Relapse of treated anti-GBM disease following hair dye use

Abstract

An 18-year-old woman was treated for acute kidney injury (AKI) secondary to antiglomerular basement membrane (GBM) disease with prednisolone, cyclophosphamide and plasma exchange. She also had epistaxis at initial presentation with no other organ involvement and achieved good recovery of her kidney function. Two weeks after completing induction treatment, she re-presented with further AKI and pulmonary haemorrhage. She was recommenced on plasma exchange and steroids and was given rituximab. She recovered from her illness with significant improvement to her kidney function. The cause of her relapse was thought to be possibly due to the use of hair dye. This case highlights the importance of acknowledging potential environmental exposures to prevent relapses of disease. We were also able to demonstrate a case of successful treatment of anti-GBM disease with rituximab.

Background

Antiglomerular basement membrane (GBM) disease, also known as Goodpasture disease, is a rare small vessel vasculitis that is characterised by the production of autoantibodies against the α-3 chain of type IV collagen located in the glomerular and alveolar basement membranes.¹ It presents clinically with acute kidney injury (AKI) due to an aggressive glomerulonephritis with or without pulmonary haemorrhage.² It is estimated to account for 5% of cases of glomerulonephritis but is overall a rare cause of end-stage renal disease.³ The mainstay of treatment of anti-GBM disease is plasma exchange, prednisolone and cyclophosphamide, and following treatment, patients have a good prognosis but only if treatment begins before severe kidney damage (creatinine<500 μmol/L).⁴ Recurrence of anti-GBM disease is very infrequent, although there have been several case reports documenting this.^5–9 Here we present a case of a relapse of anti-GBM from an uncommon precipitant just weeks following disease remission.

Case presentation

An 18-year-old woman was treated for a first presentation of anti-GBM disease. Her diagnosis was made in the context of AKI (creatinine 212 μmol/L, was 56 μmol/L 6 months previously) with an anti-GBM antibody level of 39 U/mL. A kidney biopsy showed crescentic glomerulonephritis with 55% crescents (figures 1–3). Her anti-GBM disease was treated with seven sessions of plasma exchange, oral cyclophosphamide and intravenous methylprednisolone, which was subsequently converted to a reducing course of oral prednisolone. She was also commenced on cotrimoxazole, along with cyclophosphamide as prophylaxis against Pneumocystis jirovecii infection. Her anti-GBM antibody level after treatment normalised to <0.8 U/mL and her kidney function improved with a serum creatinine of 133 μmol/L and an estimated glomerular filtration rate (eGFR) of 46 mL/min when she was discharged from the hospital 16 days after admission with planned outpatient follow-up.

Figure 1.

Renal biopsy H+E medium power image showing two glomeruli with cellular crescents (arrows). Red blood cell cats are present in tubules.

Figure 2.

Renal biopsy H&E high-power image showing a glomerulus containing an active cellular crescent.

Figure 3.

Renal biopsy immunofluorescence image showing linear glomerular basement membrane IgG deposition.

She reattended hospital 2 weeks later. She described a short history of vomiting, transient abdominal pain and a single episode of diarrhoea. At this time, she was febrile (temperature 39.5°C). On direct questioning, she mentioned dyeing her hair after discharge prior to becoming unwell again.

On examination, her blood pressure was normal. She was tachycardic (heart rate 120 beats/min). She had creps at both bases on auscultation of her chest. Her examination was otherwise unremarkable.

A few hours into her admission, she developed rapidly worsening shortness of breath and haemoptysis. She also noticed new visible haematuria.

Investigations

Her blood tests on admission revealed AKI with a peak serum creatinine of 306 μmol/L (eGFR 17 mL/min). Her anti-GBM antibody level had modestly risen but was only 5.2 U/mL.

An admission chest X-ray (CXR) (see figure 4) showed widespread opacifications in keeping with either infection or alveolar haemorrhage. CT of her chest showed patchy, ill-defined intrapulmonary ground-glass and nodular opacities in both upper and right middle lobes with more confluent opacification in both lower lobes extending to the peripheries (see figure 5), consistent with the presence of alveolar haemorrhage, and a differential diagnosis of infection.

Figure 4.

Chest X-ray demonstrating patchy opacification, with particular predominance to the right side.

Figure 5.

CT of the chest showing patchy ill-defined intrapulmonary ground-glass and nodular opacities in both upper and right middle lobes with more confluent opacification in both lower lobes extending to the peripheries.

Further microbiology testing included stool and urine cultures, viral throat swab, blood cultures and a beta-glucan which provided no evidence of infection. She underwent a bronchoalveolar lavage to rule out a superadded respiratory infection. The sample obtained was blood stained and had a negative viral screen, acid-alcohol-fast-bacilli (AAFB), culture and was negative for fungi. This provided further reassurance that there was no untreated infection.

Differential diagnosis

The challenge when this patient re-presented was to decide whether she had an acute infection or a relapse of her anti-GBM disease. Ruling out infection was a priority as she was febrile and immunosuppressed on prednisolone and cyclophosphamide. However, all subsequent investigations as detailed previously were consistent with a relapse of anti-GBM disease. Infection was considered much less likely, given the reassuring microbiology investigations.

Treatment

Initial management included transfer to the medical high-dependency unit for respiratory support with nasal high flow oxygen. Until infection could be excluded, she was treated with intravenous piperacillin/tazobactam as well as treatment dose cotrimoxazole to cover for potential P. jirovecii infection.

To treat her relapse of her anti-GBM disease, her prednisolone dose was increased to 60 mg orally and she was recommenced on plasma exchange.

Due to the atypical nature of her presentation, her case was discussed with experts in tertiary centres in London and USA who advised additional immunosuppressive treatment with rituximab.

The patient received 10 sessions of plasma exchange before receiving her first dose of 1 g rituximab. She went on to receive a total of 14 sessions of plasma exchange and had two rituximab infusions, which resulted in remission of her anti-GBM disease.

Outcome and follow-up

At 12 months after discharge when reviewed in a renal clinic, the patient was normotensive with normal kidney function. Her most recent serum creatinine (23 months after original presentation) is 58 μmol/L (eGFR>60 mL/min) with only a trace of protein in her urine (urinary albumin:creatinine ratio of 6.8 mg/mmol). Her anti-GBM antibody titres remain undetectable (<0.8 U/mL) (figure 6). A repeat CXR has shown complete resolution of her previous abnormalities (figure 7).

Figure 6.

Time-course detailing presentation and outcome. GBM, glomerular basement.

Figure 7.

Chest X-ray after treatment demonstrating resolution of previous opacification.

Discussion

The first steps in identifying the molecular basis of anti-GBM occurred in the 1960s when antibodies against the GBM were identified.^{10 11} It has since been discovered that these antibodies can be detected in the serum, and this has become an important part of the diagnostic process.¹² However, it has been found that atypical cases can often present in the absence of circulating autoantibodies and a kidney biopsy is needed for confirmation when clinical suspicion remains high.5 6 13–15

Despite an evolving understanding of the molecular mechanism for anti-GBM disease, what causes it to happen remains unclear. It is thought that there may be a genetic susceptibility and that potentially environmental exposures can trigger anti-GBM disease.^{16 17} Current associations that have been made in the literature and in case reports are smoking,^{18 19} cocaine,²⁰ hydrocarbon exposure,^{21 22} heavy metals,²³ chlorine gas²⁴ and infections such as influenza.²⁵

In this current case, the patient was known to smoke cigarettes, which is known to be associated with anti-GBM disease. However, the most likely cause to trigger a relapse in this case was thought to be the use of a hair dye. Since her discharge, she had used a red hair dye, and it is possible that one of the ingredients in this may have precipitated a relapse. The ingredients in hair-colouring products or hair dyes are among the most reactive chemicals. Hair-colouring products are divided into oxidative (permanent) and direct (temporary) dyes. Oxidative hair dyes contain the oxidiser hydrogen peroxide and a dye intermediate such as paraphenylene-diamine, resorcinol and aminophenol. Temporary hair dyes contain azo, triphenylmethane, anthraquinone or indamines dyes. Due to lack of any other plausible factors that could have caused this very rare relapse, there is good reason to think that a chemical insult such as a hair dye could cause an immunogenic response.^{26 27}

Relapse of anti-GBM disease is a rare occurrence, but it has been recognised in some published case reports; one case series has found this occurs in up to 3% patients with anti-GBM disease.^{4–9 28} Interestingly, there have been associations between relapse with ongoing smoke and hydrocarbon exposure.⁶ Case reports have also shown that the relapses do not necessarily have to be in the presence of a high titre of circulating anti-GBM antibodies, again as demonstrated in this case.^{5 8 15}

This case was also able to demonstrate the efficacy of the use of rituximab in the context of a relapse of anti-GBM disease. This patient had both full renal recovery and complete resolution of her pulmonary manifestations of the anti-GBM disease with rituximab. Rituximab has been suggested by some for the use of relapsing anti-GBM disease,¹⁷ and there have been several case reports published of its use. At present, when rituximab is used for relapsing anti-GBM disease, the impact on renal function appears to be variable, with some demonstrating no renal recovery and about half of the cases only restoring renal function to chronic kidney disease stages 3–4.^29–34 Of note, the timing and dosing of rituximab has been variable across the different case reports. Equally, one case series showed that when used in as first-line therapy, rituximab did not have an impact on renal outcome but did effectively treat the pulmonary manifestation of anti-GBM disease.³⁵

In summary, we present an unusual case of a relapse of anti-GBM disease possibly caused by the use of hair dye that was successfully treated with rituximab to restore normal kidney function.

Learning points.

• Antiglomerular basement membrane (GBM) disease is a rare small vessel vasculitis that can cause rapidly progressive glomerulonephritis and alveolar haemorrhage and must be treated urgently and aggressively.

• Relapse of anti-GBM disease is very uncommon (unlike other vasculitis).

• It is important to ask patients about potential environmental exposures which may have triggered relapse.

• Smoking, exposure to hydrocarbons and organic solvents have all been implicated in relapsing anti-GBM disease.

• Rituximab may be an alternative treatment to induce remission with restoration of renal function in anti-GBM disease.