Renal-Limited Antiglomerular Basement Membrane Disease Related To Alemtuzumab: A Case Report

Abstract

Rationale:

Alemtuzumab is a monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Many autoimmune-mediated adverse events have been associated with alemtuzumab, including renal-limited anti-glomerular basement membrane (GBM) disease.

Presenting concern:

A 52-year-old female with RRMS presented with acute kidney injury 39 months after receiving 1 cycle of alemtuzumab. She had a history of alemtuzumab-associated hypothyroidism and thrombocytopenia, urinary tract infections, and chronically abnormal urinalyses.

Diagnosis:

A diagnosis of renal-limited anti-GBM disease was made based on renal biopsy and positive anti-GBM serology. Alemtuzumab was thought to be the trigger of the anti-GBM disease as there were no other exposures or serologic findings suggesting other causes.

Interventions:

She was treated with corticosteroids, cyclophosphamide, and plasmapheresis. She required hemodialysis for acute renal failure.

Outcomes:

Despite treatment, the patient’s renal function did not recover. She remained dialysis-dependent and anti-GBM antibody titers remained elevated 6 months after presentation.

Teaching points:

Anti-GBM disease is a life-altering adverse event that can be associated with alemtuzumab. Our case highlights the limitations of monitoring urinalyses as a trigger for anti-GBM antibody testing in patients who have received alemtuzumab and have baseline abnormal urinalyses; such patients may require further protocolized anti-GBM antibody testing, although the optimal frequency of such antibody screening remains unclear.

Introduction

Anti-glomerular basement membrane (GBM) disease is a rare and often rapidly progressive form of glomerulonephritis that is caused by autoantibodies directed to a specific antigen on the GBM of the kidneys. ¹ Anti-GBM disease is estimated to affect about 0.5 to 1 patient per million. ¹ Triggers associated with anti-GBM disease include antineutrophil cytoplasmic antibodies–associated glomerulonephritis, infection, cigarette smoke, inhalation of hydrocarbons, and lithotripsy. ¹ Alemtuzumab, an approved therapy for relapsing-remitting multiple sclerosis (RRMS), has also been reported as a trigger for anti-GBM disease.^1,2 Alemtuzumab is a humanized monoclonal antibody that targets cluster differentiation (CD)-52 expressing B and T lymphocytes, which contribute to the inflammatory cascade that results in focal demyelination of the central nervous system during flares of RRMS.^1-4 Alemtuzumab leads to the selective depletion and repopulation of these lymphocytes and aims to restore the immune system’s self-tolerance networks. ² Significant secondary autoimmune adverse events (AEs) have been associated with alemtuzumab including hypo- and hyperthyroidism, immune thrombocytopenic purpura (ITP), and nephropathies such as acute interstitial nephritis, membranous glomerulonephritis, and anti-GBM disease.^2,5,6 To help with early detection of these autoimmune AEs, there are published recommendations outlining monitoring parameters for individuals treated with alemtuzumab.^5-7 However, there are limitations to these monitoring parameters. We aim to illustrate an example of these limitations by describing a case of anti-GBM disease in a patient with RRMS who received a course of alemtuzumab 39 months and had been undergoing regular post-alemtuzumab monitoring prior to presentation with acute renal failure.

Presenting Concerns

The patient is a 52-year-old female with longstanding RRMS resulting in lower extremity weakness requiring a wheelchair and neurogenic bladder requiring an indwelling urinary catheter. Her past medical history was remarkable for recurrent lower urinary tract infections (LUTI), hypothyroidism, and ITP secondary to a single cycle (ie, 5 × 12 mg intravenous infusion over 5 days) of alemtuzumab in 2016. As per the post-alemtuzumab monitoring program, she had regular testing of serum creatinine and urinalyses every 1 to 2 months for detection of immune-mediated renal complications. These urinalyses were obtained from the indwelling urinary catheter, which persistently showed nitrites and leukocyte esterase with intermittently proteinuria, hematuria, and bacteriuria for at least 2 years prior to this presentation. Cystoscopy revealed chronic bladder inflammation. Her medications were levothyroxine and vitamin D.

Twenty-one months later, the patient was seen in consultation by a nephrologist for intermittent hematuria. At that time, serum creatinine was 36 µmol/L; the usual urinalysis abnormalities were noted but without hematuria. The 24-hour urine protein was 0.37 g/d. Anti-GBM antibody was negative. The intermittent findings on urinalysis were thought to be most in keeping with chronic urinary catheter and frequent urinary tract infections (UTIs).

Seven days prior to the index presentation (ie, 39 months after receiving alemtuzumab), the patient presented to her family physician with symptoms of an LUTI and was prescribed amoxicillin for 5 days. Urinalysis via the indwelling urinary catheter was cloudy brown with specific gravity (SG) 1.020, proteinuria (1 g/L), positive leukocyte esterase (125 leukocytes/µL), 4+ blood, and negative for nitrite. Urine culture grew Escherichia coli sensitive to ampicillin. Two days after completing the antibiotics, the patient presented to a peripheral hospital’s emergency department (ED) with malaise, nausea, and low-grade fever.

Clinical Findings and Diagnostic Focus and Assessment

In the ED, the patient’s physical examination was unremarkable. Laboratory investigations were notable for acute kidney injury (AKI) (creatinine 316 µmol/L; urea 15.1 mmol/L), hyponatremia (sodium 128 mmol/L), and microcytic anemia (hemoglobin 94 g/L, mean corpuscular volume 76.8 fL). Serum creatinine was 46 µmol/L 2 months prior. Urinalysis from the urinary catheter was unchanged from previous except for increased proteinuria (>3.0 g/L). The working diagnosis was UTI with AKI secondary to volume depletion. The patient was sent home with a prescription for oral ciprofloxacin and instructed to increase her fluid intake.

The patient returned to the ED 2 days later with decreased urine output. Physical examination was notable for new hypertension (148/90 mm Hg). Laboratory investigations showed an elevated serum creatinine (429 µmol/L) and low bicarbonate (19.9 mmol/L). Urinalysis was turbid yellow, SG 1.015, proteinuria 1 g/L, leukocyte esterase 500 leukocytes/µL, 4+ blood, and nitrite negative. Urine culture from 2 days earlier had no growth. An unenhanced computed tomographic scan of the abdomen and pelvis did not show a kidney stone or hydronephrosis.

She was admitted to the peripheral hospital and given a trial of intravenous fluids with monitoring of urine output and laboratory investigations. Over the next 48 hours, the patient produced minimal urine and creatinine increased to 695 µmol/L with hyperkalemia requiring oral sodium polystyrene sulfonate. Ultrasound showed no hydronephrosis. The right and left kidney measured 11.7 and 11 cm in sagittal length, respectively. She was transferred to the nephrology service at a tertiary care center. On arrival, the patient was euvolemic, weight 97.2 kg, hypertensive (150/88 mm Hg), and anuric. Serum creatinine was 687 µmol/L. A tunneled hemodialysis catheter was inserted and she was started on hemodialysis.

An ultrasound-guided percutaneous renal biopsy was performed. Light microscopy showed a core of cortex and medulla with 17 glomeruli, one of which was globally sclerosed, and the remainder (all) showed marked global necrosis with hypercellularity and cellular crescents (Figure 1A). There was a marked active interstitial lymphoid infiltrate with acute tubular injury in a background of mild interstitial fibrosis and tubular atrophy and marked arterio- and arteriolosclerosis (Figure 1A). Immunofluorescence showed 3+ peripheral linear positivity for IgG, C3, kappa and lambda, and 1+ for C1q (Figure 1B). Electron microscopy showed glomerular necrosis and hypercellularity without presence of electron dense deposits or fibrils (Figure 1C). These features were consistent with crescentic anti-GBM disease.

Figure 1.

(A) Light microscopy, PAS-stained section, ×200 magnification; (B) immunofluorescence, IgG, ×200 magnification; and (C) transmission electron microscopy, ×4000 magnification.

Serology showed an anti-GBM antibody titer with activity index (AI) greater than 8.0, where AI ≥ 1.0 indicates a positive result with an antibody cutoff concentration that corresponds to approximately the 99th percentile of values obtained from a nondiseased population. Other serologies were negative including antineutrophil cytoplasmic antibody, antinuclear antibody screen, anti-streptolysin O titer, human immunodeficiency virus, hepatitis C and B. Hemoglobin A1C was 5.1%. Chest x-ray was normal. The etiology of the anti-GBM disease was thought to be alemtuzumab, which the patient had received 39 months prior to presentation. There were no other exposures or procedures that are known to be associated with anti-GBM disease.

Therapeutic Focus and Assessment

The patient received methylprednisolone 1 g intravenous daily for 3 days followed by prednisone 50 mg orally daily, cyclophosphamide 125 mg orally daily plus 5 plasmapheresis treatments. She was transfused with packed red blood cells to maintain a hemoglobin above 70 g/L and was started on an erythropoiesis-stimulating agent. Hypertension was controlled with amlodipine. She continued on regular hemodialysis.

Outcomes

After 6 weeks, due to lack of response, cyclophosphamide was stopped and prednisone was slowly tapered to discontinuation. The patient remained anuric and dialysis dependent 6 months after diagnosis with persisting anti-GBM antibodies with an AI of 6.6 (Figure 2).

Figure 2.

Timeline of significant events leading to the diagnosis of alemtuzumab-related anti- glomerular basement membrane disease.

Discussion

Our case adds to the body of reports describing autoimmune nephropathies associated with alemtuzumab. The incidence of autoimmune nephropathy in post-alemtuzumab monitoring programs in clinical trials and in the postmarketing setting are estimated at 0.27% to 0.34% and 0.05% to 0.17%, respectively.^5,8 While anti-GBM disease has been rarely reported in patients with RRMS in the absence of alemtuzumab therapy, anti-GBM disease is the best described and most common alemtuzumab-related autoimmune nephropathy.^5,8,9 In a review by Phelps et al, ⁸ they identified 7 cases of anti-GBM disease in patients with RRMS who had received alemtuzumab. There are many similarities between these cases and the present case. All cases presented with AKI 9 to 39 months following their last dose of alemtuzumab and almost all were female. ⁸ Renal-limited anti-GBM disease was diagnosed by renal biopsy (5 cases) and/or positive anti-GBM antibodies serology (6 cases). ⁸ They all received treatment with plasmapheresis and immunosuppression with corticosteroids and a cytotoxic agent, cyclophosphamide, or mycophenolate mofetil (1 case).^1,8

Despite treatment, anti-GBM disease carries a poor prognosis for recovery of renal function. ¹ Clinical features associated with poor renal outcomes include markedly elevated serum creatinine, oligoanuria, or need for dialysis at presentation and renal biopsy showing a high proportion of crescentic glomeruli.^8,10,11 Our patient had all of these features and remains on dialysis. Similarly, 5 of the other reported cases also remained dialysis dependent despite immunosuppressive therapy. ⁸ Only 1 case recovered renal function after immunosuppressive treatment for anti-GBM disease; this patient did not have any of the above-mentioned poor prognostic features. ¹² Although there are a limited number of patients reported, it would appear that alemtuzumab-associated anti-GBM disease has a similar outcome to that seen with the more common idiopathic form.^1,11

It is unknown which patients with RRMS are most susceptible to the autoimmune AEs of alemtuzumab. As a result, there are published recommendations outlining parameters for monitoring of post-alemtuzumab autoimmune AEs.^5-7 From a renal perspective, these include monthly urinalysis and serum creatinine measurements.^5,7 Our patient’s indwelling urinary catheter and recurrent LUTIs resulted in persisting abnormal urinalyses, thereby confounding the interpretation of changes that might suggest glomerular disease. Serum creatinine was normal up to 8 weeks before presentation. In the Belgian consensus guidelines for the monitoring and management of autoimmune AEs post-alemtuzumab, measurement of anti-GBM antibodies is recommended after detection of persistent hematuria. ⁷ However, it is unclear how frequently anti-GBM antibodies should be measured in the presence of chronic hematuria.

Conclusions

Our case highlights an infrequent but life-altering AE associated with alemtuzumab and supports the recommendations for monthly monitoring of serum creatinine and urinalysis for these complications for 4 years postdrug exposure. Our case also highlights the limitations of using urinalysis as a trigger for anti-GBM antibody testing in patients with underlying abnormal urinalyses; such patients require protocolized anti-GBM antibody testing for up to 4 years post-alemtuzumab therapy, although the optimal frequency of such antibody screening remains unclear.

Patient Perspective

“Alemtuzumab seems to have been beneficial as I have not had a flare of RRMS since receiving the medication. The renal failure happened so quickly and unexpectedly, and the sequelae of end-stage renal disease have been challenging. I often wonder if this could have been caught sooner and if so, would the outcome have been different? It is frustrating that a medication taken to help improve your quality of life can cause a different life-altering adverse event. I am now focusing on establishing a new normal. I am looking forward to my peritoneal dialysis teaching. Once I am able to do dialysis at home, I will no longer travel 1.5 hours every other day for hemodialysis.”