A case of chronic myelomonocytic related lysozyme-induced nephropathy

Abstract

Background

Lysozyme-induced nephropathy (LyN) is a rare cause of acute kidney injury (AKI) in patients with chronic myelomonocytic leukemia (CMML). Diagnosing LyN is challenging due to the numerous potential and concurrent aetiologies. Previous case reports have demonstrated the diagnostic utility of serum and urinary lysozyme measurements, which may correlate with renal dysfunction; however, the role of renal imaging remains unclear and renal biopsy remains essential for diagnosis.

Case presentation

An independent 80-year-old male presented to an Australian tertiary hospital with stage 3 AKI on a background of CMML previously treated with thioguanine and hydroxycarbamide. Renal tract ultrasound revealed expansile, non-vascular material bilaterally in renal collecting systems which was confirmed by renal biopsy to be lysozyme-induced nephropathy causing renal dysfunction. Despite escalated anti-leukaemic treatment he progressed to stage 4 chronic kidney disease contributing to increasing frailty and eventually pursued voluntary assisted dying after a fall with terminal traumatic injuries.

Conclusions

LyN is a rare cause of acute kidney injury amongst patients with chronic myelomonocytic leukaemia. This case highlights a rare instance of LyN and illustrates potential radiological markers that may aid in diagnosis. It also emphasizes the complexity of managing LyN in the context of underlying haematological malignancies.

Background

Patients with haematologic malignancies are at high risk for acute kidney injury (AKI) due to both the malignant disease and its treatment. These encompass pre-renal processes such dehydration and sepsis, renal parenchymal insults including paraprotein deposition, chemotherapy-induced nephrotoxicity or tumour lysis syndrome and post renal aetiologies such as tumour nodal obstruction.

An under-recognised cause of AKI within the chronic myelomonocytic leukaemia (CMML) cohort involves lysozyme-induced nephropathy (LyN). A limited body of research proposes lysozyme accumulation in the blood arising from the expanded myelomonocytic population causing direct proximal tubulointerstitial renal injury post filtration ​[1–5]​. Accurate diagnosis necessitates renal biopsy and although associated with unfavourable prognosis, renal recovery can be achieved with leukaemic cytoreduction utilising steroids, hydroxyurea or azacitidine ​[2–9]​.

Given the under-recognized nature of the topic, we describe a further case of LyN with emphasis on diagnostic features and review of prior cases.

Case presentation

An 80-year Caucasian male diagnosed with CMML and previously treated with thioguanine and hydroxycarbamide was admitted for investigation of worsening renal function. His background was significant for hypertension, peripheral vascular disease, deep vein thrombosis, prostate cancer treated with prostatectomy and depression. His medications included aspirin, atorvastatin, lercanidipine, prazosin, frusemide, sodium bicarbonate, darbepoetin alfa and famotidine.

On examination he was dyspnoeic at rest and demonstrated a normal jugular venous pressure to 3cm, nil cardiac murmurs, reduced breath sounds bi-basally, moderate volume ascites in conjunction with peripheral oedema and measured 5kg above his baseline weight.

Initial laboratory investigations revealed an acute kidney injury with a creatinine of 347 µmol/L and estimated glomerular filtration rate (eGFR) 13 mL/min/1.73m² (4 months prior to admission 79 µmol/L and 77 mL/min/1.73m² respectively). Electrolytes noted hyperkalaemia of 6.7 mmol/L presumed secondary to his renal dysfunction. Urine analysis was remarkable for non-nephrotic range proteinuria with a protein:creatinine ratio of 129 mg/mol and albumin:creatinine ratio of 71 mg/mmol (normally < 30 mg/mol and < 2.5 mg/mmol respectively) in addition to trace haematuria, suggesting a large non-albumin component which could represent lysozyme.

Subsequent renal tract ultrasound demonstrated bilateral prominent collecting systems filled with an expansile, non-vascular material. Both kidneys were enlarged for his age (120mm in length), which could be consistent with lysozyme-induced nephropathy. In addition, there was mild cortical thinning with subtle loss of corticomedullary differentiation (Fig. 1).

Fig. 1.

Renal ultrasound imaging demonstrating expansile material in collecting system with normal sized kidneys

His full blood count was notable for a raised monocyte count of 2.4 from < 1.0 E9/L. Bone marrow examination demonstrated CMML-1 on a background of systemic mastocytosis with a blast count increase from 3% to 8% over the three months since his prior study. Serum cryoglobulins, plasma cryofibrinogen, antinuclear antibodies and extractable nuclear antigens were unremarkable. Decreased complement c3 and c4 in conjunction with elevated serum free light chains with normal kappa:lambda ratio and an equivocal antineutrophil cytoplasmic antibody titre.

Given relapsed CMML, our patient was commenced on tapering prednisolone which partially improved his creatinine to 219 µmol/L. A renal biopsy was then arranged to help delineate a cause. Of the 20 glomeruli sampled for light microscopy, 2 were globally sclerosed. The viable glomeruli demonstrated mild mesangial hypercellularity with mesangial matrix expansion and sclerosis, and no segmental sclerosis. Mild interstitial fibrosis with dilatation of the proximal tubules was also present in addition to several Periodic acid-Schiff stain positive granular hyaline droplets within the renal tubular epithelium (Fig. 2). Immunohistochemistry demonstrated diffuse lysozyme staining within the proximal and distal tubules and to a lesser extent interstitium consistent with LyN associated with CMML. Myeloperoxidse (MPO) immunohistochemical stain did not highlight any neoplastic myeloid cells within the interstitium. Direct immunofluorescence for IgG, IgM, IgA, c3, c1q and fibrinogen were negative. Electron microscopy was not performed.

Fig. 2.

Renal histopathology. H&E Stain; Low power (× 4 magnification): demonstrates background interstitial damage. High power (X40 magnification): demonstrates eosinophilic granular deposits in proximal tubules. Periodic Acid Schiff (PAS). Lysozyme immunohistochemistry (IHC) stain; Low power (× 4 magnification): demonstrates strong diffuse staining within proximal tubules. High power image (× 40 magnification): demonstrates lysozyme within proximal tubules as well as distal tubules and interstitium

In light of the renal biopsy findings, our patient was commenced on hydroxycarbamide 1g twice daily followed by azacitidine 5-2-2 two weeks later, with some improvement in renal function with this therapy. Despite incremental improvement, his renal function never completely recovered based on a creatinine and eGFR plateau of approximately 200 µmol/L and 25 correspondingly (Fig. 3).

Fig. 3.

Renal function trends since diagnosis. Kidney function was reduced at admission with eGFR 13 mL/min/1.73m2, Creatinine 347 µmol/L, Urea 27.4 mmol/L compared to baseline 4 months prior to admission of eGFR 77 mL/min/1.73m2, Creatinine 79 µmol/L, Urea 10.5 mmol/L. After LyN diagnosis, patient began hydroxycarbamide 1g twice daily immediately and azacitidine 5–2-2 cycles two weeks later. Kidney function incrementally improved and eventually plateaued around eGFR 25 and creatinine 200 µmol/L as recorded during subsequent healthcare encounters

As a consequence of his progressive renal failure, our patient experienced increasing renal complications necessitating multiple readmissions before eventual transition to high level aged care. The patient was poorly tolerant of azacitidine therapy and ultimately proceeded to therapy with decitabine with cedazuridine which were equally poorly tolerated. As such, the patient elected for best supportive care and pursued voluntary assisted dying after a further fall resulting in terminal traumatic injuries.

Discussion and conclusions

Haematological malignancies are frequently associated with AKI due a multitude of aetiologies. LyN is becoming increasingly reported as a cause of AKI in patients with CMML. Lysosomes are low molecular weight antimicrobial enzymes secreted principally by mononuclear phagocytes which accumulate in circulation and exert direct proximal tubular injury ​[10, 11]​.

As noted in this case, renal biopsy is essential to confirming diagnosis which typically shows diffuse immunohistochemical staining for lysozyme predominantly in the proximal tubules and to a lesser extent the distal tubules and interstitium. Of the prior case reports, all patients with LyN exhibited CMML progression and received either prednisolone or azacitidine to address their underlying leukaemia which conferred improvement in renal function. Our patient was similarly commenced on prednisolone and azacitidine plus hydroxyurea for anti-leukaemic effect, in addition to intravenous fluids and red cell transfusions to optimise kidney perfusion. His renal function nevertheless continued to deteriorate despite such escalated therapy leading to stage 4 chronic kidney disease and related complications. In total, he survived 11 months beyond his LyN diagnosis which although not directly terminal, contributed notable morbidity via frailty and functional decline. The broader literature suggests variable prognoses​ [10]​ of LyN ranging from recovery of kidney function ​[12, 13]​ to continued dialysis dependency and eventual palliation ​[6]​.

Whilst prior reports indicate the diagnostic utility of serum and urinary lysozyme measurements ​[10]​ which may correlate with absolute monocyte count and renal dysfunction ​[2, 14]​, the role of renal imaging is yet to be elucidated. Subtle increase in parenchymal echogenicity has been observed, although this remains non-specific ​[15, 16]​. In contrast, our patient exhibited an expansile non-vascular material in his bilateral collecting system on renal ultrasound Doppler (Fig. 1). Given the strong lysozyme staining in all proximal tubules and the known presence of elevated urinary lysozyme in LyN, these radiological findings may be indicative of lysozyme in the urinary filtrate that was not reabsorbed due to saturating proximal tubule uptake. Non-vascular material in the collecting system may also result from various factors that may not be pertinent to this case, such as urine crystals (e.g. calcium oxalate), urinary tract infections, blood, medication precipitates, or bile casts.

Additionally, while serum lysozyme levels were not measured in our patient, previous studies have demonstrated a strong correlation between lysozyme levels and LyN [2]. Hence, both lysozyme levels and the radiological findings noted in our case may serve as superior indicators of LyN, rather than lysozyme levels alone. However, a limitation of our study is that material in the collecting ducts was not sampled, and neither serum nor urine lysozyme levels were measured, so this could not be confirmed. Renal biopsy remains the gold standard for diagnosis, and further research is needed to assess the potential of these markers as screening and diagnostic tools for LyN, which may negate the future need for renal biopsy [17].

This case demonstrates another rare cause of AKI in a patient with CMML, and highlights potential radiological markers which may aid in the diagnostic process of LyN.

Abbreviations

AKI

Acute Kidney Injury

CMML

Chronic myelomonocytic leukaemia

eGFR

Estimated Glomerular Filtration Rate

LyN

Lysozyme-induced nephropathy

MPO

Myeloperoxidse

Authors’ contributions

JR, FC and SF were involved in clinical care of patient. SD performed and interpreted the renal biopsy histopathology. JW curated histopathology images. JR conceptualised the study. AK, TP and JR collated patient information and wrote the case report. All authors read and approved the final manuscript.

Funding

None.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Ethics approval was obtained from Epworth Research Development and Governance Unit, reference number EH2023-1057.

Consent for publication

Written informed consent was obtained from our patient and is available upon request.

Competing interests

The authors declare no competing interests.