Kidney Involvement in Sarcoidosis-Lymphoma Syndrome: A Report of Two Cases

Abstract

Sarcoidosis-lymphoma syndrome, first described by Henrik Brincker in 1986, is defined by the association of sarcoidosis with lymphoid neoplasms. This condition may present with sarcoidosis preceding, occurring concurrently with, or developing after the neoplasm. Its pathogenesis remains poorly understood. Kidney involvement by granulomatous interstitial nephritis is well-documented, including in cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), where granulomas typically occur in proximity to neoplastic infiltrates. However, no prior reports in the literature describe histologically confirmed granulomatous interstitial nephritis affecting the kidney in the absence of concurrent CLL/SLL infiltration. We report two patients with a history of CLL/SLL who presented with acute kidney injury (AKI). Kidney involvement by the underlying malignancy was initially suspected, supported by radiologic findings of extensive lymphadenopathy. Unexpectedly, renal biopsies revealed diffuse granulomatous interstitial nephritis without evidence of CLL/SLL. Based on these results, both patients received immunosuppressive and/or clone-directed therapies, leading to improved kidney function.

Introduction

Sarcoidosis is characterized by the development of non-caseating granulomatous inflammation across various organ systems, aligning with recently updated diagnostic criteria [1]. It remains a diagnosis of exclusion, as no definitive etiology or pathogenesis has been established. Current evidence suggests it may represent a hypersensitivity reaction to unknown antigen(s) in genetically predisposed individuals [2]. In the kidney, sarcoidosis most commonly manifests as nephrolithiasis or nephrocalcinosis due to increased 1-alpha-hydroxylase activity and resultant hypercalcemia, alongside granulomatous interstitial nephritis. Beyond the direct effects of granulomas, one study has proposed lysozyme-induced nephropathy as a potential contributor to renal injury [3].

The term “sarcoidosis-lymphoma syndrome” was first introduced by Henrik Brincker, who demonstrated an elevated incidence of lymphoma among sarcoidosis patients [4]. Since then, a growing body of literature has documented an association between sarcoidosis and malignancies. Notably, sarcoidosis may precede, occur concurrently with, or follow a malignancy diagnosis [5, 6].

Efforts to clarify this relationship and address related controversies have included two recent meta-analyses, involving > 25,000 and 17,767 cases, and found a pooled relative risk (RR) of malignancy in sarcoidosis patients of 1.21 (95% CI 1.04–1.40) and 1.19 (95% CI 1.07–1.32), respectively [7, 8], with an RR of 1.92 (95% CI 1.41–2.62) seen specifically for hematopoietic malignancies [8]. Sarcoidosis following malignancy has also been described, with B-cell neoplasms being the most frequently reported [9–12].

In the context of CLL/SLL, granulomatous interstitial nephritis has been noted in case reports [13–15] and case series. For instance, Poitou-Verkinder et al. identified granulomatous interstitial nephritis in 6 of 15 CLL/SLL patients [16], while Nasr et al. reported five cases with granulomatous interstitial nephritis alongside CLL/SLL infiltrates [17]. However, nearly all reported patients (except one with an isolated interstitial granuloma amid extensive amyloid deposits [16]) exhibited direct renal involvement by CLL/SLL. To date, we have identified no literature describing clinically symptomatic granulomatous interstitial nephritis in the setting of CLL/SLL without concurrent neoplastic infiltration.

Case report

Patient #1

A 52-year-old male presented with AKI. Laboratory evaluation showed hypercalcemia at 14.9 mg/dL (reference range 8.9–10.3 mg/dL), suppressed parathyroid hormone (PTH) at 7 pg/mL (15–65 pg/mL); elevated 1,25-dihydroxyvitamin D (1,25[OH]₂D) at 137 pg/mL (18–72 pg/mL), serum creatinine (sCr) of 5.27 mg/dL (0.7–1.2 mg/dL; baseline 1.6 mg/dL one year prior) and angiotensin-converting enzyme (ACE) level of 132 U/L (9–67 U/L). Positron emission tomography-computed tomography (PET-CT) showed fluorodeoxyglucose (FDG)-avid enlarged lymph nodes involving neck, chest, abdomen and pelvis. Kidneys were normal in size and showed physiological FDG distribution. Lymph node biopsy showed CLL/SLL with trisomy 12 with numerous non-caseating granulomas adjacent to tumor infiltrates. Initial treatment with steroids, rituximab, pamidronate, and denosumab yielded minimal response. Subsequent therapy with bendamustine and rituximab resolved lymphadenopathy, as confirmed by PET-CT showing decreased FDG uptake in previously hypermetabolic lymph nodes. Serum calcium improved to 10.1 mg/dL, ACE level to 23 U/L, 1,25[OH]₂D to 35.7 pg/mL, and sCr to 1.88 mg/dL. The patient remained in remission for 29 months.

He presented again with increasing fatigue and AKI, attributed to recent heavy nonsteroidal anti-inflammatory drug use. On examination, he was normotensive, with an enlarged, mobile right posterior cervical lymph node and a bilateral, non-erythematous rash on the thighs and forearms. Laboratory findings showed an ACE level of 71 U/L, 1,25[OH]₂D of 80 pg/mL, and sCr of 7.0 mg/dL. Urinalysis was unremarkable, with bland urinary sediment. PET-CT revealed multifocal cervical and para-aortic lymphadenopathy, diffuse splenic enlargement with increased signal intensity, and metabolically active multifocal pulmonary parenchymal nodules. Similarly to the initial presentation, kidneys showed physiological FDG uptake. Flow cytometry of peripheral blood identified a small population of B-cells, insufficient for CLL/SLL diagnosis. Fine-needle aspiration (FNA) of the cervical lymph node showed atypical small B-cells but was inconclusive for a definitive diagnosis, with negative flow cytometry of the FNA specimen. A kidney biopsy was performed and showed diffuse non-necrotizing interstitial granulomatous inflammation (Fig. 1). No lymphoma infiltrates were identified, supported by immunohistochemical profile of the interstitial infiltrate. Detailed pathology findings are summarized in Table 1.

Fig. 1.

Kidney biopsy of patient 1. Low-power view of interstitial granulomas (A, arrows; Periodic acid-Schiff, original magnification 10×). Moderate tubular atrophy and interstitial fibrosis, with sparse interstitial lymphocytes (B, Masson’s trichrome, original magnification ×10). Higher power view of interstitial non-caseating granulomas (C, arrow; H&E, original magnification 20×) that stain positively for CD68 (D, original magnification ×20)

Table 1.

Summary of kidney biopsy findings

	Patient #1 (Fig. 1)	Patient #2 (Fig. 2)
Interstitium	Diffuse non-caseating granulomatous interstitial nephritis characterized by well-formed epithelioid granulomas with multinucleated giant cells and surrounding epithelioid macrophages. The background lymphocytic infiltrate was sparse and polymorphous, without dense, sheet-like, or monotonous lymphoid aggregates
% of interstitial involvement by granulomas	60%	50%
Degree of interstitial fibrosis	Moderate	Mild
Lymphocytic tubulitis	No	Yes
Glomeruli	Non-specific, including ischemic capillary tuft collapse and global glomerulosclerosis
% of globally sclerosed glomeruli (absolute value)	40.1% (13/32)	24.2 (8/33)
Vasculature	Mild to moderate medial hypertrophy and fibrointimal thickening
Immunofluorescence	Negative for immunoglobulins (IgG, IgA, IgM), complement components (C3, C1q), or kappa or lambda light chains
Immunohistochemistry	Scattered, predominantly CD3 and CD5 positive interstitial lymphocytes. Small foci of CD20 lymphocytes were also present, without CD5 or CD23 co-expression. CD68-positive macrophages comprised granulomas
Histochemistry	Negative Kinyoun and Gomori methenamine silver (GMS) stains
Lysozyme staining	Diffuse granular cytoplasmic staining in proximal tubular epithelium and macrophages, with stronger staining intensity compared to normal kidney controls
Electron microscopy	Non-specific findings

The patient was initiated on venetoclax 20 mg/day (escalated to 400 mg/day after one month) and rituximab, without steroid administration. A repeat PET-CT scan four months later demonstrated resolution of increased FDG uptake in all previously abnormal lymph nodes. Thirty-eight months after the current presentation, the patient remains in remission, with a serum calcium level of 10.3 mg/dL, sCr of 2.5 mg/dL and 1,25[OH]₂D of 8 pg/mL.

Patient #2

A 58-year-old female with a history of CLL/SLL with TP53 R248Q and XPO1 E571K mutations, partial deletion of the 5' portion of the IGH locus, and deletion of the 13q arm, presented for evaluation of elevated sCr. CLL/SLL was diagnosed 20 years prior to this presentation and was initially managed conservatively. Due to progressive peripheral lymphocytosis and worsening intra-abdominal lymphadenopathy, she received fludarabine and rituximab nine years prior, followed by bendamustine and rituximab six years prior. After achieving complete remission for 35 months, disease progression prompted initiation of ibrutinib. Twenty-two months prior, she developed persistent fevers, eye pain, and worsening lymphadenopathy. A repeat lymph node biopsy confirmed CLL/SLL with granulomatous lymphadenitis, and ophthalmologic examination revealed granulomatous uveitis. Oral steroids were administered, resulting in symptom improvement.

Her baseline sCr was 0.9 mg/dL (reference range: 0.6–1.1 mg/dL), but 12 months prior it rose to 1.2 mg/dL while she was on prednisone 5 mg daily. At presentation, sCr peaked at 1.9 mg/dL. She reported fatigue and anorexia, though physical examination was unremarkable, with no peripheral lymphadenopathy. Urinalysis was unremarkable and showed bland sediment. Her oral medications included prednisone 5 mg, ibrutinib 280 mg, omeprazole 20 mg, posaconazole 300 mg, and irbesartan 75 mg, all daily. Laboratory findings showed serum calcium of 9.4 mg/dL, ACE level of 42 U/L, PTH of 17 pg/mL (reference range: 12.0–88.0 pg/mL) and 1,25[OH]₂D of 69 pg/mL (reference range: 18–78 pg/mL). PET-CT revealed multiple enlarged and FDG-avid thoracic and abdominal lymph nodes. No obstructive uropathy or abnormal kidney enhancement was identified. Irbesartan was briefly discontinued, but sCr remained elevated. Kidney biopsy was performed, and, similar to the patient #1, it demonstrated diffuse non-necrotizing interstitial granulomatous inflammation and no lymphoma infiltrates (Fig. 2). Additional pathology findings are summarized in Table 1.

Fig. 2.

Kidney biopsy of patient 2. Low-power view of interstitial granulomas (A, arrows; Periodic acid-Schiff, original magnification 10×), mild tubular atrophy and interstitial fibrosis (B, Masson’s trichrome, original magnification ×10). Higher power view of interstitial non-caseating granulomas with adjacent inflammatory infiltrate (C, arrow; H&E, original magnification 20×). CD68 highlights macrophages within the granulomas (D, original magnification ×20)

The patient’s prednisone dose was increased to 20 mg daily with a slow taper, and she received four doses of rituximab 1000 mg. Fatigue and anorexia resolved, and sCr stabilized at 1.8 mg/dL. Twenty-two months after the initial consultation, she re-presented with AKI, with an sCr of 2.7 mg/dL and hypercalcemia of 11.3 mg/dL. Prednisone had been discontinued one month prior. She reported fatigue, generalized weakness, and body aches. Her medications included acalabrutinib 100 mg twice daily, acyclovir 400 mg twice daily, posaconazole 300 mg daily, amlodipine 5 mg daily, famotidine 20 mg daily, and atovaquone 750 mg daily. Physical examination was unremarkable. Laboratory results showed PTH level of 8.4 pg/mL and 1,25[OH]₂D of 57 pg/mL. Urinalysis was unremarkable, with a bland sediment. AKI was attributed to a sarcoidosis relapse, and she was started on prednisone 15 mg daily. AKI, hypercalcemia, and fatigue resolved, and she remains on prednisone 12.5 mg daily one year after the relapse.

Discussion

We presented two patients with a history of CLL/SLL who developed granulomatous interstitial nephritis without evidence of concurrent kidney infiltration by a neoplasm. In both cases no alternative etiologies for granulomatous inflammation, such as medications known to trigger sarcoid-like reactions or microorganisms identified by histochemical staining, were implicated.

While granulomatous interstitial nephritis has been described in patients with CLL/SLL, previously reported cases have invariably demonstrated concurrent neoplastic infiltration of the kidney [13–17]. Here, we describe cases of granulomatous interstitial nephritis occurring in patients with CLL/SLL in the absence of kidney involvement by CLL/SLL, a finding not previously reported to our knowledge. Although sampling error cannot be entirely excluded, this is unlikely given the typically diffuse pattern of kidney involvement by CLL/SLL when present, effectively arguing against a localized granulomatous reaction to neoplastic lymphoid cells [18].

CLL/SLL is known to cause systemic immune derangements. Paraneoplastic autoimmune complications occur in approximately 25% of CLL/SLL patients, predominantly as autoimmune cytopenias, though non-hematologic autoimmunity is rarer [19]. Among kidney pathologies linked to CLL/SLL with an autoimmune or immunological basis, membranoproliferative glomerulonephritis (20%), minimal change disease (10%), and membranous nephropathy (4%) are most common [20]. The mechanisms underlying these associations remain unclear, including whether specific molecular alterations seen in CLL/SLL or host immune factors contribute significantly. Interestingly, one study reported a higher frequency of tumor-associated granulomatous reactions in patients who later developed systemic sarcoidosis compared to those with similar tumors but without sarcoidosis [21]. In that study, 3 of 12 patients had B-cell lymphomas, though none had CLL/SLL. Our cases may reflect a similar phenomenon, as both patients demonstrated granulomatous lymphadenitis in proximity to CLL/SLL infiltrates on lymph node biopsy. In Patient 1, granulomas were identified concurrently with the initial diagnosis of CLL/SLL, whereas in Patient 2, granulomatous lymphadenitis emerged approximately 18 years into the disease course. Furthermore, Patient 2 also developed granulomatous uveitis almost contemporaneously with the diagnosis of granulomatous lymphadenitis. This provides additional support for a systemic, rather than localized, granulomatous inflammatory response and suggests a temporal association, as the patient had CLL/SLL for 18 years without developing uveitis and granulomatous nephritis until after the onset of granulomatous lymphadenitis. Whether the development of granulomatous inflammation in this context reflects the acquisition of specific molecular alterations in CLL/SLL, evolving host immune dysregulation, or a combination of both remains uncertain and warrants further investigation.

Additionally, while diffuse lysozyme staining was observed in proximal tubules in both patients, this finding is common in granulomatous diseases of various etiologies [3, 22]. Given the severe extent of granulomatous interstitial nephritis in both cases and the absence of typical features of lysozyme-induced nephropathy, we believe that the granulomatous interstitial nephritis was the primary driver of AKI, with lysozyme staining most likely representing tubular reabsorption rather than a leading mechanism of injury.

In both cases, clone-directed therapies (venetoclax and rituximab for Patient 1, and rituximab followed by acalabrutinib for Patient 2) were employed, despite the absence of tissue confirmed evidence of CLL/SLL recurrence. Treatment decisions were instead based on imaging findings of multifocal FDG-avid lymphadenopathy suggestive of recurrence. Notably, Patient 2 also received immunosuppression, whereas no immunosuppression was administered to Patient 1. Nonetheless, both patients experienced improvement in kidney function. Whether clone-directed therapy alone is sufficient, or whether combination with immunosuppression is warranted, requires larger-scale studies to determine.

In summary, our cases suggest that CLL/SLL may trigger granulomatous interstitial nephritis, potentially with a higher likelihood in patients with pre-existing peritumoral granulomas. Immunosuppression combined with clone-directed therapy (e.g., rituximab, venetoclax, or acalabrutinib) appears to be a viable treatment option, as demonstrated by clinical improvement in both patients. The differential diagnosis of impaired kidney function in patients with hematologic malignancies is broad and includes infections, drug toxicity, glomerular pathology, tumor lysis syndrome, and direct or indirect malignancy-related effects. Given the nonspecific clinical presentation and laboratory or radiologic findings in such cases, renal biopsy is a critical tool for identifying the underlying cause. Physicians should recognize the association between sarcoidosis and lymphoma and consider sarcoid-like granulomatous inflammation in the differential diagnosis for these patients, as it may respond to immunosuppressive and/or clone-directed therapies.

Funding

There was no support/funding for this work.

Declarations

Conflict of interest

Siarhei Dzedzik, Andrew D Zelenetz, Hye-Ran Park, Steven Salvatore and Surya V. Seshan declares no conflict of interest. Ilya Glezerman is supported by MSK Cancer Center Support Grant/Core Grant P30CA008748 and serves on the Advisory Board for T-knife Therapeutics, Inc.

Human and animal participants

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

Informed consent

Informed consent was obtained from all individual participants included in the study.