World J Nephrol Urol

World Journal of Nephrology and Urology, ISSN 1927-1239 print, 1927-1247 online, Open Access

Article copyright, the authors; Journal compilation copyright, World J Nephrol Urol and Elmer Press Inc

Journal website https://wjnu.elmerpub.com

Case Report

Volume 14, Number 1, June, pages 9-21

TAFRO in Disguise: Idiopathic Multicentric Castleman Disease-Like Syndrome With Renal Thrombotic Microangiopathy and Autoimmune Overlap

Figure 1. CT of chest with contrast (axial view) showing bilateral pleural effusions and adjacent atelectasis (white arrows). CT: computed tomography.

Figure 2. CT of abdomen and pelvis with contrast (coronal view) showing mild hepatosplenomegaly (black arrows). CT: computed tomography.

Figure 3. CT of abdomen and pelvis with contrast (axial view) showing retroperitoneal lymphadenopathy (white arrows). CT: computed tomography.

Figure 4. Bone marrow biopsy showing increased reticulin fibrosis (black arrows) and megakaryocytic hyperplasia with enlarged cells (blue arrows).

Figure 5. Pathogenesis of TAFRO syndrome. IL: interleukin; TAFRO: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly; TNF-α: tumor necrosis factor-alpha; VEGF: vascular endothelial growth factor.

**Table 1.** Laboratory Data on Admission and Discharge
Laboratory data	Admission	Days 7 - 10	Discharge (day 33)	Normal range
CCP: cyclic citrullinated protein; SSA: Sjogren’s syndrome-related antigen A.
White blood cells	13.9	16.2	7.2	4.8 - 10.8 × 10³ cells/µL
Hemoglobin	9.8	6.8	8.4	13.5 - 17.5 g/dL
Platelet count	144	50	113	130 - 400 × 10³ cells/µL
Sodium	128	129	139	136 - 145 mmol/L
Potassium	4.6	3.6	4.1	3.5 - 5.1 mmol/L
Bicarbonate	20	15	20	22 - 29 mEq/L
Blood urea nitrogen	35	93	34	8 - 22 mg/dL
Creatinine	1	3.46	0.59	0.7 - 1.2 mg/dL
Urine protein, random	157	57.5	-	mg/dL (no reference)
Urine protein-to-creatinine ratio	0.87	1.24	-	< 0.18
Hemoglobin A1c	5.5	-	-	4.4-5.6%
Total bilirubin	0.6	0.6	0.4	0.20 - 1.00 mg/dL
Aspartate transaminase	17	27	21	10 - 34 U/L
Alanine transaminase	8	10	70	10 - 44 U/L
Calcium	7.7	7.6	8.6	8.5 - 10.2 mg/dL
Total protein	6.2	5.1	5.6	6.1 - 8.2 g/dL
Albumin	1.7	2.2	3.5	3.3 - 5.2 g/dL
C-reactive protein	16.7	4.9	-	< 0.5 mg/dL
Ferritin	505	1,581	778	12 - 114 ng/mL
Erythrocyte sedimentation rate	61	12	6	2 - 37 mm/h
Anti-SSA antibodies	-	> 8.0	-	0.0 - 0.9 antibody index
Rheumatoid factor	77	-	-	< 14 IU/mL
Anti-CCP antibodies	-	230	-	0.0 - 2.9 U/mL
Lactate dehydrogenase	-	237	217	12 - 225 U/L
Interleukin-1β	-	< 6.5	-	< 6.5 pg/mL
Soluable IL-2 receptor	-	3,477	1,689	175 - 858 pg/dL
Interleukin-6	-	3.7	< 2	≤ 2.0 pg/mL
Interleukin-8	-	7.3	< 3	≤ 3.0 pg/mL
Tumor necrosis factor	-	2.2	1.7	≤ 7.2 pg/mL

Table 1. Laboratory Data on Admission and Discharge

Laboratory data

Admission

Days 7 - 10

Discharge (day 33)

Normal range

CCP: cyclic citrullinated protein; SSA: Sjogren’s syndrome-related antigen A.

White blood cells

13.9

16.2

7.2

4.8 - 10.8 × 10³ cells/µL

Hemoglobin

9.8

6.8

8.4

13.5 - 17.5 g/dL

Platelet count

144

113

130 - 400 × 10³ cells/µL

Sodium

128

129

139

136 - 145 mmol/L

Potassium

4.6

3.6

4.1

3.5 - 5.1 mmol/L

Bicarbonate

22 - 29 mEq/L

Blood urea nitrogen

8 - 22 mg/dL

Creatinine

3.46

0.59

0.7 - 1.2 mg/dL

Urine protein, random

157

57.5

mg/dL (no reference)

Urine protein-to-creatinine ratio

0.87

1.24

< 0.18

Hemoglobin A1c

5.5

4.4-5.6%

Total bilirubin

0.6

0.4

0.20 - 1.00 mg/dL

Aspartate transaminase

10 - 34 U/L

Alanine transaminase

10 - 44 U/L

Calcium

7.7

7.6

8.6

8.5 - 10.2 mg/dL

Total protein

6.2

5.1

5.6

6.1 - 8.2 g/dL

Albumin

1.7

2.2

3.5

3.3 - 5.2 g/dL

C-reactive protein

16.7

4.9

< 0.5 mg/dL

Ferritin

505

1,581

778

12 - 114 ng/mL

Erythrocyte sedimentation rate

2 - 37 mm/h

Anti-SSA antibodies

> 8.0

0.0 - 0.9 antibody index

Rheumatoid factor

< 14 IU/mL

Anti-CCP antibodies

230

0.0 - 2.9 U/mL

Lactate dehydrogenase

237

217

12 - 225 U/L

Interleukin-1β

< 6.5

< 6.5 pg/mL

Soluable IL-2 receptor

3,477

1,689

175 - 858 pg/dL

Interleukin-6

3.7

< 2

≤ 2.0 pg/mL

Interleukin-8

7.3

< 3

≤ 3.0 pg/mL

Tumor necrosis factor

2.2

1.7

≤ 7.2 pg/mL

**Table 2.** Comprehensive Classification of CD
Type	Lymph node involvement	Histopathological subtypes	Systemic symptoms	Key features/prognosis
CD: Castleman disease; HHV-8: human herpesvirus-8; HIV: human immunodeficiency virus; IL-6: interleukin-6; iMCD: idiopathic multicentric Castleman disease; IPL: idiopathic plasmacytic lymphadenopathy; MCD: multicentric Castleman disease; NOS: not otherwise specified; POEMS: polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes; TAFRO: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly; UCD: unicentric Castleman disease.
UCD	Single area (localized)	Hyaline vascular; plasmacytic; mixed	+/- (in few patients)	Mostly asymptomatic, may present with localized symptoms (e.g., chest or abdominal pain from mass effect). Excellent prognosis.
MCD	Multiple regions	Hyaline vascular; plasmacytic; mixed	Yes (constitutional symptoms)	Associated with IL-6-driven hypercytokinemia, organ dysfunction, hepatosplenomegaly, cytopenias. Further classified as below.
HHV-8-associated MCD	Multiple regions	Same as above	Yes	Caused by HHV-8, often in HIV+ or immunocompromised individuals. Poor prognosis without HIV control.
HHV-8-negative MCD (iMCD)	Multiple regions	Same as above	Yes	Etiology unknown, HIV and HHV-8 negative. Needs special pathological, clinical, and lab criteria for diagnosis. Variable prognosis, better with early treatment. Further subclassified below.
iMCD-POEMS	Multiple regions	Typically plasmacytic. Plasma cell neoplasm; paraneoplastic syndrome, monoclonal; often with lambda light chain restriction	Yes	Polyneuropathy, organomegaly, skin changes, endocrinopathy; often with edema and ascites. Osteosclerotic lesions on imaging. Treated as POEMS. Variable prognosis, depending on the associated genetic alteration and tumor.
iMCD-TAFRO	Multiple regions (often small)	Mixed or hypervascular	Yes, with unique lab and clinical features	Normal gamma globulins. Guarded prognosis without early treatment.
iMCD-IPL	Multiple regions	Plasmacytic or mixed	Yes	Features: thrombocytosis, hypergammaglobulinemia. Intermediate prognosis.
iMCD-NOS	Multiple regions	Variable	Yes	Does not fit POEMS, TAFRO, or IPL. Mixed clinical and lab features; etiology unknown. Variable to good prognosis.
Oligocentric CD	2 - 3 adjacent lymph node areas	Not fully defined	None or mild	Proposed subtype; overlaps more with UCD clinically and therapeutically.

Table 2. Comprehensive Classification of CD

Type

Lymph node involvement

Histopathological subtypes

Systemic symptoms

Key features/prognosis

CD: Castleman disease; HHV-8: human herpesvirus-8; HIV: human immunodeficiency virus; IL-6: interleukin-6; iMCD: idiopathic multicentric Castleman disease; IPL: idiopathic plasmacytic lymphadenopathy; MCD: multicentric Castleman disease; NOS: not otherwise specified; POEMS: polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes; TAFRO: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly; UCD: unicentric Castleman disease.

UCD

Single area (localized)

Hyaline vascular; plasmacytic; mixed

+/- (in few patients)

Mostly asymptomatic, may present with localized symptoms (e.g., chest or abdominal pain from mass effect). Excellent prognosis.

MCD

Multiple regions

Hyaline vascular; plasmacytic; mixed

Yes (constitutional symptoms)

Associated with IL-6-driven hypercytokinemia, organ dysfunction, hepatosplenomegaly, cytopenias. Further classified as below.

HHV-8-associated MCD

Multiple regions

Same as above

Yes

Caused by HHV-8, often in HIV+ or immunocompromised individuals. Poor prognosis without HIV control.

HHV-8-negative MCD (iMCD)

Multiple regions

Same as above

Yes

Etiology unknown, HIV and HHV-8 negative. Needs special pathological, clinical, and lab criteria for diagnosis. Variable prognosis, better with early treatment. Further subclassified below.

iMCD-POEMS

Multiple regions

Typically plasmacytic. Plasma cell neoplasm; paraneoplastic syndrome, monoclonal; often with lambda light chain restriction

Yes

Polyneuropathy, organomegaly, skin changes, endocrinopathy; often with edema and ascites. Osteosclerotic lesions on imaging. Treated as POEMS. Variable prognosis, depending on the associated genetic alteration and tumor.

iMCD-TAFRO

Multiple regions (often small)

Mixed or hypervascular

Yes, with unique lab and clinical features

Normal gamma globulins. Guarded prognosis without early treatment.

iMCD-IPL

Multiple regions

Plasmacytic or mixed

Yes

Features: thrombocytosis, hypergammaglobulinemia. Intermediate prognosis.

iMCD-NOS

Multiple regions

Variable

Yes

Does not fit POEMS, TAFRO, or IPL. Mixed clinical and lab features; etiology unknown. Variable to good prognosis.

Oligocentric CD

2 - 3 adjacent lymph node areas

Not fully defined

None or mild

Proposed subtype; overlaps more with UCD clinically and therapeutically.

**Table 3.** Diagnostic Criteria for iMCD
Criteria type	Criteria details	Explanation
CMV: cytomegalovirus; CRP: C-reactive protein; EBV: Epstein-Barr virus; ESR: erythrocyte sedimentation rate; HHV-8: human herpesvirus-8; HIV: human immunodeficiency virus; IL-6: interleukin-6; iMCD: idiopathic multicentric Castleman disease; LDH: lactate dehydrogenase; RA: rheumatoid arthritis; sIL-2R: soluble interleukin-2 receptor; SLE: systemic lupus erythematosus; TAFRO: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly; VEGF: vascular endothelial growth factor.
Major criteria: both must be met	1) Histopathological lymph node features consistent with Castleman disease	Hyaline vascular, plasmacytic, or mixed subtype
	2) Multicentric lymphadenopathy (≥ 2 lymph node regions)	Confirmed via imaging or physical exam
Minor criteria: at least two of the following (with ≥ 1 laboratory abnormality)	Laboratory abnormalities (≥ 1 required):
	1) Elevated CRP or ESR	Inflammatory markers
	2) Anemia	Normocytic or microcytic
	3) Thrombocytopenia or thrombocytosis	Either can occur
	4) Hypoalbuminemia	Often due to IL-6-mediated hepatic suppression
	5) Renal dysfunction	Elevated creatinine or proteinuria
	Clinical features (optional):
	1) Constitutional symptoms (fever, weight loss, fatigue, night sweats)	Common systemic symptoms
	2) Hepatosplenomegaly	Detected clinically or via imaging
	3) Fluid accumulation (ascites, pleural effusion, edema)	Seen in TAFRO variant
	4) Lymphocytic interstitial pneumonitis or other organ involvement	Based on imaging/biopsy
Exclusion criteria	All must be excluded:
	1) HHV-8 infection (especially in HIV+ patients)	By immunohistochemistry or PCR testing
	2) Malignancies (e.g., lymphoma, metastatic cancer)	Ruled out by biopsy or imaging
	3) Autoimmune/connective tissue diseases	E.g., SLE, Sjogren’s, RA assessed via serologies and clinical history
	4) Infectious diseases (e.g., EBV, CMV, tuberculosis, sepsis)	Should not explain presenting findings
Additional laboratory abnormalities that support the diagnosis but are not required	1) Elevated IL-6, sIL-2R, VEGF, IgA, IgE, LDH, and/or beta-2 microglobulin
	2) Reticulin fibrosis on bone marrow biopsy (particularly in patients with TAFRO syndrome)

Table 3. Diagnostic Criteria for iMCD

Criteria type

Criteria details

Explanation

CMV: cytomegalovirus; CRP: C-reactive protein; EBV: Epstein-Barr virus; ESR: erythrocyte sedimentation rate; HHV-8: human herpesvirus-8; HIV: human immunodeficiency virus; IL-6: interleukin-6; iMCD: idiopathic multicentric Castleman disease; LDH: lactate dehydrogenase; RA: rheumatoid arthritis; sIL-2R: soluble interleukin-2 receptor; SLE: systemic lupus erythematosus; TAFRO: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly; VEGF: vascular endothelial growth factor.

Major criteria: both must be met

1) Histopathological lymph node features consistent with Castleman disease

Hyaline vascular, plasmacytic, or mixed subtype

2) Multicentric lymphadenopathy (≥ 2 lymph node regions)

Confirmed via imaging or physical exam

Minor criteria: at least two of the following (with ≥ 1 laboratory abnormality)

Laboratory abnormalities (≥ 1 required):

1) Elevated CRP or ESR

Inflammatory markers

2) Anemia

Normocytic or microcytic

3) Thrombocytopenia or thrombocytosis

Either can occur

4) Hypoalbuminemia

Often due to IL-6-mediated hepatic suppression

5) Renal dysfunction

Elevated creatinine or proteinuria

Clinical features (optional):

1) Constitutional symptoms (fever, weight loss, fatigue, night sweats)

Common systemic symptoms

2) Hepatosplenomegaly

Detected clinically or via imaging

3) Fluid accumulation (ascites, pleural effusion, edema)

Seen in TAFRO variant

4) Lymphocytic interstitial pneumonitis or other organ involvement

Based on imaging/biopsy

Exclusion criteria

All must be excluded:

1) HHV-8 infection (especially in HIV+ patients)

By immunohistochemistry or PCR testing

2) Malignancies (e.g., lymphoma, metastatic cancer)

Ruled out by biopsy or imaging

3) Autoimmune/connective tissue diseases

E.g., SLE, Sjogren’s, RA assessed via serologies and clinical history

4) Infectious diseases (e.g., EBV, CMV, tuberculosis, sepsis)

Should not explain presenting findings

Additional laboratory abnormalities that support the diagnosis but are not required

1) Elevated IL-6, sIL-2R, VEGF, IgA, IgE, LDH, and/or beta-2 microglobulin

2) Reticulin fibrosis on bone marrow biopsy (particularly in patients with TAFRO syndrome)

**Table 4.** Five Types/Categories of TAFRO Syndrome
Type	Description	Key features
ANA: antinuclear antibody; CMV: cytomegalovirus; CRP: C-reactive protein; EBV: Epstein-Barr virus; HHV-8: human herpesvirus-8; IL-6: interleukin-6; iMCD: idiopathic multicentric Castleman disease; MDS: myelodysplastic syndrome; SLE: systemic lupus erythematosus; SSA: Sjogren’s syndrome-related antigen A; TAFRO: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly.
TAFRO with definite iMCD (iMCD-TAFRO)	Meets TAFRO clinical criteria with confirmed iMCD on lymph node biopsy (typically hypervascular type).	Histologically proven; IL-6 elevation; requires full workup including biopsy. Lymph nodes are usually smaller compared to other types of iMCD.
TAFRO with possible iMCD	TAFRO clinical features present but lymph node biopsy unavailable or non-diagnostic.	Clinical suspicion is high; supportive labs (e.g., IL-6, CRP); often treated as iMCD-TAFRO.
TAFRO associated with autoimmune diseases	Coexists with autoimmune diseases (e.g., Sjogren’s, SLE); may mimic or overlap with iMCD.	Positive autoantibodies (ANA, SSA, etc.); may respond to immunosuppression.
TAFRO associated with infections	Associated with infections (e.g., EBV, CMV, HHV-8); clinical mimic of TAFRO syndrome.	Viral serologies positive; often younger patients; may require antiviral or supportive care.
TAFRO-like syndrome	Mimics TAFRO features but occurs in malignancies or other systemic diseases (e.g., lymphoma, MDS).	Non-idiopathic; underlying pathology explains presentation; prognosis varies widely.

Table 4. Five Types/Categories of TAFRO Syndrome

Type

Description

Key features

ANA: antinuclear antibody; CMV: cytomegalovirus; CRP: C-reactive protein; EBV: Epstein-Barr virus; HHV-8: human herpesvirus-8; IL-6: interleukin-6; iMCD: idiopathic multicentric Castleman disease; MDS: myelodysplastic syndrome; SLE: systemic lupus erythematosus; SSA: Sjogren’s syndrome-related antigen A; TAFRO: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly.

TAFRO with definite iMCD (iMCD-TAFRO)

Meets TAFRO clinical criteria with confirmed iMCD on lymph node biopsy (typically hypervascular type).

Histologically proven; IL-6 elevation; requires full workup including biopsy. Lymph nodes are usually smaller compared to other types of iMCD.

TAFRO with possible iMCD

TAFRO clinical features present but lymph node biopsy unavailable or non-diagnostic.

Clinical suspicion is high; supportive labs (e.g., IL-6, CRP); often treated as iMCD-TAFRO.

TAFRO associated with autoimmune diseases

Coexists with autoimmune diseases (e.g., Sjogren’s, SLE); may mimic or overlap with iMCD.

Positive autoantibodies (ANA, SSA, etc.); may respond to immunosuppression.

TAFRO associated with infections

Associated with infections (e.g., EBV, CMV, HHV-8); clinical mimic of TAFRO syndrome.

Viral serologies positive; often younger patients; may require antiviral or supportive care.

TAFRO-like syndrome

Mimics TAFRO features but occurs in malignancies or other systemic diseases (e.g., lymphoma, MDS).

Non-idiopathic; underlying pathology explains presentation; prognosis varies widely.

**Table 5.** Clinical Manifestations of TAFRO Syndrome
Manifestation	Description	Workup
CRP: C-reactive protein; CT: computed tomography; ESR: erythrocyte sedimentation rate; MPGN: membranoproliferative glomerulonephritis; TAFRO: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly; TMA: thrombotic microangiopathy.
Thrombocytopenia	Ranges from moderate to severe; may lead to bleeding.	Complete blood count, peripheral blood smear
Anasarca	Generalized edema, pleural effusions, and ascites. Thoracocentesis and paracentesis are often required.	Physical examination, chest X-ray, CT chest, abdomen and pelvis
Fever and systemic inflammation	High-grade fevers with elevated CRP, ESR, and ferritin.	Physical examination, laboratory analysis
Reticulin fibrosis and marrow changes	Pathology shows fibrosis and megakaryocytic hyperplasia, often with larger cells.	Bone marrow biopsy
Renal dysfunction	Acute kidney injury. TMA and MPGN on biopsy.	Laboratory analysis, urine studies, renal biopsy
Organomegaly	Mild to moderate hepatosplenomegaly, and lymphadenopathy (could be multifocal).	Physical examination, laboratory analysis, CT chest, abdomen, and pelvis
Other symptoms and findings	Fatigue, weight loss, nausea, vomiting, anemia, anorexia, and hypoalbuminemia.	Physical examination, laboratory analysis
Autoimmune overlap	Patients may meet criteria for associated autoimmune conditions, such as Sjogren’s syndrome, or have features of their acute flare.	Physical examination, laboratory analysis

Table 5. Clinical Manifestations of TAFRO Syndrome

Manifestation

Description

Workup

CRP: C-reactive protein; CT: computed tomography; ESR: erythrocyte sedimentation rate; MPGN: membranoproliferative glomerulonephritis; TAFRO: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly; TMA: thrombotic microangiopathy.

Thrombocytopenia

Ranges from moderate to severe; may lead to bleeding.

Complete blood count, peripheral blood smear

Anasarca

Generalized edema, pleural effusions, and ascites. Thoracocentesis and paracentesis are often required.

Physical examination, chest X-ray, CT chest, abdomen and pelvis

Fever and systemic inflammation

High-grade fevers with elevated CRP, ESR, and ferritin.

Physical examination, laboratory analysis

Reticulin fibrosis and marrow changes

Pathology shows fibrosis and megakaryocytic hyperplasia, often with larger cells.

Bone marrow biopsy

Renal dysfunction

Acute kidney injury. TMA and MPGN on biopsy.

Laboratory analysis, urine studies, renal biopsy

Organomegaly

Mild to moderate hepatosplenomegaly, and lymphadenopathy (could be multifocal).

Physical examination, laboratory analysis, CT chest, abdomen, and pelvis

Other symptoms and findings

Fatigue, weight loss, nausea, vomiting, anemia, anorexia, and hypoalbuminemia.

Physical examination, laboratory analysis

Autoimmune overlap

Patients may meet criteria for associated autoimmune conditions, such as Sjogren’s syndrome, or have features of their acute flare.

Physical examination, laboratory analysis

**Table 6.** Diagnostic Criteria for TAFRO Syndrome
Category	Criteria	Details
CRP: C-reactive protein; iMCD: idiopathic multicentric Castleman disease; MCD: multicentric Castleman disease; TAFRO: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly; TMA: thrombotic microangiopathy.
Major criteria	All three must be present:
Thrombocytopenia	Platelet count ≤ 100,000/µL	Persistent or progressive.
Anasarca	Ascites, pleural effusion, and/or generalized edema	Clinically and/or radiologically detected.
Systemic inflammation	Fever ≥ 37.5 °C and/or CRP ≥ 2.0 mg/dL	Evidence of systemic inflammatory response.
Minor criteria (at least two required)	At least two must pe present:
Reticulin fibrosis	Bone marrow biopsy findings	Bone marrow biopsy shows reticulin myelofibrosis or megakaryocytic hyperplasia.
Renal dysfunction	Elevated serum creatinine (> 1.5 mg/dL) or proteinuria	Often reflects TMA on biopsy.
Mild organomegaly	Mild hepatomegaly, splenomegaly, and/or lymphadenopathy	Less prominent than in classic MCD or other types of iMCD.

Table 6. Diagnostic Criteria for TAFRO Syndrome

Category

Criteria

Details

CRP: C-reactive protein; iMCD: idiopathic multicentric Castleman disease; MCD: multicentric Castleman disease; TAFRO: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly; TMA: thrombotic microangiopathy.

Major criteria

All three must be present:

Thrombocytopenia

Platelet count ≤ 100,000/µL

Persistent or progressive.

Anasarca

Ascites, pleural effusion, and/or generalized edema

Clinically and/or radiologically detected.

Systemic inflammation

Fever ≥ 37.5 °C and/or CRP ≥ 2.0 mg/dL

Evidence of systemic inflammatory response.

Minor criteria (at least two required)

At least two must pe present:

Reticulin fibrosis

Bone marrow biopsy findings

Bone marrow biopsy shows reticulin myelofibrosis or megakaryocytic hyperplasia.

Renal dysfunction

Elevated serum creatinine (> 1.5 mg/dL) or proteinuria

Often reflects TMA on biopsy.

Mild organomegaly

Mild hepatomegaly, splenomegaly, and/or lymphadenopathy

Less prominent than in classic MCD or other types of iMCD.

**Table 7.** Differential Diagnosis of TAFRO Syndrome
Differential diagnosis	Key features that overlap	Distinguishing features
aHUS: atypical hemolytic uremic syndrome; ANA: antinuclear antibody; C3, 4: complement 3, 4; ds-DNA: double-stranded deoxyribonucleic acid; HLH: hemophagocytic lymphohistiocytosis; iMCD: idiopathic multicentric Castleman disease; LDH: lactate dehydrogenase; MAS: macrophage activation syndrome; POEMS: polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes; SLE: systemic lupus erythematosus; TAFRO: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly; TMA: thrombotic microangiopathy; VEGF: vascular endothelial growth factor.
Classic iMCD	Lymphadenopathy, systemic inflammation	Indolent course, more prominent lymph node involvement
SLE	Cytopenias, serositis, renal dysfunction	ANA/anti-dsDNA positivity, SLE-specific criteria: anti-Smith antibody, typical malar rash, low C3/C4, positive antiphospholipid antibodies
POEMS syndrome	Organomegaly, edema, polyneuropathy	Monoclonal plasma cell disorder, VEGF levels, and sclerotic bone lesions
Lymphoma	Lymphadenopathy, constitutional symptoms	Clonal lymphoid cells on biopsy, B symptoms
Severe infection (e.g., sepsis)	Fever, multiorgan dysfunction	Positive cultures, response to antimicrobials
aHUS	Thrombocytopenia, anemia, systemic inflammation, elevated LDH, TMA, renal failure (more acute in aHUS)	Dysregulation of the complement pathway: often low C3, normal or mildly low C4, absent or minimal lymphadenopathy, organomegaly is uncommon, and anasarca is rare.
HLH/MAS	Cytopenias, fever, hyperferritinemia	Extremely high ferritin, low natural killer cell activity, HLH criteria

Table 7. Differential Diagnosis of TAFRO Syndrome

Differential diagnosis

Key features that overlap

Distinguishing features

aHUS: atypical hemolytic uremic syndrome; ANA: antinuclear antibody; C3, 4: complement 3, 4; ds-DNA: double-stranded deoxyribonucleic acid; HLH: hemophagocytic lymphohistiocytosis; iMCD: idiopathic multicentric Castleman disease; LDH: lactate dehydrogenase; MAS: macrophage activation syndrome; POEMS: polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes; SLE: systemic lupus erythematosus; TAFRO: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly; TMA: thrombotic microangiopathy; VEGF: vascular endothelial growth factor.

Classic iMCD

Lymphadenopathy, systemic inflammation

Indolent course, more prominent lymph node involvement

SLE

Cytopenias, serositis, renal dysfunction

ANA/anti-dsDNA positivity, SLE-specific criteria: anti-Smith antibody, typical malar rash, low C3/C4, positive antiphospholipid antibodies

POEMS syndrome

Organomegaly, edema, polyneuropathy

Monoclonal plasma cell disorder, VEGF levels, and sclerotic bone lesions

Lymphoma

Lymphadenopathy, constitutional symptoms

Clonal lymphoid cells on biopsy, B symptoms

Severe infection (e.g., sepsis)

Fever, multiorgan dysfunction

Positive cultures, response to antimicrobials

aHUS

Thrombocytopenia, anemia, systemic inflammation, elevated LDH, TMA, renal failure (more acute in aHUS)

Dysregulation of the complement pathway: often low C3, normal or mildly low C4, absent or minimal lymphadenopathy, organomegaly is uncommon, and anasarca is rare.

HLH/MAS

Cytopenias, fever, hyperferritinemia

Extremely high ferritin, low natural killer cell activity, HLH criteria

**Table 8.** Treatment Modalities for TAFRO Syndrome
Treatment modality	Indication	Complications
CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone; IL-6: interleukin-6; JAK: Janus kinase; TAFRO: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly.
Glucocorticoids [7, 15, 20-22]	First-line for acute flare	Hyperglycemia, infections, and hypertension
Anti-IL-6 (siltuximab/sarilumab/tocilizumab) [24-29]	IL-6 blockade in moderate-severe disease	Risk of infection, neutropenia
Anti-IL-1 (anakinra/canakinumab) [38-40]	Refractory or exaggerated cytokine storm, autoimmune overlap, IL-6 inhibitor failure	Infections, injection site reactions
Cyclosporine [30-32]	Often used in combination with steroids; steroid/anti-IL-6 refractory cases	Nephrotoxicity, hypertension
Rituximab [33-37]	Autoimmune overlap or B-cell involvement. Used alone or in combination with siltuximab and steroids.	Infusion reactions, immunosuppression
Cyclophosphamide [41, 42]	Severe or refractory disease. Part of CHOP or in combination with bortezomib and steroids	Myelosuppression, infertility
CHOP regimen [43-45]	Suspected or confirmed overlap with lymphoma or severe inflammation	Toxicity, immunosuppression
JAK inhibitors (ruxolitinib) [25, 27]	Experimental, used in cases refractory to anti-IL-6 therapy. Successful in sporadic cases	Cytopenias, thromboembolism

Table 8. Treatment Modalities for TAFRO Syndrome

Treatment modality

Indication

Complications

CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone; IL-6: interleukin-6; JAK: Janus kinase; TAFRO: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly.

Glucocorticoids [7, 15, 20-22]

First-line for acute flare

Hyperglycemia, infections, and hypertension

Anti-IL-6 (siltuximab/sarilumab/tocilizumab) [24-29]

IL-6 blockade in moderate-severe disease

Risk of infection, neutropenia

Anti-IL-1 (anakinra/canakinumab) [38-40]

Refractory or exaggerated cytokine storm, autoimmune overlap, IL-6 inhibitor failure

Infections, injection site reactions

Cyclosporine [30-32]

Often used in combination with steroids; steroid/anti-IL-6 refractory cases

Nephrotoxicity, hypertension

Rituximab [33-37]

Autoimmune overlap or B-cell involvement. Used alone or in combination with siltuximab and steroids.

Infusion reactions, immunosuppression

Cyclophosphamide [41, 42]

Severe or refractory disease. Part of CHOP or in combination with bortezomib and steroids

Myelosuppression, infertility

CHOP regimen [43-45]

Suspected or confirmed overlap with lymphoma or severe inflammation

Toxicity, immunosuppression

JAK inhibitors (ruxolitinib) [25, 27]

Experimental, used in cases refractory to anti-IL-6 therapy. Successful in sporadic cases

Cytopenias, thromboembolism

**Table 9.** Treatment Modalities and Patient Responses in TAFRO Syndrome
Treatment modality	Summary of patient response	Type of study
IL-6: interleukin-6; TAFRO: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly.
Tocilizumab (IL-6 inhibitor)	In a systematic review of 31 patients, approximately 51.6% achieved complete response, while others had partial or no response, and some succumbed to the disease [28]. In another case with severe liver dysfunction, significant clinical improvement was noted with tocilizumab, suggesting its potential utility in TAFRO syndrome [29]	Systematic review
Siltuximab (IL-6 inhibitor)	In a randomized trial, results showed that siltuximab combined with supportive care was more effective and well tolerated than supportive care alone in symptomatic multicentric Castleman disease, offering a valuable new treatment option, including TAFRO syndrome [23]. Positive response noted at 3 months in a patient with severe renal involvement [26].	Clinical trial, case report
Anakinra (IL-1 inhibitor)	Two pediatric patients with severe, rapidly progressing TAFRO syndrome achieved remission with high-dose intravenous anakinra [40]. Another adult patient with life-threatening TAFRO syndrome showed rapid clinical improvement following anakinra therapy [39].	Case reports
Cyclosporine	Three cases that were refractory to anti-IL-6 therapy, treated with corticosteroids and cyclosporine, experienced resolution of anasarca and improved renal function [30-32].	Case reports
Rituximab	In one case, a patient responded well to rituximab combined with prednisolone as first-line treatment [33]. Multiple other case reports reported use in relapsed and refractory scenarios [34-37].	Case reports
Combination therapy	Combination of tocilizumab and siltuximab was successfully used in a patient with severe disease, without the need for immunomodulators or aggressive supportive care [24]. A severe case of TAFRO syndrome was successfully treated with a combination of rituximab, steroid pulse therapy, plasma exchange, and romiplostim, with rapid improvement of renal function, anasarca, and thrombocytopenia. In a case of severe-grade TAFRO syndrome, administration of triple therapy with corticosteroid, tocilizumab, and cyclosporine achieved successful remission of the disease with discontinuation of hemodialysis by week 5 and improved platelets by week 9 [46].	Case reports

Table 9. Treatment Modalities and Patient Responses in TAFRO Syndrome

Treatment modality

Summary of patient response

Type of study

IL-6: interleukin-6; TAFRO: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly.

Tocilizumab (IL-6 inhibitor)

In a systematic review of 31 patients, approximately 51.6% achieved complete response, while others had partial or no response, and some succumbed to the disease [28]. In another case with severe liver dysfunction, significant clinical improvement was noted with tocilizumab, suggesting its potential utility in TAFRO syndrome [29]

Systematic review

Siltuximab (IL-6 inhibitor)

In a randomized trial, results showed that siltuximab combined with supportive care was more effective and well tolerated than supportive care alone in symptomatic multicentric Castleman disease, offering a valuable new treatment option, including TAFRO syndrome [23]. Positive response noted at 3 months in a patient with severe renal involvement [26].

Clinical trial, case report

Anakinra (IL-1 inhibitor)

Two pediatric patients with severe, rapidly progressing TAFRO syndrome achieved remission with high-dose intravenous anakinra [40].
Another adult patient with life-threatening TAFRO syndrome showed rapid clinical improvement following anakinra therapy [39].

Case reports

Cyclosporine

Three cases that were refractory to anti-IL-6 therapy, treated with corticosteroids and cyclosporine, experienced resolution of anasarca and improved renal function [30-32].

Case reports

Rituximab

In one case, a patient responded well to rituximab combined with prednisolone as first-line treatment [33].
Multiple other case reports reported use in relapsed and refractory scenarios [34-37].

Case reports

Combination therapy

Combination of tocilizumab and siltuximab was successfully used in a patient with severe disease, without the need for immunomodulators or aggressive supportive care [24].
A severe case of TAFRO syndrome was successfully treated with a combination of rituximab, steroid pulse therapy, plasma exchange, and romiplostim, with rapid improvement of renal function, anasarca, and thrombocytopenia.
In a case of severe-grade TAFRO syndrome, administration of triple therapy with corticosteroid, tocilizumab, and cyclosporine achieved successful remission of the disease with discontinuation of hemodialysis by week 5 and improved platelets by week 9 [46].

Case reports