Acquired C1-inhibitor deficiency presenting with nephrotic syndrome

Abstract

Acquired C1-inhibitor (C1-INH) deficiency is a rare and potentially life-threatening disorder, which presents with recurrent attacks of non-pitting oedema to the face, airway, limbs or gastrointestinal tract. It is often associated with underlying B-cell lymphoproliferative disorders. We describe a case of a 73-year-old man with acquired C1-INH deficiency who presented with nephrotic syndrome due to glomerular IgM deposition, secondary to an underlying secretory lymphoplasmacytic lymphoma. Both the acquired C1-INH deficiency and the nephrotic syndrome resolved when the underlying B-cell lymphoma was treated with rituximab and bendamustine, suggesting the underlying lymphoproliferative malignancy was driving both disorders.

Background

C1-inhibitor (C1-INH) deficiency, also known as C1 esterase inhibitor deficiency, is a rare but potentially life-threatening condition that causes intermittent angioedema of the face, upper airway, extremities and gastrointestinal tract. It is often initially mistaken for anaphylaxis, though treatment with antihistamines and epinephrine is ineffective. It is most commonly due to an underlying inherited genetic mutation. However, it can also be acquired in later life and then is often associated with B-cell lymphoproliferative disease. To the authors’ knowledge, no previous case reports have linked acquired angioedema due to C1-INH deficiency (C1INH-AAE) with nephrotic syndrome, making this the first description of such a case.

Case presentation

We present the case of a 73-year-old man who presented to nephrology clinic with features consistent with nephrotic syndrome.

Four years earlier, he had twice presented to his general practitioner with two self-resolving episodes of asymmetrical tongue swelling. The swelling had not been painful or associated with urticaria of the skin, and had appeared to improve with antihistamine treatment. However, a week later, he represented to the emergency department with worsening facial and oropharyngeal swelling and dysphagia, and required intubation and ventilation for 2 days to maintain his airway. He was initially treated with epinephrine, steroids and antihistamines for presumed anaphylaxis. He underwent further investigation due to lack of response to treatment, and blood tests showed low levels of C1-INH at 0.05 g/L (normal range 0.18–0.54 g/L). His functional C1-INH level was 0% (normal range 70%–130%). Given his age and lack of personal or family history of symptoms of angioedema, a diagnosis of C1INH-AAE was made. In keeping with this diagnosis, serum C4 levels were undetectably low. Additional investigations revealed a raised serum IgM of 9.55 g/L (normal range 0.24–1.90 g/L) and an IgM paraprotein was detected, with normal IgA, IgG and C3 levels. Serum kappa light chains were 39.6 g/L (normal range 3.3–19.4 mg/L) with an elevated kappa/lambda ratio of 2.72 (normal range 0.26–1.65). He was treated with 1000 units of C1-INH concentrate, as well as Icatibant, a selective bradykinin B2-receptor antagonist, and rapidly improved.

Other previous medical history included postpneumonia bronchiectasis and hypertension.

He had no known allergies. He was taking azithromycin, allopurinol, carbocisteine, cetirizine, doxazosin, seretide inhalers and simvastatin. There was no history of recent surgery or dentistry work which could have triggered the angioedema attack.

He was further investigated with CT imaging of his chest, abdomen and pelvis, which was unremarkable. A diagnosis of IgM monoclonal gammopathy of undetermined significance (MGUS) was suspected, and no bone marrow biopsy performed at this time. He was commenced on tranexamic acid 1 g three times per day for prevention of further angioedema attacks. At times he had a persistent sense of a swollen tongue, but overall he had remained stable over the next 3 years, taking a slowly weaning course of tranexamic acid until on 500 mg two times per day.

Unfortunately, he represented to the emergency department seven times in 1 month with recurrent lip swelling, which was managed with additional C1-INH treatment and an increase in tranexamic acid dose back to 1 g three times per day. The frequency of attacks led to treatment with prophylactic intravenous C1-INH concentrate infusions two times per week, in order to control the recurrent angioedema episodes while he awaited further workup. Even between attacks his lips remained swollen, which affected his livelihood as a woodwind musician and teacher.

Investigations

At this time, he became unwell with night sweats, and his serum IgM rose to 13.78 g/L, with kappa light chains at 138 g/L and kappa/lambda ratio 10.5. Serum albumin was noted to be abnormally low for the first time, and he developed proteinuria.

Examination revealed peripheral oedema to his knees and hypertension (blood pressure 155/78 mm Hg). Urinalysis confirmed nephrotic range proteinuria at 477 µmol/L, and hypoalbuminaemia (30 g/L). Serum creatinine was 93 µmol/L (estimated Glomerular Filtration Rate (eGFR) of 70 mL/min/1.73²). Serum cholesterol, thyroid function studies, C reactive protein, lactate dehydrogenase and creatine kinase were all within normal limits. Cryoglobulin testing was negative on three separate occasions. HIV and hepatitis B and C screening was negative. A bone marrow biopsy (with prior C1-INH concentrate given to prevent a trauma-associated flare of angioedema) showed small lymphoid cells with no clonal plasmacytic differentiation, consistent with lymphoplasmacytic lymphoma. A renal biopsy (with prior C1-INH concentrate) showed changes consistent with IgM deposition-associated glomerulonephritis (figure 1).

Figure 1.

Renal histology following native renal biopsy. (A,B) Glomeruli showing prominent periodic acid Schiff-positive deposits in capillary lumina, capillary walls and mesangial areas (light 400×). (C,D,E) Immunofluorescence microscopy (400×) showing strong glomerular staining for (C) IgM and (D) kappa light chains with negative staining for (E) lambda light chain. (F) Electron microscopy image showing large subendothelial electron dense deposits (arrowed), consistent with IgM deposition associated glomerulonephritis (scale bar 2 µm).

Treatment

His nephrotic syndrome was initially treated with furosemide, and irbesartan (commenced with a prophylactic dose of C1-INH concentrate). The underlying lymphoplasmacytic lymphoma was treated with the monoclonal anti-B cell (CD20) antibody rituximab and alkylating agent bendamustine.

Outcome and follow-up

During the chemotherapy the nephrotic syndrome resolved, with normalisation of serum albumin, minimisation of proteinuria and resolution of peripheral oedema and he was able to discontinue two times per week infusions of C1-INH concentrate without a relapse of angioedema. His serum IgM levels fell to 1.98 g/L 8 months after starting chemotherapy (figure 2), and C4 levels normalised, having been consistently low since first measured 4 years earlier. He is able to play his woodwind instruments without impediment, and it is hopeful that he may be weaned off tranexamic acid treatment over the coming year.

Figure 2.

Timeline of presentation, showing significant events in relation to serum IgM and serum albumin levels.

Discussion

Nephrotic syndrome is well known to be associated with secretory B-cell malignancies. Membranous nephropathy has been previously reported in hereditary angioedema (HAE),¹ and the link between immunoregulatory disorders and HAE is well described. However, to the authors’ knowledge, no previous case reports have linked C1INH-AAE with nephrotic syndrome.

C1INH-AAE is a rare disorder, with crude estimates^{2 3} putting the prevalence at 1/500 000 of the population, though the actual number is likely higher as much disease burden will be undiagnosed. The presence of angioedema, along with evidence of deficiency C1-INH and hyperactivation of the classical complement system, were described as the key three features of C1INH-AAE when it was first described by Caldwell et al in 1972.⁴ The low levels of C1-INH make it a distinct form of acquired angioedema,⁵ as opposed to idiopathic or drug-induced angioedema in which C1-INH levels remain normal, such as when seen as a side-effect of ACE inhibitors. C1INH-AAE is characterised by recurrent attacks of angioedema, which is non-pitting and not associated with pruritus or urticaria. Facial swelling typically involves the lips or tongue, is painless and asymmetrical. The most concerning feature is upper airway oedema, from which mortality has been reported.⁶ Gastrointestinal oedema can also cause severe abdominal pains, though this is more common in HAE. Angioedema typically lasts for 2–5 days, with attacks occurring at unpredictable intervals. C1INH-AAE is primarily differentiated from HAE by lack of family history of angioedema and by age of onset, with C1INH-AAE presenting in the fourth decade of life or later (median age at diagnosis 64 years⁷), whereas >90% of patients with HAE present within the second decade.

C1INH-AAE is strongly associated with underlying B-cell lymphoproliferative disorders.^{2 6} It is thought that about one-third of patients with C1INH-AAE have an underlying B-cell lymphoma, and another third have an associated MGUS. Although the underlying malignancy may not otherwise require chemotherapy treatment, if associated with symptomatic C1INH-AAE this can be considered. Other associations with C1INH-AAE include adenocarcinoma and autoimmune disorders.

The pathogenesis of how C1-INH deficiency is acquired is not fully known, though in most cases neutralising autoantibodies against C1-INH are present.³ C1-INH is normally present in high concentrations in the blood, where it inhibits the first component of the complement system to prevent spontaneous complement activation. A further function is the inhibition of the protease kallikrein, which leads to a decrease in bradykinin production. With less C1-INH in circulation bradykinin levels increase, leading to the increased endothelial permeability which is thought to cause the angioedema symptoms via activation of endothelial B1 and B2 receptors, increased nitric oxide production and other pathways including via an increase in serum plasmin levels. Of relevance, an increase in bradykinin levels also drives ACE inhibitor-associated angioedema.⁸ Lymphoproliferative malignancies can produce immunoglobulins which directly and indirectly inhibit C1-INH function,⁹ and factors which cause the hyperactivation of the classical complement pathway, leading to the consumption of C1-INH and C4. The angioedema is not driven by IgE, so skin wheals are not present and antihistamines are ineffective.

This case was unusual as our patient had prompt diagnosis of C1-INH deficiency, as the average interval between initial symptoms and diagnosis is 2 years.³ However, he did present with critical upper airway oedema requiring intensive care at a hospital with tertiary immunology services on site, so prompt diagnosis was much more likely. Screening for C1INH-AAE can be performed by obtaining serum C4 levels, which due to classical pathway activation and C4 consumption are low both between and during flares, and by measuring levels of C1-INH. If both factors are low a diagnosis can be made, but if the results are indeterminate C-INH functional activity can be measured directly. Further testing for autoantibodies or interrogation of the complement system can be performed if it is unclear whether the case is of hereditary or acquired nature, but was not performed in our patient given his age at presentation and lack of family history of angioedema making it highly likely that he had an acquired disease. When C1INH-AAE is confirmed, performing screening with serum electrophoresis and CT imaging for presence and severity of any associated lymphoproliferative disease is prudent. If invasive investigations are required then C1-INH concentrate cover needs to be arranged, and this case highlighted the importance of close working relationships with immunology colleagues to arrange prophylaxis prior to renal and bone marrow biopsy.

Addressing the underlying cause of C1INH-AAE if it can be identified is often effective in controlling angioedema symptoms and can cause complete biochemical resolution,¹⁰ though given the underlying cause is often lymphoproliferative disease which would require chemotherapy, this clearly needs careful consideration. Antifibrinolytics such as tranexamic acid are often effective long-term prophylactics for C1INH-AAE, and are thought to work via their antiplasmin activity, and maintained our patient for many years. Icatibant, a selective bradykinin B2 receptor antagonist, is approved for treatment, though our patient did not find trials of using this to be effective in his care. Use of C1-INH concentrate is highly effective, usually as a rescue therapy, but in certain cases is used prophylactically.

Optimal treatment of C1INH-AAE associated with B-cell lymphoproliferative disease is unknown given paucity of evidence, and management strategy relies on case reports in the literature rather than clinical trials. Given this is the only reported case of presentation with manifestations of both C1INH-AAE and nephrotic syndrome, clearly management was based on clinical judgement rather than a literature base. Rituximab has been used in previous case reports to treat B-cell lymphoproliferative disease associated with C1INH-AAE with severe symptoms.^{10 11} The largest case series⁶ of C1INH-AAE associated with B-cell lymphoproliferative diseases (without concurrent nephrotic syndrome) showed that 21/25 patients had a decrease in angioedema attacks at 6 months in response to rituximab, of which 11 patients were given rituximab monotherapy and 14 were given it in combination with other chemotherapy.

With our patient we aimed to treat the lymphoma, and therefore also the secondary IgM paraprotein deposition-associated glomerulonephritis, with rituximab and bendamustine. As a holding measure while awaiting further investigations he was managed with prophylactic intravenous C1-INH concentrate. In other case reports, clinicians have opted to treat the underlying lymphoproliferative disorder with rituximab for severe symptoms of C1INH-AAE, so clearly there was a logical precedent to treat in this case when the patient developed the additional treatment indication of nephrotic syndrome. The benefit of removing the need for two times per week C1-INH concentrate was significant in terms of improved patient quality of life and resource allocation.

One further challenge in this case related to use of ACE inhibitors or angiotensin II receptor blockers while the patient was nephrotic and hypertensive, which is often the standard of care to reduce blood pressure, proteinuria and the risk of chronic renal impairment. However, it is known that both of these agents can increase bradykinin levels and are associated with causing angioedema,^{8 12} hence the need for very cautious introduction, at low dose and immediately following administration of prophylactic C1-INH.

Patient’s perspective.

The first indication I had that something was amiss was when I had two separate incidents of partial tongue swelling. I did not feel unduly alarmed at this time as things did settle down. However, things did get worse as I suffered extreme facial and tongue swelling and was admitted into intensive care. This was a very worrying time as I realised acquired angioedema can be life-threatening.

I suffered a further episode of lip and tongue swelling which frightened me greatly as I was concerned about my breathing. Many more lip swellings occurred which were treated with a C1-INH concentrate and I received two infusions per week to try and prevent swellings while investigations were under way to determine the cause.

Following my bone marrow biopsy, when the underlying bone marrow disorder was diagnosed I received the shock of my life as I had no inkling that I may be suffering from a form of cancer.

The finding of protein in my urine and damage to my kidneys allowed me to get a clearer picture of what was happening to me. It was explained that my abnormal immunoglobulins had damaged my kidneys and that this would hopefully recover after my bone marrow problem was treated.

When I commenced chemotherapy I was reduced to tears, I felt so awful. Thanks to the support of my family I resolved to carry on and get through it.

This was indeed an awful time, however, I had the utmost faith in the doctors directing my treatment and focused my attentions on getting well. The treatment of the bone marrow disorder has thankfully also stopped my episodes of angioedema and I have not suffered any further attacks of lip or swellings, allowing me to return to teaching music.

Learning points.

• C1-inhibitor (C1-INH) deficiency should be considered in the differential for patients presenting with facial, limb or pharyngeal swelling, especially if unresponsive to usual anaphylaxis treatment.

• Screening for C1-INH deficiency can be undertaken by measuring C4 and/or C1-INH levels.

• If acquired C1-INH deficiency is diagnosed, further screening for underlying lymphoproliferative disorders is recommended.

• Close cooperation with immunology colleagues is vital to organise C1-INH concentrate administration prior to invasive procedures such as bone marrow biopsy, to prevent a trauma-associated flare of angioedema.

• Given raised bradykinin levels drive the acquired angioedema, care must also be taken when introducing ACE inhibitors or angiotensin II receptor antagonists, which can also increase bradykinin levels.