Granulomatosis with polyangiitis with rapidly progressive glomerulonephritis treated with a multipronged approach—a case based review

Abstract

Granulomatosis with polyangiitis is an ANCA-associated vasculitis that involves small to medium-sized vessels. The extent of renal involvement varies, which is also associated with disease prognosis, with aggressive renal involvement having worse outcomes. Rapidly progressive glomerulonephritis with severe inflammatory features and extensive crescent formation can be challenging to treat. Usually, induction regimes utilize a combination of pulse dose methylprednisolone followed by rituximab or cyclophosphamide. Resistant diseases pose additional treatment challenges, and individualized treatment regimens have been described without accumulated outcome data. Cyclophosphamide, rituximab, azathioprine, methotrexate, and mycophenolate with or without plasmapheresis have been variably used, but there is a lack of consensus on a standardized regime in literature. Our case adds to the existing literature on the treatment-refractory granulomatosis with polyangiitis, which was treated with high-dose corticosteroid in combination with rituximab, low-dose cyclophosphamide, plasmapheresis, and brief use of hemodialysis. It also reiterates that the use of a variety of low-dose cyclophosphamide with rituximab could be beneficial for treatment-refractory cases or patients with severe renal involvement, in addition to better tolerance with low dose cyclophosphamide in comparison with full-dose cyclophosphamide.

Introduction

Granulomatosis with polyangiitis (GPA) is a rare systemic vasculitis characterized by necrotizing granulomatous inflammation and small to medium-sized vessel vasculitis [1]. While many organ systems are known to be involved in GPA, the renal manifestations have prognostic implications. Significant morbidity and a challenging clinical course are expected with aggressive renal features, particularly crescentic glomerulonephritis. Understanding the epidemiology, clinical features, diagnostic strategies, and management approaches specific to aggressive renal involvement in GPA is crucial for optimizing treatment outcomes and achieving remission.

Renal involvement in GPA typically presents as rapidly progressive glomerulonephritis, which can lead to severe kidney damage if left untreated. A rapidly declining renal function, severe proteinuria, and active urine sediments suggest a more aggressive renal disease [2]. Renal biopsies often reveal a pattern of pauci-immune crescentic glomerulonephritis with a necrotizing vasculitis, supporting the diagnosis of GPA-related renal disease and guiding therapeutic decisions. Immunosuppressive therapy and supportive measures remain the mainstay of treatment in such patients, with differing opinions regarding the specifics among physicians. Despite aggressive therapeutic interventions, remission rates have been variable at best, with frequent relapses, with renal replacement therapy becoming necessary for patients who progress to ESRD [3].

In this case report, we present a detailed clinical profile, diagnostic approach, and therapeutic management of a patient with GPA with aggressive renal involvement, using an aggressive approach to obtain clinical remission. By highlighting the treatment plan used in this patient, we aim to contribute to the existing knowledge and enhance understanding of the challenges and optimal management strategies for achieving remission in this complex manifestation.

Case Presentation

A 40-year-old gentleman with an unremarkable chronic past medical history was treated a month before presentation for multifocal community-acquired pneumonia with a 7-day course of Amoxycillin-clavulanate and with tamsulosin for bilateral nephrolithiasis.

After the above treatment, he presented with persistent symptoms of cough and hemoptysis, associated with malaise, epistaxis, diffuse myalgias, polyarthralgia involving the right wrist along with bilateral fingers and ankles, post-tussive emesis, polyuria, hematuria, night sweats, poor oral intake with an 18-pound weight loss over one month. He was found to have an interval progression of his multifocal bilateral reticulonodular pulmonary opacities with interval development of cavitation on chest X-ray (CXR). CT chest confirmed worsening bilateral multifocal nodular opacities. His laboratory test findings revealed an acute kidney injury (AKI) with an increase in creatinine from a baseline of 1.32 mg/dL to 3.11 mg/dL, anemia with indirect hyperbilirubinemia, mild leukocytosis, and mild hyponatremia. The respiratory viral panel for COVID-19, influenza, and RSV was negative. He was started on azithromycin and ceftriaxone.

Infectious Diseases team was consulted, and he was continued on ceftriaxone 2 g daily while switching from oral azithromycin to oral doxycycline. Blood cultures, AFB smear and cultures, AFB gene expert QuantiFERON gold, sputum culture, urine streptococcus and legionella, Histoplasma antigen testing, and MRSA swab were obtained in addition to screening for HIV, Hepatitis B, Hepatitis C, and syphilis. The infectious workup was negative, and a transthoracic echocardiogram was also performed to rule out valvular vegetation.

Initially, his AKI was attributed to poor oral intake and ibuprofen use, but it failed to improve with fluids. His urine studies demonstrated hematuria and proteinuria with a urine protein/creatinine ratio of about 1534 mg/g, raising suspicion for glomerulonephritis. Creatine kinase level and serum and urine protein electrophoresis were normal. At the same time, his anemia worsened while he continued to have hemoptysis, with a development of acute hypoxic respiratory failure requiring oxygen supplementation. A workup for hemolytic anemia with liver enzymes, LDH, haptoglobin levels, and reticulocyte count was unrevealing, and his eosinophil count was not elevated. Meanwhile, his renal function was worsening. Renal ultrasound was normal, ruling out post-renal AKI. His inflammatory markers, ESR and CRP, were markedly elevated, with the ongoing acute inflammatory arthritis.

Rheumatology, nephrology, and pulmonology teams were consulted on the third day after admission, due to concern for rapidly progressive small vessel vasculitis versus Goodpasture syndrome with concurrent renal and pulmonary involvement. Bronchoscopy with broncho-alveolar lavage confirmed alveolar hemorrhage. Autoimmune workup with ANA, serum complement C3 and C4 levels, myeloperoxidase antibody, and anti-GBM antibodies was negative, but his proteinase-3 (PR-3) antibody was positive with titers of 115.2 AI. His creatinine continued to trend upwards and peaked at 4.1 mg/dL. The patient underwent a kidney biopsy on hospital day 8, with confirmation of pauci-immune focal necrotizing and crescentic glomerulonephritis with severe inflammatory changes involving greater than two-thirds of the glomeruli. On light microscopy, 15 out of 23 non-sclerotic glomeruli that were evaluated, showed necrosis or cellular/fibrocellular crescent formation, consistent with a "crescentic" class by ANCA-Associated Glomerulonephritis Classification [4]. There was no global or segmental glomerulosclerosis, and no mesangial or endocapillary hypercellularity. Mild to moderate interstitial inflammation and multifocal tubulitis were seen as well as moderate arterial intimal fibrosis. Interstitial fibrosis and tubular atrophy were mild and involved approximately 15% of the cortex (Fig. 1). Immunoflourescence revealed granular mesangial staining for IgG (1 +), IgM (1 +), C3 (1 +), kappa (2 +) and lambda (1 +), i.e. a "pauci-immune" glomerular staining pattern, with equally distributed kappa and lambda staining throughout tubulo-interstitium, and no significant extraglomerular staining. On electron microscopy, rare mesangial immune-type electron dense deposits were seen. These results were consistent with necrotizing and crescentic glomerulonephritis, pauci-immune type. Taking the clinical presentation, serology, biopsy, imaging findings into account, a clinical diagnosis of granulomatosis with polyangiitis (GPA) was established.

Fig. 1.

a Kidney biopsy (Jones Stain 200X) demonstrating focal fibrinoid necrosis (arrow) and a cellular crescent. b Low power magnification of the biopsy core showing mild interstitial fibrosis and tubular atrophy (Trichrome Stain, 20X)

Simultaneously, on hospital day 3 when pulmonary-renal involvement was suspected, he was initiated on an induction regime with IV methylprednisolone 1000 mg daily for a total of 5 days, followed by 125 mg IV daily for a total of 2 days since he was continuing to have minimal hemoptysis, along with IV rituximab infusions 1000 mg for two doses, two weeks apart. Atovaquone for pneumocystis prophylaxis, Vitamin D, Calcium, and pantoprazole were commenced while initiating prednisone. His steroid-related side effects were managed with adjustments of carvedilol and amlodipine for hypertension and insulin glargine for steroid-induced hyperglycaemia.

After the steroid pulse and his first dose of rituximab, an improvement in the patient’s symptoms and stabilization of his kidney function was observed. His creatinine had down trended to 2.87 mg/dL, and he was discharged two days after his first rituximab dose. At discharge, he was prescribed high-dose oral prednisone 80 mg daily for one week with a subsequent taper to 60 mg for a week with a plan to receive his second rituximab infusion as an outpatient.

A few days later, when he presented to the clinic for the second rituximab infusion, he was found to have a worsening non-oliguric AKI with creatinine levels of 4.14 mg/dL and hyperkalemia of 5.8 mmol/dL. He was re-admitted to the hospital and given medical treatment for hyperkalemia. His second admission within a few days and severe inflammation involving almost two-thirds of glomeruli on kidney biopsy was concerning for inadequate response to the initial treatment. His second rituximab infusion of 1000 mg was administered, with methylprednisolone 500 mg IV daily for three doses, followed by oral prednisone 80 mg daily. With the worsening kidney function refractory to the initial treatment of two steroid bursts, two doses of rituximab, and a peak creatinine of 4.72 mg/dL, he was started on plasmapheresis by the nephrology team. He received five sessions of plasmapheresis every alternate day. His first session of plasmapheresis was three days after his second rituximab infusion. Meanwhile, his anemia worsened, requiring RBC transfusions, in addition to the development of new thrombocytopenia. The anemia was attributed to rituximab infusions, while his thrombocytopenia was considered to be secondary to plasmapharesis. For his volume overload and refractory hyperkalaemia, he needed two haemodialysis sessions.

A modest improvement in renal function and decline in ESR was noted with these interventions. Creatinine improved to 3 mg/dL. His Monthly IV cyclophosphamide at a low dose of 500 mg was initiated on the day of his 4th plasmapheresis session, with an expected nadir at about ten days, to make it more tolerable with the previously used rituximab therapy. Further improvement in his creatinine (2.7 mg/dL) was achieved, and the patient was discharged with an oral prednisone taper from 80 to 10 mg every week outpatient to a final maintenance dose of 5 mg daily. His hypoxic respiratory failure improved with no further oxygen supplementation requirements at discharge. He continued receiving IV cyclophosphamide 500 mg every four weeks for four doses and a maintenance dose of prednisone 5 mg. The urine protein/creatinine ratio improved from 6482 mg/g to 1497 mg/g and urine microalbumin/creatinine ratio improved from 5435 mg/dL to 1245 mg/dL. (Fig. 2) The previously positive ANCA serology became negative. With further improvement of his creatinine to about 1.8 mg/dl, losartan 25 mg was added for an anti-proteinuric effect. The patient remains on maintenance therapy with prednisone 5 mg and rituximab 500 mg IV infusions every 6 months, and continues to follow closely with rheumatology and nephrology outpatient, and has a stable renal function.

Fig. 2.

a and b Graphical representation of the kidney function plotted against time, showing improvement of serum creatinine, urine microalbumin/creatinine ratio and urine protein/creatinine ratio, with treatment. c Graphical representation of Erythrocyte sedimentation rate (ESR). Adm, Admission; Methylpred, Methylprednisolone; Ritux, Rituximab; PLEX, Plasma exchange; Cyclophos, Cyclophosphamide; Oct, October; Nov, November; Dec, December; Jan, January; Feb, February

Signed informed consent was obtained from the patient regarding the use of patient information for the purposes of writing case report publication.

Discussion

Renal involvement in Granulomatosis with Polyangiitis (GPA) is mainly associated with a poor prognosis, with histopathological findings of crescentic glomerulonephritis conferring a poorer prognosis still. Studies report remission rates ranging from 50 to 75% in patients with GPA-related crescentic glomerulonephritis, with a significant proportion experiencing relapses [5]. It has also been shown that approximately 20–50% of patients with GPA and severe renal involvement progress to end-stage renal disease (ESRD) within five years [3].

Symptoms in patients with GPA include nonspecific symptoms like fever, malaise, anorexia, weight loss, myalgias, and arthralgias occurring over weeks to months. However, more rapid presentations developing over days to weeks are not uncommon [6–10]. More specific exhibitions include rhinosinusitis, cough, dyspnea, and hemoptysis with ear, nose, and throat (ENT) involvement. Urinary abnormalities include hematuria, proteinuria, and active urinary sediments with or without kidney function impairment. Our patient's prior history of community-acquired pneumonia and symptoms of cough, hemoptysis, generalized malaise, epistaxis, diffuse myalgias, polyuria, hematuria, night sweats, poor oral intake, and weight loss created a diagnostic dilemma.

The differential diagnoses of small vessel vasculitis and Goodpasture syndrome were investigated because of pulmonary involvement, progressive acute kidney injury, and raised inflammatory markers. PR3 + ANCA antibody positivity with negative anti-GBM antibodies suggested a vasculitic cause. Usually, in patients with these diagnoses, kidney biopsy findings typically range from mild focal glomerulonephritis to diffuse necrotizing and crescentic glomerulonephritis, parallel to the severity of clinical presentation. Our patient had a pauci-immune, rapidly progressive focal necrotizing and crescentic glomerulonephritis with severe inflammatory changes on kidney biopsy.

Induction therapy in GPA typically includes high-dose glucocorticoids in conjunction with cyclophosphamide or rituximab [11]. A review by Chung et al. recommended using rituximab over cyclophosphamide in conjunction with steroids for remission induction in patients with active, severe GPA, citing less observed side effects and similar efficacy with the former [12]. Some experts treat with glucocorticoids in combination with both rituximab and cyclophosphamide [13]. Gulati et al. suggested the use of combination therapy with both rituximab and cyclophosphamide along with low dose steroids as more efficacious with similar side effect profile as compared to either rituximab or cyclophosphamide including regimens, likely because of the reduced adverse effects of common dose steroids [14]. There is a lack of standardized established immunosuppressive regime for treating GPA at present. In our patient, with severe inflammation involving almost two thirds of the glomeruli, the treatment response was achieved primarily due to a combination of immunosuppression after inadequate response with a single agent, placing emphasis that combination therapy may be useful when patients do not respond to initial therapy with single-agent immunosuppression. Additional therapies such as plasma exchange may be considered in select cases with severe disease, double-positive anti-GBM, ANCA-associated disease, and pulmonary hemorrhage, based on small randomized trials and meta-analysis, all of which suggested short-term improvement in kidney outcomes without any effect on mortality. Walsh et al. conducted the PEXIVAS trial and demonstrated that plasma exchange is ineffective in reducing both incidences of ESRD and death, thus not recommending its use for this purpose [15]. Chung et al. reiterated the same in their review [12]. A new drug that has been recently introduced for induction therapy is avacopan, which is a complement C5a inhibitor. It is used as an alternate agent to high-dose steroids in combination with a shorter, low-dose glucocorticoid regimen, effectively reducing the risk of glucocorticoid-related toxicity. Jayne et al. concluded that avacopan was non-inferior to glucocorticoids concerning remission at 26 weeks and superior to glucocorticoids at 52 weeks, with a similar side effect profile [16].

Maintenance immunosuppressive therapy is given in patients who have achieved complete remission. Guillevin et al. found rituximab superior to azathioprine for maintaining remission at 28 weeks [17]. Studies comparing azathioprine with methotrexate revealed similar efficacy, while studies comparing azathioprine with mycophenolate mofetil revealed superior results with azathioprine compared to mycophenolate mofetil [18, 19]. Rituximab is generally preferred, with azathioprine, methotrexate, and mycophenolate mofetil being reasonable alternatives.

Despite adequate induction therapy for six months, some patients develop resistant disease. Studies on treatment-resistant diseases are less convincing, with clinicians preferring treatment options based on smaller trials and clinical experience. After ruling out an alternate diagnosis, treatment options depend on the patient's characteristics and the initial treatment regimen. Miloslavsky et al. studied clinical outcomes in severe ANCA-associated vasculitis. They found that out of the seven patients on rituximab who did not achieve remission, six patients who were started on cyclophosphamide achieved remission, with one patient who required dialysis and who had both glomerulonephritis and pulmonary hemorrhage dying of septic shock at 11 weeks [20]. Patients treated with rituximab not achieving remission may benefit from cyclophosphamide therapy, though studies are limited. Stassen et al. suggested mycophenolate mofetil as an alternative to cyclophosphamide in patients who cannot achieve remission [21]. All studies assessing the efficacy of mycophenolate mofetil were conducted before the introduction of rituximab, with no study comparing the effect of mycophenolate mofetil with rituximab in this scenario. Patients resistant to rituximab and cyclophosphamide can be considered for mycophenolate mofetil or a combination of rituximab and cyclophosphamide. Amudala et al. described a case series of 3 patients with obinutuzumab being used effectively in patients with hypersensitivity to rituximab, making it a potential treatment option [22].

Our case was initially treated with the commonly used induction regimen of pulse methylprednisolone of 1000 mg daily for five days, followed by 125 mg daily for two days in combination with rituximab. An extended course of corticosteroids was used since he continued to have a small amount of hemoptysis despite receiving the standard three-day course of methylprednisolone. He had started to show clinical improvement with stabilization of kidney function and was discharged with a plan to deliver a second dose of rituximab in the infusion clinic. The patient was started on hemodialysis because of the worsening non-oliguric AKI with hyperkalemia. He was then managed along the lines of treatment-resistant vasculitis, having failed remission with the initial regime. Subsequently, he received five sessions of plasmapheresis and IV cyclophosphamide 500 mg monthly, after which he showed improved serum creatinine values. This case supports the role of plasma exchange in combination with rituximab and cyclophosphamide in patients with severe renal involvement and aggressive kidney biopsy changes with crescentic necrotizing glomerulonephritis. Furthermore, a low dose IV cyclophosphamide of 500 mg instead of the usual 15 mg/kg was used, which understandably has fewer side effects than the standard regimen, highlighting the potential benefits of adding it to the initial treatment protocol in patients with ANCA and crescentic RPGN. So far, the evidence and case studies highlighting treatment in resistant ANCA vasculitis are sparse, and we attempt to add this case to the existing literature.

Conclusion

Our patient with rapidly progressive and crescentic glomerulonephritis along with alveolar hemorrhage presented with a poor prognosis at the outset; multimodality treatment with pulse steroid, rituximab, plasmapheresis, and cyclophosphamide helped in achieving remission. This case supports plasma exchange combined with rituximab and low-dose cyclophosphamide in patients with GPA with severe renal involvement on kidney biopsy with crescentic necrotizing glomerulonephritis.

Author contributions

Ujjwal Madan was involved in drafting and editing the manuscript and graphical figures. Vishesh Goel was involved in drafting and editing the manuscript. Jignesh Shah was involved in editing the manuscript. Hameed Ahmad was involved in editing the manuscript. Amr Edrees was involved in editing the manuscript. Clarissa Cassol made the pathology diagnosis, wrote the pathology section, and provided biopsy pictures.

Declarations

Conflict of interests

No disclosures by authors, and this case review was not funded by any organization. Patient consent was obtained before the drafting of this manuscript, for drafting of the manuscript and publication, including publication of images.