Renal limited sarcoidosis presenting with non-caseating granulomatous interstitial nephritis in the absence of extrarenal manifestations: a case report and literature review

Abstract

Renal limited sarcoidosis is an exceptionally rare condition characterized by non-caseating granulomas confined solely to the kidneys, without involvement of other organs. Its diagnosis is challenging because of the absence of systemic manifestations. We present a case of a 74-year-old woman with a history of type 2 diabetes mellitus, papillary thyroid carcinoma, and osteoporosis, who showed progressive renal dysfunction. Laboratory findings revealed elevated serum creatinine and urinary β₂-microglobulin, indicating tubular injury. Kidney biopsy demonstrated granulomatous interstitial nephritis with non-caseating epithelioid cell granulomas. Other potential causes, including infections, drug-induced nephritis, and autoimmune diseases were excluded. Chest computed tomography and gallium-67 scintigraphy revealed no extrarenal involvement. Based on these findings, we diagnosed the patient as having renal limited sarcoidosis. The patient was treated with low dose of oral prednisolone, resulting in significant improvement in renal function and normalization of laboratory parameters. The present case underscores the importance of considering the possibility of renal limited sarcoidosis on differentiating the case with unexplained renal dysfunction, especially when non-caseating granulomas are identified on kidney biopsy and other causes have been excluded. Corticosteroids remain the cornerstone of treatment, with most patients responding favorably. However, in steroid-resistant cases, alternative immunosuppressive agents such as mycophenolate mofetil and infliximab have been employed, though their efficacy and safety require further investigation. In this article, we present this rare case in addition to providing comprehensive literature review of previously cases to summarize clinicopathological characters, treatment strategies, and renal outcomes of renal-limited sarcoidosis for future clinical management.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13730-025-01049-3.

Introduction

Sarcoidosis is a systemic granulomatous disorder due to unknown origin, typically presenting with non-caseating epithelioid cell granulomas in organs such as the lungs, eyes, skin, and lymph nodes [1]. Although there are no universally established diagnostic criteria for sarcoidosis, the diagnosis is generally based on the following three key elements: (1) clinical manifestations related to the affected organs, (2) histological confirmation of non-caseating granulomas, and (3) exclusion of other diseases that can cause granulomatous inflammation [2]. Renal involvement is rare and usually occurs alongside extrarenal disease or calcium metabolism disturbances [3]. The renal limited sarcoidosis, also known as isolated renal sarcoidosis, is a rare condition in which sarcoid lesions are confined solely to the kidneys. Due to this exclusive renal involvement, the disease is exceptionally uncommon and presents significant diagnostic challenges [4]. Therefore, the definition of renal-limited sarcoidosis demands careful exclusion of drug-induced, infectious, autoimmune diseases, and inflamed tubulointerstitial nephritis such as IgG4-related disease, through evaluation of findings from renal biopsy. We herein report a rare case of renal-limited sarcoidosis. In addition, 26 previously reported cases of renal-limited sarcoidosis were referred, and we underline the importance of appropriate differentiation and assessment of disease-characteristic biomarker in such atypical presentations.

Case presentation

A 74-year-old woman with progressive renal dysfunction was admitted. Her medical history contained type 2 diabetes mellitus diagnosed at age 50, papillary thyroid carcinoma treated with thyroidectomy and parathyroidectomy at age 60, and osteoporosis diagnosed at age 70. She had been receiving eldecalcitol and loxoprofen topical therapy for knee and lower back pain for several years. Her serum creatinine (sCr) level had been within normal range until six months prior to admission, but gradually increased to 1.84 mg/dL approximately five months before presentation. Because of the elevation of sCr level, her oral and topical medications were discontinued; however, renal function did not improve. Urinalysis revealed proteinuria with an elevated total protein-to-creatinine ratio (TP/Cre 0.8 g/gCr) and markedly increased urinary β₂-microglobulin (73,865 mg/L), indicating tubular injury. Consequently, she was subsequently referred to our hospital for further evaluation.

On admission, her height and weight were 150 cm and 52 kg, respectively. Vital signs were stable without fever; blood pressure measured 124/80 mmHg. Physical examination revealed no lymphadenopathy, rash, or uveitis. Laboratory tests (Table 1) confirmed proteinuria, glycosuria, and elevated urinary β₂-microglobulin. Blood chemistry revealed a sCr level of 2.36 mg/dL and an estimated glomerular filtration rate (eGFR) of 16 mL/min/1.73 m², indicating stage 4 chronic kidney disease. Serum calcium was within the normal range at 10.1 mg/dL, and urinary calcium excretion was also within normal range (167.9 mg/day). The level of 25-hydroxyvitamin D (25-(OH)D) was 13.0 ng/mL, indicating an insufficient level. Though serum angiotensin-converting enzyme (ACE) level was at 6.1 U/L in normal range, lysozyme levels was elevated at 35.5 µg/mL, raising suspicion for sarcoidosis-related tubular injury. Kidney biopsy was performed.

Table 1.

Laboratory data on admission

Urinalysis			Immunology
Gravity	1.018		CRP	0.38	mg/dL
pH	7.0		IgG	1269	mg/dL
Protein	(1 +)		IgA	282	mg/dL
TP/Cre	0.81	g/g・Cr	IgM	87	mg/dL
Sugar	(4 +)		IgG4	39	mg/dL
Blood	(+ -)		ANA	40	Titer
β2microglobulin	63,200	µg/L	sIL2R	1752	U/dL
Calcium	167.9	mg/day	ACE	16.1	U/L
Blood cell count			25(OH) vitamin D3	13.0	ng/mL
WBC	6000	/µL	Lysozyme	35.5	µg/mL
Hb	10.4	g/dl	Anti-SSA Ab	< 1.0	U/mL
Plt	25.1 × 104	/µL	Anti-SSB Ab	< 1.0	U/mL
Blood chemistry			MPO ANCA	< 1.0	U/mL
Total protein	7.3	g/dL	PR3 ANCA	< 1.0	U/mL
Alb	4.3	g/dL
BUN	52.8	mg/dL
Cr	2.36	mg/dL
eGFR		ml/min
Na	140	mEq/L
K	3.8	mEq/L
Cl	106	mEq/L
Corrected Ca	10.1	mg/d L
P	4.3	mg/dL

Kidney biopsy (Fig. 1, Supplemental Fig. 1) revealed 37 glomeruli, of which 32 were globally sclerosed, while the remaining glomeruli showed only minimal changes (Fig. 1d). Approximately 60% of the renal cortex exhibited tubular atrophy and interstitial fibrosis with mononuclear cell infiltration. Interstitial inflammation was also observed in the interstitium surrounding glomeruli with preserved architecture (Supplemental Fig. 1). In the cortical (Fig. 1a) and medullary interstitium (Fig. 1b), there were significant mononuclear inflammatory infiltrates accompanied by non-caseating epithelioid cell granulomas (Fig. 1c), consistent with granulomatous interstitial nephritis. In immunofluorescence using frozen kidney biopsy sample, there were no obvious depositions of immunoglobulin and complement in glomeruli and tubular basement membrane. Further, to investigate the immunological profile of the cellular components of the granulomatous lesion, immunohistochemical staining was performed for CD3 (T lymphocytes), CD20 (B lymphocytes), CD4 (helper T cells), CD8 (cytotoxic T cells), and CD68 (macrophages) (Fig. 2). In our case, numerous CD3⁺ and CD4⁺ cells were observed within the granulomatous lesions, along with CD68⁺ macrophages (Fig. 2a, b and e, respectively). CD8⁺ cells were sparsely distributed, and CD20⁺ cells were even fewer (Fig. 2c and d, respectively).

Fig. 1.

Kidney biopsy findings. a Hematoxylin and Eosin staining. In cortex, there are several global sclerotic glomeruli, and granulomatous interstitial nephritis was found. b Hematoxylin and Eosin staining. In medulla, there is also granulomatous lesion was observed, however, no significant inflammatory cell infiltration was observed. c Higher magnification of (b) showed that epithelioid macrophage aggregated to form a granulomatous lesion. d The glomeruli appeared normal and met the criteria for a minor glomerular abnormality. Bar in (a) and (b) are 250 µm. Bar in (c) is 50 µm. Bar in (d) is 25 µm

Fig. 2.

Immunohistochemical staining for (a) CD3 (T lymphocytes), (b) CD4 (helper T cells), (c) CD8 (cytotoxic T cells), (d) CD20 (B lymphocytes), and (e) CD68 (macrophages). The granulomatous lesions were mainly composed of CD3, CD4, and CD68 positive cells. All scale bar was 50 µm

Drug lymphocyte stimulation tests (DLST) for eldecalcitol and loxoprofen were negative. Immunologic evaluations including myeloperoxidase-ANCA (MPO-ANCA), proteinase 3-ANCA (PR3-ANCA), anti-glomerular basement membrane (GBM) antibodies, and cryoglobulins were all negative. Screening for mycobacterial infections, including tuberculosis-specific interferon-gamma release assays (T-SPOT) and cultures from gastric fluid, blood, urine, and stool, yielded negative results. Serum β-D-glucan was also negative. Imaging studies comprising chest computed tomography (CT) and gallium-67 (Ga) scintigraphy revealed no lymphadenopathy or abnormal uptake. An ophthalmologist examined the patient using a slit-lamp microscope, and no ocular findings indicative of sarcoidosis were observed. Electrocardiography showed no significant arrhythmias or conduction abnormalities, including bundle branch block. An echocardiogram was performed, and no abnormalities such as basal septal thinning were detected. These findings indicated no involvement of the lungs, heart, eyes, or other organs. Based on above-described findings, a diagnosis of idiopathic granulomatous interstitial nephritis was established, with elevated lysozyme levels supporting the diagnosis of sarcoidosis. Oral prednisolone was initiated at 20 mg/day, resulting in marked improvement of renal function (Fig. 3). By day 36 after treatment, sCr decreased to 1.24 mg/dL, urinary β₂-microglobulin normalized, and serum lysozyme level returned to within normal range. The patient is currently maintained on prednisolone 9 mg/day without relapse.

Fig. 3.

Clinical course and treatment of the present case. After initiation of prednisolone treatment, sCr was PSL: Prednisolone, TP/Cre: Urinary total protein-to-creatinine ratio, sCr: Serum creatinine

Discussion

The patient presented with renal dysfunction and non-caseating granulomas on kidney biopsy. After excluding other causes of granulomatous inflammation—such as tuberculosis, fungal infections, drug-induced granulomatous interstitial nephritis, and granulomatosis with polyangiitis—the diagnosis of sarcoidosis was considered most appropriate, as all three major diagnostic criteria were fulfilled. No evidence of extrapulmonary involvement was identified, leading to a diagnosis of renal limited sarcoidosis. The patient responded favorably to corticosteroid therapy (prednisolone).

Although sarcoid granulomatous lesions can occur throughout the body, the lungs are the most commonly affected organs, with pulmonary and mediastinal lymph node involvement observed in over 90% of cases. Ocular, cutaneous, and hepatic manifestations have been reported in 15–30% of patients, while neurological and cardiac involvement is less common, occurring in approximately 2–10% of cases [1]. Renal involvement in sarcoidosis is relatively rare, with histopathological findings characteristic of sarcoidosis observed in approximately 0.6% to 3.5% of cases [3, 5]. However, renal involvement in sarcoidosis is well recognized and has been reported to occur in 30–60% of patients [6], encompassing a broad spectrum of pathogenic mechanisms. Importantly, renal dysfunction in sarcoidosis is more commonly attributed to hypercalcemia-induced injury—such as nephrocalcinosis and nephrolithiasis—rather than to direct granulomatous or non-granulomatous tubulointerstitial nephritis identifiable on kidney biopsy [6]. Thus, the high frequency of renal involvement in sarcoidosis could be attributed to the occurrence of kidney injury in the absence of direct granulomatous lesions, primarily due to metabolic disturbances such as hypercalcemia.

In our case, immunohistochemical staining of the granulomatous lesions revealed a predominance of CD4⁺ T cells and CD68⁺ macrophages (Fig. 2). These findings are consistent with previously reported renal pathological features of sarcoidosis [7] and provide further supportive evidence that the present case represented renal involvement of sarcoidosis.

In the context of "renal-limited sarcoidosis," the absence of lesions in other organs is a definitive criterion, thereby necessitating the presence of granulomatous tubulointerstitial nephritis in the renal lesion as a crucial diagnostic point. Indeed, the lesion of granulomatous inflammation was observed in all previous cases within our series (Table 2). However, as aforementioned, in the view of sarcoidosis more broadly, renal involvement often presents as nonspecific tubulointerstitial nephritis without granuloma formation, which may lead to hinder to appropriate diagnose renal limited sarcoidosis in some patients. Therefore, it might be plausible that a greater number of cases with renal involvement are still uncovered. In order to exclude the involvement of other organs, this case underwent chest CT and gallium (Ga) scintigraphy. Especially, to rule out pulmonary lesions, which have been the highest prevalence in sarcoidosis, chest CT has been reported to have a sensitivity of 94% and a specificity of 86%, indicating adequate diagnostic performance [8]. Regarding Ga scintigraphy which has long been a commonly used method, several studies have reported that the sensitivity of 18F-fluorodeoxyglucose positron emission tomography (FDG PET) is higher than that of Ga scintigraphy [9, 10]. In the present case as well, performing [18]F-FDG PET would likely have provided a more accurate evaluation.

Table 2.

Previous reports of renal limited sarcoidosis and our case

No	Age	Sex	sCr (mg/dL)	U-P (g/day)	sCa (mg/dL)	U-Ca (mg/day)	U-β2MG (µg/L)	ACE (U/L)	1,25.VD3 (pg/ml)	25.VD3 (ng/mL)	Treatment	Response	References
1	44	F	7.1	Normal	(10.1–11.0)	ND	ND	ND	ND	ND	PSL	Improved	[12]
2	51	F	12.9	2 + **	Normal	ND	ND	ND	ND	ND	PSL	Improved	[13]
3	21	M	3.4	0.7	Normal	ND	ND	ND	ND	ND	PSL	Improved	[14]
4	66	F	6.6	1.2	ND	ND	ND	ND	ND	ND	PSL	Improved	[15]
5	14	F	5.1	0.4	Normal	ND	ND	Normal	ND	ND	PSL	Improved	[16]
6	35	M	5.8	< 0.5	Normal	ND	ND	Normal	ND	ND	PSL	ESRD	[17]
7	70	M	4.9	0.8	13.9	ND	ND	High 195	ND	ND	PSL	Improved	[17]
8	66	F	3.4	Normal	Normal	ND	ND	Normal	ND	ND	PSL	ESRD	[17]
9	64	F	4.9	0.4	Normal	ND	ND	Normal	ND	ND	PSL	Improved	[17]
10	69	M	5.6	0.2	10.5	ND	ND	High 160	ND	ND	PSL	Improved	[17]
11	70	M	14.1	0.9	Normal	ND	ND	Normal	ND	ND	PSL	Improved	[17]
12	72	M	4.0	Normal	Normal	ND	ND	High 55	ND	ND	PSL	Resistant	[17]
13	81	F	7.1	0.4	Normal	ND	9,600	Normal	ND	ND	PSL	Improved	[18]
14	13	M	2.4	1.2	Normal	Normal	ND	Normal	Normal	ND	PSL IFX	Improved	[19]
15	15	M	7.2	1.3*	Normal	Normal	91,136	Normal	High 87	ND	PSL MMF	Improved	[20]
16	57	M	2.9	1.4	Normal	Normal	ND	High 88	Normal	ND	PSL IFX	Resistant	[21]
17	51	F	4.5	0.4	Normal	Normal	ND	Normal	Normal	ND	PSL	Resistant	[22]
18	16	M	1.3	0.5*	Normal	ND	ND	Normal	ND	ND	PSL AZA MMF	Improved	[23]
19	56	F	9.4	0.6	Normal	ND	ND	High 189	Normal	Normal	PSL	Improved	[24]
20	37	F	5.4	ND	12.7	ND	ND	High	ND	ND	PSL	Improved	[25]
21	68	F	2.5	+ **	11.0	Normal	ND	High 26	Normal	ND	PSL	Improved	[26]
22	30	M	2.2	ND	11.5	Normal	ND	Normal	Normal	Normal	PSL	Improved	[27]
23	50	F	1.5	ND	Normal	505	ND	ND	ND	ND	PSL	Improved	[28]
24	42	F	1.7	± **	12.0	ND	ND	ND	ND	ND	PSL AZA	Improved	[29]
25	30	M	3.7	ND	11.1	ND	ND	Normal	ND	Low	PSL	ND	[4]
26	55	F	13.8	Normal	iCa 5.5	384	ND	High 168	ND	High 114	PSL	Improved	[30]
27	74	F	2.36	0.81	Normal	Normal	63,200	Normal	ND	Low 13	PSL	Improved	Our case

*(g/gCr), sCr: serum creatinine, **Semi‑quantitative test for proteinuria, U-P: urine protein, sCa: serum calcium, U-Ca: urine calcium, U-β2MG: urine β2 microglobulin, ACE: angiotensin converting enzyme, 1,25.VD₃: 1,25 dihydroxyvitamin D₃, 25.VD₃: 1,25 dihydroxyvitamin D₃, ND: no data, PSL: prednisolone, AZA: Azathioprine, IFX: Infliximab, MMF: Mycophenolate mofetil, ESRD: end stage renal disease

To the best of our knowledge, only 26 cases have been reported to date, as summarized in Table 2. In all cases, the diagnosis was made through a process consistent with current diagnostic criteria: (1) identification of non-caseating granulomas on renal histopathology, and (2) exclusion of other potential secondary causes, leading to a definitive diagnosis of sarcoidosis. The age of the patients ranged from 13 to 81 years, and 13 of the 26 were male, indicating no clear sex predilection. Those previous cases were accompanied not by nephrotic-range proteinuria, but by only mild proteinuria of around 1 g/day, which considered to be attributable to tubular damage rather than glomerular injury in kidneys. In our present case, serum calcium level was not high, within the normal range, arguing against the involvement of calcium metabolism. However, among the previously reported cases, hypercalcemia was observed in 8 out of 26 cases, whereas the remaining cases had normal range of calcium levels. Of note, among the 8 patients with hypercalcemia, nobody had concomitant elevation in 1,25-dihydroxyvitamin D (1,25(OH)₂D), suggesting no consistent correlation between elevated calcium and 1,25(OH)₂D levels. In patient with sarcoidosis, 1,25(OH)₂D levels are usually elevated due to extrarenal production by activated macrophages in granulomatous tissues. This increased conversion from 25(OH)D can lead to decreased 25(OH)D levels, as it is rapidly utilized. Both in the one previously reported case and in our current case, the 25(OH)D level was low. However, it should be noted that vitamin D status was either not assessed or not reported in most cases, thereby limiting further evaluation of its role.

In contrast, serum ACE levels were measured in 21 of the 26 reported cases, among which 9 showed elevated values, whereas our case demonstrated a normal level. This point indicates a higher detection rate than that of vitamin D abnormality, and we suggest that while neither ACE nor calcium is sufficient as a standalone diagnostic marker, both may serve as useful adjunctive indicators for renal limited sarcoidosis.

In terms of treatment, corticosteroid therapy with PSL remains the first-line approach and has proven effective in nearly all documented cases, reflecting the standard management strategy for systemic sarcoidosis [11]. In a few cases, however, steroid resistance was observed (Table 2), and two of these cases required renal replacement therapy due to end-stage renal disease (ESRD). In a subset of steroid-resistant or refractory cases, alternative immunosuppressive agents—such as infliximab, a TNF-α inhibitor, and mycophenolate mofetil (MMF)—have been employed (Table 2). However, their use in steroid-resistant sarcoidosis is based on limited data. Further studies are therefore needed to further evaluate the efficacy and safety of these non‑steroidal therapies in refractory disease.

In this case, approximately 85% of glomeruli showed obsolescence. This extensive glomerular damage likely reflects not only the impact of tubulointerstitial nephritis but also the contributions of advanced age and pre-existing diabetes mellitus. Although renal function improved with prednisolone therapy, sCr decreased only to around 1.2 mg/dL and subsequently plateaued, suggesting that irreversible glomerular injury limited the overall recovery of renal function. These findings highlight the importance of early intervention in cases of tubulointerstitial nephritis, particularly in elderly patients or those with comorbidities that predispose to chronic kidney injury.

In conclusion, kidney biopsy was useful for the diagnosis and contributed to obtaining a favorable renal outcome in our case with unexplained renal dysfunction. When non-caseating granulomas of unknown etiology are found in the kidney without evidence of lesions in other organs, renal limited sarcoidosis should be considered in the differential diagnosis. Moreover, if renal limited sarcoidosis is diagnosed, improvement can be expected with corticosteroid therapy such as prednisolone as well as systemic sarcoidosis.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

KY, KT, YW, HO, RU and YT designed the overall framework of the study. KY and KT wrote the manuscript with input from all authors. KY, KT, YW, HO, RU, SK, SS, KS, TM, SN, and YT directly treated the patient and performed kidney biopsy. KY,　KT and TA mainly assessed the renal pathology. All authors were responsible for implementation of the study. All authors critically revised the report, commented on drafts of the manuscript, and approved the final report.

Funding

Not applicable.

Data availability

All data generated or analyzed during this study are included in this published article.

Declarations

Conflict of interest

All authors declare that they have no conflict of interest.

Ethics approval

This article does not contain any studies with human participants performed by any of the authors.

Informed consent.

Informed consent was obtained from the individual participant included in the study.