Overlap of PR3-Positive ANCA-Associated Vasculitis and Primary Focal Segmental Glomerulosclerosis: A Case Report,Patient Perspective,and Review of the Literature

Abstract

Anti-neutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) and primary focal segmental glomerulosclerosis (FSGS) are distinct glomerular diseases that rarely occur together. When present concurrently, they may produce overlapping nephritic and nephrotic features that complicate diagnosis and management. We report a case of a 63-year-old man who presented with four weeks of progressive anasarca and several months of cognitive changes, blurry vision, and paresthesia. Investigations demonstrated nephrotic-range proteinuria (8.25 g per day), hypoalbuminemia, hematuria, acute kidney injury, and hypertension. Kidney biopsy demonstrated two concurrent pathologies: FSGS with complete podocyte foot process effacement and pauci-immune glomerulonephritis with focal active crescents. Serology confirmed proteinase 3 antibody (PR3)-ANCA positivity, establishing active AAV alongside primary FSGS. Treatment included pulse intravenous methylprednisolone followed by oral prednisone and rituximab for induction and maintenance of AAV. Because nephrotic syndrome persisted, calcineurin inhibitor therapy was initiated for steroid-resistant FSGS (cyclosporine followed by tacrolimus). Adjunctive antiproteinuric therapies included renin-angiotensin system blockade, sodium-glucose cotransporter-2 inhibition, and later a nonsteroidal mineralocorticoid antagonist. The patient eventually achieved partial remission with resolution of his nephrotic syndrome and undetectable PR3 titers. After 2.5 years of follow-up, kidney function stabilized at an estimated glomerular filtration rate (eGFR) of 29 mL/min/1.73 m² with persistent urine albumin-to-creatinine ratio (ACR) of 163 mg/mmol despite maximal antiproteinuric therapy. Long-term complications included diabetes mellitus related to immunosuppression. This case illustrates the rare coexistence of primary FSGS and PR3-positive AAV requiring simultaneous treatment, with differing responses to therapy. It highlights the challenges of assessing treatment response in dual glomerular pathology while balancing aggressive immunosuppression against systemic toxicity. Incorporation of the patient perspective in this case report highlights the lived experience and burden of managing concurrent FSGS and AAV.

Introduction

Anti-neutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) and focal segmental glomerulosclerosis (FSGS) are distinct causes of glomerular disease, typically associated with rapidly progressive glomerulonephritis (RPGN) and nephrotic syndrome, respectively.^1,2 While each condition has a well-described pathophysiology and treatment paradigm, their concurrent presentation in a single patient is exceedingly rare and not well-described in the literature. The overlapping clinical features of hematuria, proteinuria, acute kidney injury, and systemic symptoms can complicate timely diagnosis and therapeutic decision-making, especially when features of both nephritic and nephrotic syndromes are present.

In this report, we describe a unique case of a 63-year-old man who presented with generalized edema and was found to have biopsy-proven FSGS alongside pauci-immune glomerulonephritis in the setting of proteinase 3 antibody (PR3)-positive AAV. This case highlights the diagnostic complexity and therapeutic challenges posed by concurrent glomerular pathologies. Further, the patient has contributed their perspective to this case report to describe the tremendous impact of complex glomerular diseases on patient quality of life.

Presenting Concerns

A 63-year-old male presented to hospital with a 4-week history of progressive anasarca and worsening hypertension. This was on the baseline of a three-month history of brain fog, intermittent blurry vision, and bilateral lower extremity paresthesia. His remaining review of systems was negative. His medical profile was significant for hypertension, dyslipidemia, and gastroesophageal reflux disease.

Prior to this presentation, outpatient investigations conducted by the patient’s primary care physician revealed a serum albumin of 24 g/L, rising serum creatinine from prior baseline of 75 to 119 μmol/L, urinalysis with proteinuria and red blood cells (previously normal two years earlier), and 24-hour urine protein of 8.25 g per day; this prompted referral to a tertiary care center.

“I went to my local emergency department several times with systolic blood pressure readings over 180 mmHg, but was sent home each time. Living in a rural area likely contributed to a delay in my diagnosis.” (Quote from patient)

Clinical Findings

Upon presentation, a physical examination revealed a temperature of 36.5 °C, blood pressure of 171/98 mm Hg, heart rate of 80 beats per minute, respiratory rate of 20 breaths per minute, and oxygen saturation of 97% on room air. His physical examination was significant for symmetrical pitting edema of lower extremities extending to the hips and abdominal wall as well as fine bibasilar crackles.

Timeline

Table 1 outlines the relevant clinical events and investigations surrounding the initial presentation.

Table 1.

Timeline of Relevant Clinical Events, Starting Prior to Hospital Admission and Continuing Through to Discharge.

Date	Clinical event
Day −86	Routine outpatient labs demonstrated serum creatinine 75 μmol/L, eGFR 93 mL/min/1.73 m2.
Day −25	Outpatient labs due to progressive edema demonstrated creatinine 119 μmol/L, eGFR 56 mL/min/1.73 m2, urinalysis with 2.0 g/L protein and dipstick positive for hemoglobin but without RBCs.
Day 0	Presented to hospital with anasarca and associated symptoms.
	Initial laboratory values
	Hgb (g/L): 124 (135-175)	Cl (mmol/L): 110 (98-112)	Albumin (g/L): 20 (30-45)
	WBC (109/L): 6.8 (4-11)	HCO3 (mmol/L): 23 (20-32)	PR3 (C-ANCA): 2.9 (0-0.9)
	Plt (109/L): 194 (140-400)	Creatinine (μmol/L): 198	MPO (P-ANCA): <0.2 (0-0.9)
	Na (mmol/L): 140 (135-145)	Urea (mmol/L): 14.9 (3-9)	Anti-GBM: <0.2 (0-0.9)
	K (mmol/L): 4.7 (3.5-5.0)	eGFR (mL/min/1.73 m2): 30	ANA: 1:80
Day 1	Initiated on methylprednisolone 500 mg IV daily for three days.
Day 2	Kidney biopsy performed.
Day 4	Prednisone 75 mg daily initiated.
Day 5	Creatinine rose to a maximum of 501 μmol/L
Day 9	Received first of two rituximab induction doses (1 g once every two weeks for two doses).
Day 14	Discharged home from hospital. Creatinine upon discharge was 188 μmol/L (corresponding eGFR 32 mL/min/1.73 m2).

Note. ANA, anti-nuclear antibody; Anti-GBM, glomerular basement membrane antibody; Cl, chloride; eGFR, estimated glomerular filtration rate; HCO3, bicarbonate; Hgb, hemoglobin; IV, intravenous; K, potassium; MPO, myeloperoxidase antibody; Na, sodium; Plt, platelet; PR3, proteinase 3 antibody; RBC, red blood cell; WBC, white blood cell.

Diagnostic Focus and Assessment

Relevant Investigations

Laboratory Results

Initial hospital laboratory tests were significant for serum creatinine 198 μmol/L, serum albumin 20 g/L, and PR3 ANCA positive at 2.9 antibody index (AI) units (normal 0.0-0.9). Urinalysis was positive for >5 g/L protein and six to ten red blood cells (RBCs) per high-powered field. Urine microscopy demonstrated >10 dysmorphic RBCs per high-powered field, one RBC cast, and multiple granular casts. An infectious workup was negative for hepatitis B, hepatitis C, HIV, tuberculosis (via QuantiFERON), and group A Streptococcus (via an antistreptolysin O titer).

Imaging and Diagnostics

Chest x-ray demonstrated atelectasis/consolidation at the lung bases with small bilateral pleural effusions and mild vascular redistribution. An abdominal ultrasound demonstrated a 11.4-cm right kidney and a 12.6-cm left kidney, with no hydronephrosis, nephrolithiasis or ascites present.

Electromyography (EMG) and nerve conduction studies demonstrated a length dependent sensorimotor axonal polyneuropathy without significant asymmetry, favored to be a neuropathy secondary to vasculitis.

Diagnostic Reasoning

An urgent kidney biopsy was arranged during the admission. While he presented with nephrotic syndrome, he also had overlapping features of a RPGN with hematuria, hypertension, and subacute kidney injury. Prior to his biopsy results, his ANCA serology returned positive for PR3 antibodies, which accounted for his RPGN and polyneuropathy symptoms. Subsequently, his kidney biopsy demonstrated the following: (1) segmental glomerulosclerosis in one glomerulus with complete (100%) podocyte foot process effacement confirmed with electron microscopy; (2) focal active glomerular crescents in one glomerulus with negative immunofluorescence (including no punctate podocyte dusting for IgG or other immunoglobulins); (3) mild arteriosclerosis; (4) background of 6/33 globally sclerotic glomeruli and <10% interstitial fibrosis and tubular atrophy (Figure 1).

Figure 1.

First kidney biopsy. (A) PAS stain, ×20 magnification demonstrating glomerulus with segmental active crescent. (B) PAS stain, ×40 magnification demonstrating glomerulus with intra-capillary foam cell at the glomerular tip consistent with a tip FSGS lesion (at 7 to 8 o’clock). (C) Toluidine blue-silver stain, ×20 magnification demonstrating glomerulus with intra-capillary foam cell at the glomerular tip consistent with a tip FSGS lesion (at 3 o’clock). (D) Electron microscopy image demonstrating extensive podocyte foot process effacement.

The presence of an FSGS lesion with complete podocyte foot effacement, in the context of clinical nephrotic syndrome and absence of an identifiable secondary cause, was most consistent with primary FSGS. Concurrently, the pauci-immune crescentic lesion on biopsy together with positive PR3-ANCA serology strongly supported AAV. Taken together, these findings suggested the presence of two active primary glomerular processes.

Therapeutic Focus and Assessment

Given the patient’s presentation consistent with RPGN, he was promptly initiated on pulse-dose glucocorticoids with methylprednisolone 500 mg IV daily for three days, followed by transition to high-dose oral prednisone (75 mg daily) prior to receipt of the kidney biopsy results.

Following kidney biopsy demonstrating two active primary processes with minimal chronicity, an aggressive treatment approach was pursued targeting both pathologies. High-dose glucocorticoids were continued given their central role in the management of both disease processes, with plans to maintain steroid therapy until clinical remission of his nephrotic syndrome, defined as proteinuria <300 mg/day and serum albumin >35 g/L. For his AAV, induction therapy with rituximab (two doses) was administered in combination with glucocorticoids, with continuation for maintenance. Once his kidney function stabilized in the outpatient setting (eGFR of approximately 30 mL/min/1.73 m²), adjunctive antiproteinuric therapy was initiated with an angiotensin-converting enzyme (ACE) inhibitor, followed by addition of a sodium-glucose cotransporter-2 (SGLT2) inhibitor.

“The high-dose steroids had a significant impact on me including hallucinations, insomnia, mood swings, and muscle loss. I required a walker to ambulate in hospital, and when I was discharged home, I still had significant leg edema.” (Quote from patient)

Follow-up and Outcomes

The patient has been closely followed by nephrology since his initial presentation. For his AAV, he remained on rituximab for maintenance therapy, with CD19+ B-cell levels monitored at six-month intervals and consistently undetectable (0%), confirming sustained peripheral B-cell depletion. In terms of his primary FSGS, after four months of high-dose prednisone, he had not achieved remission, as evidenced by ongoing nephrotic-range proteinuria and hypoalbuminemia. Consequently, cyclosporine was initiated and prednisone was tapered according to the PEXIVAS protocol. ³ At that time, his eGFR had peaked at approximately 50 mL/min/1.73 m² and his PR3 titer had normalized to 0.6 AI units.

Four months later (eight months post initial presentation), he continued to exhibit persistent nephrotic syndrome, with proteinuria of 6.85 g/day and serum albumin of 23 g/L, along with clinically significant edema requiring high-dose furosemide. He also developed cyclosporine-induced gingival hypertrophy and was transitioned to tacrolimus. A repeat kidney biopsy at this time demonstrated FSGS with extensive foot process effacement and ongoing active AAV with focal fibrocellular and cellular crescents in three of 22 glomeruli (Figure 2). Given the predominance of podocyte injury and lack of response to prior glucocorticoids and rituximab, treatment was directed toward the podocytopathy with calcineurin inhibition. In addition, given stable kidney function, normalized PR3 titer, absence of extra-renal manifestations, and the preference for rituximab in PR3-associated disease, escalation to cyclophosphamide was deferred.

Figure 2.

Second kidney biopsy. (A) PAS, ×40 magnification demonstrating glomerulus with segmental sclerosis. (B) PAS, ×40 magnification demonstrating glomerulus with segmental fibrocellular crescent. (C) Electron microscopy image demonstrating glomerular capillary loop with extensive podocyte foot process effacement.

After four months of tacrolimus therapy, the patient achieved partial remission, with improvement in serum albumin to 30 g/L and urine albumin-to-creatinine ratio (ACR) of 155 mg/mmol. Now, 2.5 years from his initial presentation, he remains on tacrolimus and rituximab for maintenance, with steroids fully weaned off. His kidney function has stabilized at an eGFR of 29 mL/min/1.73 m² and urine ACR of 163 mg/mmol. Notably, he developed diabetes in the context of prolonged steroid and calcineurin inhibitor exposure, which is currently being managed with oral hypoglycemic agents. Finerenone was added as an adjunctive treatment in addition to his immunosuppression, ACE inhibitor, and SGLT2 inhibitor. Lastly, he has been referred for genetic testing given his steroid-resistant FSGS.

“It was difficult going through treatments that didn’t help at first, but since starting tacrolimus, I’ve noticed an improvement in my strength and energy. Even so, I still have days when I’m too fatigued to make plans, which was never an issue before my illness.” (Quote from patient)

Discussion

This case describes a rare co-presentation of primary FSGS and PR3-positive AAV in a patient who presented with features of nephrotic and nephritic syndromes. The coexistence of these two distinct glomerular pathologies underscores the importance of kidney biopsy in establishing an accurate diagnosis and guiding nuanced treatment decisions.

While secondary FSGS can arise from a variety of underlying conditions, including ANCA-associated glomerulonephritis, primary FSGS arises from direct podocyte injury, historically attributed to circulating permeability factors.^2,4 More recently, circulating autoantibodies directed against slit diaphragm proteins, most notably anti-nephrin, have been identified in a subset of patients with minimal change disease and primary FSGS, supporting a potential antigen-specific autoimmune mechanism distinct from the non-antigen-specific permeability factor hypothesis. ⁵ Although testing for these antibodies is not routinely available and was not performed in our patient, it raises the speculative possibility that shared autoimmune dysregulation could contribute to the coexistence of both pathologies observed in our case. Alternatively, genetic forms of FSGS represent a mechanistically distinct entity from presumed immune-mediated primary FSGS and should be considered in cases of steroid resistance. ⁴ Accordingly, this was pursued in our patient.

The index biopsy demonstrated tip-variant FSGS, a histologic subtype generally associated with greater steroid responsiveness and more favorable renal outcomes compared with other Columbia variants,^2,6 although this was not redemonstrated on repeat biopsy. Transition between FSGS morphologic variants on repeat biopsy, has been reported and may reflect disease progression. ⁷ Furthermore, the repeat kidney biopsy continued to show evidence of active AAV, suggesting ongoing inflammatory and podocyte injury contributing to a more treatment-resistant course.

PR3-positive AAV is characterized by necrotizing small-vessel vasculitis and frequently involves the kidneys. ¹ Compared with myeloperoxidase (MPO)-positive AAV, PR3-positive AAV tends to be more responsive to treatment and is associated with a lower risk of progression to kidney failure, but a higher likelihood of relapse. ¹ Factors associated with increased relapse risk include persistent ANCA positivity, prior relapses, lower serum creatinine and pulmonary involvement. ⁸

The management of concurrent glomerular diseases presents a significant clinical challenge, both in selecting appropriate therapy and in assessing treatment response. In our case, treatments including corticosteroids and rituximab offered potential efficacy across both disease processes.^8,9 However, in this case the FSGS induced proteinuria did not respond to corticosteroids or rituximab, necessitating additional immunosuppression with a calcineurin inhibitor. The use of second-line therapies for steroid-resistant FSGS, such as calcineurin inhibitors must be balanced against their nephrotoxic potential, especially in the setting of active vasculitis. ⁹ Similar challenges have been described in other dual-glomerulopathy scenarios, such as AAV overlapping with IgA nephropathy, where aggressive combined immunosuppression is often required to achieve disease control. ¹⁰ Repeat kidney biopsy is essential not only in establishing the diagnosis and assessing for disease relapse (AAV in particular) but also in guiding the intensity and duration of dual-directed therapy. Further, given the difficulty in managing this patient’s high-grade proteinuria with multitargeted therapy, genetic testing to identify predisposing risk factors is important.

Only one other case report has documented the coexistence of primary FSGS and AAV in the same patient. ¹¹ In that case, a 60-year-old female was initially diagnosed with FSGS based on kidney biopsy, with serological testing revealing PR3 ANCA positivity during evaluation for acute kidney injury. A decade later, she re-presented with acute kidney injury and repeat biopsy revealed pauci-immune glomerulonephritis with focal crescents, consistent with AAV, without evidence of FSGS. Notably, that case involved 2 temporally distinct disease processes and did not require simultaneous treatment for both glomerular pathologies, in contrast to our patient who required concurrent management of active FSGS and AAV.

In conclusion, this case highlights the rare simultaneous presentation of primary FSGS and PR3-positive AAV in a patient presenting the nephrotic syndrome, rapidly rising creatinine, hematuria, and hypertension. We describe two distinct glomerular diseases with differing treatment responses, underscoring the challenges in assessing response and formulating an effective treatment strategy. This case raises important pathophysiologic considerations, including the possibility of shared autoimmune mechanisms contributing to dual glomerular injury; however, this remains speculative given the current state of knowledge. From a clinical perspective, our experience supports the need for an aggressive, individualized treatment approach when managing co-existing active glomerular diseases, while balancing the impact of these diseases and therapies on patient quality of life.

Patient Perspective

“I’ve felt very supported by the strong communication between my family physician, pharmacist, and nephrologist, which has allowed me to receive coordinated care at home, even though I live 2.5 hours from an urban center. Despite this support, my life has completely changed – I no longer work as I once did, and travel is now limited to cruises due to physical weakness and the unpredictability of my day-to-day energy.” (Quote from patient)