INTRODUCTION — Clinically important kidney involvement occasionally occurs in sarcoidosis. Kidney manifestations include abnormal calcium metabolism, nephrolithiasis and nephrocalcinosis, and acute interstitial nephritis with or without granuloma formation. The classic kidney lesion is noncaseating granulomatous interstitial nephritis. However, this lesion rarely causes clinically significant kidney disease. 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 pulmonary 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 larger cohort (ie, more than 1200 patients with pulmonary sarcoidosis) found that kidney manifestations were present in 12 percent of cases [9].
Several studies have examined the relative prevalence of the various kidney lesions associated with sarcoidosis:
●Overall, nephrocalcinosis is estimated to occur in 5 percent of patients with sarcoidosis [10]. Nephrocalcinosis is a significant cause of chronic kidney disease (CKD) [1,8,11]. (See "Nephrocalcinosis".)
●Nephrolithiasis occurs in approximately 1 to 14 percent of patients with sarcoidosis [1,6,12,13].
●Interstitial nephritis with granuloma formation occurs in approximately 20 percent of patients [12]. However, kidney function impairment is not always present (picture 1) [2,14-17]. 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 [18-20]. Patients who have interstitial nephritis may also have nephrolithiasis or nephrocalcinosis [21]. In one study that included a cohort of 27 patients with renal sarcoidosis (four of them with isolated renal; all the others with systemic sarcoidosis), the most commonly observed histologic lesion was nongranulomatous tubulointerstitial nephritis (44 percent), followed by granulomatous tubulointerstitial nephritis (30 percent), immunoglobulin A (IgA) glomerulonephritis (26 percent), and nephrocalcinosis (11 percent) [22]. Another series of 34 patients with sarcoidosis and kidney function impairment reported tubulointerstitial disease in 71 percent [4].
●Glomerular involvement is rare. A variety of different lesions have been described in isolated cases, including membranous nephropathy, IgA nephropathy, minimal change disease, a proliferative or crescentic glomerulonephritis, and focal segmental glomerulosclerosis [2,23-27].
●Urinary tract obstruction is very rare among patients with sarcoidosis.
PROGNOSIS — End-stage kidney disease (ESKD) requiring some form of kidney replacement therapy is uncommon. When it occurs, ESKD is most often due to hypercalcemic nephropathy rather than granulomatous nephritis or a glomerulonephropathy, although nephrocalcinosis is less common overall than interstitial nephritis. In the largest observational study, among 46 patients with sarcoidosis-related interstitial nephritis, only two progressed to ESKD (at 15 and 2 years after presentation) [21]. 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.
In a second study of 34 patients with sarcoidosis-related kidney disease, eight patients (24 percent) progressed to ESKD [4]. Risk factors for ESKD included advanced age at the time of kidney disease diagnosis, granulomatous tubulointerstitial nephritis, and interstitial fibrosis.
NEPHROLITHIASIS AND NEPHROCALCINOSIS
Pathogenesis — Nephrocalcinosis and nephrolithiasis are caused by hypercalcemia and/or hypercalciuria.
Hyperabsorption of dietary calcium occurs in up to 50 percent of cases of sarcoidosis [1]. The excess calcium is excreted in the urine, leading to hypercalciuria in approximately 40 percent and, in 2 to 20 percent of cases, to hypercalcemia [1,2,18-20].
This abnormality in calcium metabolism 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 the absence of feedback inhibition, which normally limits enzyme expression [28]. (See "Hypercalcemia in granulomatous diseases".)
Clinical manifestations — Nephrolithiasis may be the presenting feature of sarcoidosis [1,6,12,13]. Signs and symptoms of nephrolithiasis are discussed elsewhere. (See "Kidney stones in adults: Diagnosis and acute management of suspected nephrolithiasis" and "Kidney stones in adults: Diagnosis and acute management of suspected nephrolithiasis", section on 'Clinical manifestations'.)
●In a retrospective study of 618 patients with sarcoidosis, kidney calculi were the first manifestations in 14 (2.2 percent) [29]. 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 [30].
The stones are usually of calcium oxalate, sometimes mixed with calcium phosphate.
Patients with nephrocalcinosis may present only with an elevated creatinine and benign urinalysis. Such patients will generally be found to have hypercalciuria with or without hypercalcemia. (See "Nephrocalcinosis", section on 'Clinical presentation'.)
Patients with nephrocalcinosis may have polyuria, which is caused by hypercalcemia and possibly hypercalciuria, resulting in reduced responsiveness to antidiuretic hormone [31]. Polyuria in sarcoidosis may also reflect central diabetes insipidus (ie, lack of antidiuretic hormone) or primary polydipsia due to granulomatous infiltration of the hypothalamus [32] (see "Clinical manifestations and causes of nephrogenic diabetes insipidus" and "Evaluation of patients with polyuria"). Hypercalcemia may also cause a decreased glomerular filtration rate (GFR) through preglomerular arteriolar vasoconstriction [33].
Diagnosis — The evaluation of nephrolithiasis and nephrocalcinosis is discussed elsewhere. (See "Kidney stones in adults: Diagnosis and acute management of suspected nephrolithiasis" and "Nephrocalcinosis".)
Differential diagnosis — The differential diagnosis of sarcoidosis-related nephrocalcinosis and nephrolithiasis includes conditions that cause hypercalcemia and hypercalciuria (primary hyperparathyroidism, vitamin D therapy, milk-alkali syndrome, other granulomatous diseases, and congenital hypothyroidism) and conditions that cause hypercalciuria in the absence of hypercalcemia (distal renal tubular acidosis, medullary sponge kidney, neonatal nephrocalcinosis and loop diuretics, inherited tubulopathies, and chronic hypokalemia). (See "Nephrocalcinosis".)
Treatment — Glucocorticoids (which decrease inflammatory activity and therefore calcitriol synthesis), chloroquine, hydroxychloroquine, and ketoconazole can improve calcium metabolism in patients with sarcoidosis. A more complete discussion of the pathogenesis and treatment of this problem is presented separately. (See "Hypercalcemia in granulomatous diseases".)
INTERSTITIAL NEPHRITIS
Pathogenesis — The pathogenesis of granuloma formation in sarcoidosis is extensively discussed elsewhere. (See "Pathology and pathogenesis of sarcoidosis".)
Clinical manifestations — Sarcoid-related interstitial nephritis is usually identified on the initial presentation of sarcoidosis and rarely develops among patients who have a longstanding diagnosis of sarcoidosis [21]. This was demonstrated in a retrospective review of 47 patients with biopsy-proven interstitial nephritis (37 with noncaseating granulomas and 10 with interstitial nephritis without granulomas) [21]. Among 38 patients (81 percent), the kidney lesion was diagnosed concurrently with at least one other site of sarcoidosis involvement.
Most patients with interstitial nephritis present with an elevated creatinine that is detected on routine screening or as part of their initial evaluation for sarcoidosis. In a study cited above, among 47 patients with sarcoidosis interstitial nephritis, 46 presented with an elevated creatinine at diagnosis [21].
Twenty-nine patients (62.5 percent) were already in stage 4 or 5 of chronic kidney disease (CKD) at presentation [21].
Most patients with kidney involvement have clear evidence of diffuse active sarcoidosis [14,21,34-36]. As an example, among 47 patients, 42 (90 percent) had thoracic involvement identified on chest radiograph [21]. Systemic symptoms, including fatigue, weight loss, and fever, were present in 20 patients (42 percent).
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 sarcoidosis interstitial nephritis, sterile pyuria, hematuria, glycosuria, and hypercalciuria were identified in 33, 21, 12, and 8 percent, respectively [10]. Significant proteinuria is uncommon. In a prospective review of 191 sarcoid patients, proteinuria, defined as urine protein/creatinine ratio equal to or exceeding 0.3 mg/mg, was found in 7 percent of patients [37]. 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 sarcoidosis interstitial nephritis should be suspected among patients who present with an elevated serum creatinine and bland urine sediment and have either a known diagnosis or characteristic presentation of extrarenal sarcoidosis. (See "Clinical manifestations and diagnosis of pulmonary sarcoidosis".)
The diagnosis of sarcoidosis interstitial nephritis is strongly suggested by kidney biopsy. Kidney biopsy reveals normal glomeruli; interstitial infiltration, mostly with mononuclear cells; noncaseating granulomas in the interstitium; tubular injury; and, with more chronic disease, interstitial fibrosis.
However, these findings are suggestive, but not diagnostic, of sarcoidosis. In one retrospective review of 40 cases of renal granulomatoses, 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) [38]. No etiology could be identified in five cases in this study.
There is no single diagnostic test for sarcoidosis. Thus, in the setting of granulomatous interstitial nephritis, one must rely upon the exclusion of other etiologies of interstitial nephritis and upon the demonstration of extrarenal manifestations of sarcoidosis to be confident of the diagnosis.
●(See "Clinical manifestations and diagnosis of acute interstitial nephritis", section on 'Histology'.)
●(See "Clinical manifestations and diagnosis of pulmonary sarcoidosis", section on 'Diagnostic approach'.)
Occasionally, patients with renal sarcoidosis 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 computed tomography (CT) scan to evaluate for pulmonary sarcoidosis. (See "Clinical manifestations and diagnosis of pulmonary sarcoidosis", section on 'Diagnostic approach'.)
Measurement of serum calcium, 24-hour urinary calcium concentration, and a serum angiotensin-converting enzyme (ACE) concentration may also provide support for the diagnosis of sarcoidosis.
Differential diagnosis — Among patients with interstitial nephritis, other conditions that must be considered include drug-induced interstitial nephritis, tuberculosis, other mycobacterium infections, GPA, brucellosis, histoplasmosis, tubulointerstitial nephritis with uveitis (TINU) syndrome, and, rarely, Crohn disease [38-40]. (See "Clinical manifestations and diagnosis of acute interstitial nephritis".)
Treatment — We treat all patients who have a reduced estimated glomerular filtration rate (eGFR) related to biopsy-demonstrated sarcoidosis interstitial nephritis with glucocorticoids. Glucocorticoids (up to 1 mg/kg/day) have been shown to be effective among such patients, although the recovery is often incomplete due to longstanding disease with irreversible kidney damage [14,17,21,34]. The response to glucocorticoids was best noted in a study of 47 patients with renal sarcoidosis [21]. All patients received prednisone, while 10 also received intravenous (IV) pulse methylprednisolone. At a median follow-up of 24 months, the following was noted:
●A complete and partial response occurred in 30 and 5 patients, respectively.
●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 interpretation of this study is limited by the fact that the reported results were not adjusted for other factors that may have affected response to therapy.
There are limited data to guide glucocorticoid therapy. Based on the study cited above, we suggest oral prednisone 1 mg/kg/day for 6 to 12 weeks, followed by a slow taper thereafter to a maintenance dose of 10 to 20 mg for an additional six to nine months [21]. Relapses can occur in responders if glucocorticoids are tapered too rapidly, and some patients need low doses indefinitely. In one series of five patients, the only individual who relapsed received <20 mg/day of prednisolone for the first three months of therapy [16].
In patients with sarcoidosis 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, chloroquine, azathioprine, a combination of these drugs, or, as a last resort, tumor necrosis factor antagonists or their biosimilars [41,42]. (See "Treatment of pulmonary sarcoidosis refractory to initial therapy".)
Glucocorticoid therapy can lead to osteoporosis. Given that ectopic hydroxylation of vitamin D may occur in sarcoid granulomas, there is some concern about using calcium and vitamin D supplements to prevent osteoporosis in such patients [43-45]. However, supplementation with modest doses of calcium and vitamin D is generally appropriate and safe in patients with sarcoidosis treated with glucocorticoids [46]; our approach to supplementation is presented in detail elsewhere. (See "Treatment of pulmonary sarcoidosis: Initial approach to treatment".)
GLOMERULONEPHRITIS — Patients with sarcoidosis occasionally present with glomerulonephritis, although the mechanism of glomerular injury is not known, nor is the relationship to sarcoidosis proven [25,47]. As an example, as noted above, in one study that included 27 patients with biopsy-proven sarcoidosis, 26 percent had immunoglobulin A (IgA) nephropathy [22]. Another report described a patient with sarcoidosis and crescentic glomerulonephritis with interstitial granuloma formation in association with a positive antineutrophil cytoplasmic antibody (ANCA) test, thereby confounding a possible relationship between the glomerular disease and sarcoidosis [47]. Other forms of glomerulonephritis that have been described in patients with sarcoidosis include membranous glomerulonephritis, focal segmental glomerulonephritis, and membranoproliferative glomerulonephritis [27,48]. Patients with glomerulonephritis present with significant proteinuria or red cell casts, differentiating them from those with interstitial nephritis.
Like in other chronic inflammatory diseases, AA amyloidosis has also been described and found in the kidney biopsy of a patient with systemic sarcoidosis [49].
As in other forms of sarcoid nephropathy, the administration of glucocorticoids appears to improve kidney function [22,25,47].
URETERAL OBSTRUCTION AND OTHER KIDNEY MANIFESTATIONS — Ureteral obstruction may result from retroperitoneal lymph node involvement, retroperitoneal fibrosis, kidney stones, and direct ureteral involvement by sarcoid [50-52] (see "Clinical manifestations and diagnosis of retroperitoneal fibrosis"). Obstructive uropathy due to retroperitoneal involvement may be responsive to glucocorticoids, but invasive urologic decompression or hemodialysis may be required prior to a clinically significant response [2,50]. (See "Treatment of retroperitoneal fibrosis".)
Retroperitoneal fibrosis, which is rare in sarcoidosis, can also involve the renal artery, which may be affected by sarcoid angiitis. When present, vasculitis of the renal artery is commonly associated with hypertension [53].
KIDNEY TRANSPLANTATION — The outcome of kidney transplantation is not well known. The best data are from a retrospective review of 18 patients from eight French kidney transplantation departments [54]. In 10 patients, kidney failure was due to granulomatous interstitial nephritis; in eight other patients, no kidney biopsy was done. At the end of a median follow-up of four years, patient and death-censored graft survival was 94 percent. The mean glomerular filtration rate (GFR) was 60 mL/min/1.73 m2.
Recurrence of renal sarcoidosis has been described [54,55]. In one report, sarcoidosis recurred in five patients (27 percent), including two who had extrarenal involvement and three who had kidney involvement [54]. The patients who had renal recurrence had a lower median estimated GFR (eGFR; 31 mL/min/1.73 m2) compared with the entire cohort. Recurrence was observed a median of 13 months after transplantation. The relatively high rate of recurrence in patients with sarcoidosis-related primary kidney disease suggests that specific clinical and histologic monitoring may be warranted during the early posttransplant period.
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
●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 is commonly undetected. Primary kidney manifestations are nephrolithiasis and nephrocalcinosis and acute interstitial nephritis with or without granuloma formation. The classic kidney lesion is noncaseating granulomatous interstitial nephritis, but this lesion rarely causes clinically significant kidney disease. 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. (See 'Introduction' above and 'Epidemiology' above.)
●Nephrocalcinosis and nephrolithiasis are caused by hypercalcemia and/or hypercalciuria, resulting from hyperabsorption of ingested calcium due to increased production of calcitriol by activated mononuclear cells. The stones are usually composed of calcium oxalate, sometimes mixed with calcium phosphate. Patients may have polyuria and a decreased glomerular filtration rate (GFR) due to hypercalcemia-induced preglomerular arteriole vasoconstriction. Glucocorticoids (which decrease inflammatory activity and therefore calcitriol synthesis), chloroquine, hydroxychloroquine, and ketoconazole can improve calcium metabolism in patients with sarcoidosis. (See 'Nephrolithiasis and nephrocalcinosis' above and "Kidney stones in adults: Diagnosis and acute management of suspected nephrolithiasis" and "Nephrocalcinosis" and "Hypercalcemia in granulomatous diseases".)
●Patients with sarcoidosis interstitial nephritis present with an elevated serum creatinine that is detected on routine screening or as part of their initial evaluation for sarcoidosis. Most patients have clear evidence of diffuse active sarcoidosis elsewhere. The urinalysis is usually normal or shows sterile pyuria or mild proteinuria. (See 'Pathogenesis' above and 'Clinical manifestations' above.)
●There is no single diagnostic test for sarcoidosis. The diagnosis of sarcoidosis interstitial nephritis is suggested by kidney biopsy, which shows an interstitial mononuclear infiltrate, noncaseating granulomas, tubular injury, and, with more chronic disease, interstitial fibrosis. These findings are suggestive, but not diagnostic, of sarcoidosis. In the setting of interstitial nephritis, one must rely upon the exclusion of other etiologies and upon the demonstration of extrarenal manifestations of sarcoidosis to be confident of the diagnosis. (See "Clinical manifestations and diagnosis of acute interstitial nephritis", section on 'Histology' and "Clinical manifestations and diagnosis of acute interstitial nephritis", section on 'Establishing the cause' and "Clinical manifestations and diagnosis of pulmonary sarcoidosis", section on 'Diagnostic approach'.)
●Occasionally, patients with renal sarcoidosis have no extrarenal manifestations of sarcoidosis upon presentation. Thus, all patients who have granulomatous interstitial nephritis detected on biopsy should have a chest radiograph, pulmonary function tests, and, if these are nondiagnostic, a high-resolution chest computed tomography (CT) scan to evaluate for pulmonary sarcoidosis. (See "Clinical manifestations and diagnosis of pulmonary sarcoidosis", section on 'Diagnostic approach'.)
●Glucocorticoids have been shown to be an effective treatment for patients with interstitial nephritis related to sarcoidosis, although the recovery may be incomplete due to longstanding disease with irreversible kidney damage. For all patients who have a reduced estimated GFR (eGFR) related to biopsy-demonstrated sarcoidosis interstitial nephritis, we suggest a trial of oral prednisone (Grade 2C). The optimal dose is not known. A suggested regimen is prednisone 1 mg/kg/day for 6 to 12 weeks, with a slow taper thereafter to a maintenance dose of 10 to 20 mg for an additional six to nine months. (See 'Treatment' above.)
●Patients occasionally present with glomerulonephritis, although the relationship to sarcoidosis has not been proven. As in other forms of sarcoid nephropathy, the administration of steroids appears to improve kidney function.
●Ureteral obstruction may result from retroperitoneal lymph node involvement, retroperitoneal fibrosis, kidney stones, and direct ureteral involvement by sarcoid. Obstructive uropathy due to retroperitoneal involvement may be responsive to glucocorticoids, but invasive urologic decompression or hemodialysis may be required prior to a clinically significant response.
●ESKD requiring some form of kidney replacement therapy is uncommon, although many patients may have a reduced eGFR. (See 'Prognosis' above.)
