Recurrent Fibrillary Glomerulonephritis Secondary to Chronic Lymphocytic Leukemia: Remission of Kidney Disease with Ibrutinib

Fibrillary glomerulonephritis (FGN) is a rare form of glomerular disease that accounts for less than 1 percent of all renal biopsies [1, 2]. It is characterized by pathognomonic electron microscopy findings of fibrillar deposits in the mesangium and glomerular capillary walls. They are distinguished from amyloid fibrils by their size (16–24 nm in FGN vs. 10 nm in diameter in amyloidosis) and congo-red negativity. Often grouped together with immunotactoid glomerulopathy as part of non-amyloid glomerular diseases both are entirely distinct disorders [1, 2]. The identification of DNAJ heat shock protein family (Hsp40) member B9 (DNAJB9) in the glomeruli of patients with FGN but not in those with immunotactoid glomerulopathy [3‒5] separates the two entities.

FGN was initially considered to be an idiopathic disorder [1]. However, approximately 30–50 percent of patients have an identifiable secondary cause, such as a history of malignancy (4–23 percent), monoclonal gammopathy (4–16 percent), or autoimmune disease (13–30 percent of patients) [6, 7]. A link between FGN and hepatitis C has also been described [8‒10]. When FGN is linked to monoclonal gammopathy, it is termed monoclonal gammopathy of renal significance (MGRS) [11].

Chronic lymphocytic leukemia (CLL) is a well-known cause of glomerular disease with a membranoproliferative pattern of glomerular injury and is the most common lesion observed on light microscopy [12, 13]. However, FGN is uncommon and has been reported in only 1 patient in each of the two large case series published to date [12, 13]. Data on treatment are lacking, and overall it carries a very poor renal prognosis.

We present a case of FGN secondary to CLL successfully treated with chemotherapy to first achieve remission and subsequently treat a relapse. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000539742).

A 69-year-old man with renal impairment and peripheral edema was referred to the renal clinic by a general practitioner in 2016. He described a gradual onset of leg swelling and lethargy. He denied fever, shortness of breath, cough, or urinary symptoms. There was no preceding weight loss or night sweats and his appetite was normal. His medical history was significant for severe systolic heart failure and CLL, which had been diagnosed in 2013 based on a slightly raised lymphocyte count of 5 × 109/L and confirmed by bone marrow biopsy. This was managed conservatively, as his parameters did not fulfill the requirement for treatment. The response of CLL was assessed using the 2008 IWCLL guidelines. He was under regular follow-up in the hematology clinic, and the CLL disease was monitored by lymphocyte count and CT scan both of which showed stable disease, with normal bone marrow function and lymphadenopathy of <2 cm. However, there was a modest increase in lymphocyte count to 9.2 × 109 L at the time of referral to renal clinic. The patient’s family history was unremarkable. Drug history included furosemide, bisoprolol, aspirin, omeprazole, co-codamol, and gabapentin. The patient did not smoke or drink alcohol. On examination, the patient had bilateral pitting leg edema up to the thighs. His vital signs were normal with no palpable cervical, axillary, or inguinal lymphadenopathy. His baseline creatinine level in the preceding year was 150 µmol/L (2.0 mg/dL). A urine dip in the clinic revealed 4+ protein and a trace of blood. An initial workup was performed as shown in Table 1.

The patient subsequently underwent a kidney biopsy, which showed mesangial expansion and thickening of the peripheral capillary loops with spikes and double contours on light microscopy (Fig. 1a, b). Immunohistochemistry revealed diffuse and global C3d expression in a diffuse and global peripheral granular pattern. IgA staining mainly showed background staining. IgG was expressed in a pattern similar to that observed for C3d (Fig. 1c). DNAJB9 was not available at this time. Electron microscopy revealed large subepithelial deposits with extensive lamellation of the basement membrane. The deposits displayed fibrillary substructures. The fibrils were straight, non-branching, not felt to be hollow, and randomly oriented (average diameter of 15 nm), confirming the diagnosis of FGN. Severe effacement of the foot processes was also noted (Fig. 1d).

Renal pathology was deemed secondary to CLL due to a corresponding rise in lymphocyte count around the same time and therefore treatment was initiated with bendamustine and rituximab along with aciclovir, co-trimoxazole, and brief allopurinol prophylaxis. After 8 weeks, his renal function started to show improvement with a reduction in the albumin-to-creatinine ratio from 1,151 to 262 mg/mmol (Fig. 2).

For the next 3 years, the biochemistry and proteinuria levels remained stable. In late 2020, his leg swelling returned, and he developed nephrotic syndrome with an albumin-to-creatinine ratio >1,000 mg/mmol and an albumin level of 14 g/L. The patient underwent a repeat renal biopsy, which was consistent with further FGN. DNAJB9 staining was negative; however, the electron microscopy features were consistent with fibrillary GN (distinct appearances of the substructures). It was not clear if this was related to an increase in activity in his CLL as the lymphocyte count was unchanged; therefore, a bone marrow trephine biopsy was also performed, which showed infiltration by low-grade non-Hodgkin B-cell lymphoma with features consistent with CLL (approximately 25–30% of the total nucleated cells histologically). There was no evidence of diffuse large B-cell lymphoma, classical Hodgkin’s lymphoma, or any other high-grade transformation. A repeat CT scan was done which showed increased abdominal lymphadenopathy confirming the progression of his CLL.

After discussion with the hematology team, the patient was started on ibrutinib (a tyrosine kinase inhibitor) due to increasing evidence of its improved efficacy and reduced toxicity as compared with older regimes including chemotherapeutic agents. His renal function and proteinuria stopped deteriorating, and over the following year, it started to show signs of improvement (Fig. 3).

The patient remains in partial remission of FGN, with proteinuria less than 3 g/day and near-normal albumin levels. The patient remained on ibrutinib therapy. Additionally, he has remained on maximally tolerated doses of angiotensin 2 receptor blockers since the first renal biopsy in 2016.

Medical literature provides limited data on the prognosis of FGN. The reported cases paint a gloomy picture of the outcome. One case series of 61 patients described the median time to end-stage renal failure as 24.4 months. Predictors of outcome in the multivariate analysis of this cohort were serum creatinine level at baseline and the degree of interstitial fibrosis [1]. A report from the Mayo group reported that 44% of patients reached end-stage renal failure within a median follow-up period of 52.3 months [6]. The response to treatment in the literature has not been in favor of immunosuppression. In general, treatment has been directed at the kidney, with steroids or rituximab delivered at doses akin to the treatment of other forms of glomerulonephritis. Javaugue et al. [8] reported that 5 out of 7 patients with FGN treated with rituximab achieved partial remission (defined by a >50% decrease in 24-h urine protein and <15% decline in eGFR compared to baseline).

MGRS is a well-recognized umbrella term [14]. Clonal diseases resulting in differing disease processes within the kidney are defined as MGRS. When an underlying clonal disorder is detectable, treatment of the underlying clone can result in disease stabilization or remission [15‒17].

DNAJB9 is a highly specific (>99%) and sensitive (98%) marker for idiopathic FGN [18]. In this case, at the time of initial diagnosis, DNAJB9 was not discovered yet. However, the second biopsy in 2020 was stained to look for DNAJB9 and this was negative. DNAJB9 staining in patients with FGN is in keeping with idiopathic FGN that lack of staining therefore is more consistent with a secondary cause of FGN.

The use of tyrosine kinase inhibitors in kidney diseases is controversial. Hypertension and proteinuria have been described as potential side effects [19], which may lead to concerns regarding their use in patients with proteinuric renal disease. To date, the literature on the use of tyrosine kinase inhibitors is limited owing to the rare nature of the spectrum of diseases. Wang et al. reported successful use in a patient with CLL-associated C3 glomerulopathy [20]. There is a case report of a second-generation tyrosine kinase inhibitor causing FGN [21], but the mechanism of action is not clear.

Our case highlights the success of treating an identifiable underlying cause of FGN. This highlights that even at disease relapse, stabilization and improvement in both proteinuria and renal function are possible when appropriate therapy is directed at the identified source. This is the first reported case of the use of a tyrosine kinase inhibitor to successfully treat CLL-associated FGN.

This retrospective review of patient data did not require ethical approval in accordance with local/national guidelines. Written informed consent was obtained from the patient to publish the details of his medical case and accompanying images of the kidney biopsy.

The authors have no conflicts of interest to declare.

No funding source was required for this case report.

Rafeea Shah: involved in gathering the data and writing the case report. Bindu Vydianath: provided histopathology support and images for the case. Jennifer Pinney: identified the case for publication, was involved in providing data, writing the case report, and final proofreading. Guy Pratt: involved in writing the case report and final proofreading.

All data generated or analyzed during this study are included in this article (and its online supplementary material files). Further inquiries can be directed to the corresponding author.