Introduction

Paediatric rheumatological diseases are a group of multi-systemic inflammatory diseases affecting children and young people. The most common childhood rheumatic condition is juvenile onset arthritis (JIA) that has an incidence of up to 20 per 100,000 child population, in contrast to childhood systemic lupus erythematosus (cSLE) that has an incidence of about 0.2 per 100,000 child population [1, 2]. Primary vasculitis, whilst rarer, has been found to account for approximately 2–10% of paediatric rheumatology workload captured from registry data in North America [3]. The kidneys constitute a target organ during the acute presentation and the disease course of multi-systemic inflammatory conditions such as primary vasculitis and cSLE, and unlike adults, where there may be pre-existing concomitant kidney disease, children are more likely to have an acute, potentially reversible inflammatory process that requires prompt intervention [4]. There remains much unknown about the pathophysiology of these conditions, and due to the rarity of these diseases in children, recruitment to drug trials can be challenging, resulting in the use of data extrapolated from adult studies and slow improvements in clinically meaningful outcomes for children. In general, children with inflammatory diseases are at a greater risk of accelerated cardiovascular consequences, and this risk rises with the presence of persisting proteinuria and/or low glomerular filtration rate (GFR) [5]. There is therefore a lot to be gained by focusing on improving kidney outcomes in childhood-onset rheumatic diseases. The aim of this review article is to summarise the epidemiology and kidney outcomes of paediatric rheumatic diseases that commonly involve the kidney, including cSLE, IgA vasculitis, ANCA-associated vasculitis (AAV) and those where kidney involvement is less commonly involved such as polyarteritis nodosa (PAN). The article also provides additional information on screening to detect the presence of active kidney inflammation to guide clinicians.

Childhood-onset systemic lupus erythematosus (cSLE)

cSLE is a chronic, lifelong autoimmune multi-systemic disorder that has an onset in childhood in about a fifth of all diagnosed patients [6]. Common clinical features of cSLE include joint pain, malaise, fatigue, fever, weight loss and the characteristic ‘butterfly’ malar rash [7]. The median age at presentation is 12–13 years in childhood-onset disease. Although rare, cSLE has an incidence of around 0.2–3 cases per 100,000 childhood population and the prevalence is reported to be 2–34 per 100,000; however, these figures vary across the world and according to ethnicity, with cSLE being more prevalent in Asian, Afro/Caribbean and Hispanic individuals [2]. In children, the gender difference is less striking than in adult-onset SLE (aSLE), where around 90% of patients are female; in cSLE, the male to female ratio is around 1:5, with a drift in post-pubertal teenagers towards a gender distribution more similar to adults [2]. Three different classification criteria have been developed and validated in adult-onset disease but need further evaluation in cSLE [8,9,10]. The SLICC criteria importantly allow the classification of patients who have histological evidence of lupus nephritis (LN) plus positive antibodies even in the absence of other clinical features. Whilst not fully understood, it is believed that a combination of genetic predisposition, immune dysregulation and environmental and hormonal factors contribute to the production of self-antibodies against the nuclear components of cells that drive the early pathophysiology of this disease. Childhood SLE is associated with a more aggressive clinical course than aSLE, greater severity of complications and higher morbidity and mortality [2, 11].

Frequency and diagnosis of kidney involvement

Kidney manifestations, termed lupus nephritis (LN), range from the presence of microscopic urine abnormalities to acute kidney failure [12]. LN is more commonly seen in cSLE than in aSLE, with reported rates of 50–82% in children and 20–40% in adults [13,14,15], with the highest incidence being reported in children of non-Caucasian ethnicity [16]. KDIGO alongside European guidelines advise that urinalysis (dipstick and sediment), proteinuria estimation, blood tests (serum creatinine, albumin and eGFR) and serology (anti-dsDNA and complement specifically) be performed to screen for kidney involvement at presentation and subsequent clinical reviews. Proteinuria severity can fluctuate, even in cases of severe active nephritis, and may appear relatively minor at times. Hence, repeated investigations over time are important in guiding clinical management decisions [17, 18]. A kidney biopsy should be considered in cases with reproducible proteinuria of > 0.5 g/24 h (equivalent to a urine protein to creatinine ratio > 50 mg/mmol) and/or impaired estimated glomerular filtration rate (eGFR) [19, 20]. The biopsy threshold for proteinuria is somewhat lower than for other causes of glomerulonephritis due to the likelihood of detecting LN at these levels. LN is diagnosed histologically according to the 2003 International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification system (Table 1) [21]. The histological class of LN has been shown to correlate with disease severity, long-term kidney outcome and morbidity [22] and is used to guide treatment [18].

Table 1 International society of nephrology/renal pathology society 2003 classification of lupus nephritis (LN) [21]
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Management and kidney outcome

The treatment target for LN should be the achievement of complete remission [18]. If a complete response is achieved, patients are far less likely to have subsequent flares. Figure 1 outlines the typical treatments used according to the histological class of LN derived from European agreed guidelines [18]. Supportive treatments such as proteinuria management using angiotensin-converting enzyme (ACE) inhibitors, antihypertensive treatments, the use of hydroxychloroquine and minimising thrombotic risk are also important. In children with LN, 40–60% will achieve complete remission. Data on progression to chronic kidney disease (CKD) in children is limited, with a reported rate of 3.8% in 6.6 years of follow-up, with most cases being CKD stage 2 [23]. The risk of kidney failure is 1–14% depending on follow-up, and the median age for requiring a kidney transplant is 24 years. With regards to outcomes, a Chinese cohort study involving 92 children with SLE reported a mortality rate in childhood-onset LN of 2.1/1000 patient-years, with kidney failure and CKD occurring in 3% and 5% of patients respectively [24]. A large multicentre cohort study demonstrated increased renal morbidity in children and a clinically significant twofold greater mortality in cSLE patients when compared to aSLE, although it did not reach statistical significance (19.4% vs. 10.4%, p = 0.337) [25]. Predictors of poorer kidney outcomes in LN include increased serum creatinine concentrations, baseline proteinuria and histological features of activity and chronicity. The outcome data for LN demonstrates the importance of the need for a very long-term follow-up of patients with cSLE, even after they transition into adult care.

Fig. 1
figure 1

Overview of 2003 ISN/RPS classification criteria for lupus nephritis and SHARE recommendations for management [18, 21].

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IgA vasculitis (Henoch-Schönlein purpura)

Immunoglobulin A vasculitis (IgAV), also known as Henoch-Schönlein purpura (HSP), is a leukocytoclastic small-vessel vasculitis, and it is by far the most common vasculitis in children with an incidence of 3 to 27 cases per 100,000 children [26]. The peak age of incidence in children is between 4 and 7 years old [26]. The pathogenesis of IgA vasculitis is incompletely understood, but it is thought to be associated with the production of galactose-deficient IgA1 from the mucosa of the oral cavity and/or gastrointestinal (GI) tract. IgAV presents as a purpuric, symmetrical, non-blanching rash on the lower limbs, and it is associated with any combination of the following triad: joint involvement (arthralgia/arthritis), GI involvement and kidney involvement (nephritis) [27]. It is generally accepted that the 2008 EULAR/PRINTO/PRES criteria should be used to classify IgAV because it has been validated specifically in children, with a sensitivity of 100% and a specificity of 87% (Table 2) [28].

Table 2 EULAR/PRINTO/PRES criteria for IgAV and classification definition. Patients must have purpura/petechiae and of the following: abdominal pain, histopathology, arthritis or arthralgia and kidney involvement [28]
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Frequency and diagnosis of kidney involvement

IgAV nephritis (IgAVN) is the main cause of morbidity in patients with IgAV [29], and it can affect 40–50% of children [27, 30]. It can present with a spectrum of manifestations ranging from microscopic haematuria with or without proteinuria that typically self-resolves over subsequent weeks to an acute nephrotic or nephritic syndrome which is more severe and less common [31]. Due to the risk of nephritis, all patients with IgAV should be routinely monitored for at least 6 months using urinalysis testing as a minimum (for example, weekly for the first 4–6 weeks and then monthly) alongside BP measurements at diagnosis and if investigations reveal evidence of nephritis [31, 32]. The key goal is early detection of kidney involvement, and published examples of monitoring templates exist within the literature, as reproduced in Fig. 2 [33]. The severity of kidney involvement was classified by the SHARE initiative based on urinary findings and/or renal histology (Table 3) [31]. In children with suspected evolving IgAVN, usually detected due to rising proteinuria, a kidney biopsy is indicated to confirm the diagnosis and classify the extent of inflammation to guide treatment choices. Indications for consideration of a kidney biopsy include persisting proteinuria with a urine protein to creatinine ratio > 250 mg/mmol (approx. equivalent to 2.5 g/day) for 4 weeks, acute kidney injury and nephrotic or nephritic syndrome [31]. The proteinuria threshold for when to biopsy remains higher in this condition compared to other forms of glomerulonephritis due to the high rates of spontaneous remission. Histological features include immunofluorescence demonstrating predominant IgA1 deposits in the mesangium region often alongside glomerular deposits of C3. Histological classification is based on the International Study of Kidney Disease in Children (ISKDC) (Table 4), with potential benefit from additional activity and chronicity descriptors [34].

Fig. 2
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Proposed follow-up pathway for children with IgA vasculitis, adapted from Watson et al. [33].

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Table 3 Suggested definitions of the severity of kidney involvement IgAV nephritis, adapted from Ozen and colleagues [31]
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Table 4 The grading system of the International Study of Kidney Disease in Children (ISKDC) classification for pathological scoring of IgAVN in children [34]
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Management and kidney outcome

Management recommendations for IgAVN are determined by the histological features and clinical disease severity in terms of proteinuria and kidney function. First-line treatment for histological class III or above with persisting clinical features is usually oral corticosteroids together with a disease-modifying antirheumatic drug (DMARD) as a steroid-sparing agent [31]. Patients with persistent proteinuria (> 3 months) should be treated with an ACE inhibitor or angiotensin receptor blocker [31]. For children with IgAV, the use of prophylactic corticosteroid treatment during the initial presentation to prevent the onset of nephritis is not indicated, as several randomised controlled studies have shown no significant benefit [17, 35]. Most children with IgAVN will make a complete recovery without any treatment; therefore, the risk of long-term kidney failure in all children presenting with IgAV is relatively low (1–7%), even in those with minor isolated urine abnormalities [29, 31, 36]. However, this risk significantly increases by 12 times in children who present with nephrotic and/or nephritic syndrome (up to 19.5% would develop permanent kidney impairment) [31, 36]. In children who had a kidney biopsy for IgAVN, about 66% will have a normal outcome, and a third will develop long-term proteinuria with progression to eventual CKD over 20 years [27]. Histological factors that are associated with progression to kidney failure include tubular atrophy, interstitial fibrosis, glomerular sclerosis and crescents, especially in patients presenting with mixed nephrotic and nephritic syndrome [34, 37].

ANCA-associated vasculitis

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAVs) is an umbrella term for a group of rare multi-systemic small and medium-vessel vasculitides including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA) [38]. These diseases are associated with a fulminant presentation in children, often with multiple organ involvement and subsequently recurrent disease relapses. AAVs are extremely rare in childhood, with an estimated incidence of 0.45 cases/million children/year (GPA and MPA) according to a French nationwide study [39]. However, a Canadian study reported a much higher incidence of GPA of 6.39 cases/million children/year, suggesting that there may be geographical variation or inaccuracies in the epidemiological data due to the low number of cases [40]. The precise incidence of MPA and EGPA in childhood remains unknown. There are no validated diagnostic criteria for GPA, MPA or EGPA in children. For GPA, the EULAR/PRINTO/PRes-endorsed 2008 classification criteria should be used in the paediatric population [41]. MPA and EGPA are defined in the Chapel Hill (2012) nomenclature and can be used in children for research purposes but are not validated clinically [41, 42].

Frequency and diagnosis of kidney involvement

In children with AAVs, kidney manifestations are very common and heavily contribute to morbidity and mortality. GPA is commonly associated with high levels of anti-PR3 antibodies depicted by cytoplasmic staining of neutrophils (cANCA), whereas MPA and EGPA are more frequently associated with anti-MPO antibodies that cause perinuclear staining of neutrophils (pANCA) [41]. Kidney involvement is most common in children with MPA (75–90% at presentation) and follows a more aggressive clinical course than either GPA or EGPA [43]. Kidney involvement in GPA is seen in around 75% of patients at presentation, and half of these patients will present with reduced kidney function (eGFR < 60 ml/min/m2). In children with AAV, nephritis will present with clinical features such as haematuria and proteinuria, hypertension and oedema [43]. Initial kidney screening should include renal function tests, urinalysis (dipstick with an estimation of proteinuria if necessary) and BP measurements. Twenty-four-hour BP and four-limb BP measurements may be considered depending on the presenting symptoms [41]. Rapidly progressive glomerulonephritis with acutely deteriorating kidney function is common at presentation in AAV. Pauci-immune necrotising glomerulonephritis (PINGN), the most common cause of crescentic glomerulonephritis, is a severe manifestation of AAV that presents with a very rapid decline in kidney function, often leading to irreversible kidney failure [44]. Patients with PINGN or ANCA-associated glomerulonephritis (AAV-GN) without other organ involvement are said to have renal limited vasculitis (RLV). The ‘gold standard’ method for confirming AAV-GN is a kidney biopsy [43]. According to the paediatric AAV-GN classification, histological categories should be grouped into focal, crescentic, mixed and sclerotic [45]. There are no internationally agreed thresholds acting as indications for when to conduct a kidney biopsy in AAV; however, due to the high risk of rapid disease progression and kidney failure, it is of the authors’ opinion that delays in receiving treatment should be avoided.

Management and kidney outcome

The management of paediatric AAVs is based on the adult European Vasculitis Study (EUVAS) guidelines [41]. Induction regimens are determined by the extent and severity of the disease. For a severe, life-threatening or refractory disease with kidney involvement, rituximab, IV cyclophosphamide, plasma exchange and/or intravenous immunoglobulin (IVIG) should be considered after IV methylprednisolone in an attempt to achieve rapid remission [41, 43]. A multi-centre study evaluating the outcomes of 46 children with AAV reported a 55% rate of CKD at 1 year after diagnosis, of which 20% of patients had CKD stages 3–5 and 17% had kidney failure requiring dialysis or a kidney transplant [46]. After 5 years of follow-up, the rate of dialysis or kidney transplantation had risen to 22%, indicating that most morbidity occurs at presentation or in the first few years. The authors also reported a 6.5% mortality rate, demonstrating the concerning outcomes for children with this condition compared to other inflammatory diseases. A smaller study involving 8 patients reported long-term outcomes after a median of 19 years; 1 patient had developed kidney failure, 1 had died and the median eGFR in the other 6 children was 76 ml/min/m2 (equivalent to CKD stage 2) [47].

Other childhood rheumatic conditions that may involve the kidneys

Polyarteritis nodosa (PAN)

Polyarteritis nodosa (PAN) is a rare type of vasculitis caused by damage to small and medium-sized arteries. Due to its rarity, little epidemiological data exists, and the true incidence of PAN in children is unknown. Childhood-onset PAN presents with clinical symptoms associated with cutaneous, intestinal, musculoskeletal and kidney inflammation, such as muscle pain, weight loss, fever and hypertension [48]. Kidney manifestations of PAN at presentation include hypertension, proteinuria, haematuria and impaired kidney function. A UK-based single-centre retrospective study of 69 children treated over a period of 32 years found that 13 (19%) children with PAN had kidney involvement at presentation and 10 (15%) children had a significant decrease in eGFR [48]. The EULAR/PRINTO/PRES criteria for childhood-onset PAN state that patients must have histopathology or angiographic abnormalities plus one of the following: skin involvement, myalgia/muscle tenderness, hypertension, peripheral neuropathy or kidney involvement [28]. A targeted tissue biopsy should be performed when PAN is suspected; however, caution is needed due to the risk of aneurysm rupture and haemorrhage [41]. Catheter digital subtraction arteriography is the gold standard investigation for PAN in childhood but can only be performed in specialist paediatric centres [41]. The severity and extent of childhood-onset PAN vary significantly, and management can be challenging. First-line management for PAN typically involves the use of corticosteroids and either mycophenolate mofetil or cyclophosphamide [49].

Takayasu arteritis (TA)

Takayasu arteritis (TA) is a large-vessel vasculitis predominantly affecting the aorta and its main branches [50]. The estimated annual incidence of TA in all ages is between 0.3 and 3.3 per million population, and it is highest in females of childbearing age [50]. The incidence of paediatric-onset TA is not well established. In children and adolescents, TA presents with non-specific symptoms in the early latent phase including fever, arthralgia, headaches, hypertension and weight loss. The diagnosis of TA in children can be challenging, involving a combination of clinical, laboratory, imaging and histological criteria. The EULAR/PRINTO/PRES classification for paediatric-onset TA relies heavily on vascular imaging [28]. Unless early treatment is commenced, irreversible blood vessel damage can occur, leading to stenosis, fibrosis and potential thrombus or aneurysm formation; thus, it typically presents with features of end-organ damage, such as stroke, leg claudication or kidney infarction [50]. A study involving 179 patients with TA, of whom 25 patients had paediatric-onset TA, found that children had increased inflammatory markers, a greater extent of vascular injury and more critical clinical manifestations when compared to adults [51]. The most common kidney complication of TA in children is renovascular hypertension, caused by renal artery stenosis [50]. Rarely, renal artery stenosis may also result in renal artery aneurysms that can rupture and cause life-threatening bleeding [52]. No consensus exists for treatment, but biologic agents such as TNFα, IL-6 and JAK inhibitors may have a role, and early reports support their effectiveness. Antiplatelet therapy is often used despite no evidence supporting its role [50]. In children with renal artery stenosis, interventional revascularisation procedures such as percutaneous transluminal renal angioplasty (PTRA), kidney auto-transplantation and surgical bypass may be performed with reasonable success [53].

Systemic sclerosis

Juvenile-onset systemic sclerosis (jSSc) is characterised by skin sclerosis and the involvement of blood vessels and internal organs. Scleroderma renal crisis is a rare but serious complication of SSc that can lead to rapid deterioration of kidney function. Kidney involvement is uncommon in all jSSc cohorts (4–13%), with renal crisis being extremely rare (< 4%) [54]. Patients present with severe hypertension reduced eGFR, haematuria and haemolytic anaemia, and the diagnosis is confirmed through a kidney biopsy [54].

Sjogren syndrome

Sjogren syndrome (SS) is a chronic systemic autoimmune disease characterised by chronic lymphocytic infiltration of the exocrine glands, predominantly the lacrimal and salivary glands, resulting in characteristic mouth and/or eye dryness (sicca symptoms) and leading to progressive glandular destruction. Childhood-onset SS (cSS) is rare, with an unknown incidence, and only a few hundred cases have been reported in the literature [55]. Children often present due to parotitis or non-specific symptoms such as arthralgia [55]. Clinicians rely on clinical judgement and experience, guided by adult criteria, to diagnose cSS [56]. Kidney involvement in cSS is rare and estimated to affect 10% of paediatric patients [57, 58]. It mainly presents as tubular interstitial nephritis (TIN) due to lymphocytic infiltration with tubular dysfunction, resulting in renal tubular acidosis (RTA, usually distal), hypokalaemia, nephrocalcinosis or renal Fanconi syndrome. Glomerulonephritis is rare but has been described [59]. Even though the long-term kidney outcome in cSS is typically favourable, the ongoing need for immunosuppression due to kidney involvement is linked to a poorer prognosis [58, 59].

IgG4-related disease

IgG4-related disease (IgG4-RD) is a rare fibro-inflammatory condition characterised by tumour-like lymphoplasmacytic infiltrations, typically exhibiting tissue fibrosis and extremely elevated serum IgG4 levels. Epidemiological paediatric data are lacking, and 82 cases of childhood-onset IgG4-RD have been reported in the literature [60]. There are no diagnostic criteria for paediatric IgG4-RD, but the revised comprehensive diagnostic criteria, validated in adults, can be used, comprising 3 domains (clinical and radiological features, serological raised serum IgG4 > 135 mg/dL and pathological features) [61]. Kidney manifestations in children are rare and reported in 6–32% of patients aged < 25 years old [60]. It mainly occurs in the form of TIN, sometimes membranous glomerulonephritis or obstructive acute kidney injury due to retroperitoneal fibrosis [62]. Despite being extremely rare, a diagnosis should be considered in children with laboratory evidence of kidney damage/decline in kidney function or abnormalities in kidney imaging with known pre-existing disease or clinical suspicion of IgG4-RD [62]. The disease can cause end-organ damage if left untreated and usually responds to corticosteroids.

Conclusion

The kidney is a target organ in a wide range of rheumatological diseases affecting children, most commonly seen in cSLE, IgAV and AAVs. It is less commonly seen in PAN, TA, systemic sclerosis, IgG4-related disease and Sjogren’s syndrome. Kidney involvement is extremely rare in JIA and therefore not addressed in this review [63]. Although with varying degrees of rarity, clinicians should remain vigilant and aware of potential kidney manifestations of rheumatological diseases in children since they can result in significant morbidity in adulthood [64]. Advances have been made in standardising definitions to classify these diseases, and management strategies have been published to align care. Children should at least undergo a baseline urinalysis and blood pressure check as a minimum in diseases where kidney involvement is a recognised complication, and a summary of other kidney-specific investigations is presented in Table 5. Urinalysis is inexpensive and should ideally be repeated during each clinical review, even if negative previously. The kidney biopsy is an important investigation, and histological features will often guide treatment. The timing of conducting a biopsy will depend on the natural history of the disease, with more urgency in conditions that have a high risk of rapidly progressive glomerulonephritis. Despite current management strategies, children with rheumatological diseases continue to suffer from suboptimal rates of complete remission and poor long-term kidney outcomes. Further research is needed to fully understand the complex pathophysiology that drives these diseases to target the kidney and to discover better ways to intervene as we strive to improve long-term kidney outcomes for children.

Table 5 Investigations to evaluate kidney involvement in children with suspected or proven rheumatological disease
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