**Sarcoidosis and Kidney Disease**

Tulsi Mehta, Anirban Ganguli and Mehrnaz Haji-Momenian

*Department of Medicine, Washington Hospital Center, Washington DC, USA* 

#### **1. Introduction**

86 Chronic Kidney Disease

Yoshihara, A.; Seida, Y.; Hanada, N; et al. (2004). A longitudinal study of the relationship

older adults. *J Clin Periodontol*, 31, pp. 680-684.

between periodontal disease and bone mineral density in community-dwelling

Sarcoidosis is an illness of granulomatous inflammation with multi-organ association. While most individuals exhibit pulmonary pathology, renal involvement is not without prevalence or significance. This chapter will review the current epidemiology of the disease and explore the two major pathways in the pathogenesis of renal sarcoidosis, mainly granulomatous deposition and deranged calcium management. With these concepts addressed, further inquiries into intrinsic renal disease will be provided along with explanations of renovascular complications, obstructive nephropathy, and transplant pathology. Each ailment will be accompanied by common presentation, more detailed pathophysiology, appropriate diagnostics, and current treatment recommendations. This chapter will seek to purvey a comprehensive but concise exploration of renal sarcoidosis.

#### **2. Epidemiology & susceptibility**

Sarcoidosis can affect a wide range of racial and ethnic groups but it has high prevalence in northern European countries, Japan, and the United States1. Certain countries have skewed incidences, for example: black Americans are three times more likely than white Americans to develop the disease (Iannuzzi et al. 2007). However, across the racial and ethnic groups, females are more prone to the illness than males (Iannuzzi et al. 2007). The disease manifests itself typically in patients less than 50 years of age and mainly in the third of fourth decade of life (Iannuzzi et al. 2011). A patient with a first degree relative with the disease has a fivefold increase of developing sarcoidosis. Nevertheless, this risk still does not exceed 1% (Iannuzzi et al. 2011). Patient susceptibility also increases with certain associations of genetics and environmental factors. Discoveries into HLA gene products and the butyrophilin-like2 (BTNL2) gene are the latest areas of genetic interests (Iannuzzi et al. 2007). A variety of environmental triggers including wood-burning stoves, tree pollen, inorganic particles, insecticides, and mold have also been scrutinized in addition to mycobacteria and propionibacteria antigens (Iannuzzi et al. 2007, 2011). In fact, combinations of genetic and environmental activators have also been examined, for example: HLA-DQB1 and water damage or high humanity in the workplace (Iannuzzi et al. 2007). However, it seems that a ubiquitous number of agents may initiate a similar immunologic pathway that is pathognomonic for sarcoidosis.

Sarcoidosis and Kidney Disease 89

(Iannuzzi MC et al. N Engl J Med 2007;357:2153-2165.)

and possibly corticosteroid therapy (Sharma 1996).

Fig. 1. Hypothesized Immunopathogenesis of Granuloma Formation.

causing disturbed calcium homeostasis. This not only causes hypercalcemia, hypercalciuria and possibly subsequent nephrolithiasis and nephrocalcinosis, which itself is the most common cause of progressive renal failure. The clinical consequences of each imbalance range from trivial presentation to overt pathology including dehydration, renal colic, and end-stage renal disease. Diagnosis may be established by laboratory findings, ultrasonography, and computed tomography. General treatments incorporate adequate oral hydration, minimization of dietary calcium and vitamin D, avoidance of UV light exposure,

#### **3. Manifestations & pathogenesis**

Sarcoidosis mainly affects the pulmonary system, with an over 90% occurrence rate in the afflicted, presenting as mostly hilar lymphadenopathy but also including pulmonary hyperternsion and obstructive and restrictive airway disease (Iannuzzi et al. 2011). Other major organ systems disturbed include the skin, the eye, the heart, and the nervous system with approximately 25 to 30% involvement (Iannuzzi et al 2011). Renal sarcoidosis is in fact rare with exact number relating prevalence difficult to come by. Unfortunately, the etiology for nephron-related disease is quite vast and it has been hard to delineate pure renal manifestations from simple metabolic disturbances (Berliner et al 2006). In order to understand the extent and pathogenesis of renal involvement, two central pathways for nephron insult has been validated including granulomatous deposition and deranged calcium management. While these pathways are by no means the only two routes of renal involvement, they are the most significant and the overriding themes for renal insult.

#### **3.1 Granuloma formation**

Many aspects of this process still require elucidation yet strong evidence reveals that granuloma formation centers on T cells reacting with unclear triggers and certain gene products to illicit cascades that either lead to complete resolution of inflammation or to irreversible fibrosis (Iannuzzi et al. 2007). Specifically, antigen presenting cells including macrophages with susceptible HLA or BTNL2 gene products present triggers including organic, inorganic, and infectious agents to the CD4 T cell. Once initiated, numerous peripheral cytokines, interleukins, and immune modulators steer T cells into a T Helper 1 or T Helper 2 response; where with the former, resolution of inflammation is more probable but with the later, fibrosis and irreversible damage is more probable (Iannuzzi et al. 2007, 2011). This deposition of macrophages, giant cells, and T helper cells form the pathognomonic, non-caseating granulomas that defines sarcoidosis (Casella and Allon 1983) See Figure 1. In renal disease, these granulomas are primarily in the cortex but may also be found in the medulla or capsule (Casella and Allon 1983). This process is the basis for granulomatous interstitial nephritis, which will be further discussed subsequently.

#### **3.2 Deranged calcium management**

Despite the granulomatous inflammation that marks sarcoidosis, deranged calcium homeostasis has a greater effect on the kidneys than the invasive granulomas themselves. Activated pulmonary macrophages express 1-α hydroxylase, which has important implications in maintaining appropriate levels of calcium in the body. In normal physiology, calcium balance is attained through the intricate interactions of parathyroid hormone (PTH), calcium, phosphorus, and Vitamin D. PTH upregulates renal 1-α hydroxylase, a cytochrome P450 enzyme located in the proximal tubule, to metabolize 25-hydroxy vitamin D to 1, 25 dihydroxy vitamin D, the bioactive form of Vitamin D, also known as calcitriol. Calcitriol, in turn, promotes calcium absorption in the intestines, kidneys, and bones. When calcium levels are adequate, normal physiological negative feedback mechanisms halt the PTH and calcitriol cycle. However, in sarcoidosis, extra-renal production of 1-α hydroxylase inappropriately increases calcitriol levels thereby increasing serum calcium and decreasing PTH. Unlike its renal equivalent, the granulomatous 1-α hydroxylase is immuned from the normal negative feedback mechanisms of hypercalcemia and is therefore unregulated,

Sarcoidosis mainly affects the pulmonary system, with an over 90% occurrence rate in the afflicted, presenting as mostly hilar lymphadenopathy but also including pulmonary hyperternsion and obstructive and restrictive airway disease (Iannuzzi et al. 2011). Other major organ systems disturbed include the skin, the eye, the heart, and the nervous system with approximately 25 to 30% involvement (Iannuzzi et al 2011). Renal sarcoidosis is in fact rare with exact number relating prevalence difficult to come by. Unfortunately, the etiology for nephron-related disease is quite vast and it has been hard to delineate pure renal manifestations from simple metabolic disturbances (Berliner et al 2006). In order to understand the extent and pathogenesis of renal involvement, two central pathways for nephron insult has been validated including granulomatous deposition and deranged calcium management. While these pathways are by no means the only two routes of renal

involvement, they are the most significant and the overriding themes for renal insult.

granulomatous interstitial nephritis, which will be further discussed subsequently.

Despite the granulomatous inflammation that marks sarcoidosis, deranged calcium homeostasis has a greater effect on the kidneys than the invasive granulomas themselves. Activated pulmonary macrophages express 1-α hydroxylase, which has important implications in maintaining appropriate levels of calcium in the body. In normal physiology, calcium balance is attained through the intricate interactions of parathyroid hormone (PTH), calcium, phosphorus, and Vitamin D. PTH upregulates renal 1-α hydroxylase, a cytochrome P450 enzyme located in the proximal tubule, to metabolize 25-hydroxy vitamin D to 1, 25 dihydroxy vitamin D, the bioactive form of Vitamin D, also known as calcitriol. Calcitriol, in turn, promotes calcium absorption in the intestines, kidneys, and bones. When calcium levels are adequate, normal physiological negative feedback mechanisms halt the PTH and calcitriol cycle. However, in sarcoidosis, extra-renal production of 1-α hydroxylase inappropriately increases calcitriol levels thereby increasing serum calcium and decreasing PTH. Unlike its renal equivalent, the granulomatous 1-α hydroxylase is immuned from the normal negative feedback mechanisms of hypercalcemia and is therefore unregulated,

Many aspects of this process still require elucidation yet strong evidence reveals that granuloma formation centers on T cells reacting with unclear triggers and certain gene products to illicit cascades that either lead to complete resolution of inflammation or to irreversible fibrosis (Iannuzzi et al. 2007). Specifically, antigen presenting cells including macrophages with susceptible HLA or BTNL2 gene products present triggers including organic, inorganic, and infectious agents to the CD4 T cell. Once initiated, numerous peripheral cytokines, interleukins, and immune modulators steer T cells into a T Helper 1 or T Helper 2 response; where with the former, resolution of inflammation is more probable but with the later, fibrosis and irreversible damage is more probable (Iannuzzi et al. 2007, 2011). This deposition of macrophages, giant cells, and T helper cells form the pathognomonic, non-caseating granulomas that defines sarcoidosis (Casella and Allon 1983) See Figure 1. In renal disease, these granulomas are primarily in the cortex but may also be found in the medulla or capsule (Casella and Allon 1983). This process is the basis for

**3. Manifestations & pathogenesis** 

**3.1 Granuloma formation** 

**3.2 Deranged calcium management** 

(Iannuzzi MC et al. N Engl J Med 2007;357:2153-2165.)

Fig. 1. Hypothesized Immunopathogenesis of Granuloma Formation.

causing disturbed calcium homeostasis. This not only causes hypercalcemia, hypercalciuria and possibly subsequent nephrolithiasis and nephrocalcinosis, which itself is the most common cause of progressive renal failure. The clinical consequences of each imbalance range from trivial presentation to overt pathology including dehydration, renal colic, and end-stage renal disease. Diagnosis may be established by laboratory findings, ultrasonography, and computed tomography. General treatments incorporate adequate oral hydration, minimization of dietary calcium and vitamin D, avoidance of UV light exposure, and possibly corticosteroid therapy (Sharma 1996).

Sarcoidosis and Kidney Disease 91

are usually necessary to normalize these parameters as they can decrease inflammatory

(Frailly et al 1990). Sarcoidosis has also been shown to be responsible for bilateral hydronephrosis on the basis of retroperitoneal lymph node enlargement, with resolution

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

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

Retroperitoneal lymph nodes can enlarge sufficiently to cause urethral obstruction.

activity and reduce calcitriol syntheses.

**5.1 Membranous glomerulonephritis** 

et al 2001).

sarcoidosis.

after corticosteroid treatment. (Miyazaki 1995).

**5. Glomerular diseases associated with sarcoidosis** 

Hypercalcemia may cause decrease glomerular filtration rate by vasoconstricting the afferent arterioles and thereby decreasing renal blood flow (Berliner et al 2006). Additionally, it may cause tubular necrosis, tubulointerstitial non-granulomatous inflammation with calcium deposits ultimately causing nephrocalcinosis and chronic kidney disease (Berliner et al 2006). Hypercalciuria, which is three times as more common as hypercalcemia, predisposes patients to calcium oxalate nephrolithiasis, which may ultimately lead to obstruction or chronic pyelonephritis (Berliner et al 2006 and Sharma 1996). Renovascular complications as well as obstructive nephropathy will also be further discussed subsequently.
