A Patient Presenting with AKI, Proteinuria, and Anasarca

Abstract

Case Description

A 44-year-old woman with no medical history presented with edema and dyspnea of 4-week duration. Imaging revealed bilateral pleural effusions and mild anasarca. Serum creatinine was 1.57 mg/dl, and urine protein was 1.336 g/24 h. The patient was anemic (Hgb 8.2), thrombocytopenic (plt 29), and hypertensive (BP 184/109). A kidney biopsy showed a glomerular thrombotic microangiopathy (TMA)–like pattern without true fibrin thrombi and no fibrosis (Figure 1, A and B). A bone marrow biopsy showed reactive megakaryocyte hyperplasia. Serologic testing also revealed active hepatitis C (viral load 1.19M). ANA, RF, ANCA, C3, C4, ADAMTS13, SPEP, and HIV were normal or negative. There was no history of diarrhea or fever. A working diagnosis of complement-mediated atypical hemolytic uremic syndrome was made, and anticomplement C5 therapy was initiated. The patient received an eculizumab infusion and two outpatient ravulizumab infusions every 8 weeks. Intravenous immunoglobulin was also administered for potential hepatitis C (HCV)-associated immune thrombocytopenia.

Figure 1.

(A) A representative glomerulus displays microangiopathy with endothelial injury and mesangiolysis but no true fibrin thrombi (upper panel—hematoxylin and eosin ×400, lower panel—periodic acid Schiff, ×400). (B) The glomerular basement membranes display subendothelial widening and electron lucent material (electron microscopy, ×6000). (C) The lymph node shows Castleman disease with several atretic regressively transformed germinal centers and expanded mantle zones (arrowheads and inset, hematoxylin and eosin ×100 and ×400).

Five months later, the patient returned with worsening anasarca and kidney failure (serum creatinine 3.32 mg/dl) requiring hemodialysis. The HCV viral load remained elevated (3.98M), and imaging again showed pleural effusions but now also diffuse lymphadenopathy. An excisional axillary lymph node biopsy showed HHV8-negative Castleman disease (Figure 1C). At this point, a diagnosis of idiopathic multicentric Castleman disease (iMCD) with TAFRO syndrome was suspected. TAFRO is an acronym for thrombocytopenia, anemia, fever, reticulin myelofibrosis/renal dysfunction, and organomegaly.¹ The patient was afebrile, but a C-reactive protein was elevated (153 mg/L [normal <3.1]) fulfilling this criterion and indicating a proinflammatory state. The original bone marrow biopsy was reviewed and showed focal reticulin myelofibrosis. Subsequent imaging also confirmed hepatosplenomegaly.

Discussion

The pathogenesis of iMCD-TAFRO is not well characterized, but cytokine disarray and increased IL-6 levels are likely central, and anti–IL-6 mAb therapy is a first-line option.² Our patient instead received an attenuated R-CHOP regimen (50% dose of cyclophosphamide and doxorubicin). Ten days after the first cycle, the patient recovered kidney function (serum creatinine 1.09 mg/dL). Improved thrombocytopenia (plt 148) and anemia (Hgb 10.3) followed the second cycle. HCV therapeutic options are also being explored.

The AKI in iMCD-TAFRO syndrome typically corresponds to glomerular endothelial injury (i.e., microangiopathy) or a TMA-like pattern without true fibrin thrombi on biopsy.^3,4 Chronic cases report a membranoproliferative glomerulonephritis or chronic TMA pattern without immune complex deposition. This case highlights a diagnostic challenge where the kidney dysfunction preceded other symptoms including significant lymphadenopathy, a finding which ultimately allowed for accurate diagnosis and treatment. This case also demonstrates the lack of efficacy of anticomplement C5 inhibition in TAFRO syndrome. And to our knowledge, this is the first case of iMCD-TAFRO syndrome with concurrent active HCV infection. Most cases of iMCD-TAFRO are not associated with chronic infection, although EBV,⁵ HBV, and C. Jejuni have all been reported. It is interesting to consider a possible role for HCV in the patient's presentation as HCV can increase serum IL-6, the proposed mediator of TAFRO syndrome. Importantly, iMCD-TAFRO syndrome should be considered in kidney biopsies showing glomerular microangiopathy because disease progression can be highly morbid, and effective therapies are available.

Teaching Points

• Kidney biopsy in acute iMCD-TAFRO syndrome shows a glomerular TMA-like microangiopathy and chronically an MPGN or chronic TMA pattern of injury.

• Lymphadenopathy in iMCD-TAFRO syndrome may be mild or lag behind other symptoms, and excisional lymph node biopsy is critical for diagnosis.

• Concurrent chronic infection in iMCD-TAFRO syndrome is rare, and the role of this patient's active HCV infection is uncertain but potentially contributory.

Disclosures

The authors have nothing to disclose.

Funding

None.

Author Contributions

D. Luitel, M. Luna, and P. Rosenstiel conceptualized the study; D. Luitel and P. Rosenstiel wrote the original draft; and all authors reviewed and edited the manuscript.