IgA vasculitis with severe renal manifestation

Abstract

IgA vasculitis is a rare systemic vasculitis in adults, frequently more severe than in paediatric age. It manifests with cutaneous, articular, gastrointestinal and renal involvement.

We present a case of a man in his 40s diagnosed with IgA vasculitis with cutaneous, joint, gastrointestinal and renal disease. Significant proteinuria and renal biopsy findings demonstrating crescentic glomerulonephritis led to the onset of early immunosuppression with corticoid and cyclophosphamide. This case report reflects a case of more severe renal impairment due to IgA vasculitis with good outcome with the chosen therapy. The findings in the renal biopsy after treatment supported the good response to the chosen immunosuppression.

Background

IgA-mediated vasculitis is a common systemic vasculitis in paediatric age but with a lower incidence in adults. The presentation of the disease is often multisystemic and includes skin, articular, gastrointestinal and renal manifestations.^1–3 The classification criteria for IgA vasculitis are American College of Rheumatology (ACR) classification (1990) and European League Against Rheumatism/Paediatric Rheumatology International Trials Organisation/Paediatric Rheumatology European Society (EULAR/PRINTO/PRES) (EULAR/PRINTO/PRES) classification (2010).⁴

Renal involvement is more frequent and more severe in older children and adults, and it is associated with greater morbidity and mortality.³

Treatment of IgA vasculitis with renal involvement in adulthood has been poorly investigated but the diagnosis of this entity is essential to guide immunosuppressive treatment and prevent permanent kidney damage.^{3 5}

Case presentation

A man in his 40s with no significant medical history presents with additive arthralgias, asymmetrical with inflammatory pattern, of tibiotarsals, knees, wrists and elbows with 2 months of evolution and confluent maculopapular purpuric lesions and some localised haemorrhagic blisters to the lower limbs, abdomen and dorsal region (figure 1), which appeared 1 week before. He denied fever, weight loss, sweating, change in urine colour, abdominal pain or other symptoms. He also denied recent infections, introduction of new drugs or recent travel.

Figure 1.

Purpuric lesions in the lower limbs with confluence for haemorrhagic bullae.

Investigations

Analytically on admission to the hospital, there was an increase in acute phase parameters (sedimentation rate 17 mm/hour, C reactive protein 6.11 mg/dL), without renal dysfunction (creatinine 0.93 mg/dL, urea 38 mg/dL), urine II with proteinuria (+) and no haematuria, no change in blood count (haemoglobin 155 g/L, leucocytes 5.13×10⁹/L, platelets 298×10⁹/L), serum albumin 4.3 g/L, no ionic or hepatic enzymological changes (table 1).

Table 1.

Evolution of analytical parameters

Parameter (units)	Normal range	Admission	Peak	3 months	6 months	12 months	24 months	30 months
Haemoglobin (g/L)	135–175	160	116	136	134	143	152	151
Leucocytes (×109/L)	4.00–10.00	7.12	17.73	6.02	6.99	7.62	7.58	7.46
PCR (mg/dL)	<0.50	4.66	6.11	<0.5	0.13	1.77	0.11	0.10
Creatinine (mg/dL)	0.7–1.30	0.93	1.34	1.13	1.20	1.08	0.97	0.98
Urea (mg/dL)	19–49	32	50	46	43	44	35	45
Proteinuria (mg/24 hours)	<150	180	3200	1632	546	770	222	147

He was admitted for an aetiological study. We identified an increase in total IgA (510 mg/dL) and a negative autoimmune and infectious study (antinuclear antibodies, antineutrophil cytoplasmic antibodies, rheumatoid factor, lupus anticoagulant, anti-glycoprotein and cardiolipin negative, without consumption of complement; immunoglobulin quantification within normal range except for IgA; HIV, hepatitis B and C negative). He performed a skin biopsy that revealed leucocytoclastic vasculitis (immunofluorescence was not performed on this sample). Reporting arthralgias and skin involvement associated with IgA vasculitis, therapy was started with prednisolone 40 mg/day.

During hospitalisation and despite the treatment started, there was an extensive worsening of skin lesions, important inflammatory arthritis of small and medium articulations, bloody diarrhoea and abdominal pain associated with deterioration of renal function (creatinine 1.05 mg/dL and urea 50 mg/dL), with haemato-proteinuria (24-hour proteinuria assay revealed 3.2 g/day) and serum albumin 2.2 g/dL. A renal biopsy was performed and showed crescentic glomerulonephritis (13 glomeruli with 9 of them presenting cellular crescents) with endocapillary proliferation, some fibrinoid necrosis and mesangial proliferation within the remaining glomerulus (figure 2), interstitial area and tubules without alterations with tubular haematuria. Immunofixation revealed deposits of IgA and C3 (figure 3).

Figure 2.

Silver stain, with 400× magnification, where it is possible to see a glomerulus with proliferation, rupture of the capsule and formation of cellular crescents.

Figure 3.

Immunofluorescence labelled for IgA with mesangial deposits.

The diagnosis of IgA vasculitis was made and included cutaneous, articular, gastrointestinal involvement, as well as severe renal involvement, with proteinuria >1.5 g/day and the presence of crescents in the renal biopsy supporting the rapidly progressive evolution. The patient fulfils the ACR and EULAR/PRINTO/PRES classification criteria for IgA vasculitis.

Treatment

Nephroprotective measures were initiated with ACE inhibitor and blood pressure control (with ramipril 10 mg, lercanidipine 10 mg and bisoprolol 5 mg).

He was medicated with methylprednisolone 1 g/day for 3 days, followed by oral prednisolone 1 mg/kg/day (80 mg/day) and went on cyclophosphamide (750 mg/m² each 4 weeks, 6 infusions). After completing six cycles of cyclophosphamide, he had no recurrence of arthralgias, cutaneous lesions or gastrointestinal manifestation. He maintained a normal renal function but a proteinuria of 546 mg/24 hours persisted (figure 4), and the choice for maintenance therapy was azathioprine (150 mg/day) associated with tapered corticosteroids. About 4 months after initiation of azathioprine, he presented with cytopenia and azathioprine was discontinued, maintaining a low dose of prednisolone.

Figure 4.

Graphical evolution of creatinine and proteinuria.

Outcome and follow-up

One year after the initiation of therapy, as he maintained proteinuria (table 1, figure 4), a new renal biopsy was performed that revealed eight glomeruli and showed glomeruli and tubules without sclerosis, with some interstitial oedema, but no signs of vasculitis; immunofluorescence revealed discrete mesangial deposits of IgA. Despite the renal biopsy providing only a sample of the kidney, the absence of glomerulosclerosis is suggestive of a good response to immunosuppression, as there is no sclerosis observed on the sample obtained. Currently, after 2 years and a half of follow-up, under 5 mg of prednisolone, he is clinically stabilised, maintains haematuria (+) on type II urine but the proteinuria has substantially improved with 147 mg on 24-hour proteinuria. He did not present any recurrence of skin, articular or gastrointestinal manifestations.

Discussion

IgA vasculitis is often associated with a paediatric disease, with a lower incidence in adults, reported at 0.8–1.8 per 100 000.^{1 3}

IgA vasculitis can affect virtually all organs pathophysiologically characterised by vascular injury caused by the deposition of immune complexes that are histologically visualised by immunofluorescence techniques and presence of polymorphonuclear leucocytic infiltrate of vessel walls.^{2 6}

IgA vasculitis with renal involvement and IgA nephropathy show similar histological changes, suggesting the sharing of pathogenesis in both entities.⁷ There is a clear difference in the age of diagnosis, with the peak of IgA vasculitis being 1–19 and 60–69 years and IgA nephropathy 30–39 years. Renal involvement in adults with IgA vasculitis occurs in 45%–85% cases. A Japanese study reported lower incidence of crescents on biopsy of IgA vasculitis when compared with IgA nephropathy.⁸

Severe renal involvement in IgA vasculitis is defined by presence of nephrotic syndrome (plasma albumin <2.5 g/dL and proteinuria >3.5 g/day) with or without peripheral oedema and/or nephritic syndrome (haematuria associated with two of the following: hypertension, increased urea or creatinine and oliguria); renal failure occurs when serum creatinine is 125% greater than the upper limit or glomerular filtration rate is lower than 60 mL/min.⁶

Regarding the histological findings of renal biopsies, the most frequent finding is the presence of mesangial IgA deposits, class 2 or 3 glomerulonephritis and fibrinoid necrosis.^{2 3} The presence of crescents on renal biopsy reflects a rapidly progressive disease that is very uncommon in this entity and imposes an early onset of aggressive immunosuppression.^{5 9} Presentation with nephrotic syndrome is uncommon in IgA vasculitis.^{10 11}

Bad prognostic factors in IgA vasculitis with renal involvement are the presence of >50% crescents on biopsy, alteration in renal function at presentation, proteinuria >1.5 g/day and hypertension.¹² A Chinese multicentre study by Lv et al found that crescentic IgA nephropathy had a poor prognosis, and nearly 70% of these patients progressed to end-stage renal disease (ESRD) in 5 years, including those patients who had received immunosuppressive therapy; however, the percentage of crescents was not independently associated with the occurrence of ESRD.¹³ Another Chinese cohort from Huang et al studied patients with IgA vasculitis-related nephritis and found that patients with more crescents had more severe renal manifestations and poorer treatment responses.¹⁴ In the treatment of IgA vasculitis, it is currently indicated to use renal nephroprotection, including ACE inhibitors and blood pressure control. The initiation of immunosuppressive treatment with corticoids and cyclophosphamide is recommended in the most severe forms of the disease. More recently, rituximab has emerged as a drug to be considered.^{5 15}

The role of renal biopsy is well established in the moment of diagnosis: the presence of IgA deposits in the immunofluorescence confirms the diagnosis and there are histological findings that are associated with worse prognosis as already described.^{2 5} However, the role of kidney biopsy is not yet established after treatment.

The presence of antineutrophil cytoplasmic antibodies (ANCA), more frequently myeloperoxidase, has been found in a minority of patients with IgA vasculitis; and although its role is not fully understood, it should be actively researched as in its presence the therapeutic approach changes and should be approached as ANCA vasculitis.^{5 16}

In conclusion, we report a case that assumes special importance as we highlight the multisystemic involvement including extensive cutaneous, articular, gastrointestinal and renal manifestations. An unusual and severe presentation of renal manifestation detected pendant hospital staying and various poor prognostic factors were present, namely the presence of >50% crescents in renal biopsy, hypertension and proteinuria >1.5 g/day, which led to the choice of aggressive immunosuppressive therapy. The presence of crescents in renal biopsy is also uncommon and suggestive of a rapidly progressive evolution. The patient has responded favourably to corticosteroid therapy associated with cyclophosphamide followed by azathioprine and low dose of prednisolone and maintained clinical stability. The second biopsy performed 6 months after initiating therapy showed no glomerulosclerosis and that supported the efficacy of the treatment that was initiated promptly after detecting significant proteinuria.

Learning points.

• IgA vasculitis is a multisystemic disease, and the renal involvement has particular importance regarding the choice of immunosuppression.

• The presence of crescents on renal biopsy reflects rapidly progressive disease that is very uncommon in IgA vasculitis.

• Bad prognostic factors in IgA vasculitis include presence of >50% crescents on biopsy, alteration in renal function at presentation, proteinuria >1.5 g/day and hypertension.

• The initiation of immunosuppressive therapy is critical in severe disease particularly when there is renal involvement.

• The renal biopsy can present useful information in the course of the disease: to confirm the diagnosis, give information related to its severity and can be a tool to access clinical response to treatment.

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