Unusual cause of light chain cast nephropathy
- 1 Nephrology Department, Betsi Cadwaladr University Health Board, Wrexham, UK
- 2 Haematology Department, Betsi Cadwaladr University Health Board, Wrexham, UK
- 3 Histopathology Department, Betsi Cadwaladr University Health Board, Rhyl, UK
- Correspondence to Dr Kai Wen Chen; kaiwenchen8@gmail.com
Abstract
Acute kidney injury due to light chain cast nephropathy is increasingly recognised in patients with haematological malignancies; however, the management and prognosis of this disease remain poorly understood. We describe a case of a 78-year-old woman with known chronic lymphocytic leukaemia (CLL) who presented with fatigue and weight loss. She was found to have acute kidney injury, which rapidly worsened during admission. Kidney biopsy showed light chain cast nephropathy and bone marrow biopsy confirmed B-cell CLL. She was started on ibrutinib, halting further deterioration in her renal function and avoiding renal replacement therapy in the first 8 months.
Background
There are approximately 3800 new cases of chronic lymphocytic leukaemia (CLL) diagnosed each year in the UK.1 Patients are usually managed with watchful waiting approach. Renal insufficiency is known to occur in patients with CLL through several mechanisms such as glomerular disease, electrolyte imbalance, adverse effects from medication, leukaemic infiltration and tumour lysis syndrome.2 The International Kidney and Monoclonal Gammopathy Research Group (IKMG) first introduced the term monoclonal gammopathy of renal significance in 2012 to emphasise the causal link between renal impairment and monoclonal gammopathy.3 This prompts early intervention of the underlying haematological disease to improve renal prognosis. IKMG recently updated the definition to include low-grade CLL with associated renal disease.4 The most frequent renal pathological findings in case reports and case series of patients with CLL is membranoproliferative glomerulonephritis.5 6 A relatively rare finding such as light chain cast nephropathy has been described in patients with CLL.6
Here, we present a case of 78-year-old woman with new onset of acute kidney injury in the background of untreated CLL. Both kidney and bone marrow biopsies were performed, which confirmed the diagnosis of light chain cast nephropathy caused by CLL.
Case presentation
A 78-year-old Caucasian woman presented to hospital with acute severe kidney injury and several months of fatigue and weight loss. She has a medical history of hypertension, type 2 diabetes mellitus, hyperlipidaemia and untreated CLL. In the view of altered bowel habit and lethargy, her general practitioner (GP) arranged a faecal immunochemical testing, which came back elevated. CT of colon revealed mild uncomplicated diverticula change in the sigmoid colon and no other abnormality. She then developed persistent urinary symptoms with klebsiella pneumoniae grown on urine culture, which was treated with a course of trimethoprim.
The patient continued to experience lethargy and loss of appetite. She was found to have stage 3 acute kidney injury on blood test performed by her GP, with a raised creatinine of 478 umol/L and a white cell count of 23.7×109/L with 57% lymphocytes (table 1). A blood test performed 3 months previously showed a serum creatinine of 71 μmol/L and a white cell count of 19.2×109/L. She was admitted to hospital. Urine culture was sent which showed mixed growth of 107–108 cfu/L. Ultrasonography of her urinary tract demonstrated right kidney with increased echogenicity of the parenchyma, suggestive of inflammation. There was no structural abnormality in her left kidney. Urine protein: creatinine ratio was 184 mg/mol. Serum protein electrophoresis demonstrated IgG kappa level of 5.4 g/L and urine protein electrophoresis also confirmed the presence of free kappa light chains. Serum kappa: lamda ratio was elevated at 91.065. Autoimmune screen was negative (table 1).
Blood result on admission
| White cell count | 25.4×109 /L | (4.0–11.0 × 109 /L) |
| Lymphocytes | 14.6×109 /L | (1.0–4.5 × 109 /L) |
| Haemoglobin | 109 g/L | (115–165 g/L) |
| Creatinine | 481 µmol/L | (46–92 µmol/L) |
| Protein: creatinine ratio | 184 mg/mmol | (<50 mg/mmol) |
| Total protein | 62 g/L | (60–80 g/L) |
| Albumin | 33 g/L | (35–50 g/L) |
| Kappa light chains | 3689.94 mg/L | (3.30–19.40 mg/L) |
| Lambda light chains | 40.52 mg/L | (5.70–26.30 mg/L) |
| Kappa: Lambda ratio | 91.065 | (0.37–3.1) |
| Antineutrophil cytoplasmic antibody | Negative | |
| Antinuclear antibody | Negative | |
| Antidouble stranded DNA antibody | Negative | |
| Antiglomerular basement membrane antibody | Negative |
The renal function failed to improve with intravenous fluids and continued to peak to a creatinine of 604 µmol/L. She became hypertensive and peripherally oedematous. Doxazosin and lercanidipine were initiated. She underwent kidney biopsy. On H&E staining, the biopsy showed acute tubular damage, active interstitial infiltrate and dry, cracked casts with associated cellular reaction (figure 1). Patient was started on oral prednisolone 60 mg one time a day regimen for presumed interstitial nephritis.
Renal biopsy showing acute tubular damage, active interstitial filtrate and dry, cracked casts with associated cellular reaction (H&E staining, ×20).
Additional kidney biopsy studies revealed morphological features compatible with light chain cast nephropathy. Congo red stain was negative. Immunoperoxidase showed minimal IgM deposition within mesangium with no significant IgG, IgA, C3 or C1q in glomeruli. Immunohistochemistry demonstrated that there was kappa light chain restriction within tubular casts and no lambda light chain deposited (figure 2A,B). She underwent bone marrow biopsy, which showed CLL with no evidence of multiple myeloma. Flow cytometry obtained from bone marrow sample showed presence of B-cell clone, representing 96% of the lymphocytes (48% of nucleated cells). Immunophenotyping result was consistent with B-cell CLL (table 2) and immunohistochemistry also revealed a clear kappa light chain restricted plasma cell population in the bone marrow.
Light chain cast nephropathy. (A) Kappa light chain deposition within tubular casts (dotted arrow). (B) No lambda light chain deposited (solid arrow).
Lymphoproliferative disorder screen
| CD 2 | Negative |
| CD 5 | 99% |
| CD 10 | Negative |
| CD 19 | 96% |
| CD 20 | 48% (weak) |
| CD 23 | 53% |
| FMC 7 | Negative |
| CD 79b | Negative |
| CD 200 | 96% |
| CD 43 | 75% |
| CD 19 positive cells | Kappa positive (48%), Lambda positive (48%) |
| CD 19+/CD 5+ | 95% |
| CD 19+/CD 23+ | 59% |
Differential diagnosis
Current use of a proton pump inhibitor is known to have an increased risk of drug-induced acute interstitial nephritis (AIN).7 On the grounds of active interstitial inflammatory infiltrate on patient’s preliminary renal biopsy and her current use of omeprazole, drug-induced AIN was first considered as the provisional diagnosis. Omeprazole was discontinued and a trial of prednisolone was initiated. Consequently, patient improved clinically and there was a minor improvement in her renal function. Firm diagnosis of medication-related AIN became less likely considering light chain cast nephropathy shown on the additional kidney biopsy. Interstitial nephritis was described as one of the key diagnostic features in patients with light chain case nephropathy.8 Bone marrow biopsy revealed B-cell CLL which was viewed as the main culprit accounting for the renal failure in this patient.
Outcome and follow-up
Renal function improved slightly after prednisolone was commenced (figure 3). She was discharged 24 days after admission and remains well with active outpatient follow-up. Prednisolone did not demonstrate a significant positive effect on patient’s renal function. While tapering off prednisolone, she was started on ibrutinib 420 mg one time a day regimen on day 38. As seen in figure 4, following initiation of immunosuppression, her lymphocytes count decreased. Patient’s renal function has remained stable for the first 8 months avoiding renal replacement therapy. She was recently started on haemodialysis 8 months following initial presentation.
Creatinine over time with day −110 showing baseline creatinine. Day 0 is the day of admission; day 9 (black dotted line) is the day patient was given the first dose of prednisolone and day 38 (black solid line) is the day patient was given the first dose of ibrutinib.
White cell count including lymphocytes over time with day −110 showing baseline white cell count. Day 0 is the day of admission; day 9 (black dotted line) is the day patient was given the first dose of prednisolone and day 38 (black solid line) is the day patient was given the first dose of ibrutinib.
Discussion
Cast nephropathy is developed from the interaction and aggregation of excessive filtered free light chains and Tamm-Horsfall protein produced by the thick ascending loop of Henle, leading to the intratubular obstruction and damage.9 In our case, the features on kidney histology in keeping with light chain cast nephropathy were pale eosinophilic casts and faint kappa restriction. This correlates with the raised serum free light chain (sFLC). Both Sarris et al and Adam et al support the prognostic significance of sFLC to be used in initial workup of patients with CLL as increased level of sFLC is associated with poor prognostic indicator.10 11 The progression of disease towards tubular injury and interstitial inflammation can result in irreversible renal damage.12 Early reduction of sFLC is the critical determinant of renal recovery. This is demonstrated in a multivariate analysis that 80% of patients require a reduction of 60% in sFLC by day 21 to achieve a significant renal recovery, which is an independent survival predictor.13 However, there are no clear guideline or treatment target for the management in these patients with renal failure secondary to CLL.
Light chain cast nephropathy is commonly found in multiple myeloma. As in our case, where Bence Jones protein is detected, it is important to investigate for the possibility of multiple myeloma. Our patient’s bone marrow histology showed B-cell CLL and no evidence of multiple myeloma. With the evidence of B-cell malignancy as the underlying cause of renal failure, ibrutinib is chosen as the treatment of choice in targeting B-cell receptor.14 Ibrutinib is a once-daily oral inhibitor of Bruton’s tyrosine kinase that has pivotal role in many countries as a first-line treatment option in B-cell CLL. It is an acceptable treatment of choice for less fit patients with CLL outlined in British Society for Haematology Guideline.15 The randomised phase 3 studies (RESONATE-2 trial) provides an extensive clinical evidence supporting the superiority of monotherapy ibrutinib in newly diagnosed older patients with CLL compared with chlorambucil, which is a standard first-line cytotoxic chemotherapy.16 This clear benefit in overall survival and long-term safety outcomes was also described in a network meta-analysis.17 Ibrutinib has the lowest risk of treatment discontinuations owing to less frequent adverse events.17 In addition, ibrutinib-treated patients may have their bone marrow function restored.18 Following 3 months treatment with ibrutinib, our patient’s serum Kappa light chains reduced significantly to 402.67 mg/L, which may have slowed the progression to end-stage renal failure. Therefore, one should consider early measurement of sFLC in patients with CLL and unexplained renal failure to allow early initiation of disease-specific treatment.
Patient’s perspective
I was extremely concerned when I started to lose my appetite leading to a significant weight loss. I was previously fit and healthy 6 months ago until I visited my GP. I was shocked when I was told that my blood result showed deranged kidney function and that I needed to attend emergency department immediately for further management. I felt like I was dying. Though I was worried about the test results, I was grateful for the dignity and respect I was provided by the healthcare professionals. There had been discussions on dialysis as treatment option in the first month and I was first reluctant to accept as it is an invasive procedure. I was staying on a renal ward surrounded by patients who were on dialysis and I was able to observe directly how dialysis worked. I am relieved that my condition improves with oral medication and I was able to stay off dialysis in the first 8 months.
Learning points
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Both serum full blood count and bone marrow biopsy can be crucial in establishing the underlying pathology of cast nephropathy and guide management plan.
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Early evaluation of serum free light chain should be considered when patients with chronic lymphocytic leukaemia (CLL) present with unexplained renal failure to allow early initiation of disease-specific treatment.
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Renal involvement is a relatively late sign of untreated CLL, and closer surveillance may prevent irreversible kidney damage.
Ethics statements
Patient consent for publication
Footnotes
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Contributors KWC conducted literature review and wrote case report. DOW supervised and edited case report. DW provided haematology guidance and edited case report. MO-C interpreted slides and provided images of slides.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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