Kikuchi-Fujimoto-Like Renal Involvement in Autoimmune Disease

Abstract

Introduction

Kikuchi-Fujimoto Disease (KFD) is a rare, self-limiting disorder primarily involving lymph nodes and characterized by necrotizing lymphohistiocytic inflammation with prominent apoptotic debris. Extranodal involvement has been described, but KF-like necroinflammation has only rarely been documented in kidney biopsies.

Methods

We retrospectively reviewed data from 3 institutions over 20 years and identified 9 patients with native kidney biopsies showing KF-like interstitial necroinflammation and compared the clinical and pathologic features with 8 patients with systemic KFD and kidney biopsies.

Results

A total of 8 of 9 patients with KF-like necroinflammation had previously diagnosed or suspected evolving systemic lupus erythematosus (SLE); none had systemic KFD. The most prominent finding in kidney biopsies was an atypical necroinflammatory interstitial infiltrate composed of histiocytes and lymphocytes with areas of brisk apoptosis, karyorrhectic debris, mitotic activity, and occasional large, atypical nuclei. The majority had limited or no glomerular involvement, and when present, this usually consisted of focal, mild active or chronic lesions with modest immune complex deposition. In comparison, in the 8 patients with systemic KFD, kidney biopsy findings were attributable to lupus nephritis (LN) in 4 of 5 patients with SLE, including 3 with membranous LN. No patient with systemic KFD had KF-like renal interstitial necroinflammation.

Conclusions

Although lymphohistiocytic inflammation with prominent karyorrhexis most commonly manifests as a necrotizing lymphadenitis or dermatitis in both KFD and SLE, our study reveals that this distinctive pattern may also be recognized as an unusual interstitial nephritis, most commonly associated with SLE and seen in biopsies with limited glomerular involvement.

Graphical abstract

KFD, or KF histiocytic necrotizing lymphadenitis, most commonly affects younger patients of Asian descent and is characterized by tender cervical lymphadenopathy and fever, as well as rash, cytopenias or leukocytosis, arthritis, fatigue, and/or hepatosplenomegaly in a minority of cases.¹ KFD may mimic, be triggered by, or evolve into other entities, particularly SLE, infection (especially Epstein–Barr virus [EBV], HHV6 and 8, HIV, parvovirus B19, tuberculosis, Bartonella, and others), and lymphomas.¹ Histologically, lymph nodes in patients with KFD show patchy necrosis, histiocytic and T-cell rich inflammation with scant B-cells, abundant karyorrhectic debris, and scattered immunoblasts, without associated neutrophilic or eosinophilic infiltrate. SLE lymphadenitis may show a greater degree of polyclonal plasma cell infiltrate but otherwise be histologically indistinguishable from KFD.^2,3 The pathogenesis of KFD and SLE lymphadenitis and the immunologic mechanisms of the characteristic inflammation are unknown. Extranodal involvement has been described in KFD and most commonly involves the skin, with skin biopsies showing a similar pattern of lymphohistiocytic inflammation with karyorrhectic debris as seen in involved lymph nodes4, 5, 6, 7; skin biopsies from patients with cutaneous lupus can have a similar KF-like inflammatory pattern.⁸

However, Kikuchi-Fujimoto-like renal involvement with necrotizing lymphohistiocytic inflammation has only rarely been documented in kidney biopsies, limited to 4 cases in abstract form^9,10 without other published reports to our knowledge. Herein, we report 9 patients from 3 institutions with native kidney biopsies showing KF-like interstitial necroinflammation and compare the clinical and pathologic features with those of 8 patients with systemic KFD who also underwent kidney biopsy.

Methods

Kidney biopsy records and associated clinical data from 2006 to 2026 at 3 institutions (Arkana Laboratories, Renopath Center for Renal and Urological Pathology in Chennai, India, and Oregon Health & Science University) were searched for (1) terms including Kikuchi-like, necroinflammatory, necrotizing lymphadenitis, atypical hematopoietic infiltrate, and (2) patients with previously diagnosed KFD and available kidney biopsy. Immunofluorescence (IF) was performed on all biopsies (17 with frozen IF, 1 with paraffin IF only due to lack of tissue submitted for frozen) and electron microscopy was performed on 14 biopsies (1 had no tissue available for electron microscopy). Immunohistochemical and special staining to further characterize the interstitial infiltrate and/or exclude a viral or infectious process were performed in 5 of 9 KF-like renal necroinflammation cases. Not all clinical variables were available for each patient; for variables with missing data, the denominator is provided.

Results

Patients With KF-Like Renal Necroinflammation on Kidney Biopsy

Clinical Presentation

A total of 9 patients (Cases 1–9) with kidney biopsies showing KF-like interstitial necroinflammation were identified (Table 1), with a median age of 21 years (range 14–40 years) and 2:1 female-to-male ratio. In terms of ethnicity, there was a predominance of African American patients (4/9), followed by Hispanic (2/9), Native American, Asian, and unknown (1 each). Overall, 7 patients had a prior diagnosis of SLE), including 1 SLE/mixed connective tissue disease overlap, 1 SLE/rheumatoid arthritis/psoriatic arthritis overlap, and 1 with possible additional hemophagocytic lymphohistiocytosis. Only 2 did not have a rheumatologic diagnosis documented at the time of kidney biopsy, although 1 of these had suspected evolving lupus. None had known positive antineutrophil cytoplasmic antibody testing or a clinical diagnosis of KFD. Only 1 patient with SLE had high plasma EBV DNA.

Table 1.

Clinical features of patients with KF-like necroinflammation on kidney biopsy vs. patients with systemic KFD and kidney biopsy

Case	Age, Sex	Auto-immune dx	Serologic & laboratory findings	Other systemic features	Reason for kidney biopsy	Summary bx dx
Patients with KF-like necroinflammation on kidney biopsy
1	14 F	SLE, IBD	+ANA, ↓C3 and C4, ↑LFTs, pancytopenia	LAD, fever, rash, ulcers	Nephrotic syndrome. Cr 0.7	Atypical interstitial process Lupus podocytopathy Class III LN
2	40 M	SLE/ MCTD	+ANA, ↑LFTs, leukopenia	LAD, fever, arthralgias	Hem, prot (3+)	Necrotizing TI inflammation
3	21 F	New SLE	+ANA, +dsDNA, ↓C3 and C4, ↑LFTs, pancytopenia	Fever, weight loss, rash	AKI (Cr 1.5), hem, prot	Atypical TI inflammation Class I LN
4	14 F	SLE, possible HLH	+ANA, +dsDNA, ↓C3 and C4, +Smith, ↑LFTs, pancytopenia	Fever, weight loss, rash, oral ulcers	Prot (uPCR 1.6). Cr 0.35	Interstitial necroinflammation Class III LN
5	20 M	SLE	↑LFTs, pancytopenia	Fever	Nephrotic syndrome. Cr 0.6	Lupus podocytopathy Interstitial necroinflammation Class I LN
6	48 F	SLE	+ANA, +dsDNA, +Smith, ↓C3 and C4	LAD, fever	Hem, prot (uPCR 1.3). Cr 0.76.	Atypical acute TI nephritis
7	34 F	NA	↓Plts, ↑LFTs	LAD, fever	AKI (Cr 2.67), hem, prot	Acute TI nephritis ATI with myoglobin casts
8	25 M	SLE/ RA	+ANA, +dsDNA, ↓C3 and C4, ↓Hb, ↑plasma EBV	Arthralgias, seizures/ cerebritis	Hem, prot (uPCR 2). Cr 1.01	Necroinflammation TI process with abundant karyorrhexis. Class III LN
9	20 F	Suspected SLE	+ANA, +dsDNA, ↓C3 and C4, pancytopenia, +Smith, +type III cryo	LAD, fever, weight loss, arthralgias, rash	Hem. uPCR 0.6, Cr 0.63	Atypical hematopoietic infiltrate. Rare intracap IgM, cryo or immune complex GN
Patients with systemic KFD and kidney biopsy
10	18 M	None	Pancytopenia	LAD, fever, weight loss, arthralgias	AKI (Cr 11.8), nephrotic syndrome	Collapsing FSGS
11	37 M	SLE	NA	LAD	AKI	Class II LN
12	40 F	SLE	NA	Arthralgias, rash	Hem, prot (1+)	Arterionephrosclerosis
13	24 M	SLE	+ANA, +dsDNA, ↓C3 and C4, pancytopenia	LAD, fever, weight loss, rash	AKI (Cr 1.53), prot (uPCR 4)	Class III and V LN, EXT1 positive
14	21 M	HLH	NA	LAD, fever, weight loss, arthralgia, rash	Prot. Cr 0.68	Mild mes immune complex deposition (IgM, C3)
15	63 F	SLE/ MCTD	+ANA, +dsDNA, +Smith, ↓C3 and C4	NA	Hem, prot	Class III and V LN, EXT1 negative
16	23 F	No	↓Plts	LAD, fever	Prot (uPCR 4.1). Cr 0.46	Endocap prolif GN (IgG, C3, C1q) with focal crescents
17	48 F	SLE	+ANA, ↓Hb, ↓plts	LAD, fever, weight loss, arthralgias	Prot (uPCR 8.7). Cr 0.6	Class V LN

AKI, acute kidney injury; ANA, antinuclear antibody; ATI, acute tubular injury; C3, complement C3; C4, complement C4; Cr, serum creatinine in mg/dL; Cryo, cryoglobulin; dsDNA, antidouble-stranded DNA antibody; Dx, diagnosis; Dz, disease; EBV, Epstein-Barr virus; Endocap, endocapillary; EXT, exostosin; F, female; FSGS, focal and segmental glomerulosclerosis; GN, glomerulonephritis; Hb, hemoglobin; Hem, refers to microscopic, not gross, hematuria; HLH, hemophagocytic lymphohistiocytosis; IBD, inflammatory bowel disease; LAD, lymphadenopathy; LFT, liver function tests, including AST, or aspartate aminotransferase, and ALT, or alanine aminotransferase; LN, lupus nephritis; M, male; MCTD, mixed connective tissue disease; Mes, mesangial; NA, not available; Plts, platelets; Prot, proteinuria; RA, rheumatoid arthritis. SLE, systemic lupus erythematosus; TI, tubulointerstitial; uPCR, urine protein to creatinine ratio in mg/mg.

Systemic symptoms at the time of kidney biopsy included cervical (in 5/7 patients with available data) and/or generalized (4/7) lymphadenopathy, fever (8/9), weight changes (loss in 3, gain in 2), arthralgias (3/5), and rash (4/7); 1 patient had seizure activity. Laboratory evaluation revealed a positive antinuclear antibody (7/7), antidouble stranded DNA antibody (5/5), anti-Smith antibody (3/3), low C3 and C4 (6/6), as well as anemia (6/9), thrombocytopenia (6/8), leukopenia (6/8), hypoalbuminemia (7/7), and transaminitis (8/8). Kidney biopsies were generally performed for proteinuria (7/9 with subnephrotic range proteinuria; 2/9 with nephrotic syndrome) and microscopic hematuria (6/9), with preserved renal function (2/8 with acute kidney injury).

Pathologic Findings

The most prominent finding in the kidney biopsies (Table 2) was an atypical necroinflammatory interstitial infiltrate (Figures 1 and 2), generally composed of histiocytes and lymphocytes, some with large, atypical nuclei. Foci of brisk apoptosis and karyorrhectic debris were present, as were zones of mitotic activity and small areas of geographic necrosis without fibrin deposition. Immunohistochemistry performed in 5 of 9 biopsies showed that the infiltrate consisted predominantly of histiocytes and monocytic lineage cells (CD33, CD68 positive), including a subset that coexpressed myeloperoxidase, and/or CD8+ T-cells; a high Ki-67 proliferative rate was present. This infiltrate usually had patchy, nondiffuse cortical involvement and could also be observed in peritubular capillaries, but generally not in glomeruli. EBV by in situ hybridization was negative in all tested cases (5/5), including in the patient with high plasma EBV DNA. Cytomegalovirus testing was performed on one case and was negative. No fungal or acid-fast organisms were identified. One biopsy also had acute tubular injury with frequent myoglobin-positive casts.

Table 2.

Pathologic features of patients with KF-like necroinflammation on kidney biopsy

Case	Tubulointerstitium	Glomeruli	IF	EM	Biopsy diagnosis	Treatment	Follow-up
1	Mixed acute TI inflammation, apoptosis, atypical cells, fibrin	Mes prolif, fibrous crescents, no active lesions	Predominantly mes IgG (2+), IgM (1+), C3 (2+), C1q (1+)	Diffuse FPE, mes dep	Lupus podocytopathy. Atypical interstitial process. Class III LN.	Pred, HCQ	Biopsy 1 yr later: class III LN
2	Interstitial necrosis with associated histiocytes	Normal	Tissue ANA. Otherwise, negative	No dep, focal FPE	Necrotizing TI inflammation. No lupus GN.	Pred, MMF	Biopsy 3 yrs later: class V LN
3	Marked TI inflammation with histiocytes, CD8+ T-cells, apoptosis	Normal	Mes IgG (3+), IgA (3+), IgM (1+), C3 (3+), C1q (3+). TBM dep	Mes dep	Atypical TI inflammation. Class I LN.	Solu-medrol	NA
4	Histiocyte and lymphocyte rich TI infiltrate with karyorrhexis	Rare intracap “plugs”/ hyaline pseudo-thrombi	Mes and seg PCW IgG (3+), IgA (3+), IgM (3+), C3 (3+), C1q (3+). TBM dep	Mes, rare subendo dep	Interstitial necroinflammation. Class III LN.	High dose steroids, HCQ	NA
5	Mononuclear cell infiltrate with prominent apoptosis and karyorrhexis	Minimal mes expansion, no active lesions	Mes IgG (1-2+), IgA (1+), IgM (2+), C3 (1+), C1q (2-3+). Tissue ANA. PTC dep	Diffuse FPE, mes dep	Lupus podocytopathy. Interstitial necroinflammation. Class I LN.	Methylpred	NA
6	Mixed TI inflammation with karyorrhexis	Normal	Tissue ANA. Otherwise, negative	Focal FPE	Atypical acute TI nephritis. No lupus GN.	NA	NA
7	Lymphocyte, histiocyte, and plasma cell rich infiltrate. ATI myoglobin+ casts	Normal	Negative	Focal FPE	Acute TI nephritis. ATI with myoglobin+ casts. No lupus GN.	NA	NA
8	Zones of geographic TI necrosis, brisk apoptosis and karyorrhectic debris, inflammation	Rare EH and fibro-cellular crescent, FSGS	Mes and intracap IgG (1+), IgM (1+), C3 (2+), C1q (2+)	Mes, rare subendo dep, TRIs	Necroinflammatory TI process with abundant karyorrhexis. Class III LN.	Pred, HCQ, MMF	Biopsy 10 yrs later: class IV and V LN
9	Atypical mononuclear infiltrate with large nuclei, focally prominent apoptotic debris and mitoses	Rare intracap “plugs”/ hyaline pseudo-thrombi	Intracap IgM (1-2+) on P-IF	NA	Atypical hematopoietic infiltrate. Rare intracapillary IgM suggestive of cryo or immune complex GN	Pred, HCQ, MMF	Later dx with lupus and cryo

ANA, anti-nuclear antibody; ATI, acute tubular injury; Aza, azathioprine; Cryo, cryoglobulinemia; Dep, deposits; EH, endocapillary hypercellularity; EM, electron microscopy; FPE, podocyte foot process effacement; FSGS, focal segmental glomerulosclerosis; GN, glomerulonephritis; HCQ, hydroxychloroquine; IF, immunofluorescence; Intracap, intracapillary; LN, lupus nephritis; Mes, mesangial; Methylpred, methylprednisolone; MMF, Mycophenolate mofetil; NA, not available; P-IF,paraffin IF; PCW, peripheral capillary wall; Pred, prednisone; PTC, peritubular capillary; Subendo, subendothelial; Subepi, subepithelial; TBM, tubular basement membrane; TI, tubulointerstitial; TRI, tubuloreticular inclusions; Yrs, years.

Case 9 had P-IF only, no tissue submitted for frozen IF or EM.

Figure 1.

Kidney biopsy findings in patients with interstitial KF-like necroinflammation (Case 1 and 2). (a) Well demarcated interstitial inflammatory infiltrate admixed with prominent karyorrhectic debris (PAS, 100x), (b) Tubular injury and surrounding interstitial inflammation with prominent karyorrhectic debris (H&E, 400x), (c) Glomerulus with segmental mild mesangial hypercellularity (PAS, 400x), (d) Immunohistochemical staining for CD3 highlighting a T-cell-rich interstitial inflammatory infiltrate (100x).

Figure 2.

Kidney biopsy findings in patients with interstitial KF-like necroinflammation (Case 8 and 9). (a) Small zones of geographic necrosis (H&E, 400x), and (b) areas with enlarged atypical cells with apoptotic debris and mitotic figures (PAS, 200x). Similar to that seen in systemic KFD, the KF-like necroinflammatory infiltrate in kidney biopsies was composed predominantly of (c) CD8+ T cells and (d) MPO-positive histiocytes. Glomerular findings were comparatively limited in most cases; (d) rare intracapillary glomerular “plugs” or “hyaline pseudothrombi” which stained for (IgM, paraffin IF) seen in Case 9 (arrows).

Glomerular light microscopic findings were comparatively limited in most cases and ranged from no glomerular abnormalities (4/9) to mild mesangial expansion (1/9) in the majority. A total of 4 cases had focal active or chronic lesions which were limited in extent (< 20% of glomeruli), consisting of focal intracapillary hyaline pseudothrombi or subendothelial deposits (2/9), focal endocapillary hypercellularity and karyorrhexis with fibrocellular crescents (1/9) and/or focal fibrous crescents (1/9). No case had cellular crescents, diffusely active International Society of Nephrology/Renal Pathology Society (ISN/RPS) class IV LN, a membranoproliferative pattern, thrombotic microangiopathy, or a substantial component of membranous LN (class V).

IF microscopy revealed no deposits or a “tissue antinuclear antibody”-only pattern in a third of cases (3/9). Cases with immune deposits were mesangial-predominant (5/6) and showed “full house” staining (5/6) with extraglomerular deposits (tubular basement membrane: 2, peritubular capillary: 1). One patient with a type III cryoglobulin had only paraffin IF available which showed IgM-dominant deposits with focal intracapillary plugs (Case 9). No cases had monotypic deposits. Electron microscopy revealed diffuse podocyte foot process effacement in 2 patients with nephrotic syndrome, consistent with lupus podocytopathy (Cases 1, 5).

Overall kidney biopsy diagnoses were atypical interstitial necroinflammation (9/9) without glomerular findings in 3 patients, and with associated focal LN in 3 patients (ISN/RPS class III), lupus podocytopathy in 2 patients, minimal mesangial LN in 2 patients (ISN/RPS class I), and/or rare intracapillary IgM deposits suspicious for cryoglobulinemic or other focal immune complex glomerulonephritis.

Treatment and Follow-up

All patients with available treatment data were treated with immunosuppressive agents (7/7), including steroids,⁷ hydroxychloroquine,⁴ and/or mycophenolate.³ A total of 3 patients underwent repeat kidney biopsy, revealing the following: (1) mesangial proliferative LN with associated chronic injury (ISN/RPS class III) and without interstitial infiltrates (at 1 year), (2) class V LN with focal aggregates of interstitial histiocytes (at 3 years), and (3) class IV and V LN without interstitial infiltrates (at 10 years). A patient with suspected evolving SLE and an atypical hematopoietic infiltrate on kidney biopsy (Case 9) had a lymph node biopsy negative for neoplasm or KF-like necroinflammation, a skin biopsy showing leukocytoclastic vasculitis with IgM and IgG deposits without KF-like inflammation, and a type III cryoglobulin identified weeks after biopsy; she was treated as lupus with stable renal findings but worsening systemic symptoms at 6 months.

Kidney Biopsy Findings From Patients With Systemic KFD

Clinical Presentation

A total of 8 patients (Cases 10–17) with a diagnosis of systemic KFD who had kidney biopsies were included for comparison (Tables 1 and 3). These patients had a median age of 31 years (range, 23–63 years), a 1:1 female-to-male ratio, and were African American (2/8), South Indian (2/8), Hispanic (1/8), White (1/8) or unknown race or ethnicity (2/8). KFD diagnosis was recent in 7 patients and preceded kidney biopsy by 8 years in 1 patient. Of these, 5 patients had a concurrent diagnosis of SLE, including 1 with SLE/mixed connective tissue disease/Sjögren syndrome/sarcoidosis; 1 had hemophagocytic lymphohistiocytosis, and the 2 remaining patients had no prior rheumatologic diagnosis. All patients had a lymph node biopsy showing necrotizing histiocytic lymphadenitis characteristic of KFD. None had an underlying malignancy, known active EBV, or other acute infectious disease.

Table 3.

Pathologic features of patients with systemic KFD and kidney biopsy

Case	Tubulo interstitium	Glomeruli	IF	EM	Biopsy diagnosis	Treatment	Follow-up
10	Microcystic tubular dilatation	Collapsing FSGS	Negative	Diffuse FPE	Collapsing glomerulopathy	NA	NA
11	ATI	Mes prolif	Mes IgG (1+), IgM (tr), C3 (1+)	Mes dep, diffuse FPE	Class II LN	NA	NA
12	Mild IFTA	Normal	Negative	Mild FPE	Arterionephrosclerosis	NA	NA
13	Focal mild TI inflammation	Mes prolif, focal EH	Mes and PCW IgG (3+), IgA (2+), IgM (2+), C3 (2+), C1q (2+)	Mes, subendo, subepi dep, severe FPE	Focal proliferative immune complex GN, MN, EXT1 positive	Pred	NA
14	Normal	Mild mes expansion	Mes IgM (1+), C3 (1+)	Mes dep, mild FPE	Mild mes immune complex deposition	Pred	NA
15	Focal mild TI inflammation	Mes prolif, focal EH, MN, FSGS	Mes and PCW IgG (3+), IgA (tr), IgM (1+), C3 (1+), C1q (2+)	Mes, subepi dep, diffuse FPE	Class III and V LN, EXT1 neg	NA	NA
16	Focal mild TI inflammation	Mild mes prolif, focal EH, crescents	Mes and PCW IgG (2+), C3 (2+), C1q (1+)	NA	Endocap proliferative GN with focal crescents	Methyl pred, HCQ, MMF	NA
17	Normal	Mild mes prolif, focal MN features	Mes and PCW IgG (3+), C3 (2+), C1q (2+)	NA	Class V LN	NA	NA

Dep, deposits; EH, endocapillary hypercellularity; EM, electron microscopy; EXT, exostosin; FPE, podocyte foot process effacement; FSGS, focal segmental glomerulosclerosis; GN, glomerulonephritis; HCQ, hydroxychloroquine; IF, immunofluorescence; LN, lupus nephritis; Mes, mesangial; Methylpred, methylprednisolone; MMF, Mycophenolate mofetil; NA, not available; PCW, peripheral capillary wall; Subepi, subepithelial; TI, tubulointerstitial.

Systemic symptoms at the time of kidney biopsy included cervical (6/7) and/or generalized (5/6) lymphadenopathy, fever (5/6), weight loss (4/6), arthralgias (4/5), rash (3/5), and paresthesia (2/4). Laboratory evaluation revealed variably positive antinuclear antibody (3/5), double stranded (2/4), anti-Smith (1/3), low C3 and C4 (2/4), anemia (3/5), thrombocytopenia (4/5), and leukopenia (2/5). Kidney biopsies were performed for proteinuria (7/8, including 4 with nephrotic-range proteinuria, including 1 patient with nephrotic syndrome), acute kidney injury (3/6) and microscopic hematuria (2/7). There were no significant differences in any of the above demographic or laboratory variables between patients with systemic KFD and patients with KF-like renal necroinflammation.

Pathologic Findings

In patients with systemic KFD, kidney biopsy findings (Table 3 and Figure 3) were attributable to LN in 4 of the 5 patients with SLE, including ISN/RPS class III, class II, and class V (in 3). Most notably, none of the biopsies showed an atypical lymphohistiocytic inflammatory infiltrate with karyorrhectic debris. Other diagnoses included endocapillary proliferative glomerulonephritis with focal crescents, mild mesangial immune complex deposition in a patient with hemophagocytic lymphohistiocytosis, collapsing glomerulopathy, and arterionephrosclerosis.

Figure 3.

Glomerular histopathology seen in patients with systemic KFD. (a,b) Collapsing glomerulopathy (Case 10), (a) Jones methenamine silver stain showing glomerular capillary tuft collapse with overlying epithelial cell hyperplasia (400x, scale bar = 20 μm), (b) PAS stain showing collapsing glomerulopathy in a background of acute tubular injury and microcystic tubular dilation (200x, scale bar = 50 μm); (c–h) Focal lupus nephritis and EXT-positive membranous lupus nephritis (Case 13); (c) Jones methenamine silver stain showing a glomerulus with prominent capillary loops with formation of holes (400x, scale bar = 20 μm), (d) PAS stain showing a glomerulus with intracapillary hyaline pseudothrombi (400x, scale bar = 20 μm), (e) Direct immunofluorescence for IgG showing granular mesangial and capillary loop staining (400x, scale bar = 20 μm), (f) Direct immunofluorescence for C1q showing granular mesangial and segmental capillary loop staining (400x, scale bar = 20 μm), (g) Ultrastructural photomicrograph showing subepithelial and intramembranous electron dense immune-type deposits, (h) Paraffin immunofluorescence for EXT1 showing granular positivity along the glomerular capillary loops (600x, scale bar = 20μm).

Discussion

In this clinicopathologic cohort, we examine a distinctive but rare finding in kidney biopsies—tubulointerstitial involvement by KF-like necroinflammation and cell turnover. We found that these cases were derived largely from patients with previously diagnosed or suspected lupus and suggest that many of them represent lupus-associated interstitial necroinflammation, a novel form of interstitial nephritis. Although taken in the setting of clinically and serologically active lupus with other systemic symptoms, these kidney biopsies were relatively distinct from the glomerular and immune-complex-mediated injury common in LN. Specifically, the majority had limited or no glomerular involvement, and when present, this usually consisted of focal, mild active or chronic lesions with modest immune complex deposition, or podocytopathy. Our findings expand the renal manifestations observed in LN as well as the differential for necrotizing lymphohistiocytic inflammation on kidney biopsy and raise questions about the involved mechanisms and significance of KF-like renal necroinflammation. Beyond the unusual histology, we did not identify other consistent, clinically distinct features in patients within this cohort with regard to presentation or outcome, albeit with a small sample size and limited follow-up data.

An interstitial necroinflammatory infiltrate with high apoptotic and mitotic activity and large nuclei without a prominent glomerulonephritis can raise concern for infection, vasculitis, hematopoietic malignancy, septic emboli from endocarditis, or potentially an unusual infarct, autoimmune phenomenon, or hemophagocytic lymphohistiocytosis, the latter of which can also have LN and focal cortical necrosis.¹¹ In settings of limited tissue, KF-like necroinflammation can often be highlighted by CD8 and myeloperoxidase,^12,13 but an expanded immunohistochemical staining panel may be required to exclude a malignant hematopoietic infiltrate or infection depending on the morphology and clinical history. Although 1 patient with lupus also had active EBV, no infectious agent was detected in kidney biopsy tissue in this or any other case, and no patient was subsequently found to have an underlying hematopoietic malignancy or infectious driver of the kidney inflammation.

KFD may overlap with autoimmune diseases including SLE, antiphospholipid antibody syndrome, Sjögren syndrome, and systemic sclerosis.¹⁴ Although not the primary focus of this investigation, the 8 patients reported herein represent the largest series of patients with KFD who underwent kidney biopsy. Previously reported kidney biopsy findings in patients with KFD include PLA2R-negative membranous nephropathy,¹⁵ ISN/RPS class I LN,¹⁶ class IV proliferative LN,¹⁷ and class V LN¹⁸ In patients with KFD without kidney biopsy, acute kidney injury¹⁹ and acute kidney injury in the setting of atypical hemolytic uremic syndrome²⁰ have also been reported. In our cohort, biopsy was generally prompted by proteinuria. LN was present in 4 of 8 patients with KFD undergoing kidney biopsy, with 3 of these showing class V LN, including 2 cases of Exostosin 1 positive membranous LN. Although this represents a small subset of patients with KFD, it adds data to the connection between membranous nephropathy and KFD, particularly in patients with SLE.

None of the patients with systemic KFD had KF-like necroinflammation on kidney biopsy, suggesting that although the unique pattern of inflammation is shared, other factors may determine the degree of organ involvement and clinical manifestations. The strength of this conclusion is somewhat limited by the lack of histologic evaluation of other organs (lymph nodes, skin) in 8 of 9 patients with KF-like necroinflammation on kidney biopsy, all of whom also had a constellation of systemic features common in both KFD and active SLE.^21,22 Case reports and small series highlighting parallel histology of lymphohistiocytic inflammation with karyorrhectic debris in both lymph nodes and skin in patients with KFD and SLE4, 5, 6, 7, 8, as well as 1 previously reported patient with systemic KFD and necrotizing lymphohistiocytic inflammation in both kidney and lymph node biopsies¹⁰, together suggest that this pattern of inflammation is shared by KFD and SLE and may be seen in multiple organs. However, larger studies of patients with untreated SLE and lymphadenopathy suggest that Langerhans cell infiltration—rather than KF-like necroinflammation—may be the more prevalent immunologic process.²³

Conclusion

In conclusion, although lymphohistiocytic inflammation with prominent karyorrhexis most commonly manifests as a necrotizing lymphadenitis or dermatitis in both KFD and SLE, our study reveals that this distinctive pattern may also be recognized as an unusual interstitial nephritis. It is most commonly associated with SLE and is present without the usual type or extent of glomerular inflammation or immune complex deposition that typically characterizes kidney biopsies in active SLE.

Disclosure

All the authors declare no competing interests.