Clinicopathological Characteristics and Long-Term Kidney Outcomes in Biopsy-Proven Renal Sarcoidosis

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Abstract

Key Points

• Preexisting CKD, elevated serum creatinine, and severe interstitial fibrosis and tubular atrophy were linked to poor renal prognosis in renal sarcoidosis.

• Steroid therapy was strongly associated with renal recovery and improved long-term outcomes in renal sarcoidosis.

• Early detection and management of renal involvement in sarcoidosis are critical to preventing irreversible kidney damage.

Background

Renal sarcoidosis (RS) is a rare but potentially severe manifestation of sarcoidosis, primarily affecting the kidneys through granulomatous interstitial nephritis and calcium metabolic disturbances. This study evaluates the clinicopathologic features and renal outcomes of biopsy-proven RS, focusing on identifying predictors of renal recovery and disease progression.

Methods

This retrospective study included 43 biopsy-proven RS at Mayo Clinic (2012–2024). Demographic, clinical, laboratory, and histopathologic data were analyzed. Renal recovery within 6 months was classified as complete, partial, or no recovery based on serum creatinine (sCr) changes. Long-term adverse composite outcomes included the CKD onset, CKD progression, ESKD, dialysis initiation, or death. Logistic regression and Cox proportional hazards regression were used to assess predictors of renal outcomes.

Results

Among the cohort, 84% exhibited interstitial nephritis, with granulomatous interstitial nephritis in 33%. Calcium phosphate deposits were found in 58% of cases. Hypercalciuria (90%) was more common than hypercalcemia (74%). Within 6 months, 86% achieved recovery (74% complete, 12% partial), while 40% experienced long-term adverse composite outcomes. Higher sCr at biopsy (≥2.4 mg/dl) and moderate-to-severe interstitial fibrosis and tubular atrophy were associated with reduced complete recovery and worse long-term outcomes, while preexisting CKD significantly increased the risk of adverse long-term outcomes. Steroid therapy significantly increased the likelihood of complete recovery and reduced the risk of adverse long-term outcomes.

Conclusions

Preexisting CKD, elevated sCr at biopsy, interstitial fibrosis and tubular atrophy, and steroid therapy are key predictors of renal outcomes in RS. Early diagnosis and intervention are crucial to preventing irreversible kidney damage.

Introduction

Sarcoidosis is a systemic granulomatous disorder that can affect multiple organs, with pulmonary involvement being the most common.^1–3 The exact etiology of sarcoidosis remains unknown, but it is believed to result from immune dysfunction triggered by environmental or genetic factors.⁴ Renal involvement in sarcoidosis is considered rare, but its exact incidence remains unclear. Renal sarcoidosis (RS) primarily affects the kidneys through granuloma formation, leading to interstitial nephritis, or through metabolic disturbances, such as hypercalcemia and hypercalciuria, which can cause nephrocalcinosis and renal dysfunction. Although granulomatous interstitial nephritis (GIN) is the hallmark histologic feature of RS, it may be absent in some cases. Tubular damage and secondary glomerular diseases such as membranous nephropathy (MN) have also been reported.^5,6

The clinical manifestation of RS is highly variable. Although often asymptomatic, renal involvement can lead to AKI and progressive kidney impairment, including CKD and ESKD.^7,8 Although several studies have explored the clinicopathologic features of RS,^9–12 a comprehensive understanding of its long-term renal progression and associated risk factors remains incomplete.

This study aims to evaluate the clinical, laboratory, histologic, and outcome characteristics of patients diagnosed with RS, with the goal of enhancing the understanding of disease presentation, prognosis, and potential predictors of renal recovery.

Methods

Patient Population

This retrospective study includes patients diagnosed with RS through kidney biopsy from Mayo Clinic between January 2012 and December 2024. The study excluded patients 18 years or younger, those with kidney transplant, or those who were already on dialysis before biopsy. This study was approved by Institutional Review Board (No. 24-011942) of Mayo Clinic. The diagnosis of RS was established based on clinical manifestations and kidney biopsy findings, which include interstitial nephritis with or without granulomata and/or calcium phosphate deposits, following the exclusion of infection and drug-induced acute interstitial nephritis.

Data Collection

The study collected data on demographics, clinical information, and laboratory (Table 1), as well as histologic findings (Table 2) and immunosuppressive therapy (Table 3). Biopsy time was established as the baseline.

Table 1.

Clinical and laboratory findings

Characteristics	All Patients (n=43)
Age at the biopsy (yr)	59.7±9.5
Male sex, n (%)	17 (38.6)
White race, n (%)	38/42 (90.5)
BMI (kg/m2)	28.8±6.5
Comorbidities, n (%)	29 (67.4)
Hypertension	26 (60.5)
Diabetes	8 (18.6)
Pulmonary disease	11 (25.6)
Malignancy	6 (14.0)
Smoking, n (%)	13 (30.2)
Kidney stone, n (%)	12 (27.9)
Sarcoidosis diagnosis, n (%)
Before renal biopsy	28 (65.1)
After renal biopsy	15 (34.9)
Symptoms, n (%)
Weight loss > 5 kg	11 (25.6)
Weakness or fatigue	20 (46.5)
Fever (≥38°C)	2 (4.7)
Renal-limited sarcoidosis, n (%)	5 (11.6)
Non–renal-limited sarcoidosis, n (%)	38 (88.4)
Intrathoracic lesions	25/38 (65.8)
Extrathoracic lesions	5/38 (13.2)
Both intrathoracic and extrathoracic lesions	8/38 (21.1)
Extrathoracic lesions, n	13
Liver, n (%)	4/13 (30.8)
Bone, n (%)	4/13 (30.8)
Cardiac, n (%)	3/13 (23.1)
Ocular, n (%)	3/13 (23.1)
Neuromuscular, n (%)	2/13 (15.4)
Skin, n (%)	2/13 (15.4)
Parotid, n (%)	2/13 (15.4)
Baseline CKD, n (%)	28/41 (68.3)
Baseline sCr (mg/dl)	1.6 (1.1–2.3)
sCr with CKD	1.8 (1.6–2.6)
sCr without CKD	1.0 (1.0–1.1)
Laboratory at biopsy
sCr (mg/dl)	2.4 (1.8–3.0)
sCr with CKD (mg/dl)	2.6 (2.0–2.8)
sCr without CKD (mg/dl)	2.0 (1.4–3.7)
Albumin (g/dl)	4.0±0.5
Corrected calcium (mg/dl)a	11.4±1.7
Hypercalcemia, n (%)	32 (74.4)
25-hydroxy vitamin D (ng/ml)b	25 (19–35)
<20 ng/ml, n (%)	10/36 (27.8)
1,25-dihydroxy vitamin D (pg/ml)c	72 (49–95)
>78 pg/ml, n (%)	15/32 (46.9)
Serum ACE (U/L)d	74 (31–105)
>85 U/L, n (%)	12/27 (44.4)
Serum PTH (pg/ml)e	11 (7.1–22)
<15 pg/ml, n (%)	22/35 (62.9)
CRP (mg/dl)f	4.7 (3.0–12.2)
ESR (mm/h)g	40 (11–57)
Urinary analysis
Microscopic hematuria, n (%)h	8/41 (19.5)
Sterile pyuria, n (%)h	4/41 (9.8)
Urine RTE cell present, n (%)	2/41 (4.9)
Urine cast present, n (%)	3/41 (7.3)
Glycosuria, n (%)	3/41 (7.3)
Eosinophiluria, n (%)h	3/6 (50.0)
Hypercalciuria, n (%)h,i	17/19 (89.5)
24-h proteinuria (g/24-h)	0.33 (0.16–0.66)
Kidney ultrasound or CT, n (%)
Normal	31 (72.1)
Kidney stone	9 (20.9)
Small kidney	1 (2.3)
Nephrocalcinosis	1 (2.3)
Medullary sponge kidney	1 (2.3)

Results are presented as mean±SD or median (interquartile range) for continuous variables and as n (%) for categorical variables. ACE, angiotensin-converting enzyme; BMI, body mass index; CT, computed tomography; CRP, C-reaction protein; ESR, erythrocyte sedimentation rate; PTH, parathyroid hormone; sCr, serum creatinine; RTE, renal tubular epithelial.

^aNormal range of serum calcium: 8.8–10.2 mg/dl, and hypercalcemia was defined as a corrected serum calcium level exceeding 10.2 mg/dl.

^bNormal range of 25-hydroxy vitamin D: 20–50 ng/ml.

^cNormal range of 1,25-dihydroxy vitamin D: 18–78 pg/ml.

^dNormal range of serum angiotensin-converting enzyme: 16–85 U/L.

^eNormal range of serum parathyroid hormone: 15–65 pg/ml.

^fNormal range of C-reaction protein: <5 mg/L.

^gNormal range of erythrocyte sedimentation rate: 0–29 mm/h.

^hMicroscopic hematuria was defined as the presence of ≥3 red blood cells per high-power field. Sterile pyuria was defined as >3 white blood cells/high-power field in males and >10 white blood cells/high-power field in females. Hypercalciuria was characterized by daily urinary calcium excretion of ≥200 mg or a calcium-to-serum creatinine ratio >0.27 mg/mg. Eosinophiluria was defined urine eosinophils comprising more than 1% of the total urinary leukocytes.

ⁱAmong the 17 patients with hypercalciuria, only five (29%) had a history of kidney stones.

Table 2.

Indications for kidney biopsy and corresponding findings

Kidney Biopsy	All Patients (n=43)
Indications for kidney biopsy, n (%)
CKD	17 (39.5)
AKI	13 (30.2)
AKI on CKD	11 (25.6)
Proteinuriaa	2 (4.7)
Hypercalcemiab	4 (9.3)
Biopsy findings
Interstitial nephritis, n (%)	36 (83.7)
GIN	14 (32.6)
Non-GIN	22 (51.2)
Calcium phosphate deposits, n (%)c	25 (58.1)
MN secondary to sarcoidosis, n (%)d	2 (4.6)
Other histologic findings
Global glomerulosclerosis (%)	0 (0–20)
ATN, n (%)	14 (32.6)
IFTA, n	39
None, n (%)	12 (30.8)
Mild, n (%)	10 (25.6)
Moderate, n (%)	11 (28.2)
Severe, n (%)	6 (15.4)
Vessels
Normal	15 (34.9)
Arteriosclerosis	26 (60.5)
Mild, n (%)	12 (27.9)
Moderate, n (%)	14 (32.6)
Severe, n (%)	0 (0)
Arteriolar hyalinosise	7 (16.3)
Coexisting glomerular disease, n (%)	8 (18.6)
IgANf	4 (9.3)
DNg	2 (4.7)
Glomerulomegalyg	1 (2.3)
Microangiopathic changesg	1 (2.3)

ATN, acute tubular necrosis; DN, diabetic nephropathy; GIN, granulomatous interstitial nephritis; IFTA, interstitial fibrosis and tubular atrophy; IgAN, IgA nephropathy; MN, membranous nephropathy.

^aBoth patients demonstrated membranous nephropathy on biopsy.

^bAmong the four patients, two had CKD, one had AKI on CKD, and one had AKI. All three patients with CKD or AKI on CKD exhibited nongranulomatous interstitial nephritis with calcium phosphate deposits, while the patient with AKI presented with nongranulomatous interstitial nephritis.

^cAmong the 25 patients, eight exhibited granulomatous interstitial nephritis, while 13 exhibited nongranulomatous interstitial nephritis.

^dBoth patients lacked interstitial nephritis and calcium deposits but exhibited intrathoracic sarcoidosis lesions.

^eFive patients also had arteriosclerosis.

^fOne patient exhibited granulomatous interstitial nephritis with calcium deposits, while two patients exhibited nongranulomatous interstitial nephritis with calcium deposits. The other one patient exhibited sarcoidosis lesions affecting both intrathoracic and extrathoracic regions, including bone involvement. Despite the absence of interstitial nephritis and calcium deposits, renal sarcoidosis was strongly suspected based on clinical findings with limited renal biopsy sample and steroid treatment before kidney biopsy. In biopsy, the four patients exhibited only slight mesangial expansion or evidence of IgA-positive immunofluorescence staining. As their renal manifestations were more consistent with sarcoidosis involvement, treatment decisions were primarily guided by sarcoidosis management protocols.

^gThese patients also exhibited nongranulomatous interstitial nephritis with calcium deposits.

Table 3.

Treatment of renal sarcoidosis

Immunosuppressive Therapy	All Patients (n=43)
Steroids, n (%)	37 (86.0)
Initial dose of steroids (mg)	40 (30–60)
Maintenance therapy of steroids, n (%)	13/37 (35.1)
Maintenance dose of steroids (mg)	5 (5–12.5)
Duration of steroid therapy (mo)	9 (5–20)
Initial intravenous steroid therapy, n (%)	6/37 (16.2)
Additional immunosuppressive therapy, n (%)	14/37 (37.8)
MMF	9/14 (64.3)
RTXa	2/14 (14.3)
MTXb	3/14 (21.4)
Infliximab	1/14 (7.1)
Azathioprine	1/14 (7.1)
Adalimumab	1/14 (7.1)
Hydroxychloroquinec	1/14 (7.1)
Tacrolimusa	1/14 (7.1)
Duration of additional immunosuppressants (mo)	23 (8–44)
Indications for additional immunosuppressive therapy, n (%)
Disease flare	7/14 (50.0)
Steroid-sparing	4/14 (28.6)
Steroid resistance	3/14 (21.4)
Without immunosuppressive therapy, n (%)d	6 (14.0)

MMF, mycophenolate mofetil; MTX, methotrexate; RTX, rituximab.

^aThe three patients also used mycophenolate mofetil.

^bNo adverse effects—including gastrointestinal symptoms, infections, hepatotoxicity, or significant eGFR decline—were observed during methotrexate therapy.

^cThis patient also used methotrexate.

^dAmong the six patients, four exhibited chronic interstitial nephritis, one had calcium phosphate deposits but did not have interstitial nephritis, and one was on ongoing infectious workup for granuloma.

Kidney Outcome Definitions

The primary renal outcome within 6 months postbiopsy was evaluated based on serum creatinine (sCr) changes. Complete recovery was defined as sCr returning to within 25% of baseline or falling below 1.4 mg/dl if baseline sCr was unknown. Partial recovery was characterized by a reduction in sCr of at least 50% from its peak without reaching the complete recovery threshold. Cases that did not meet criteria for complete or partial recovery, or those requiring ongoing KRT, were classified as having no recovery.

The long-term adverse composite outcome, assessed beyond 6 months postbiopsy and until the end of 2024, included the onset of CKD, CKD progression, ESKD, initiation of dialysis, or death. CKD is defined as an eGFR of <60 ml/min per 1.73 m² for at least 3 months, while CKD progression as a sustained increase of 50% or more in sCr from baseline over a period of 6 months to a year.¹³ ESKD was defined as an eGFR below 15 ml/min per 1.73 m² or the initiation of dialysis or a kidney transplant, whichever occurred first. The eGFR was calculated using the 2021 race-neutral CKD Epidemiology Collaboration formula.

Statistical Analyses

All data are reported as mean±SD, median and interquartile range (IQR), or as counts with percentages. Comparisons of sCr levels between groups were evaluated using the Wilcoxon rank-sum test. Longitudinal changes in sCr levels were analyzed using ANOVA. Logistic regression was performed to identify factors associated with complete recovery. Cox proportional hazards regression was applied to evaluate factors associated with the long-term adverse outcomes. Kaplan-Meier methods were used to estimate event-free survival probabilities for long-term adverse outcomes, with between-group comparisons assessed using the log-rank test. Patients were followed on the occurrence of incident CKD, CKD progression, ESKD occurrence, dialysis initiation, death, loss to follow-up, or the study's end date. The results are presented as odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs). Statistical significance was defined as a P value of ≤0.05. Statistical analyses were performed using JMP Pro 18.0 (Cary, NC).

Results

Clinical and Laboratory Features

A total of 43 biopsy-confirmed RS cases were analyzed (Supplemental Figure 1), with the incidence of 51.7% (44 of 85) among all sarcoidosis. Clinical and laboratory characteristics are presented in Table 1. The average age at biopsy was 59.7±9.5 years, with 39% being men. A history of kidney stones was reported in 28% of patients (n=12). Notably, sarcoidosis was diagnosed after kidney biopsy in 35% of patients (n=15), with 12% having renal-limited disease (n=5). Among those with non–renal-limited sarcoidosis, intrathoracic and extrathoracic lesions were identified in 66% and 13% of cases, respectively, while 21% had both.

Sixty-eight percent of patients had CKD at baseline and 74.4% exhibited hypercalcemia. The median 25-hydroxy vitamin D level was 25 ng/ml (IQR, 19–35), while the median 1,25-dihydroxy vitamin D level was 72 pg/ml (IQR, 49–95). The median serum angiotensin-converting enzyme (ACE) level was 74 U/L (IQR, 31–105), and parathyroid hormone (PTH) was 11 pg/ml (IQR, 7.1–22). Specifically, 46.9% and 44.4% of patients had elevated 1,25-dihydroxy vitamin D and ACE levels, respectively, while 62.9% had reduced PTH levels.

Urinalysis showed that 20% of patients had microscopic hematuria and 10% had sterile pyuria. Urinary casts and renal tubular epithelial cells were detected in 7% and 5% of patients, respectively. Ninety percent exhibited hypercalciuria, 50% had eosinophiluria, and only 7% presented with glycosuria. The 24-hour proteinuria level was 0.33 g (IQR, 0.16–0.66).

Histologic Findings

The primary indications for kidney biopsy were CKD (n=17; 40%), AKI (n=13; 30%), and AKI on CKD (n=11; 26%; Table 2). Hypercalcemia was another reason for biopsy, accounting for only 9% of cases (n=4). Among the four patients with hypercalcemia, two had CKD, one had AKI on CKD, and one had AKI. In addition, 5% (n=2) underwent biopsy for proteinuria.

In the overall cohort (Table 2), 84% (n=36) exhibited interstitial nephritis, with 14 (33%) classified as GIN and 22 (51%) as non-GIN. Calcium phosphate deposits were observed in 58% of patients (n=25). Among these 25 patients, eight had GIN, while 13 had the non-GIN. In addition, 5% (n=2) did not present with interstitial nephritis or calcium phosphate deposits but were diagnosed with MN secondary to sarcoidosis based on clinical manifestations such as intrathoracic sarcoidosis lesions and negative phospholipase A2 receptor in the tissue.

Global glomerulosclerosis was minimal. Acute tubular necrosis was identified in 14 patients (33%), while moderate-to-severe interstitial fibrosis and tubular atrophy (IFTA) was observed in 17 patients (44%). In addition, eight patients (19%) had coexisting glomerular diseases, including diabetic nephropathy (DN) in two (5%), IgA nephropathy (IgAN) in four, glomerulomegaly in one (2%), and microangiopathic changes in one (2%).

Treatment of RS

As presented in Table 3, 86% (n=37) received steroid therapy for a median duration of 9 months (IQR, 5–20). Among them, 14 patients (38%) were treated with additional immunosuppressants. These included mycophenolate mofetil in nine patients, rituximab in two, methotrexate in three, as well as infliximab, azathioprine, adalimumab, hydroxychloroquine, and tacrolimus (n=1 for each). The median duration of additional immunosuppressant therapy was 23 months (IQR, 8–44). Among patients without immunosuppressive therapy, four had pure chronic interstitial nephritis, one had calcium phosphate deposits without interstitial nephritis, and one was undergoing an infectious workup for granuloma.

Longitudinal Changes in sCr Levels

In the overall cohort, the median baseline sCr was 1.6 mg/dl (IQR, 1.1–2.3), which significantly increased to 2.4 mg/dl (IQR, 1.8–3.0) by the time of biopsy (P < 0.0001). Patients were followed for a median duration of 28 months (IQR, 10–55) postbiopsy. Starting from the first month after biopsy, sCr declined significantly, returning to baseline (Figure 1A and Supplemental Table 1). Specifically, in patients without preexisting CKD, sCr began to decrease at 2 months postbiopsy. However, in those with baseline CKD, sCr remained unchanged throughout biopsy and the follow-up period compared with baseline. Notably, when compared with the sCr at biopsy, a decline was observed at both 1 and 3 years after biopsy (Figure 1B and Supplemental Table 1). Individual sCr changes are shown in Supplemental Figure 2.

Figure 1.

Longitudinal changes in sCr levels. (A) sCr trends in the overall cohort, presented with median values and IQRs. (B) Comparison of sCr changes between patients with and without baseline CKD. The graph displays the median, IQR, minimum and maximum values, along with all individual data points. *P < 0.05 versus baseline, #P < 0.05 versus time of biopsy. IQR, interquartile range; sCr, serum creatinine.

Outcomes of RS

As presented in Table 4, sarcoidosis flare occurred in nine patients (2%). Hemodialysis was required in three patients (7%), and four patients (9%) died at a median of 2.6 years (IQR, 0.7–4.6) after biopsy. Within 6 months postbiopsy, recovery was achieved in 86% (n=37) of patients: 32 complete recovery and five partial recoveries.

Table 4.

Outcomes of renal sarcoidosis

Outcomes	All Patients (n=43)
Sarcoidosis flare, n (%)a	9 (2.1)
Dialysis required, n (%)	3 (7.0)
Dialysis initiation after biopsy (d)	23 (1–330)
Death, n (%)b	4 (9.3)
Time from biopsy to death (yr)	2.6 (0.7–4.6)
Recovery within 6 mo, n (%)	37 (86.0)
Complete recovery	32 (74.4)
Partial recovery	5 (11.6)
Nonrecovery	6 (14.0)
Composite outcomes, n (%)c	17 (39.5)
CKD progression	8 (18.6)
Deathb	4 (5.5)
CKD onsetd	3 (7.0)
ESKD or dialysis	3 (7.0)

^aAmong the nine patients who experienced disease flare, seven resumed steroid therapy (with one patient additionally receiving methotrexate and hydroxychloroquine), one was treated with azathioprine, and one received methotrexate monotherapy. Clinical outcomes in flared patients were comparable to nonflared cases: 89% (8/9) achieved complete renal recovery within 6 months (versus 71% [24/34] in nonflared patients, P = 0.41), while 33% (3/9) showed CKD progression (versus 41% [14/34] in nonflared patients, P = 0.99).

^bOne patient died 10 months after dialysis.

^cAmong 26 patients without composite outcomes, 15 patients had CKD and their CKD did not progress, 11, including nine AKI and two with proteinuria, achieved normal renal function.

^dThe three patients presented AKI at the time of biopsy.

Forty percent of patients (n=17) developed long-term adverse outcomes (Table 4), including the onset of CKD (n=3), CKD progression (n=8), death (n=4), or ESKD/dialysis (n=3). All three patients who developed incident CKD initially presented with AKI at biopsy. Conversely, 26 did not experience long-term adverse outcomes. Among them, 15 had CKD that remained stable without progression, while 11 patients—including nine with AKI and two with proteinuria—achieved normal renal function.

Factors Associated with Complete Recovery

Univariable analysis identified higher sCr levels at biopsy and the presence of moderate/severe IFTA as factors associated with a reduced complete recovery, with ORs of 0.49 (95% CI, 0.27 to 0.75; P = 0.001) and 0.14 (95% CI, 0.02 to 0.71; P = 0.017), respectively (Table 5). Specifically, patients with sCr levels ≥2.4 mg/dl at biopsy had a significantly lower probability of achieving complete recovery compared to those with sCr <2.4 mg/dl (OR, 0.17; 95% CI, 0.02 to 0.80; P = 0.024). By contrast, higher 1,25-dihydroxy vitamin D levels and steroid use were associated with an increased complete recovery, with ORs of 1.04 (95% CI, 1.00 to 1.10; P = 0.025) and 8.57 (95% CI, 1.40 to 71.70; P = 0.021), respectively. Although patients with GIN had a lower probability of complete recovery, the association was not statistically significant (OR, 0.28; 95% CI, 0.06 to 1.15; P = 0.07). Other variables, including baseline sCr, preexisting CKD, serum calcium, ACE, and PTH levels at biopsy, as well as kidney stone history and calcium phosphate deposits, showed no association with complete recovery.

Table 5.

Univariable analysis of factors associated with complete recovery

Variables	OR (95% CI)a	P Value
Age at biopsyb	1.03 (0.96 to 1.11)	0.43
Male	0.44 (0.10 to 1.76)	0.24
Prior diagnosis of sarcoidosis	1.09 (0.24 to 4.47)	0.91
Renal-limited sarcoidosis	1.43 (0.18 to 29.72)	0.76
Comorbidity	1.26 (0.28 to 5.22)	0.76
Baseline sCr (mg/dl)b	0.75 (0.33 to 1.75)	0.48
sCr at biopsy (mg/dl)b	0.49 (0.27 to 0.75)	0.001c
sCr at biopsy ≥2.4 mg/dl (versus <2.4 mg/dl)	0.17 (0.02 to 0.80)	0.024c
24 h proteinuria (g/24 h)b	0.86 (0.49 to 1.54)	0.55
Baseline CKD	0.55 (0.07 to 2.74)	0.48
AKI on CKD (versus AKI)	0.78 (0.14 to 4.39)	0.77
AKI on CKD (versus CKD)	0.38 (0.06 to 2.15)	0.27
Kidney stone	0.62 (0.13 to 3.43)	0.56
Corrected calcium (mg/dl)b	1.20 (0.80 to 1.95)	0.39
Hypercalcemia	2.04 (0.43 to 9.04)	0.35
25-hydroxy vitamin D (ng/ml)b	0.97 (0.90 to 1.04)	0.31
1,25-dihydroxy vitamin D (pg/dl)b	1.04 (1.00 to 1.10)	0.025c
Serum ACE (U/L)b	1.00 (0.98 to 1.03)	0.67
Serum PTH (pg/ml)b	0.98 (0.96 to 1.01)	0.12
Microscopic hematuria	1.11 (0.12 to 23.90)	0.93
Sterile pyuria	1.25 (0.21 to 8.64)	0.89
Glycosuria	0.71 (0.06 to 16.33)	0.79
GIN	0.28 (0.06 to 1.15)	0.07
Calcium phosphate deposits	3.34 (0.83 to 15.22)	0.09
Moderate/severe IFTA	0.14 (0.02 to 0.71)	0.017c
Steroid use	8.57 (1.40 to 71.70)	0.021c
Sarcoidosis flares	3.33 (0.51 to 65.99)	0.23

ACE, angiotensin-converting enzyme; CI, confidence interval; GIN, granulomatous interstitial nephritis; IFTA, interstitial fibrosis and tubular atrophy; OR, odds ratio; PTH, parathyroid hormone; sCr, serum creatinine.

^aOdds ratio with 95% confidence interval and P values were calculated using logistic regression model.

^bOdds ratio is per unit change in regression.

^cP < 0.05.

Factors Associated with Long-Term Adverse Composite Outcomes

In univariable Cox proportional hazards regression analyses, higher sCr levels at biopsy, preexisting CKD, and moderate-to-severe IFTA were associated with an increased risk of long-term adverse outcomes. The respective HRs were 1.32 (95% CI, 1.04 to 1.67; P = 0.018), 5.89 (95% CI, 1.29 to 26.88; P = 0.022), and 2.94 (95% CI, 1.03 to 8.37; P = 0.043; Table 6). Specifically, patients with sCr levels ≥2.4 mg/dl at biopsy had a significantly higher risk of long-term adverse outcomes compared with those with sCr <2.4 mg/dl (HR, 4.24; 95% CI, 1.21 to 14.87; P = 0.024). Similarly, patients with AKI superimposed on CKD had a significantly greater risk of long-term adverse outcomes compared with those with AKI alone (HR, 4.04; 95% CI, 1.14 to 14.33; P = 0.030). Although higher baseline sCr was associated with an elevated risk of long-term adverse outcomes, this relationship did not reach statistical significance (HR, 1.70; 95% CI, 0.88 to 2.98; P = 0.08). By contrast, steroid use was associated with a lower likelihood of experiencing long-term adverse outcomes, with an HR of 0.27 (95% CI, 0.08 to 0.84; P = 0.023). Other variables, including serum calcium, ACE, and PTH levels at biopsy, as well as GIN, kidney stone history and calcium phosphate deposits, were not significantly associated with long-term adverse outcomes.

Table 6.

Proportional hazard risk of adverse composite outcome

Variables	HR (95% CI)a	P Value
Age at biopsyb	1.00 (0.96 to 1.05)	0.86
Male	1.85 (0.71 to 4.79)	0.21
BMIb	0.95 (0.88 to 1.03)	0.24
Prior diagnosis of sarcoidosis	1.44 (0.52 to 3.94)	0.48
Renal-limited sarcoidosis	0.44 (0.06 to 3.38)	0.43
Comorbidity	1.14 (0.40 to 3.23)	0.81
Baseline sCr (mg/dl)b	1.70 (0.88 to 2.98)	0.08
sCr at biopsy (mg/dl)b	1.32 (1.04 to 1.67)	0.018c
sCr at biopsy ≥2.4 mg/dl (versus <2.4 mg/dl)	4.24 (1.21 to 14.87)	0.024c
Baseline CKD	5.89 (1.29 to 26.88)	0.022c
AKI on CKD (versus AKI)	4.04 (1.14 to 14.33)	0.030c
AKI on CKD (versus CKD)	2.62 (0.84 to 8.19)	0.098
Kidney stone	1.04 (0.30 to 3.63)	0.95
24 h proteinuria (g/24 h)b	1.02 (0.68 to 1.28)	0.92
Corrected calcium (mg/dl)b	0.89 (0.65 to 1.16)	0.41
Hypercalcemia	0.49 (0.19 to 1.30)	0.15
25-hydroxy vitamin D (ng/ml)b	1.02 (0.97 to 1.06)	0.33
1,25-dihydroxy vitamin D (pg/ml)b	0.99 (0.97 to 1.00)	0.17
Serum ACE (U/L)b	0.99 (0.98 to 1.01)	0.83
Serum PTH (pg/ml)b	1.01 (0.99 to 1.02)	0.26
Microscopic hematuria	0.98 (0.13 to 7.61)	0.98
Sterile pyuria	1.44 (0.47 to 4.43)	0.53
Glycosuria	2.42 (0.53 to 11.09)	0.26
GIN	1.98 (0.74 to 5.29)	0.17
Calcium phosphate deposits	0.47 (0.18 to 1.27)	0.14
Moderate/severe IFTA	2.94 (1.03 to 8.37)	0.043c
Steroid use	0.27 (0.08 to 0.84)	0.023c
Sarcoidosis flares	0.58 (0.17 to 2.02)	0.39

ACE, angiotensin-converting enzyme; BMI, body mass index; CI, confidence interval; GIN, granulomatous interstitial nephritis; HR, hazard ratio; IFTA, interstitial fibrosis and tubular atrophy; PTH, parathyroid hormone; sCr, serum creatinine.

^aHazard ratio with 95% confidence interval and P values were calculated using Cox proportional hazards regression model.

^bHazard ratio is per unit change in regression.

Notably, 16 patients were on calcium or vitamin D supplements before or at the time of the kidney biopsy (Supplemental Table 2). Renal complete recovery rates did not significantly differ between patients with versus without vitamin D supplementation (62.5% versus 81.5%, P = 0.28). However, the long-term adverse outcomes were more frequent in supplemented patients (62.5% versus 25.9%, P = 0.03). Univariable analysis indicated that vitamin D supplements increased the likelihood of long-term adverse outcomes (HR, 2.72; 95% CI, 1.02 to 2.74; P = 0.045).

As shown in Figure 2, Kaplan-Meier survival analysis demonstrated that patients with preexisting CKD and those with sCr levels ≥2.4 mg/dl at biopsy had significantly lower event-free survival for long-term adverse outcomes compared with those without baseline CKD and those with sCr <2.4 mg/dl (log-rank test P = 0.011 and P = 0.014, respectively). Conversely, steroid therapy was associated with improved event-free survival for long-term adverse outcomes (log-rank test P = 0.015). GIN did not significantly affect event-free survival for long-term adverse outcomes (log-rank test P = 0.16).

Figure 2.

Kaplan-Meier curves for long-term adverse composite outcomes. (A) Event-free survival for adverse composite outcomes in patients with and without baseline CKD (log-rank test P = 0.01). (B) Event-free survival for adverse composite outcomes in patients with sCr ≥2.4 versus <2.4 mg/dl at biopsy (log-rank test P = 0.01). (C) Event-free survival for adverse composite outcomes in patients with and without GIN (log-rank test P = 0.16). (D) Event-free survival for adverse composite outcomes in patients with and without steroid therapy (log-rank test P = 0.02). GIN, granulomatous interstitial nephritis.

Discussion

This study enhances the understanding of RS by offering detailed insights into its clinical presentation, histopathologic characteristics, and outcomes. It identifies key factors associated with long-term adverse outcomes, including preexisting CKD, elevated sCr at biopsy (≥2.4 mg/dl), moderate-to-severe IFTA, and steroid therapy. These findings underscore the importance of measuring sCr and conducting calcium metabolic analysis such as serum calcium and urinary calcium excretion in patients with a history of sarcoidosis to facilitate early diagnosis of renal involvement, enabling timely intervention to prevent or delay kidney disease progression.

Our data showed that the incidence of biopsy-proven RS among all sarcoidosis patients was 51.7%. It should be highlighted that biopsy-confirmed cases show significant variation, reported in <5% to as much as 50% of patients.^3,5,14 This variability is likely due to the absence of large-scale epidemiologic studies, inconsistencies in diagnostic criteria, variations in systematic screening approaches, and differences in ethnic or geographic populations. In our cohort, women were predominant, consistent with findings from a large cohort study of 305 sarcoidosis patients.¹⁵ However, our study did not demonstrate a female advantage in achieving complete recovery within 6 months or in long-term event-free composite outcomes. In our cohort, most patients had multisystem sarcoidosis, with intrathoracic involvement being the most common, followed by liver, bone, cardiac, and ocular involvement. Notably, 12% of patients had renal-limited sarcoidosis. Although more than half of the patients were diagnosed with sarcoidosis before undergoing kidney biopsy, nearly 70% progressed to CKD. This aligns with previous studies reporting abnormal renal function in 30%–60% of patients with known RS.^9,16,17

Urinary analysis revealed that, as previously reported,⁵ a small subset of patients exhibited microscopic hematuria and mild proteinuria, along with sterile pyuria, positive casts, and renal tubular epithelial cells. Hypercalciuria, a hallmark of sarcoidosis, was detected in 89.5% of patients. Prolonged hypercalciuria can result in nephrocalcinosis, a major contributor to CKD in sarcoidosis.⁵ Consistent with prior findings,^15,18 hypercalciuria was more prevalent than hypercalcemia, with nearly 90% of patients affected compared with 74% with hypercalcemia. Kidney ultrasound or computed tomography detected nephrocalcinosis in only 2% of patients, consistent with findings from a previous study with a similar sample size.¹⁹ However, other studies have reported a higher prevalence, ranging from 11% to 27%.^9,11,14,16 Interestingly, our study found that one third of patients had a history of kidney stones, supporting previous observations that nephrocalcinosis occurs less frequently than nephrolithiasis in sarcoidosis.^5,20 Disrupted calcium metabolism is a key feature of renal involvement in sarcoidosis.^5,21 The median 25-hydroxy vitamin D level was 25 ng/ml (IQR, 19–35), within the normal range (20–50 ng/ml), whereas the median 1,25-dihydroxy vitamin D level was 72 pg/ml (IQR, 49–95), approaching the upper limit of normal range (18–78 pg/ml). Notably, nearly half of the patients had elevated 1,25-dihydroxy vitamin D levels. Pathophysiologically, 1,25-dihydroxy vitamin D, commonly produced in granulomatous,¹⁸ increases serum calcium through multiple mechanisms, including enhanced osteoclast activity leading to bone resorption, increased calcium absorption in the gastrointestinal tract, and augmented renal tubular calcium reabsorption.²² A progressive rise in plasma calcium can subsequently suppress PTH secretion through direct or indirect feedback mechanisms.²² This phenomenon was observed in our cohort, where 63% of patients exhibited low PTH levels. The resultant PTH deficiency diminished calcium reabsorption in the distal tubule, exacerbating hypercalciuria.²² In addition, univariable analysis indicated a potential association between vitamin D/calcium supplements and increased risk of long-term adverse outcomes. However, this association should be interpreted with caution given potential confounding variables, although supplementation was promptly discontinued in all cases where hypercalcemia, hypercalciuria, or calcium deposits were detected during follow-up. Notably, elevated 1,25-dihydroxy vitamin D may reflect an adaptive response of inflammation.^23,24 Steroids could suppress this response by reducing 1,25-duhydroxy vitamin D levels, potentially offsetting its beneficial immunomodulatory effects.^25,26 These findings emphasize that vitamin D and calcium supplementation should be strictly individualized in RS, particularly in patients with preexisting hypercalcemia, hypercalciuria, or elevated 1,25-dihydroxy vitamin D. Measuring serum calcium, 1,25-dihydroxy vitamin D, and 25-hydroxy vitamin D, as well as urinary calcium excretion, is considered a first-line laboratory approach for screening calcium abnormalities in sarcoidosis,²⁷ facilitating early detection and management of calcium metabolic disturbances. Regular monitoring these metrics is also essential for disease activity assessment, especially during steroid therapy, which may further perturb vitamin D metabolism.^26,28

The direct formation of granulomas within kidney tissue can cause interstitial nephritis. The exact incidence of GIN remains uncertain. In our cohort of biopsy-proven RS, GIN was present in only one third of cases, consistent with previous studies.^10,14,16,17 However, several other studies reported a significantly higher prevalence, reaching approximately 80%.^9,11,19 Two studies suggested that GIN is more common in patients with advanced CKD stages or more severe AKI,^16,19 although this association was not observed in our study. Further validation in larger cohorts is needed to clarify these discrepancies. Another notable histopathologic feature observed at biopsy was calcium phosphate deposits, present in nearly 60% of cases (n=25). Among these, only four cases exhibited isolated calcium phosphate deposits, while eight also had GIN, and 13 had non-GIN renal pathology. The overlap of different histologic manifestations in RS has been previously reported,^9,19 including MN,^29,30 IgAN,^31,32 FSGS,¹⁹ mesangioproliferative GN, and crescentic GN.³³ In our cohort, there were two cases of MN, four of IgAN, and two of DN. Notably, although the two MN cases did not exhibit GIN, sarcoidosis-related MN was diagnosed based on clinical features, including intrathoracic involvement and phospholipase A2 receptor-negative status. MN is the most common glomerular disease in patients with sarcoidosis, although a causative relationship has not been firmly established.^6,34 Among the four IgAN cases, three had calcium phosphate deposits alongside either GIN or non-GIN pathology, while the fourth had sarcoidosis lesions affecting both intrathoracic and extrathoracic regions. The two remaining DN cases exhibited non-GIN pathology with calcium phosphate deposits. In addition, we identified one patient with glomerulomegaly and another with microangiopathic changes, both of whom exhibited non-GIN pathology with calcium phosphate deposits. Importantly, distinguishing sarcoidosis-associated glomerulopathy from primary glomerular diseases remains challenging, complicating differential diagnosis and treatment decisions.²¹

Currently, no standardized treatment guidelines exist for RS due to the absence of clinical trials. However, corticosteroid therapy remains the cornerstone of therapy,³⁵ while long-term renal prognosis varies depending on disease severity at presentation, histologic findings, and the extent of fibrosis. Our data support the effectiveness of corticosteroid therapy in RS, with a high proportion of patients achieving recovery within 6 months. A significant association between steroid use and improved recovery rates or better long-term event-free adverse outcomes was demonstrated. However, despite an initial response to steroids, approximately 40% of patients experienced long-term adverse outcomes. This suggests that while immunosuppressive therapy is beneficial, it may not fully prevent disease progression in all cases, particularly in patients with advanced fibrosis at diagnosis. The association between preexisting CKD and poorer renal outcomes highlights the importance of early recognition and intervention. Patients presenting with severe renal dysfunction (sCr ≥2.4 mg/dl) at biopsy had a significantly lower likelihood of complete recovery, a finding that has been previously reported in similar cohorts.^7,21,36 The recovery of sCr levels was significantly delayed in patients with preexisting CKD compared with those without CKD. In addition, the presence of moderate/severe IFTA emerged as a significant predictor of incomplete renal recovery, further emphasizing the role of histologic severity in determining long-term prognosis.³⁶ Consistent with previous reports,⁹ our findings did not indicate an association between sarcoidosis relapse and renal outcomes, suggesting that relapse may not be a prognostic factor in RS.

We acknowledge several limitations in the study. First, its retrospective design introduces potential selection bias and limits the ability to establish causality between identified risk factors and renal outcomes. Second, the relatively small sample size reduces statistical power and may not capture the full heterogeneity of disease presentation and progression. In addition, the study lacks a control group of sarcoidosis patients without renal involvement, restricting comparisons that could help identify disease-specific risk factors. Despite these limitations, the study provides valuable insights into the clinical and histopathologic characteristics of RS and highlights key predictors of renal recovery and progression, warranting further prospective studies to validate these findings.

In conclusion, our findings identified preexisting CKD, sCr levels at biopsy, IFTA, and steroid therapy as key factors influencing outcomes in RS. Although corticosteroids remain the primary treatment, our findings highlight the importance of routine renal function monitoring in sarcoidosis patients, particularly those with hypercalcemia, hypercalciuria, or unexplained renal dysfunction, to facilitate early detection of renal involvement. Given the heterogeneity in RS presentation and outcomes, further prospective studies are needed to refine diagnostic criteria and optimize treatment strategies. A multidisciplinary approach involving nephrologists, pulmonologists, and rheumatologists is essential to ensure comprehensive care and improve patient outcomes.

Supplementary Material

kidney360-6-1780-s001.pdf ^{(1.5MB, pdf)}

kidney360-6-1780-s002.pdf ^{(1MB, pdf)}

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/KN9/B85.

Funding

This study was supported by MCHS Discretionary Funding.

Author Contributions

Conceptualization: Wisit Cheungpasitporn, Jing Miao, Charat Thongprayoon.

Data curation: Jing Miao, Charat Thongprayoon.

Formal analysis: Jing Miao.

Investigation: Alessia Buglioni, Wisit Cheungpasitporn, Fernando Fervenza, Jing Miao, Charat Thongprayoon, Ladan Zand.

Methodology: Jing Miao.

Project administration: Jing Miao.

Validation: Jing Miao.

Writing – original draft: Jing Miao.

Writing – review & editing: Alessia Buglioni, Wisit Cheungpasitporn, Fernando Fervenza, Jing Miao, Charat Thongprayoon, Ladan Zand.

Data Sharing Statement

Partial restrictions to the data and/or materials apply. Data are available upon reasonable request to the corresponding author.

Supplemental Material

This article contains the following supplemental material online at http://links.lww.com/KN9/B84.

Supplemental Table 1. Changes in sCr during follow-up in the overall cohort.

Supplemental Table 2. Characteristics of patients with versus without vitamin D and calcium supplements.

Supplemental Figure 1. Patient recruitment and analysis.

Supplemental Figure 2. Individual sCr changes during follow-up in the overall cohort.