid vasculitis, Fernandes et al, noted that most cases were children and clinical presentation resembled hypersensitivity vasculitis, Takayasu's arteritis, polyarteritis nodosa or microscopic polyangitis. (Fernandes 2000) Clinical features included fever, peripheral adenopathy, hilar adenopathy, rash, pulmonary parenchymal disease, musculoskeletal symptoms, and scleritis or iridocyclitis with biopsy showing necrotizing sarcoid granulomata. Interestingly, no renal involvement was noted. Notably the authors found large vessel vasculitis largely in the African American population while small vessel vasculitis predominantly affected white races. Godin et al described a known case of pulmonary sarcoidosis with persistent hypertension. (Godin et al 1980) Diagnostic evaluation for renovascular hypertension included aortography which showed severe stenosis of right renal artery. Surgical exploration showed extensive periaortic and perirenal fibrosis with extrinsic compression of renal artery. Pathological examination of the kidney revealed epitheloid infiltration of the adventia of renal artery suggestive of sarcoid angitis. Surgical biopsy was performed on both kidneys. The right kidney, protected by arterial stenosis, was slightly altered, while the left kidney showed extensive interstitial, tubular, and glomerular lesions which included focal and segmental hyalinosis. Marcussen et al, reported an autopsy case of a middle aged man who died of myocardial infarction secondary to fulminent vasculitis. (Marcussen and Lund 1989) Pathology showed widespread giant cell vasculitis with simultaneous involvement of the renal arteries, veins, and arterioles along with typical interstitial sarcoid granuloma. Shintaku et al, showed granulomatous inflammation of small renal vessels and crescentric GN on the autopsy of a patient with pulmonary hemorrhage and rapidly progressive renal failure. (Shintaku et al 1989) Thus, sarcoid angitis, especially causing small vessel vasculitis in the kidney may represent a very severe form of sarcoidosis. In their review, Fernandes et al, noted that four out of six patients responded well to steroid treatment alone but had relapses when attempts were made to taper or withdraw steroids. (Fernandes 2000) Frequently, there is an overlap between sarcoidosis and well known causes of granulomatous vasculitis. For instance, Watson et al described a case of longstanding pulmonary sarcoidosis presenting with rapidly progressive renal failure with p-ANCA positivity. (Watson 1996) Renal biopsy demonstrated focal and segmental fibrinoid necrosis with crescentric GN and focal fibrinoid necrosis in arterial wall, but no granulomata and pauci-immune deposits on immunofluorescence. Unlike patients with ANCA positive vasculitis, the index case responded poorly to pulse steroids and cyclophosphamide and progressed rapidly to end stage renal disease.

include risk of lymphoma and reactivation of latent tuberculosis (Denys et al 2007). These agents may hold promise for the future once large scale randomized studies are available to

Renovascular diseases secondary to sarcoidosis are distinctly rare and attributed to a form of secondary vasculitides. Systemic vasculitis associated with sarcoidosis has been reported as an isolated entity in the literature after excluding other common causes of vasculitis. It is predominantly large vessel vasculitis although few instances of small vessel vasculitis have been reported. In a large case series and review of literature on sarcoid vasculitis, Fernandes et al, noted that most cases were children and clinical presentation resembled hypersensitivity vasculitis, Takayasu's arteritis, polyarteritis nodosa or microscopic polyangitis. (Fernandes 2000) Clinical features included fever, peripheral adenopathy, hilar adenopathy, rash, pulmonary parenchymal disease, musculoskeletal symptoms, and scleritis or iridocyclitis with biopsy showing necrotizing sarcoid granulomata. Interestingly, no renal involvement was noted. Notably the authors found large vessel vasculitis largely in the African American population while small vessel vasculitis predominantly affected white races. Godin et al described a known case of pulmonary sarcoidosis with persistent hypertension. (Godin et al 1980) Diagnostic evaluation for renovascular hypertension included aortography which showed severe stenosis of right renal artery. Surgical exploration showed extensive periaortic and perirenal fibrosis with extrinsic compression of renal artery. Pathological examination of the kidney revealed epitheloid infiltration of the adventia of renal artery suggestive of sarcoid angitis. Surgical biopsy was performed on both kidneys. The right kidney, protected by arterial stenosis, was slightly altered, while the left kidney showed extensive interstitial, tubular, and glomerular lesions which included focal and segmental hyalinosis. Marcussen et al, reported an autopsy case of a middle aged man who died of myocardial infarction secondary to fulminent vasculitis. (Marcussen and Lund 1989) Pathology showed widespread giant cell vasculitis with simultaneous involvement of the renal arteries, veins, and arterioles along with typical interstitial sarcoid granuloma. Shintaku et al, showed granulomatous inflammation of small renal vessels and crescentric GN on the autopsy of a patient with pulmonary hemorrhage and rapidly progressive renal failure. (Shintaku et al 1989) Thus, sarcoid angitis, especially causing small vessel vasculitis in the kidney may represent a very severe form of sarcoidosis. In their review, Fernandes et al, noted that four out of six patients responded well to steroid treatment alone but had relapses when attempts were made to taper or withdraw steroids. (Fernandes 2000) Frequently, there is an overlap between sarcoidosis and well known causes of granulomatous vasculitis. For instance, Watson et al described a case of longstanding pulmonary sarcoidosis presenting with rapidly progressive renal failure with p-ANCA positivity. (Watson 1996) Renal biopsy demonstrated focal and segmental fibrinoid necrosis with crescentric GN and focal fibrinoid necrosis in arterial wall, but no granulomata and pauci-immune deposits on immunofluorescence. Unlike patients with ANCA positive vasculitis, the index case responded poorly to pulse steroids and

show consistent benefits with minimal side effects.

**7. Renovascular diseases associated with sarcoidosis**

cyclophosphamide and progressed rapidly to end stage renal disease.

### **8. Kidney transplantation in patients with sarcoidosis**

The usual cause of end stage renal disease in sarcoidosis requiring renal replacement therapy is usually due to hypercalcemic nephropathy rather than granulomatous interstitial nephritis or a glomerular disease. The outcome in renal transplantation in patients with sarcoidosis has been described in the literature. The first recurrence of sarcoid GIN in renal allograft was diagnosed 6 years after deceased donor kidney transplantation in a patient that was diagnosed with GIN before transplantation ( Shen et al 1986). A recent French study aimed to describe a multicenter experience with kidney transplantation in patients with sarcoidosis. (Aouizerate et al 2010) In this study, the authors retrospectively identified 18 patients who underwent renal transplantation. Patient medical charts, demographics were reviewed. The median time between the last sarcoidosis episode and renal transplantation was 78 (8 to 900) months. Only 3 out of 18 patients had been on immunosuppression prior to transplantation. Vast majority of the patients had in the past received steroids and other immunosuppression for their sarcoid before transplantation. Renal disease was attributable to biopsy proven renal sarcoid in 10 out of the 18 patients and was attributed to other causes in 8 patients. Mean age of transplantation was 43. 5 +/- 11 years. 17 out of 18 patients had a deceased donor transplant. Mean donor age was 36. 5 +/ 15 years. Mean cold ischemia time was 16. 6 +/- 8 hours. 11 patients received induction therapy with anti-thymocyte globulin or Il-2 receptor antagonists. Maintenance immunosuppression included calcineurin inhibitor (CNI) for all patients, mycophenolate mofetil or azathiporine, sirolimus and corticosteroids for 16 out of the 18 patients. At the end of the 42 month follow up period, patient and death censored graft survival was 94. 4% and mean GFR was 60 cc/min per 1. 73 m2. Recurrence of sarcoidosis after renal transplantation was observed in 5 (27%) of patients. The median period between renal transplantation and recurrence was 13 months and four of five patients exhibited recurrence in the first 18 months after renal transplantation. Recurrences involved in the same organ in four of five patients and included renal involvement in three patients and lung and liver involvement in one patient. Mean GFR at end of follow-up was significantly lower in the three patients with recurrence than that for the entire cohort. (31 versus 60 cc/min per 1. 73 m2). Analysis of the recurrences showed that they occur in the first 18 months after transplantation. Primary disease related to sarcoidosis was strongly associated with recurrence (40% in the group with renal sarcoidosis versus 12. 5% in a group with a primary nephropathy, and median period between last episode of sarcoidosis and renal transplantation was shorter in the case of sarcoidosis recurrence (42 versus 78 months respectively). This study showed that patients with initial renal involvement display sensitivity to disease recurrence in allograft. The incidence of recurrence was significant as all patients were maintained on triple immunosuppressive therapy including steroids and mycophenolate mofetil. This study showed that renal transplant can be conducted safely in transplant patients with sarcoidosis, but recurrences do occur and affect overall graft outcome.

Kukura reported a case of recurrence of sarcoidosis in the renal allograft during pregnancy. (Kukura et al 2004) This was a 27 yr old female diagnosed with sarcoidosis at age 14 by lacrimal and parotid gland biopsy. 4 years after presentation, she developed hypertension and renal insufficiency. Kidney biopsy showed interstitial nephritis and nephrosclerosis, but no granulomas. Patient was eventually started in hemodialysis and underwent kidney

Sarcoidosis and Kidney Disease 103

Ahmed MM, Mubashir E, Dossabhoy NR. Isolated renal sarcoidosis: a rare presentation of a rare disease treated with infliximab. Clin Rheumatol. 2007; 26(8):1346-9. Ahuja TS, Mattana J, Valderrama E, Sankaran R, Singhal PC, Wagner JD: Wegener's

Aouizerate, Jessie, Matignon, Marie et al: Renal Transplantation in Patients with Sarcoidosis:

Auinger M, Irsigler K, Breiteneder S, Ulrich W: Normocalcemic hepatorenal sarcoidosis with crescentic glomerulonephritis. Nephrol Dial Transplant. 1997; 12:1474 -1477. Baughman, R. P, Lynch, J. Difficult treatment issues in sarcoidosis. J Intern Med. 2003 Jan;

Berliner AR, Haas M, Choi MJ. Sarcoidosis: The Nephrologist's Perspective. Am J Kid Dis

Brause M, Magnusson K, Degenhardt S, Helmchen U, Grabensee B: Renal involvement in

Denys, B. Bogaerts, Y. Coenegrachts, K. Et al. Steroid-resistant sarcoidosis: is antagonism of

Dimitriades C, Shetty AK, Vehaskari M, Craver RD, Gedalia A: Membranous nephropathy associated with childhood sarcoidosis. Pediatr Nephrol. 1999;13:444 -447. Farge D, Loite F, Turner M. Granulomatous nephritis and chronic renal failure in

Fernandes SR, Singsen BH, Hoffman GS. Sarcoidosis and systemic vasculitis. Semin

Foster S. Ocular manifestations of sarcoidosis preceding systemic manifestations. In: Grassi

Fraioli P, Montemurro L, Castrignano L, Rizzato G. Retroperitoneal involvement in

Gobel U, Kettritz R, Schneider W, Luft F. The protean face of renal sarcoidosis. J Am Soc

Godin M et al. Sarcoidosis, retroperitoneal fibrosis, renal artery involvement and unilateral focal glomerulosclerosis. Archives of Internal Medicine. 1980;140:1240-1242 Guenel J and Chevet D. Interstitial nephropathies in sarcoidosis. Effect of corticosteroid

Gupta, R. Beaudet, Lisa and Mehta, Tulsi. Treatment of sarcoid granulomatous interstitial

Hannedouche, T., Grateau, G., Noël, et al. Renal Granulomatous Sarcoidosis: Report of Six

Hiatt R, Dales L. Friedman G. Frequency of urolithiasis in a prepaid medical care program.

nephritis with adalimumab. NDT Plus. 2008;2(2): 139-142.

Cases. Nephrolo Dial Transplant. 1990;5(1):18-24.

Americal Journal Epidemiol 1982: 115: 255-65.

sarcoidosis. Long term follow up studies in two patients. American J Nephrol. 1986;

C. Rizzato G, Pzzi E, eds. *Sarcoidosis and other granuloamtous disorders.* Amsterdam:

therapy and long-term evolution. Retrospective study of 22 cases. Nephrologie.

sarcoidosis: A report of 6 cases. Clin Nephrol. 2002; 57 :142– 148. Casella FJ, Allon M. The Kidney in Sarcoidosis. J Am Soc Nephrol 1993; 3: 1555-1562.

TNF-α the answer? Clinical Science. 2007; 11: 281–289.

Arthritis Rheum. 2000 Aug; 30(1):33-46.

sarcoidosis. Sarcoidosis. 1990;7(2):101.

Elsevier; 1988: 1977-81.

Nephrol. 2001; 12:616–623.

1988;9(6):253-7.

granulomatosis followed by development of sarcoidosis. Am J Kidney Dis. 1996;

A French Multicenter Study. Clinical Journal of American Society of Nephrology

**10. References**

28:893 -898. 47.

2010 5: 2101-2108.

2006; 48(5):856-870.

253(1):41-5.

6:22-27.

transplantation with excellent graft function with a creatinine of 1. 32 mg/dl and a negative urinalysis. Patient was maintained on cyclosporine, azathioprine and prednisone 25 mg by mouth daily. 2 years after transplantation once the steroids were withdrawn, patient continued to have good kidney function with an allograft biopsy showing mild chronic allograft nephropathy only. Immunosuppression consisted of azathioprine and cyclosporine. At 3 years after kidney transplantation, patient became pregnant. 29 weeks into pregnancy, renal function worsened. Biopsy showed numerous noncaseating granulomas bound to the arteries, initial arteritis in one artery, mild interstitial mononuclear inflammation and tubulitis. Graft function improved with pulse methylprednisolone and tapered steroids were used. After delivery, renal allograft biopsy was performed 6 months which showed baseline disease of mild chronic allograft nephropathy and sporadic granulomas. This case demonstrates that steroid withdrawal after kidney transplantation may lead to sarcoidosis recurrence.

The implication that sarcoid reflects a disease phenomena related to the immunologic stimulus makes sarcoidosis an unlikely diagnosis to be made in an immunosuppressed patient such as an organ transplant recipient. However, Schmidt et al showed that after kidney transplantation, sarcoidosis can occur in the lung and pleura. (Schmidt et al 1999) In this case, a 41 yr old with history of IgA nephropathy and no past medical history received a living related kidney transplant and had been receiving tacrolimus therapy. He was found to have a large pleural effusion 17 months after kidney transplant. Diagnosis of sarcoidosis was established by identifying noncaseating granulomas, some with multinucleated giant cells in the pleural and lung tissue. All viral and bacterial workup was negative. The effusion resolved after initiating corticosteroid therapy. One month into therapy, the effusion resolved and patient continued to be asymptomatic twenty months after therapy. The authors did not speculate on the pathogenesis of granuloma formation since both tacrolimus and corticosteroids interfere with T lymphocyte function and granuloma formation. They speculated that activation of tissue chemokines of the IP-10 type during the posttransplant period, along with subsequent recruitment of lymphocytes and macrophages may have resulted in the sarcoidosis.

#### **9. Conclusion**

Sarcoidosis is a disease that primarily affects the reticuloendothelial system but can affect all tissues and organ systems. In this chapter, we described the effects of sarcoidosis on the kidneys. This disease affects patients worldwide and is defined pathologically by the presence of noncaseating granulomas in the involved tissue. The etiology of sarcoidosis has yet to be determined but some have proposed a possible infectious etiology. Commonly sarcoid patients present with hypercalcemia, hypercalcuria, and nephrolithiasis due to the overproduction of calcitriol from the epitheliod granulomas. We also described the rare glomerular and renovascular manifestations of sarcoidosis. Granulomatous interstitial nephritis is most commonly associated with sarcoidosis. It is a histological diagnosis and can be treated with both steroids and TNF-alpha antagonists. Kidney transplantation is safe in patients with sarcoidosis but we must keep in mind the disease can recur in the allograft. In conclusion, sarcoidosis is a complex disease and presents both a diagnostic and management challenge to the physician.

#### **10. References**

102 Chronic Kidney Disease

transplantation with excellent graft function with a creatinine of 1. 32 mg/dl and a negative urinalysis. Patient was maintained on cyclosporine, azathioprine and prednisone 25 mg by mouth daily. 2 years after transplantation once the steroids were withdrawn, patient continued to have good kidney function with an allograft biopsy showing mild chronic allograft nephropathy only. Immunosuppression consisted of azathioprine and cyclosporine. At 3 years after kidney transplantation, patient became pregnant. 29 weeks into pregnancy, renal function worsened. Biopsy showed numerous noncaseating granulomas bound to the arteries, initial arteritis in one artery, mild interstitial mononuclear inflammation and tubulitis. Graft function improved with pulse methylprednisolone and tapered steroids were used. After delivery, renal allograft biopsy was performed 6 months which showed baseline disease of mild chronic allograft nephropathy and sporadic granulomas. This case demonstrates that steroid withdrawal after kidney transplantation

The implication that sarcoid reflects a disease phenomena related to the immunologic stimulus makes sarcoidosis an unlikely diagnosis to be made in an immunosuppressed patient such as an organ transplant recipient. However, Schmidt et al showed that after kidney transplantation, sarcoidosis can occur in the lung and pleura. (Schmidt et al 1999) In this case, a 41 yr old with history of IgA nephropathy and no past medical history received a living related kidney transplant and had been receiving tacrolimus therapy. He was found to have a large pleural effusion 17 months after kidney transplant. Diagnosis of sarcoidosis was established by identifying noncaseating granulomas, some with multinucleated giant cells in the pleural and lung tissue. All viral and bacterial workup was negative. The effusion resolved after initiating corticosteroid therapy. One month into therapy, the effusion resolved and patient continued to be asymptomatic twenty months after therapy. The authors did not speculate on the pathogenesis of granuloma formation since both tacrolimus and corticosteroids interfere with T lymphocyte function and granuloma formation. They speculated that activation of tissue chemokines of the IP-10 type during the posttransplant period, along with subsequent recruitment of lymphocytes and macrophages

Sarcoidosis is a disease that primarily affects the reticuloendothelial system but can affect all tissues and organ systems. In this chapter, we described the effects of sarcoidosis on the kidneys. This disease affects patients worldwide and is defined pathologically by the presence of noncaseating granulomas in the involved tissue. The etiology of sarcoidosis has yet to be determined but some have proposed a possible infectious etiology. Commonly sarcoid patients present with hypercalcemia, hypercalcuria, and nephrolithiasis due to the overproduction of calcitriol from the epitheliod granulomas. We also described the rare glomerular and renovascular manifestations of sarcoidosis. Granulomatous interstitial nephritis is most commonly associated with sarcoidosis. It is a histological diagnosis and can be treated with both steroids and TNF-alpha antagonists. Kidney transplantation is safe in patients with sarcoidosis but we must keep in mind the disease can recur in the allograft. In conclusion, sarcoidosis is a complex disease and presents both a diagnostic and

may lead to sarcoidosis recurrence.

may have resulted in the sarcoidosis.

management challenge to the physician.

**9. Conclusion**


Sarcoidosis and Kidney Disease 105

Muther, R., Mc Carron D et al. Renal manifestations of sarcoidosis. Arch Intern Medicine

Nishiki M, Murakami Y, Yamane Y, Kato Y: Steroid-sensitive nephrotic syndrome,

O'Riordan E, Willert RP, Reeve R et al. Isolated sarcoid granulomatous interstitial nephritis: review of five cases at one center. Clin Nephrol. 2001 Apr;55(4):297-302. Parry RG, Falk C: Minimal change disease in association with sarcoidosis. Nephrol Dial

Rajakariar, E., Sharples, J et al. Sarcoid tubulo-interstitial nephritis: Long-term outcome and

Rizzato G, Fraioli P, Montemurro L. Nephrolithiasis as a presenting feature of chronic

Robson MG, Banerjee D, Hopster D, Cairns HS: Seven cases of granulomatous interstitial

Schmidt, R., Bender, f. Change, W: Sarcoidosis After renal Transplantation. Transplantation

Shen S, Hall-Craggs, M. et al : Recurrent sarcoid granulomatous nephritis and reactive

Shintaku M, Mase K, Ohtsuki H, Yasumizu R, Yasunaga K, Ikehara S: Generalized

Sinnamon, T. Courtney, Harron, C et al. Tubulointerstitial nephritis and uveitis (TINU)

Taylor JE, Ansell ID: Steroid sensitive nephrotic syndrome and renal impairment in a patient with sarcoidosis. Nephrol Dial Transplant. 1996; 11:355 -356. Tchenio X et al. Amylose renale AA au cours d'une sarcoidose. Revue des Maladies

Thumfart J. Isolated sarcoid granulomatous interstitial nephritis responding to infliximab

Tsiouris N, Kovacs B, Daskal I I, Brent LH, Samuels A. End stage renal disease in sarcoidosis

Ulz JP, Limper AH, Kalra S, et al. Etanercept for the treatment of stage II and III progressive

Vanhille, Ph et al. Glomerulonephrite rapidement progressive a depots mesangiuax d'IgA

nephritis in the absence of extrarenal sarcoid. Nephrol Dial Transplant. 2003 ;18

tuberculin skin test in a renal transplant recipient. American Journal of Medicine

sarcoidlike granulomas with systemic angiitis, crescentic glomerulonephritis, and pulmonary hemorrhage. Report of an autopsy case. Arch Pathol Lab Med. 1989;

syndrome: epidemiology, diagnosis and management. Nephrol Dial Transpl Plus.

Rainfray M. Renal amyloidosis complicating sarcoidosis. Thorax. 1988;43:422-423.

response to corticosteroid therapy. Kid Int. 2006; 70: 165–169.

Sharma OP. Vitamin D, Calcium, and Sarcoidosis. Chest 1996; 109(2): 535-539. Sheffield EA: Pathology of sarcoidosis. Clin Chest Med. 1997;18: 741-753.

sarcoidosis, and thyroiditis: A new syndrome? Nephrol Dial Transplant. 1999;

1981;141 :643-645.

Transplant. 1997;12 : 2159-2160.

sarcoidosis. Thorax 1995; 50:555.

Rizzato G: Sarcoidosis in Italy. Sarcoidosis 9(supl): 145-147. 1995

14:2008 -2010.

:280– 284.

68(9) 1420-1423, 1999.

80:699-702, 1986.

113:1295 -129.

2008; 2(1): 112-116.

Respiratoires. 1996; 13. 601-602.

therapy. Am J Kidney Dis 2005;45:411-414.

pulmonary sarcoidosis. Chest 2003;124:177.

of the kidney. 1999. Am J Kidney Disease. 1999;34: E21

au cours d'une sarcoidose. Nephrologie. 1986;5: 207-209.


Iannuzzi MC, Rybicki BA, Teirstein AS. Medical Progress: Sarcoidosis. N Engl J Med 2007:

Iannuzzi MC, Fontana JR. Sarcoidosis: Clinical Presentation, Immunopathogenesis, and

Ito, Shuichi, Harada, Tomonori, Nakamura, Tomoko et al. Mizoribine for renal sarcoidosis:

Johnson C, Wilson D, O'Fallon W et al. Renal stone epidemiology: a 25 year study in

Joss, Nicola, Morris, Scott and Young, B et al. Granulomatous Interstitial Nephritis. CJASN

Kettritz, R**,** Goebel U, Fiebeler, A, et al. The protean face of sarcoidosis revisited. Nephrol

Khan IH, Simpson JG, Catto GR, MacLeod AM: Membranous nephropathy and granulomatous interstitial nephritis in sarcoidosis. Nephron. 1999 66: 459 -461. Kukura S, Viklicky o, Lacha J, et al: Recurrence of sarcoidosis in renal allograft during

Lebacq E, Desmet V, Verhaegen H. Renal involvement in sarcoidosis. Postgrad Med J 1970;

Mahévas M, Lescure FX, Boffa J et al. Renal sarcoidosis: clinical, laboratory, and histologic presentation and outcome in 47 patients. Medicine (Baltimore). 2009;88(2):98. Marcussen N and Lund C. Combined sarcoidosis and disseminated visceral giant cell

Maruyama S, Cantu E 3rd, Demartino C, Vladutiu A, Caldwell PR, Wang CY, D'Agati V,

Mery, Jean-Phillippe. The patient with sarcoidosis. Oxford textbook of Clinical Nephrology,

Mery J. P., Kenouch S. Les atteintes de l'interstitium rénal au cours des maladies systémiques. Seminares d'uro-nephrologie Pitie-Salpetriere, 1988; 57-89 Moudgil, A., Przygodzki, R. and Kher. K. Successful steroid-sparing treatment of renal

Michaels S, Sabnis SG, Oliver JD, Guccion JG: Renal sarcoidosis with superimposed

Mills, PR, Burns AP, Dorman AM, Sweny PJ, Moorhead JF. Granulomatous sarcoid

Miyazaki E, Tsuda T, et al. : Sarcoidosis presenting as bilateral hydronephrosis. Intern Med

Mundlein E, Greten T, Ritz E: Graves' disease and sarcoidosis in a patient with minimalchange glomerulonephritis. Nephrol Dial Transplant. 1996; 11:860 -862.

Godman G, Stern DM, Andres G. Membranous glomerulonephritis induced in the pig by antibody to angiotensin-converting enzyme: considerations on its relevance to the pathogenesis of human idiopathic membranous glomerulonephritis. J Am

limited sarcoidosis with mycophenolate mofetil. Pediatric Nephrol 2006;21(2):281-

glomerulonephritis presenting as acute renal failure. Am J Kidney Dis. 2000; 36:1 -6.

nephritis presenting as frank haematuria. Nephrol Dial Transplant. 1994;9(11):1649-

Rochester, Minnesota. Kidney International 1979: 16: 624-31.

pregnancy. Nephrology Dialysis Transplant 2004; 19: 1640-1642.

vasculitis. Pathology, Research and Practice. 1989;184:325-330.

3rd Edition (2005), Volume 1, Oxford University Press:733-740.

effective steroid tapering and prevention of recurrence. Pediatr Nephrol 2009;

357(21). 2153-2165.

2007; 2(2); 222-230.

24:411-414.

46: 526.

285.

51.

35: 579-582, 1996

Therapeutics. JAMA 2011; 305(4):391-399.

Dial Transplant 2006**;** 21:2690-2694.

Soc Nephrol. 1999 Oct;10(10):2102-8.


**7**

*The Netherlands* 

**Origins of Cardiorenal Syndrome and**

*1Dept. of Cardiology, University Medical Center Utrecht, Utrecht 2Dept. of Nephrology, University Medical Center Utrecht, Utrecht* 

In recent years, the relationship between the heart and the kidneys in disease has received increasing attention from the clinical and scientific medical community. This was initiated by epidemiological observations in the late 1990's of increasing patient numbers with concurrent heart and kidney problems, and the association with a significantly higher mortality ratio. This has led to intense discussions about the value of the recognition of cardiorenal disease on the one hand, and the existence of a specific "cardiorenal syndrome"

The idea of specific interaction between heart and kidneys is not new. There are numerous examples and anecdotes that show that people in the past from various societies considered

The Egyptian "Book of the Dead" (1600-1240 B.C.), which served as a reference work to assist the deceased in the afterlife, is one of the first known texts that mentions the heart and

*"Homage to thee, O my heart! Homage to you, O my kidneys!".11*

The heart and the kidneys were the only organs left inside the body during the process of mummification. The heart was weighed against the feather of truth by the jackal-headed Anubis (Figure 1), but the exact role of the kidneys for the passage into afterlife is uncertain. Blood vessels are well preserved in mummies, and there is evidence that cardiovascular

"[T]he kidneys are mentioned five times in the Bible as the organs examined by God to pass judgment on a person. They are mentioned either before or after but always in parallel with the heart, as for example, "*I, the Lord, search the heart, I try the reins, even to give every man according to his ways, and according to the fruit of his doings*" (Jer. 17:10), and,

"*Examine me, O Lord, and prove me; try my reins and my heart*" (Psalms 26:2)."

disease affecting both the heart and the kidneys were not uncommon.12

**1. Introduction** 

on the other hand.1-10

kidneys in parallel:

the heart and the kidneys to have a special relationship.

**1.1 Heart and kidneys in ancient times** 

Eknoyan13 researched the Bible and found that:

**the Cardiorenal Connection** 

L. G. Bongartz1,2, M. J. Cramer1 and J. A. Joles2

