Kidney disease in sarcoidosis

INTRODUCTION — Clinically important kidney involvement occasionally occurs in sarcoidosis. Kidney manifestations include interstitial nephritis with or without granuloma formation, and nephrocalcinosis and/or nephrolithiasis resulting from abnormal calcium homeostasis. The classic kidney lesion is noncaseating granulomatous interstitial nephritis. However, hypercalciuria and hypercalcemia are most often responsible for clinically significant kidney disease. Glomerular disease, obstructive uropathy, and end-stage kidney disease (ESKD) may also occur but are uncommon [1,2].

The kidney manifestations of sarcoidosis will be reviewed here. General issues related to sarcoidosis and its pathogenesis are discussed separately:

●(See "Clinical manifestations and diagnosis of sarcoidosis".)

●(See "Pathology and pathogenesis of sarcoidosis".)

EPIDEMIOLOGY — The incidence and prevalence of kidney involvement in sarcoidosis remain uncertain [3]. The reported prevalence ranges widely due to the variation in study design and enrolled patient populations and due to the heterogeneity and often asymptomatic nature of kidney disease.

Several small series have suggested that kidney involvement (as defined by either histologic changes in the kidney or a decline in kidney function in the absence of a biopsy) occurs in approximately 10 to 50 percent of patients with sarcoidosis [4-8], although the disease may be silent and undetected for many years (or forever). A large study examining more than 1200 hospitalized patients with sarcoidosis reported that kidney manifestations were present in approximately 6 percent of cases [9].

Several studies have examined the relative prevalence of the various kidney lesions related to sarcoidosis: the most common manifestations include interstitial nephritis, nephrolithiasis, and nephrocalcinosis [1,6,10-12]. In one study that reported kidney biopsy results from 27 patients with sarcoidosis and kidney disease, nongranulomatous or granulomatous tubulointerstitial nephritis was observed in 74 percent and nephrocalcinosis was observed in 11 percent [13]. Patients who have interstitial nephritis also may have nephrolithiasis or nephrocalcinosis [14]. (See 'Tubulointerstitial nephritis' below and 'Kidney stones' below and 'Nephrocalcinosis' below.)

Sarcoidosis-associated glomerular involvement (such as membranous nephropathy, focal segmental glomerulosclerosis, immunoglobulin A (IgA) nephropathy, and crescentic glomerulonephritis) and other kidney manifestations of sarcoid (such as granulomatous kidney masses or urinary tract obstruction due to retroperitoneal lymph node involvement, retroperitoneal fibrosis, or direct ureteral involvement) are rare. (See 'Uncommon causes' below and 'Other kidney manifestations' below.)

PATHOGENESIS — The pathogenesis of inflammation and granuloma formation that leads to interstitial nephritis in sarcoidosis is discussed elsewhere. (See "Pathology and pathogenesis of sarcoidosis".)

Hypercalciuria with or without hypercalcemia in many patients with sarcoidosis may cause nephrocalcinosis and/or nephrolithiasis. Intestinal hyperabsorption of dietary calcium occurs in up to 50 percent of cases of sarcoidosis [1]. The excess calcium leads to hypercalciuria in approximately 40 percent of cases and to hypercalcemia in 2 to 20 percent [1,2,15-17].

This abnormality in calcium homeostasis is not limited to sarcoidosis, as it occurs in many other chronic granulomatous diseases. The defect in these disorders is increased production of calcitriol (1,25 dihydroxyvitamin D, the most active metabolite of vitamin D) by activated mononuclear cells (particularly macrophages) in granulomas, the lung, and lymph nodes. Increased calcitriol production appears to be due both to markedly enhanced activation and production of 1-alpha-hydroxylase, the enzyme that converts 25-hydroxyvitamin D to calcitriol, and inadequate feedback inhibition, which normally limits enzyme expression [18]. (See "Hypercalcemia in granulomatous diseases".)

IMPAIRED KIDNEY FUNCTION

Initial evaluation — Sarcoid-related kidney disease should be considered in all patients with sarcoidosis who present with acute kidney injury (AKI) or chronic kidney disease (CKD). It should also be considered in all patients with AKI or CKD who have hypercalcemia (or serum calcium levels at the higher end of the reference range); most other causes of AKI or CKD are associated with low-normal serum calcium levels because of decreased kidney calcitriol production.

Because AKI and/or CKD in patients with sarcoidosis is not always due to sarcoidosis, patients should be evaluated thoroughly for other causes of kidney function impairment, using the same approach as that for patients without sarcoidosis. This is discussed in detail elsewhere. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting" and "Chronic kidney disease (newly identified): Clinical presentation and diagnostic approach in adults".)

The targeted laboratory and imaging studies routinely obtained in all patients with newly identified CKD or AKI usually detect or suggest sarcoid-associated kidney disease. As examples, a kidney ultrasound is an effective means of identifying nephrocalcinosis, and urine studies showing sterile pyuria without heavy proteinuria suggest interstitial nephritis.

Common causes — Nephrocalcinosis is a significant cause of CKD in patients with sarcoidosis [1,8,19]. Sarcoid-related interstitial nephritis can cause AKI and/or CKD, depending on the severity and course of kidney inflammation.

Nephrocalcinosis — Sarcoid is one of many causes of nephrocalcinosis. Nephrocalcinosis has been reported in between 5 and 13 percent of patients with sarcoidosis [8,10].

●Clinical manifestations and diagnosis – Nephrocalcinosis is generally asymptomatic and slowly progressive. Patients may present only with an elevated creatinine and benign urinalysis, with or without hypercalcemia. Some patients also may have nephrolithiasis and/or polyuria due to hypercalciuria [20]. The diagnosis of nephrocalcinosis is usually made with kidney imaging (preferably ultrasound or computed tomography [CT]), though it is also apparent on kidney biopsy. The clinical presentation and diagnosis of nephrocalcinosis are discussed in detail elsewhere. (See "Nephrocalcinosis", section on 'Diagnosis' and "Nephrocalcinosis", section on 'Clinical features'.)

●Evaluation after diagnosis – Because nephrocalcinosis has multiple causes, it should be attributed to sarcoidosis only after the demonstration of hypercalcemia and/or hypercalciuria and excessive 1-alpha-hydroxylase activity (ie, elevated serum levels of 1,25 dihydroxyvitamin D with low or low-normal levels of parathyroid hormone). The evaluations of hypercalcemia, if present, and nephrocalcinosis are discussed in detail elsewhere. (See "Diagnostic approach to hypercalcemia" and "Nephrocalcinosis", section on 'Subsequent evaluation for underlying causes'.)

●Treatment – Interventions to delay or stop the progression of sarcoid-mediated nephrocalcinosis are generally the same as those used to prevent recurrent sarcoid-mediated nephrolithiasis and depend on the presence or absence of hypercalcemia. However, for patients with nephrocalcinosis who have neither hypercalcemia nor recurrent kidney stones, we generally do not use pharmacologic agents to inhibit excess production of 1,25 dihydroxyvitamin D; in these patients the risks of such therapy outweigh potential benefits. (See 'Kidney stones' below.)

For patients with nephrocalcinosis, data to support specific measures that increase the solubility of urinary calcium phosphate or calcium oxalate (eg, increased fluid intake to increase urine volume) are extrapolated from studies of patients with kidney stones (see 'Kidney stones' below). The general management of CKD, regardless of cause, is discussed elsewhere. (See "Overview of the management of chronic kidney disease in adults".)

Tubulointerstitial nephritis — Interstitial nephritis occurs in approximately 20 percent of patients with sarcoidosis [11]. However, kidney function impairment is not always present (picture 1) [2,21-24]. As an example, a survey of all kidney biopsies over a six-year period at three general hospitals found clinically significant sarcoid granulomatous interstitial nephritis in only four cases [15-17].

Clinical manifestations — Sarcoid-related tubulointerstitial nephritis is usually identified in patients with a new diagnosis of sarcoidosis who have diffuse active disease [14,21,25-27]; interstitial nephritis infrequently develops among patients with a longstanding history of sarcoidosis [14]. Many patients with interstitial nephritis have advanced CKD at presentation [14]. These clinical features are illustrated by a retrospective review of 47 patients with biopsy-proven interstitial nephritis (37 with noncaseating granulomas and 10 with interstitial nephritis without granulomas) that reported the following [14]:

●Elevated serum creatinine when diagnosed with sarcoidosis – 98 percent (n = 46)

●Stage 4 or 5 CKD at presentation – 63 percent (n = 29)

●Symptoms due to extrarenal sarcoidosis involvement at time of kidney diagnosis – 81 percent (n = 38)

●Thoracic involvement on chest radiograph – 90 percent (n = 42)

●Systemic symptoms, including fatigue, weight loss, and fever – 42 percent (n = 20)

The urinary manifestations of interstitial nephritis are relatively nonspecific. The urinalysis is either normal or shows only sterile pyuria or mild proteinuria. In a review of 52 cases of sarcoid-related interstitial nephritis, sterile pyuria, hematuria, glycosuria were identified in 33, 21, and 12 percent, respectively [10].

Significant proteinuria is uncommon. In a prospective review of 191 sarcoid patients, proteinuria, defined as urine protein-to-creatinine ratio equal to or exceeding 0.3 mg/mg, was found in 7 percent of patients [28]. More than half of these patients had a known risk factor for proteinuria (diabetes, hepatitis B or C infection, human immunodeficiency virus [HIV], systemic lupus erythematosus, or congestive heart failure).

Diagnosis — The diagnosis of sarcoid-related interstitial nephritis should be suspected among patients who have an elevated serum creatinine, a bland urine sediment or sterile pyuria, and either a known diagnosis or characteristic presentation of extrarenal sarcoidosis. Among such patients, an elevated (or high-normal) serum calcium level also is suggestive. (See "Clinical manifestations and diagnosis of sarcoidosis".)

A definitive test for sarcoid-associated interstitial nephritis does not exist. The diagnosis requires three elements:

●Extrarenal manifestations of sarcoidosis (see "Clinical manifestations and diagnosis of sarcoidosis", section on 'Diagnostic approach')

●Interstitial nephritis demonstrated by kidney biopsy (see "Clinical manifestations and diagnosis of acute interstitial nephritis", section on 'Histology')

●Exclusion of other etiologies of interstitial nephritis (see "Clinical manifestations and diagnosis of acute interstitial nephritis", section on 'Establishing the cause')

Histology indicative of interstitial nephritis includes normal glomeruli; interstitial infiltration, mostly with mononuclear cells; tubular injury; and, with more chronic disease, interstitial fibrosis. Kidney biopsy findings of noncaseating granulomas in the interstitium are suggestive, but not diagnostic, of sarcoidosis. Granulomas are not seen in all biopsies of patients with sarcoid-associated interstitial nephritis, and they may be seen in other conditions. In one retrospective review of 40 patients with granulomas on kidney biopsy, 20 were due to sarcoidosis, and the remainder resulted from drug reactions (seven cases), tuberculosis (three), granulomatosis with polyangiitis (GPA; two), leprosy (one), mycobacterium avium (one), and Crohn disease (one) [29].

Rarely, patients with sarcoid-associated interstitial nephritis have no extrarenal manifestations of sarcoidosis upon presentation. Thus, all patients who have granulomatous interstitial nephritis detected on biopsy should have a chest radiograph and pulmonary function tests and, if these are nondiagnostic, a high-resolution chest CT scan to evaluate for pulmonary sarcoidosis. (See "Clinical manifestations and diagnosis of sarcoidosis".)

Differential diagnosis — Among patients with interstitial nephritis, other conditions that must be considered include drug-induced interstitial nephritis, tuberculosis, other mycobacterial infections, GPA, brucellosis, histoplasmosis, tubulointerstitial nephritis with uveitis (TINU) syndrome, and, rarely, Crohn disease [29-31]. (See "Clinical manifestations and diagnosis of acute interstitial nephritis".)

Treatment — The treatment of sarcoid-associated interstitial nephritis is discussed below. The general management of patients with AKI or CKD, regardless of cause, is discussed elsewhere. (See "Overview of the management of acute kidney injury (AKI) in adults" and "Overview of the management of chronic kidney disease in adults".)

●Glucocorticoids as first-line therapy – For most patients with active tubulointerstitial nephritis due to sarcoidosis, we suggest treatment with glucocorticoids. Patients with irreversible kidney damage (indicated by fibrosis on biopsy) are unlikely to recover kidney function fully; glucocorticoid therapy among such patients is directed at attempting to slow the course of the disease. However, in patients with severe interstitial fibrosis on biopsy (ie, >50 to 75 percent), the risks of immunosuppressive therapy often outweigh the benefits. In patients with active tubulointerstitial nephritis who also have severe fibrosis on biopsy, our approach depends on kidney size as assessed by ultrasound:

•For patients with small kidneys (eg, <9 cm), we generally do not treat with immunosuppressive medications.

•For patients without small kidneys, the decision to treat with prednisone is determined by shared decision-making and is based on the individual patient's comorbidities and risk tolerance.

The optimal dosing regimen for and course of glucocorticoid therapy are unclear. We use prednisone 1 mg/kg per day (up to a maximum dose of 80 mg daily) for six to eight weeks, followed by a slow taper thereafter during the next four to five months to a maintenance dose of 10 mg for an additional six to nine months. Relapses can occur in responders if glucocorticoids are tapered too rapidly [23], and some patients need low doses indefinitely. The precise glucocorticoid regimen may also depend on the course of extrarenal disease, though in general glucocorticoid doses used to treat pulmonary sarcoidosis are lower than doses used for kidney sarcoidosis. (See "Treatment of pulmonary sarcoidosis: Initial approach".)

Data to support the use of glucocorticoids for sarcoid-associated interstitial nephritis are limited primarily to case series [14,32]. In a study of 47 patients with kidney sarcoidosis who were treated with prednisone (with 10 also receiving intravenous [IV] pulse methylprednisolone), the following outcomes were observed [14]:

•A complete and partial response occurred in 30 and 5 patients, respectively. However, 66 percent of patients had an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² at a median follow-up of 24 months.

•No response was reported in those with >50 percent fibrosis by histologic examination.

•The presence of hypercalcemia on presentation correlated with a complete response to glucocorticoid therapy at one year (odds ratio [OR] 16, 95% CI 1.8-137).

The addition of pulse IV methylprednisolone to oral glucocorticoid regimens does not appear to confer benefit; in a trial that randomly assigned 40 patients with sarcoidosis-associated interstitial nephritis to pulse IV methylprednisolone followed by oral prednisone or to oral prednisone alone, kidney outcomes were similar in each group [33].

●Complications of glucocorticoid therapy – Systemic glucocorticoid therapy can lead to numerous adverse effects, including osteoporosis, diabetes mellitus, and opportunistic infection. Given that ectopic hydroxylation of vitamin D may occur in sarcoid granulomas, there is concern about using calcium and vitamin D supplements to prevent osteoporosis in such patients [34-36]. However, supplementation with modest doses of calcium and vitamin D, with appropriate monitoring of serum and 24-hour urine calcium, is safe in many patients with sarcoidosis who are treated with glucocorticoids [37]. Our approaches to calcium and vitamin D supplementation, and to diabetes and opportunistic infection, in patients with sarcoidosis who are undergoing glucocorticoid therapy are presented elsewhere. (See "Treatment of pulmonary sarcoidosis: Initial approach", section on 'Adverse effects'.)

●Alternative therapies – In patients with sarcoidosis-related interstitial nephritis who cannot tolerate or who do not respond to glucocorticoids, alternative therapies that are effective in pulmonary sarcoidosis may be attempted, such as methotrexate, azathioprine, mycophenolate mofetil, a combination of these drugs, or, as a last resort, tumor necrosis factor antagonists or their biosimilars [38,39]. Effects of these agents on kidney disease are uncertain. (See "Treatment of pulmonary sarcoidosis refractory to initial therapy".)

Uncommon causes — Uncommon causes of impaired kidney function in patients with sarcoidosis include inflammatory glomerulonephritis, obstruction without kidney stones, and reduced glomerular perfusion due to hypercalcemia.

●Glomerulonephritis – Patients with sarcoidosis occasionally present with inflammatory glomerulonephritis [40,41], although the mechanism of glomerular injury is not known nor is the relationship to sarcoidosis proven. Patients with glomerulonephritis have significant proteinuria and hematuria (with or without red cell casts), differentiating them from those with interstitial nephritis. The evaluation of inflammatory glomerulonephritis is discussed elsewhere; treatment depends on the cause and is the same in patients with and without sarcoidosis. (See "Glomerular disease: Evaluation and differential diagnosis in adults", section on 'Glomerulonephritis (hematuria with proteinuria, kidney function impairment, or other manifestations)'.)

In one study that reported kidney biopsy results in 27 patients with sarcoidosis, 26 percent had IgA nephropathy [13]. Crescentic glomerulonephritis and membranoproliferative glomerulonephritis due to various causes have been reported in patients with sarcoidosis [42], as have cases of antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis [43].

●Obstruction without kidney stones – Ureteral obstruction may result from retroperitoneal lymph node involvement, retroperitoneal fibrosis, and direct ureteral involvement by sarcoid [44-46]. Obstructive uropathy due to sarcoidosis may be responsive to glucocorticoids, but invasive urologic decompression or hemodialysis may be required prior to a clinically significant response [2,44].

●AKI due to hypercalcemia – Marked hypercalcemia from any cause, including sarcoidosis, leads to preglomerular arteriolar vasoconstriction [47], which is sometimes severe enough to cause AKI [48]. AKI solely due to severe hypercalcemia usually resolves with treatment. (See "Treatment of hypercalcemia" and "Hypercalcemia in granulomatous diseases".)

KIDNEY STONES

Clinical manifestations and diagnosis — Nephrolithiasis occurs in approximately 1 to 14 percent of patients with sarcoidosis [1,6,11,12]. The stones are usually comprised of calcium oxalate, sometimes mixed with calcium phosphate. The clinical presentation and diagnosis of nephrolithiasis are discussed in detail elsewhere. (See "Kidney stones in adults: Diagnosis and acute management of suspected nephrolithiasis".)

Calcium nephrolithiasis may be the presenting feature of sarcoidosis [1,6,11,12]:

●In a retrospective study of 618 patients with sarcoidosis, kidney calculi were the first manifestations in 14 (2.2 percent) [49]. In another nine patients who presented with pulmonary involvement, persistent hematuria or pyuria led to the discovery of asymptomatic calculi via ultrasonography or intravenous (IV) pyelography. Thus, 23 patients (3.7 percent) had kidney calculi at presentation.

●In a prospective study, nephrolithiasis was the presenting feature of the disease in 4 percent of 204 consecutive patients with sarcoidosis [50].

Evaluation after diagnosis — Because calcium kidney stones are so common, calcium nephrolithiasis should be attributed to sarcoidosis only after the demonstration of hypercalcemia and/or hypercalciuria with evidence of excessive 1-alpha-hydroxylase activity (ie, elevated serum levels of 1,25 dihydroxyvitamin D with low or low-normal levels of parathyroid hormone). The evaluations of hypercalcemia, if present, and recurrent calcium kidney stones are discussed in detail elsewhere. (See "Diagnostic approach to hypercalcemia" and "Kidney stones in adults: Evaluation of the patient with established stone disease".)

Prevention — Prevention of sarcoid-associated kidney stones involves sufficient fluid intake and managing hypercalcemia and/or hypercalciuria.

As for all patients with kidney stones, fluid intake should be maintained to produce at least 2 liters of urine per day. Patients with sarcoid-associated stone disease generally should avoid vitamin D supplements, which may increase the abnormal production of 1,25 dihydroxyvitamin D. Other interventions to prevent sarcoid-mediated kidney stone formation depend on the presence or absence of hypercalcemia:

●Hypercalcemia – For patients with hypercalcemia due to sarcoidosis, the primary means of preventing recurrent calcium kidney stones is to lower serum calcium levels; this usually requires treatment with pharmacologic agents that inhibit the excess production of 1,25 dihydroxyvitamin D either by treating granulomatous inflammation (eg, glucocorticoids) or by inhibition of 1-alpha-hydroxylase (eg, ketoconazole). Decreasing calcium intake may improve hypercalcemia. The treatment of hypercalcemia in patients with sarcoidosis is discussed in detail elsewhere. (See "Hypercalcemia in granulomatous diseases", section on 'Treatment'.)

Thiazide diuretics, which are often used to treat recurrent calcium stones due to hypercalciuria, are contraindicated in patients with hypercalcemia and in patients taking pharmacologic agents to control hypercalcemia. These agents lead to calcium retention and can further increase serum calcium levels.

●Normocalcemia – For patients without hypercalcemia, dietary interventions to prevent calcium stone recurrence (eg, limiting sodium intake) are the same as those for patients without sarcoidosis. (See "Kidney stones in adults: Prevention of recurrent kidney stones".)

Drug therapy is generally indicated if the stone disease remains active or if there is insufficient improvement in the 24-hour urine chemistries despite attempted dietary modification. Oral alkali (eg, potassium citrate or potassium bicarbonate) and allopurinol are therapeutic options for patients with low urine citrate and high urine uric acid, respectively; the use of these agents is discussed in detail elsewhere. (See "Kidney stones in adults: Prevention of recurrent kidney stones", section on 'Preventive measures for specific stone types'.)

For patients with sarcoid-mediated stone disease who do not have low urine citrate or high urine uric acid, or who have ongoing stone formation despite appropriate treatment with oral alkali and/or allopurinol, pharmacologic treatment is directed at lowering urine calcium. Medications used for this purpose include thiazide diuretics and alternative agents as discussed below:

•Thiazide diuretics – Patients with hypercalciuria due to sarcoidosis are at high risk of thiazide-induced hypercalcemia. If a thiazide challenge is pursued in a patient with sarcoidosis, serum calcium levels should be checked one week following, and then every two to three months. The thiazide should be stopped if hypercalcemia develops, and patients with sarcoidosis may not be able to tolerate thiazide dose escalation. Thiazide use for the prevention of calcium stones is discussed in detail elsewhere. (See "Kidney stones in adults: Prevention of recurrent kidney stones", section on 'High urine calcium'.)

•Alternative agents – For patients with sarcoidosis who have recurrent, severe calcium stone disease and do not respond to or tolerate a thiazide diuretic, agents normally reserved for the treatment of sarcoid-mediated hypercalcemia (eg, low-dose glucocorticoids) may be considered as an alternative means of lowering urine calcium. These therapies have adverse side effects and should be discontinued if they do not lower 24-hour urine calcium excretion. These medications are discussed separately. (See "Hypercalcemia in granulomatous diseases", section on 'Pharmacologic therapy'.)

Monitoring the response to dietary and/or drug interventions is discussed elsewhere. (See "Kidney stones in adults: Prevention of recurrent kidney stones", section on 'Monitoring the response'.)

OTHER KIDNEY MANIFESTATIONS

●Nephrotic syndrome – Patients with sarcoidosis may present with nephrotic syndrome (eg, heavy proteinuria, hypoalbuminemia, and peripheral edema), although the relationship to sarcoidosis is unknown. The evaluation and treatment of protein losing nephropathies are the same in patients with and without sarcoidosis and are discussed elsewhere. (See "Glomerular disease: Evaluation and differential diagnosis in adults", section on 'Proteinuria' and "Overview of heavy proteinuria and the nephrotic syndrome".)

Membranous nephropathy is the most common cause of protein-losing nephropathy in patients with sarcoidosis [51-53], although focal segmental glomerulosclerosis also has been observed [42]. In a study of 26 patients with sarcoidosis who had clinical evidence of glomerular disease, 11 had membranous nephropathy [53]. Phospholipase A2 receptor (PLA2R) antibodies are frequently observed in patients with sarcoidosis and membranous nephropathy [54].

As in other chronic inflammatory diseases, kidney AA amyloidosis has been reported in patients with sarcoidosis [55].

●Kidney mass – Granulomatous kidney infiltration rarely may manifest as a kidney mass [56,57].

PROGNOSIS

Risk of end-stage kidney disease — End-stage kidney disease (ESKD) due to sarcoidosis is uncommon. When it occurs, ESKD is due to nephrocalcinosis and/or interstitial nephritis. In the largest observational study, among 47 patients with sarcoidosis-related interstitial nephritis, only two progressed to ESKD (at 15 and 2 years after presentation) [14].

Patients with more severe manifestations of sarcoidosis may be more likely to develop ESKD. In a study of 78 patients with sarcoidosis who required hospitalization due to the disease, 34 had kidney involvement. Of the 34 patients with sarcoid-related kidney disease, eight (24 percent) eventually progressed to ESKD [4]. Risk factors for ESKD included advanced age at the time of kidney disease diagnosis and interstitial fibrosis on kidney biopsy.

Outcomes after kidney transplantation — The outcome of kidney transplantation in patients with sarcoidosis is not well known. The best data are from a retrospective review of 18 patients with sarcoidosis from eight French kidney transplantation centers [58]. In 10 patients, ESKD was due to granulomatous interstitial nephritis; in eight other patients, ESKD was attributed to causes other than sarcoidosis. At the end of a median follow-up of four years, patient and death-censored graft survival was 94 percent.

Recurrence of kidney sarcoidosis after transplantation has been described [58,59]. In the French study above, kidney sarcoidosis recurred in 3 of 10 patients [58]. The patients who had kidney recurrence had a lower median estimated glomerular filtration rate (eGFR; 31 mL/min/1.73 m²) compared with the entire cohort. Recurrence was observed a median of 13 months after transplantation.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Kidney involvement, defined by either histologic changes in the kidney or a decline in kidney function, occurs in approximately 10 to 50 percent of patients with sarcoidosis, though it is often undetected. The most common kidney manifestations of sarcoidosis include nephrocalcinosis, nephrolithiasis, and interstitial nephritis. Sarcoidosis-associated glomerular involvement is rare. (See 'Epidemiology' above.)

●Pathogenesis – Hypercalciuria with or without hypercalcemia may cause nephrocalcinosis and/or nephrolithiasis and is due to increased production of calcitriol (1,25 dihydroxyvitamin D, the most active metabolite of vitamin D) by activated mononuclear cells (particularly macrophages) in granulomas. The pathogenesis of inflammation and granuloma formation that leads to interstitial nephritis in sarcoidosis is discussed elsewhere. (See 'Pathogenesis' above and "Pathology and pathogenesis of sarcoidosis".)

●Impaired kidney function – The most common sarcoid-specific causes of impaired kidney function are nephrocalcinosis, which can cause chronic kidney disease (CKD), and tubulointerstitial nephritis, which can cause CKD or acute kidney injury (AKI) depending on the severity and course of kidney inflammation.

•Initial evaluation – Patients with sarcoidosis-related AKI or CKD may have hypercalcemia or serum calcium levels in the higher range of normal; by contrast, most other causes of AKI or CKD are associated with low-normal serum calcium levels because of decreased kidney calcitriol production. The targeted laboratory and imaging studies routinely obtained in all patients with newly identified CKD or AKI usually detect or suggest sarcoidosis-associated kidney disease. (See 'Initial evaluation' above.)

•Nephrocalcinosis – Nephrocalcinosis is generally asymptomatic and slowly progressive. Patients may present only with an elevated creatinine and benign urinalysis, with or without hypercalcemia. The diagnosis of nephrocalcinosis is usually made with kidney imaging (preferably ultrasound or computed tomography [CT]), though it is also apparent on kidney biopsy. Interventions to delay or stop the progression of sarcoid-mediated nephrocalcinosis are generally the same as those used to prevent recurrent sarcoid-mediated nephrolithiasis and depend on the presence or absence of hypercalcemia. (See 'Nephrocalcinosis' above.)

•Tubulointerstitial nephritis – The diagnosis of sarcoid-related interstitial nephritis should be suspected among patients who have an elevated serum creatinine, a bland urine sediment or sterile pyuria, and either a known diagnosis or characteristic presentation of extrarenal sarcoidosis. The diagnosis requires interstitial nephritis demonstrated by kidney biopsy, exclusion of other etiologies of interstitial nephritis, and extrarenal manifestations of sarcoidosis. For most patients with active tubulointerstitial nephritis due to sarcoidosis, we suggest treatment with glucocorticoids rather than no immunosuppressive therapy or other immunosuppressive agents (Grade 2C). (See 'Tubulointerstitial nephritis' above.)

●Kidney stones – Calcium nephrolithiasis may be the presenting feature of sarcoidosis. Because calcium kidney stones are so common, calcium nephrolithiasis should be attributed to sarcoidosis only in those with hypercalcemia and/or hypercalciuria who have evidence of excessive 1-alpha-hydroxylase activity (ie, elevated serum levels of 1,25 dihydroxyvitamin D with low or low-normal levels of parathyroid hormone). Prevention of sarcoid-associated kidney stones involves sufficient fluid intake and managing hypercalcemia and/or hypercalciuria. (See 'Kidney stones' above.)

●Prognosis – End-stage kidney disease (ESKD) due to sarcoidosis is uncommon. When it occurs, ESKD is due to nephrocalcinosis and/or interstitial nephritis. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Gianfranco Rizzato, MD, who contributed to earlier versions of this topic review.