Recurrence of disease following organ transplantation in autoimmune liver disease and systemic lupus erythematosus

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Recurrence of disease following organ transplantation in autoimmune liver disease and systemic lupus erythematosus Atsushi Tanakaa, Hajime Konoa, Patrick S.C. Leungb, M. Eric Gershwinb, a b

⁎

Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan Division of Rheumatology Allergy and Clinical Immunology, University of California School of Medicine, Davis, CA, United States

ABSTRACT

Disease recurrence after organ transplantation associated with graft failure is a major clinical challenge in autoimmune diseases. Primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and autoimmune Hepatitis (AIH) are the three most common (autoimmune liver diseases) ALD for which liver transplantation (LT) is the most effective treatment option for patients with end-stage diseases. Although the 5- and 10-year survival rates of post-LT patients are remarkable (80–84% and 71–79% in PBC, 73–87% and 58–83% in PSC, 76–79% and 67–77% respectively in AIH patients), post-LT disease recurrence is not uncommon. Here, we summarize literature findings on disease recurrence of these ALD with emphasis on the incidence, risk factors and impact on long-term outcome. We noted that the incidence of disease recurrence varies between studies, which ranges from 53% to 10.9% in PBC, 8.2% to 44.7% in PSC and 7% to 42% in AIH. The variations are likely due to differences in study design, such as sample size, duration of studies and follow up time. This is further compounded by the lack of precise clinical diagnosis criteria and biomarkers of disease recurrence in these ALD, variation in post-LT treatment protocols to prevent disease recurrence and a multitude of risk factors associated with these ALD. While recurrence of PBC and AIH does not significantly impact long term outcome including overall survival, recurrent PSC patients often require another LT. Renal transplantation, like LT, is the treatment of choice in patients with end-stage lupus nephritis. While calcineurin inhibitor (CNI) and immunosuppressive drugs have improved the survival rate, post-transplant recurrence of lupus nephritis from surveillance-biopsy proven lupus nephritis range from 30% to 44%. On the other hand, recurrence of post-transplant lupus nephritis from registry survey analysis were only 1.1% to 2.4%. In general, risk factors associated with an increased frequency of post-transplant recurrence of autoimmune diseases are not clearly defined. Large scale multi-center studies are needed to further define guidelines for the diagnosis and clinical management to minimize disease recurrence and improve outcomes of post-transplant patients.

1. Introduction Disease recurrence after organ transplantation associated with graft failure is a major clinical challenge in autoimmune diseases. The target organs of autoimmune diseases in which transplantation is a choice of treatment at the end stage mainly include liver and kidney. Autoimmune liver diseases (ALD) represent about 5% of all liver diseases. Primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) are the three most common ALD. Recent epidemiological studies indicated an increasing trend of prevalence of ALD worldwide [1–3]. Although knowledge on the natural history of ALD has significantly advanced our understanding on

their etiopathology [4–8] and long-term outcomes have remarkably improved with medical treatment [9], liver transplantation (LT) still remains the only and the most effective treatment option for patients with the end-stage ALD. However, recurrence of ALD after LD could undermine patient and graft survival, leading to deterioration of longterm outcome. Lupus nephritis is a subtype of systemic lupus erythtematosus (SLE) affecting kidneys. Progress in treating lupus nephritis with immunosuppressive regimens has greatly improved long-term outcome of lupus nephritis over time [10]. Renal transplantation, like LT, is the treatment of choice for end-stage chronic kidney disease, and posttransplant recurrence of lupus nephritis is the main concern. In this

Abbreviations: AIH, autoimmune hepatitis; ALD, Autoimmune liver diseases; ALP, alkaline phosphatase; AMA, anti-mitochondrial antibodies; ANA, anti-nuclear antibodies; ANCA, anti-neutrophil cytoplasmic antibodies; APS, Anti-phospholipid antibody syndrome; ASMA, anti-smooth muscle antibodies; BEC, biliary epithelial cells; CNI, calcineurin inhibitor; CNSDC, chronic non-suppurative destructive cholangitis; CMV, cytomegalovirus; DDLT, deceased donor liver transplantation; ELTR, european Liver Transplant Registry; ESRD, end-stage renal disease; GGT, gamma-glutamyl transferase; IBD, inflammatory bowel diseases; LDLT, Living donor liver transplantation; LT, liver transplantation; MELD, end-stage liver disease; OCA, obeticholic acid; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; SLE, systemic lupus erythtematosus; UDCA, ursodeoxycholic acid; UK, United Kingdom; UNOS, United Network for Organ Sharing; USRDS, United States renal data system ⁎ Corresponding author. E-mail address: [email protected] (M. Eric Gershwin). https://doi.org/10.1016/j.cellimm.2019.104021 Received 3 September 2019; Received in revised form 1 November 2019; Accepted 15 November 2019 0008-8749/ © 2019 Elsevier Inc. All rights reserved.

Please cite this article as: Atsushi Tanaka, et al., Cellular Immunology, https://doi.org/10.1016/j.cellimm.2019.104021

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Unlike PBC in which the presence of anti mitochondrial antibodes (AMA) provides more than 90% of specificity and sensitivity, there is no identified biomarker with acceptable sensitivity and specificity for the diagnosis of AIH [22,23]. Hence, a diagnostic scoring system consisting of several clinical items is used for diagnosis [24,25]. Immunosuppressive agents such as corticosteroids or azathioprine are established as a first-line treatment of AIH [5,26], and LT-free survival of patients with AIH is comparable to those in the general population when treatment response is favorable. However, long-term outcome is poor in patients with inadequate treatment response, such as more than two relapses despite corticosteroid treatment during clinical course [27]. For AIH patients with end-stage disease, LT is the only treatment option for survival. Furthermore, AIH could be presented as acute severe hepatitis, occasionally progressing to acute or acute-on-chronic liver failure. Although indication or timing of LT in this situation can be controversial, some patients with acute severe AIH can benefit from an emergent LT [28]. The overall survival rate seems to be excellent in AIH with LT; the 5- and 10-year recipient survival rates are 76–79% and 67–77%, which are higher than most other indications for LT [11–13] (Table 1).

review, we discuss the incidence, presentation, diagnosis, risk factors and impact on outcomes of recurrence of PBC, PSC and AIH in the liver, and lupus nephritis in the kidney. 2. Recurrence of autoimmune diseases in the liver after transplantation Overall, long-term outcome of ALD patients who undergo LT is excellent. According to registry data from the US, Europe and Japan, the 10-year survival rates of PBC patients after LT in US, Europe and Japan were similar (71–79%,) while those in PSC varied between 83% in the US, 70% in Europe, and 58% in Japan [11–13]. The 10 year survival rate for AIH after LT are 67% and 77% in Europe and Japan respectively (Table 1). Despite the high survival rate of ALD patients with LT, disease recurrence also occurs and negatively affects graft as well as overall survival. In particular, recurrence of PSC develops in at least 25% of patients and is definitely associated with poor outcome [14]. Although recurrence of PBC is believed to have little impact on graft and prognosis [15], a recent international study with a large cohort demonstrated that graft and patient survival are significantly impaired by recurrence of PBC [16]. Meanwhile, we noted that the incidence of disease recurrence varies between studies, which ranges from 10.9% to 53% in PBC, 8.2% to 44.7% in PSC and 7% to 42% in AIH (Table 2–4). The variations are likely due to differences in study design, such as sample size, duration of studies and follow up time [17]. This is further compounded by the lack of precise clinical diagnosis criteria and biomarkers of disease recurrence in these ALD, variation in post-LT treatment protocols to prevent disease recurrence and multitude of risk factors associated with these ALD [16,18,19]. Large scale multi-center studies are needed to further define guidelines for the diagnosis and clinical management to minimize disease recurrence and improve outcomes of ALD post-transplant patients.

2.1.1. Incidence and diagnosis of recurrent AIH While immunosuppressive drugs that are very effective for treatment of AIH are inevitably administered after LT, AIH can recur in the graft after LT. Although the incidence of recurrent AIH ranges between 7 and 42% [29–39] (Table 2), it is very challenging to define the recurrent AIH and to determine the incidence. The inconsistency mostly arises from differences in diagnostic criteria, histological analysis (protocol or event-driven biopsy), small sample size in each study (no study with more than 100 patients enrolled) and follow-up time [40,41]. The rate of recurrence increases as follow-up time increases after LT [30,36,37]. Novel therapeutics targeting the pathophysiology of AIH may help to reduce disease recurrence after LT [42]. In the diagnosis of AIH prior to LT, the revised AIH criteria [24] and the simplified score [25] have been proposed by the International AIH Group. However, both have not been validated for the diagnosis of recurrent AIH developed in the graft liver. Recurrent AIH is diagnosed when the followings are met: presence of the diagnosis of AIH before LT, elevation of transaminases, detection of autoantibodies (ANA, ASMA), elevation of IgG, and histological findings including interface hepatitis or perivenular lymphoplasmacytic infiltrates. A comprehensive analysis of the clinical phenotypes is necessary in the diagnosis of post-LT diseases recurrence [43].

2.1. Autoimmune hepatitis (AIH) AIH is characterized as a chronic necroinflammatory hepatocellular damage, leading to cirrhosis and hepatic failure if left untreated. Autoimmune reactions against hepatocytes play a crucial role, although targeted autoantigens on hepatocytes remain unidentified and the etiology is largely unsolved [20]. While middle-aged women have the highest risk for developing AIH, it is not uncommon in patients in childhood or adolescence as well. Clinically, AIH is diagnosed when patients have elevation of aspartate/alanine transferases, detectable anti-nuclear antibodies (ANA) or anti-smooth muscle antibodies (ASMA), elevated serum IgG levels, and interface hepatitis or plasma cell infiltration in liver histology [21]. Table 1 Patient and graft survival at 5 and 10 years after LT in PBC, PSC and AIH. Region

N

*1

Patient survival

Graft survival

5 yr.

10 yr.

5 yr.

10 yr.

PBC

Europe USA Japan *2

4,515 3,052 710

80 84 79

71 79 74

75 78 79

66 72 73

PSC

Europe USA Japan *2

3,582 3,854 232

78 87 73

70 83 58

69 81 71

57 78 50

AIH

Europe Japan *2

1,892 104

76 79

67 77

69 NA

59 NA

2.1.2. Risk factors of recurrent AIH A number of factors are reported to be associated with recurrence of AIH, including severity of pretransplant AIH (high transaminases or histologically moderate to severe inflammation), high serological IgG levels, HLA locus mismatching, early withdrawal of corticosteroids, and comorbidity of other autoimmune disorders [29,36]. HLA locus mismatching is identified as a risk factor for recurrence [44] in one study but not in others [34–36,39]. Early cessation of corticosteroids has been associated with higher risk of recurrent AIH [34,37]. A recent study from UK demonstrated that the 5- and 10-year recurrence rates after LT were 6% and 11%, respectively. Their cohort consisted of 69 patients with AIH, in which 87% of patients were under long-term maintenance treatment with corticosteroid after LT [33]. Compared with their 1999 report, with a recurrence rate of 27% in patients without long-term corticosteroid therapy [34], the authors concluded that long-term corticosteroid use in combination with immunosuppressive agents was associated with a lower frequency of recurrence.

LT, liver transplantation; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; AIH, autoimmune hepatitis. *1 Registry data from Europe [11], USA [12] and Japan [13]. *2 Living-related LT in all.

2.1.3. Impact of recurrent AIH on long-term outcomes In general, progressing to cirrhosis and graft failure requiring retransplantation is uncommon even when recurrence of AIH is noted in 2

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Table 2 Incidence and risk factors of recurrence of AIH after LT. Center sites

Time period

Year

N

Follow-up year (median)

Incidence

Time to recurrence (yrs.)

Spain [37] Birmingham, UK [34] Paris, France [38] New York, US [39] Boston, US [29] Rochester, US [32] Dallas, US [35] Paris, France [31] Colorado, US [30] Alberta, Canada [36] Birmingham, UK [33]

1988–1996 NA *2 1985–1992 1988–1995 1983–1998 1985–1998 1984–1998 1985–1992 1988–2006 NA 1999–2014

1998 1999 1999 2000 2000 2001 2002 2003 2008 2009 2016

27 47 15 24 12 41 55 17 66 46 69

– – 5.3 (mean) – – – 2.4 greater than10 6.8 4.3 8

9 (33%) 13 (28%) 3 (20%) 6 (25%) 5 (42%) 7 (17%) 11 (20%) 7 (41%) 23 (34.8%) 11 (24%) 5 (7%)

2.6 ± 1.5 2.4 (0.5–5.3) 1.6 (1–2.5) 1.3 ± 0.2 NA 4.6 ± 1 NA 2.5 ± 1.7 4.3 4 ± 1.3 3.8 (1.5–7.3)

*1

*1 Time to recurrence was shown as median (range), or mean ± SD. *2 NA: not available.

the graft [40]. Although treatment strategy of recurrent AIH is empiric and depends highly on the clinical experience of physicians, intensive immunosuppressive regimens are commonly given. It should be noted, however, development of cirrhosis followed by graft loss requiring retransplantation could occur due to recurrence of AIH despite intensive immunosuppressive treatment.

Indeed, the introduction of UDCA into clinical practice clearly altered the natural history of PBC [17]. A recent study employing the European Liver Transplant Registry (ELTR) indicated a significant decrease of LT due to PBC over the last 30 years [63]. The proportion of LT for PBC decreased from 20% of all LT cases in 1986 to 4% in 2015 (p < 0.001). The absolute number of transplants was the highest in 1994 (n = 279) which decreased to an average of 200 in the last decade. This decrease is strikingly in contrast to the substantial increase of prevalence of PBC at the same time [1]. Overall, the long-term outcome after LT for PBC is remarklable (Table 1) [11–13]. Nevertheless, about 30–40% of patients are refractory to UDCA and could progress to end-stage liver disease requiring LT, undoubtedly indicating the necessity of second-line treatment which could halt progression to cirrhosis. In 2016, obeticholic acid (OCA) was officially approved as a second-line drug but the long-term efficacy has not been demonstrated [64]. Bezafibrate is another promising drug as a secondline treatment, as demonstrated by a prospective randomized controlled clinical trial in France [65] and a large-scale retrospective study in Japan [66].

2.2. Primary biliary cholangitis (PBC) Primary biliary cholangitis (PBC; formally known as primary biliary cirrhosis until 2016 [45]) is characterized as chronic cholestatic liver disorder, which can eventually result in cirrhosis and hepatic failure, if not given appropriate treatment [46–48]. PBC is considered a prototypic autoimmune disease because of its distinct female predominance [49], association with other autoimmune diseases [9,50–52], specificity of anti-mitochondrial autoantibodies (AMAs) [53–56] and highly focused immune mediated destruction of intrahepatic biliary epithelial cells (BECs) [57–60]. Histopathologically, PBC is characterized as chronic non-suppurative destructive cholangitis with granuloma formation in the liver and the degeneration of BECs, which subsequently lead to the disappearance of small or middle-sized intrahepatic bile ducts [46]. Ursodeoxycholic acid (UDCA) has been frequently demonstrated to improve LT-free survival and is currently recommended as a first-line treatment for PBC by clinical practice guidelines [47,61,62].

2.2.1. Incidence and diagnosis of recurrent PBC Meanwhile, recurrence of PBC after LT is not uncommon. The incidence of recurrent PBC is reported to range widely from11% to 53% (Table 3). As observed in recurrent AIH, this difference in the incidence

Table 3 Incidence and time to recurrence of PBC after LT. Center sites

Time period

Year

N

Follow-up year (median)

Incidence

Time to recurrence (yrs.)*1

Birmingham, UK [69] Rochester, US [139] Dallas, US [72] Boston, US [140] Birmingham, UK [71] St. Louis, US [141] Berlin, Germany [142] Rochester, US [68] New York, US [143] London, UK [144] Alberta, Canada [70] Cambridge, UK [67] Alberta, Canada [145] France and Switzerland [85] Japan*3 [74] Toronto, Canada*4 [107] Japan [75] North America and Europe [16]

1982–1999 1985–1997 1985–1999 1983–2001 1982–2002 1985–1997 1989–2003 1985–2005 1989–1999 1988–2008 1989–2008 NA 1989–2010 1988–2010 1994–2010 2000–2015 1994–2010 1983–2016

2001 2003 2003 2003 2004 2005 2006 2007 2009 2010 2010 2013 2013 2015 2016 2016 2017 2019

400 100 156 43 485 48 154 100 44 103 108 248 103 123 444 69 388*5 785

4.7 (mean) 4.7 (mean) 6 – 6.6 4.2 (mean) 10.8 (mean) 9.8 2.8 9 6.9 – – 11.7 (mean) 7.5 – – 6.9

68 (17%) 17 (17%) 17 (10.9%) 8 (18.6%) 114 (23%) 17 (35.4%) 52 (34%) 14 (14%) 7 (15.9%) 36 (35%) 28 (26%) 105 (42.3%) 26 (25%) 48 (53%) 65 (14.6%) 9 (13%) 58 (14.9%) 240 (31%)

3.0 (0.3–11.7) 3.1 (0.3–7.9) 4.1 (1.1–7.1) 6.7 (0.1–14) NA*2 3.3 ± 2.8 3.5 (0.3–18.1) 5.1 (3.0–10.2) 2.8 (1.1–8.8) 3.7 (0.8–16.7) 5.8 (0.5–15.6) 5.1 (1.4–8.6) 15.3 ± 1.0 6.4 ± 5.0 5.1 NA NA 4.4 [3.4–5.1]

*1 *2 *3 *4 *5

Time to recurrence was shown as median (range), median [interquartile range], or mean ± SD. NA: not available. All living donor liver transplantation (LDLT). 30 deceased donor liver transplantation, 39 LDLT. Female patients only. 3

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Table 4 Incidence and risk factors of recurrence of PSC after LT. Center sites

Time period

Year

N

Incidence

Time to recurrence (yrs.)

Los Angeles, US [89] Dallas, US [104] Rochester, US [146] Gothenburg, Sweden [90] San Francisco, US [147] Boston, US [148] Denver, US [149] Oslo, Norway [99] Japan*3 [150] Seattle, US [98] Denver, US [151] London, UK [100] Birmingham, UK [93] New York, US [152] Alberta, Canada [106] Japan*4 [101] UK [96] Germany [95] North America*5 [103] Toronto, Canada*6 [107] Kyoto, Japan [88] Nordic countries [97] Prague, Czech [91]

1984–1996 1985–1995 1985–1996 1985–1998 1988–1997 1983–2000 1988–2000 1984–2003 1993–2003 1990–2003 1988–2006 1989–2004 1986–2006 1995–2007 1989–2006 1996–2008 1990–2010 1990–2006 1998–2013 2000–2015 1996–2015 1984–2007 1994–2015

1997 1998 1999 2001 2002 2003 2003 2005 2007 2008 2008 2008 2009 2010 2010 2011 2015 2016 2016 2016 2017 2018 2018

127 100 120 61 49 42 71 49 44 69 130 53 230 58** 59 96 565 305 307 138 40 440 47

11 (8.6%) 18 (18%) 24 (20%) 5 (8.2%) 7 (14%) 6 (14%) 15 (21%) 9 (18%) 11 (25%) 7 (10%) 22 (16.9%) 7 (13.2%) 54 (23.5%) 11 (19%) 15 (25%) 26 (27%) 81 (14%) 62 (20.3%) 34 (11%) 32 (23%) 16 (40%) 85 (19%) 21 (44.7%)

NA*2 1.8 ± ± ± 0.6 0.7 (0.3–3.5) NA NA NA 4.4 (1.0–9.2) NA NA 5.7 (2.0–11.2) NA 5.0 (0.3–10.0) 4.6 (0.5–12.9) NA 3.4 (1.6–5.5) 2.4 (0.7–6.6) NA 4.6 (0.5–14.3) NA NA 2.5 (0.8–6.3) NA 5.3 (1.0–15.0)

*1 *2 *3 *4 *5 *6

*1

Time to recurrence was shown as median (range), or mean ± SD. NA: not available. 44 deceased donor liver transplantation (DDLT), 14 living donor liver transplantation (LDLT). All LDLT. 65 DDLT, 242 LDLT. 70 DDLT, 68 LDLT.

autoantigens [73], the difference in outcome of these two immunosuppressive drugs on recurrence of PBC is likely due to the more potent immunosuppressive effect of tacrolimus, which might facilitate alloreactivity against graft liver through infection [62]. On the other hand, the effect of tacrolimus for recurrent PBC may not be the same in other ethnicities. Recently two cohort studies from Japan demonstrated that the increased frequency of recurrent PBC is associated with initial treatment with cyclosporine after LT, not with tacrolimus [74,75]. In the first study, they also demonstrated that the switch from tacrolimus to cyclosporine treatment decreased the frequency of recurrence. This finding suggests that the timing of selection or change of calcineurin inhibitors and the way immunosuppressive agents used in clinical practice, may partly account for the difference in the association with recurrence between the East and the West. On the other hand, it is well known that genetics play a crucial role in susceptibility to PBC [76–84], and this difference in the role of calcineurin inhibitors may suggest that genetics may also contribute to recurrence of PBC after LT, as indicated by another study suggesting the influence of the IL12A locus [67]. Meanwhile, we should note that these two studies from Japan were performed by the same study group and subjects in these two studies partially overlapped; amongst 516 patients who underwent LT for endstage PBC from 1994 to 2010, both living donor LT (LDLT) and deceased donor LT (DDLT), of both genders were included in the first study [74]. However, only LDLT and female were included, and patients who did not survive for 1 year were excluded in the second study [75]. A recent, large-scale, retrospective cohort study on demonstrated that severe biochemical cholestasis within the first 12 months following LT was associated with higher risk of PBC recurrence [16]. Notably, the role of cholestasis as a risk factor for recurrence had been never reported. This retrospective study was the largest conducted with longer follow-up periods, allowing for these findings. This observation may be due to infections caused by the use of strong immunosuppression postLT, leading to tolerance breakdown against biliary epithelial cells.

of recurrent PBC is due to a combination of various factors such as variation in sample size, follow-up period, and in particular, difficulty in the diagnosis of recurrent PBC. Indeed, it is extremely challenging to make a correct diagnosis of recurrent PBC. AMA, a serological hallmark of PBC, remains readily detectable after LT and is therefore not a reliable test for recurrence. In addition, cholestatic enzymes, another important diagnostic component of PBC, are frequently elevated after LT due to multiple other reasons, including acute and chronic rejection, graft-versus-host disease, biliary stricture/obstruction, drug-induced liver injury. As a result, liver histology findings are the most important and vital for determination of disease recurrence in PBC. Key findings for diagnosis of recurrent PBC are similar to those in pre-transplant PBC, such as florid duct lesions and lymphoplasmacytic infiltrates. However, other causes of bile duct injury may also mimic these typical findings, including ischemia-reperfusion injury, acute cellular rejection, humoral/chronic rejection, drug-induced liver injury, vascular complications, and graft-versus-host disease. In addition, recurrence of PBC may develop little or no symptoms. Therefore, protocol liver biopsy rather than event-driven biopsy is required for detection of recurrent PBC. Whether protocol biopsy is scheduled, or event-driven biopsy is performed can have an enormous impact on the difference in incidence of recurrent PBC 2.2.2. Risk factors of recurrent PBC Several studies have reported risk factors associated with recurrence of PBC, and most of them constantly demonstrated that use of tacrolimus is definitely associated with an increased risk of recurrence [67–72]. For example, a recent study on 785 PBC patients from North America and Europe that underwent LT from February 1983 to June 2016 indicated the 5-year probability of PBC recurrence PBC to be 28% and 11% in patients receiving tacrolimus and cyclosporine, respectively (p < 0.001). Thus, tacrolimus was significantly associated with recurrence of PBC, while use of cyclosporine was protective [16]. The reasons for this phenomenon are unclear. Since infection of bacteria or viruses may be associated with tolerance breakdown against 4

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Additional studies are needed to clarify the link between cholestasis and PBC recurrence. It should be noted that the probability of PBC recurrence within a year is < 10%. In this regard, intervention with UDCA soon after LT to prevent severe cholestasis is a reasonable approach to reduce PBC recurrence [85].

modalities such as endoscopic ultrasound, intraluminal sonography, or transpapillary cholangioscopy. Inflammatory bowel diseases (IBD) is also frequently observed as a concomitant disease in more than 60% of patients with PSC. The natural courses of PSC greatly vary between patients. A number of prognostic indices such as serum ALP or bilirubin levels, fibrosis staging in liver histology and non-invasive fibrosis markers have been proposed [14,86]. However no consensus on surrogate endpoints has been uniformly acquired [87], making the design of clinical trials difficult. There is no established medical treatment to improve long-term outcome in PSC. Although UDCA is currently the most commonly-administered first-line drug in PSC, data on its efficacy in improving LT-free survival has not been established. When no medical treatment is effective in patients with PSC, LT is regarded as the single treatment option for the end-stage PSC. Overall, post-transplant patient and graft survival in PSC is comparable to those in PBC in Europe and the US, but siginificanltly lower in Japan according to the registry data (Table 1). As shown, the 5- and 10-year patient survival rates were 78% and 70% in Europe, and 87% and 83% in the US [11,12]. The 5-year survival in Europe improved to 82% in recent years (1999–2009) [11]. However, there is a marked difference in the survival rate of Japanese patients underwent LT, with a 5- and 10-year patient survival rate of 73% and 58%, respectively [13]. Although graft survival rate was not reported in this registry data, a recent single center study in Japan reported that the 5-year graft survival rate was 55.4% [88], which is substantially lower than that in Europe (69%) and the US (81%). This striking difference is partly explained by the frequent recurrence of PSC in living donor liver transplant (LDLT) and graft failure thereafter. The percentage of LDLT was 100% in the Japanese registry [13] and 87% (39/45) in a single center report in Japan [88].

2.2.3. Impact of recurrent PBC on long-term outcomes Until recently, it was believed that recurrence of PBC does not have a significant impact on long-term outcome such as patient and graft survival. A retrospective study in the United Kingdom (UK) on 400 PBC patients who received LT between 1983 and 1999 demonstrated that recurrent PBC was confirmed in 68 (17%) subjects but without affecting patient and graft survival and with an average 56 months follow-up [69]. More recently, a French-Swiss collaborative study was conducted on 123 patients with PBC who underwent LT. Their data showed that recurrence of PBC was observed in 48 subjects (53%) with an average of 11.7 years of follow-up period, and neither recurrence nor preventive UDCA use had a significant impact on survival [85]. Both Japanese studies described earlier also suggested that recurrent PBC does not impact survival [74,75]. Surprisingly, however, a recent study on 785 PBC patients from 13 centers in North America and Europe who received LT with a median follow-up of 6.9 years (IQR 6.1–7.9) reported opposite and unexpected results. In this large-scale retrospective cohort study, they found that disease recurrence was found in 240 patients (31%), and importantly, both graft and patient survival were significantly impaired in those with recurrent PBC (P = 0.004 and 0.001, respectively) [16]. This study covers by far the largest cohort with long-term follow-up on PBC recurrence after LT. This multicenter collaborative study also suggested that although UDCA treatment seemed to be effective in improving markers of cholestasis, it might not effectively reduce the frequency and risk of recurrence of PBC after LT [85]. Thus development of effective strategy to halt recurrence of PBC is urgently needed. It is necessary to keep in mind that there might be a number of varying factors among centers that affect the conclusion such as treatment protocols of immunosuppressants, the manner of biopsy (protocol or event-driven), diagnosis of recurrent PBC and the use of UDCA as prevention and/or treatment of PBC, which could affect the conclusion. Nevertheless, it is imperative to determine whether recurrent PBC really has a significant impact on patient and graft survival.

2.3.1. Incidence and diagnosis of recurrent PSC The incidence of recurrent PSC is higher than PBC. As shown in Table 3, PSC recurs in 8.6 to 44.7% of patients after LT within a median of almost 1–5 years. Of note, lower recurrence rates were observed in the earlier studies with relatively shorter follow-up time [89,90]. Indeed, the highest recurrence rate of 44.7% (21/47) was recently reported from a single center, where the follow-up period of the patients after LT was a median of 10.2 (range, 5.0–20.8) years, the longest among all cohorts [91]. Therefore, the incidence of recurrent PSC seems increase along with longer observation and intensive surveillance, presumably because no therapeutic intervention is available to prevent recurrence. The diagnosis of recurrent PSC is very challenging, as in recurrent AIH and PBC. As described above, there are no PSC-specific diagnostic biomarkers, hence cholangiography by ERCP or MRCP is the most important tool for pre-transplant diagnosis. After LT, imaging studies of biliary tree may reflect a variety of physiological and pathological conditions that mimics PSC, including organ preservation, ischemiareperfusion injury, hepatic artery stenosis or thrombosis, chronic ductopenia rejection, bile duct anastomosis, ABO incompatibility, and drug-induced liver injury. For diagnosis of recurrent PSC, the criteria proposed by Graziadei et al. should be strictly used [92]. Accordingly: a) the diagnosis of PSC must be present before LT; b) cholangiographic findings (biliary structuring, beading, and irregularity lasting more than 90 days) and/or histological features (fibrous cholangitis and/or fibroobliterative lesions with or without ductopenia, biliary fibrosis, or biliary cirrhosis) are required for diagnosis of recurrent PSC and c) other conditions mimicking to PSC must be excluded [92].

2.3. Primary sclerosing cholangitis (PSC) PSC is another chronic cholestatic liver disease. Unlike PBC in which small- or medium-sized intrahepatic bile ducts are impaired, PSC mainly affects large sized, both intra- and extrahepatic large-sized bile ducts, which are easlily recognized by imaging studies. Although PBC and PSC share several clinical characteristics as cholestatic liver diseases, including elevation of cholestatic enzymes and possibility of progression to biliary cirrhosis, a number of distinct features differentiate PSC from PBC (Table 5) [14,86]. Unlike PBC and AIH, PSC is more common in males than in females; adolescents and young adults are at the highest risk for developing PSC. Diagnosis of PSC could be challenging even in pre-transplant patients because of a lack of diseasespecific biomarkers or histological findings. Anti-nuclear antibodies (ANA) are occasionally detectable in sera of patients with PSC but disease-specific autoantibodies are lacking in PSC [59]. While onionskin periductal fibrosis is a histological characteristic in PSC, it can be detected in only 30% or less of patients with PSC. As a result, the diagnosis of PSC eventually relies much on imaging studies of biliary tracts, with endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP). However, the interpretation of cholangiographic findings could be very challenging and requires differentiation from sclerosing cholangitis cause by other etiolologies including IgG4-related sclerosing cholangitis, or concomitant cholangiocarcinoma, necessitating more intensive

2.3.2. Risk factors of recurrent PSC Proposed risk factors for recurrent PSC include recipient’s age, gender, history of cholangiocarcinoma, model for end-stage liver disease (MELD) score at pre-transplantation, status of IBD, donor and recipient’s age gender/cytomegalovirus (CMV) mismatch and firstdegree relative donors[40,41]. Acute cellular rejection (steroid5

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Table 5 Difference of clinical characteristics of PBC and PSC.

Age at the highest risk Male:female ratio Affected bile ducts Elevated liver enzymes Autoantibodies Imaging findings Histology Concomitant diseases Treatment

PBC

PSC

50–60 1:4–1:6 intrahepatic, small-middle sized ALP GGT AMA (> 90%) normal florid duct lesions, lymphoplasmacytic infiltrates rheumatoid arthritis,thyroiditis UDCA

20–40, 60–70 1:0.5–1:1 intra & extrahepatic large-sized ALP GGT ANA, pANCA (low frequency) dilatation of bile ducts biliary strictures segmental dilatations (normal in small bile duct PSC) onion-skin fibrosis IBD no

PBC: primary biliary cholangitis, PSC: primary sclerosing cholangitis, ALP: alkaline phosphatase, GGT: gamma-glutamyl transferase, AMA: anti-mitochondrial antibodies, ANA: anti-nuclear antibodies, ANCA: anti-neutrophil cytoplasmic antibodies, IBD: inflammatory bowel disease, UDCA: ursodeoxycholic acid.

resistant) is also reported to be another risk for recurrent PSC. It should be noted that these studies vary in their sample size, extent and depth of the collected dataset, difference in patient populations and ethnicities The impact of IBD on recurrent PSC is an important and debated issue. An active IBD after LT is also associated with increasing recurrence rate of PSC [88,93–96]. A recent study in the Czech Republic reported that de novo colitis was present in 12/47 (25.5%) of PSC patients between 17 and 87 months (median 45 months) post-LT and a significant number of them (11/12) were also confirmed with recurrent PSC with a median of 72 months post-LT. [91]. These observations surely underlined the importance of a gut-liver axis in PSC pathophysiology, and also pointed us to the recommendation of preventable colectomy prior to LT [93,97]. However, another recent large-scale cohort study did not show a preventable effect of colectomy on recurrence of PSC [96]. Further prospective studies are warranted to determine whether pre-LT colectomy is significantly associated with a decreased risk of recurrent PSC. Very recently, a meta-analysis by Steenstraten et al. reviewed 14 retrospective studies regarding recurrent PSC [92,93,95–106] and established a cohort consisting of 2159 patients [19]. They demonstrated that colectomy before LT is a risk factor for recurrent PSC with marginal significance (HR 0.65, 95%CI 0.42–0.99). Other risk factors identified in this meta-analysis included cholangiocarcinoma before LT (HR 2.42, 95%CI 1.20–4.86), IBD (HR 1.73, 95%CI 1.17–2.54), donor age per ten years (HR 1.24, 95%CI 1.0–1.45), MELD score per point (HR 1.05, 95%CI 1.02–1.08), and acute cellular rejection (HR 1.94, 95%CI 1.32–2.83). Another important issue regarding risk factors of recurrence is LDLT. In Japan, where LDLT is dominant, the recurrence rate of PSC after LT is relatively higher compared to other regions (Table 4). Egawa et al. demonstrated that first-degree-relative donor was identified as a significant risk factor for recurrence [101]. However, this is not the case in North America. In a large-scale North American cohort of patients with PSC (n = 307), it was observed that PSC recurrence rate was not significantly different for LDLT versus deceased donor liver transplant (DDLT) recipients (p = 0.36). In this study, the risk factors identified were high MELD score, biliary complication, cholangiocarcinoma, and high donor age in both LDLT and DDLT, while first-degree relative donor was not significantly associated with recurrence [103]. Another recent cohort study from Canada included 72 PSC patients who received LDLT from a first degree living-related donor, 56 PSC patients who received LDLT from a distinct/unrelated donor, and 135 PSC patients who received LDLT from a deceased donor. This study indicated that that first-degree living-related donor did not confer a significant increase in recurrent risk of recurrent PSC after LT [107]. It remains unclear whether these apparent differences between the East and West arise from either variance in study design (i.e. definition and diagnosis of recurrent PSC, sample size, follow-up period) or genetic backgrounds. We believe that global prospective and collaborative registry studies will be needed to solve the role of LDLT in recurrent PSC. This is

particularly important in the current era with shortage of deceased donor worldwide. 2.3.3. Impact of recurrent PSC on long-term outcomes Unlike AIH and PBC, recurrent PSC has a huge impact on mortality and morbidity, and retransplantation due to graft failure is not uncommon. In a UK study with a large cohort consisting of 565 patients, the 5- and 10-year graft survival rates were 88% and 82% in patients without recurrent PSC, and 84% and 56% in those with recurrent PSC, respectively. The presence of recurrent PSC increased the risk of both graft failure (HR = 8.15, 95%CI = 5.59–11.89) and of graft failure or death (HR = 4.71, 95%CI = 3.39–6.56) [96]. Another large-scale cohort involving 335 patients with IBD who underwent LT for PSC in Germany also indicated significantly poorer graft and recipient overall survival, with 91.4% vs 79% (p = 0.02) and 85.1% vs 61.3% (p < 0.001) in recipient survival [95]. As a result, a substantial portion of PSC patients after LT are awaiting their second graft. At present, there are no medical treatment for PSC patients to prevent the development of recurrent PSC after LT. Although UDCA is frequently used after LT, its efficacy in preventing disease recurrence is unclear. Clearly, the development of new drugs for preventing recurrence of PSC is an unmet need. In this regard, it is notable that a retrospective study of induction with rituximab for ABO blood type incompatible LDLT with 12 subjects demonstrated no recurrence of PSC with an excellent graft function in 5 recipients for more than 7 years [108]. 3. Recurrence of autoimmune diseases in the kidneys after transplantation Most patients with systemic lupus erythematosus have clinical evidence of renal disease at some point in the course of the disease. Clinically evident renal involvement occurs in approximately one-half of patients with SLE [109]. Up to 10 percent of patients with lupus nephritis develop end-stage renal disease, and patients with lupus nephritis have higher mortality than SLE patients without lupus nephritis [110]. End-stage renal disease (ESRD) is a significant cause of mortality and morbidity in patients with SLE. Renal transplantation is a treatment of choice for end-stage renal disease. In general, a successful kidney transplant improves the quality of life and reduces the mortality risk for most patients when compared with maintenance dialysis [111]. A recent study of lupus nephritis on the real transplant waitlist also showed that renal transplant was associated with reduced all-cause mortality [112]. The reduction of all-cause mortality is attributed to the decreased deaths from cardiovascular diseases and infection [112]. Before 1975, lupus nephritis has been considered a contraindication for renal transplantation. Because SLE is an autoimmune-mediated disease, high likelihood of the risk of recurrence, and the risk of rejection of renal transplant were presumed. The progression to the ESRD is a result of an exacerbation of lupus nephritis, meaning that the lupus 6

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activity could not have been appropriately treated. In 1975, a Renal Transplant Registry study indicated that the outcome of renal transplantation of 56 lupus nephritis patients was comparable with other causes, including diabetes. More importantly, there has been no case of recurrent lupus nephritis within the period of an average of 2 years follow up [113]. Since then, ESRD due to lupus nephritis has been treated with renal transplantation. Although rejection was a significant problem in the early stages of kidney transplantation, the advent of calcineurin inhibitor (CNI) decreased acute rejection and markedly improved the short-term survival rate. Furthermore, extensive immunosuppressive treatments for rejection improved the outcome in patients with immunologically high-risk cases. Historically, graft and patient survival are similar in patients with ESRD caused by lupus nephritis and patients with ESRD from other causes. An analysis of of 32,644 patients in the United States Renal Data System (USRDS) between 1987 and 1994 showed that 722 of them had lupus nephritis [114]. Analysis of kidney transplantation for lupus nephritis in 1170 out of 43,821 United Network for Organ Sharing (UNOS) databases from 1996 to 2000 showed that there was no significant difference in the engraftment rate of kidney transplantation cases for lupus nephritis compared to other groups [115]. Also, the analysis of USRDS and UNOS database was conducted on patients with SLE, with a median of 4.7 years after transplantation in 2886 people from 1990 to 1999 [116]. This paper indicated that SLE as a cause of ESRD in renal transplant recipients is associated with worse allograft and recipient survival when compared to diabetes mellitus, especially in the recipients of the deceased donor. Table 6 summarizes allograft and patient survival of 5 and 10 years from 2 recent literature. A most recent analysis of USRDS/UNOS on 5884 SLE patients with a median of 5.5 years after transplantation in 5884 SLE patients from 1996 to 2011 [117] indicated that graft and patient survival is comparable compared with other causes of ESRD, including various glomerulonephritis, diabetic nephropathy, and autosomal dominant polycystic kidney diseases. Another recent analysis of patients of New Zealand and Australia between 1998 and 2012 showed that the ESRD of lupus nephritis was associated with worse dialysis and transplant patient survival but comparable renal allograft survival compared with other causes of ESRD [118]. Primarily, lupus nephritis transplant patients with a first renal allograft, older age at transplant, and deceased donor type were associated with higher mortality [118]. Some discrepancies among reports may be attributed to differences in transplant eras, ethnic composition, and the comparator groups. In summary, the patient and allograft survival of lupus nephritis are comparable with other causes of ESRD.

Table 6 Patient and graft survival at 5 and 10 years after renal transplant in SLE. Region

Cause of ERSD

N

Australia and New Zealand [118]

SLE Other causes

US [117]

SLE IgAN FSGS MN MPGN Vasculitis DN ADPKD

3.1. Incidence and diagnosis of recurrent lupus nephritis Even before having an actual recurrence of lupus nephritis following transplantation, patients with lupus nephritis were generally not offered renal transplantation due to a belief that the immune-mediated renal toxicity would attack transplanted kidney again. The allograft failure of renal transplant is not only caused by acute and chronic rejection but also by thrombosis, medication-related renal injury (e.g., CNIs), viral nephropathy and secondary glomerulonephritis including recurrence of lupus nephritis. Therefore, the recurrence of lupus nephritis can be detected only with a renal biopsy of the allograft. Table 7 summarizes the incidence of recurrent lupus nephritis in the literature. Throughout the several decades, the recognition of recurrent lupus nephritis of clinical indication is not high, considering the ESRD was led by lupus nephritis. The analysis of Australia and New Zealand Registry indicated that the biopsy-confirmed recurrence rate of lupus nephritis after renal transplantation was 2.3% (4 out of 176 patients) in the contemporary cohort (1998–2012) after a median time periods of 4.6 years [118]. This value is similar to the retrospective analysis of the UNOS database of 2.4% recurrence of lupus nephritis, which reported 167 kidney transplant recipients with recurrent lupus nephritis between 1987 and 2006 in a group of 6850 recipients [119]. In the most recent UNOS database analysis, lupus nephritis recurred in 67 out of 5884 recipients between 1996 and 2011 was (1.1%) [117]. In contrast to these registry surveys, the recurrence rate of lupus nephritis is high in comprehensive surveillance biopsy-based studies. Nyberg et al reported 7 cases out of 16 biopsies (44%) in 1992 [120]; Goral et al reported 15 cases out of 50 patients (30%) in 2003 [121]; Norby et al reported 22 recurrence out of 41 patients (54%) in 2010 [122]. Most recurrences found in the surveillance-biopsy proven lupus nephritis are classified as class I and II and seem to be related to deteriorated renal function. This discrepancy of biopsy-proven recurrence rate between registry surveys and comprehensive biopsy-based studies is not surprising given that the patients underwent renal biopsy only when it is indicated in registry surveys (e.g., declining in renal function, proteinuria or hematuria). Thus, a clear distinction needs to be made between pathologic-only recurrence and clinicopathologic recurrence. It is intriguing why the clinical recurrence is not high in the transplant of lupus nephritis. One of the reasons is that the immunosuppressive regimen (the combination of glucocorticoid, calcineurin inhibitor, and mycophenolate mofetil) for prevention of chronic rejection is similar to the regimen to treat the proliferative lupus nephritis [123,124]. However, this explanation seems inadequate, considering the same protocol could not appropriately control lupus nephritis of the native kidneys. Another reason is the immunomodulating effect of uremia, or “burn out” of lupus activity during the development of ESRD [125]. In addition to uremia, dialysis is also associated with a decrease in the systemic activity and decreased steroid requirements of many SLE patients [126].

*1.

Patient survival

Graft survival

5 yr.

10 yr.

5 yr.

10 yr.

176 8541

95 96

88 91

88 89

73 75

5884 7379 13,272 2249 1980 1367 57,190 18,457

94.5 96.7 93.9 93.0 93.7 91.5 83.2 93.7

89.4 93.1 87.1 84.2 88.0 81.6 67.2 84.5

81.6 89.5 84.9 83.7 78.5 90.0 86.4 91.5

67.8 76.9 68.3 70.1 64.1 78.8 75.7 83.7

3.2. Risk factors of recurrent lupus nephritis Recurrent lupus nephritis could be prevented by extensive immunosuppression including calcineurin inhibitor, mycophenolate mofetil, and glucocorticoid. In this context, the poor adherence to the medication can be a risk for recurrence. It was shown that poor adherence to immunosuppressive therapy is associated with a trend towards increased graft failure in patients with lupus nephritis [127]. The association of adherence with graft survival can be attributed to both rejection and recurrence of lupus nephritis. The following risk factors for recurrent lupus nephritis have been identified: female gender, younger age, African-American or nonHispanic ancestry, the presence of anti-phospholipid antibodies and living kidney donation [122,119,128,129]. Recurrent lupus nephritis is known to be associated with African American ethnicity, which results in an allograft and possibly with decreased survival [128]. This

FSGS, focal segmental glomerulosclerosis; IgAN, IgA nephropathy; MN, membranous nephropathy; MPGN, membranoproliferative GN; DN, diabetic nephropathy; ADPKD, autosomal dominant polycystic kidney. 7

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Table 7 Incidence of recurrence of lupus nephritis after renal transplantation. Center sites

Time period

Year

N

Follow-up year (median)

Incidence

Time to recurrence (yrs.)

US (Renal Transplant Registry) [113] London, UK [153] Madison, US [154] Palo Alto, US [155] Chicago, US [156] Dallas, US [157] London, UK [158] Miami, US [159] Minneapolis, US [160] New York US [125] Madrid, Spain [161] Rotterdam, Netherland [162] St Louis, US [163] Brooklyn, US [164] Paris, France [165] Los Angeles, US [166] Madison, US [167] Hannover, Germany [168] Tokyo, Japan [169] Ann Arbor, US [170] Paris, France [137] San Francisco, US [171] San Paulo, Brazil [172] US (USRDS) [114] Hong Kong, China [173] Philadelphia, US [121] Nijmegen, Netherlands [174] Chicago, US [175] A Coruña, Spain [176] Milano, Italy [129] Ankara, Turkey [177] Athens, Greek [178] Urmia, Iran [179] Birmingham, US [128] US (UNOS) [119] Oslo, Norway [122] OPTN/UNOS, US [180] Taichung, Taiwan [181] OPTN/UNOS, US [182]

−1973 1967–1982 1971–1982 1969–1980 1971–1981 NA 1964–1982 1979–1985 1969–1987 1970–1987 1982–1986 1980–1988 1963–1990 1983–1990 1979–1991 1979–1992 1971–1994 1980–1995 1970–1997 1983–1997 1971–1993 1984–1996 1975–1994 1987–1994 1986–1998 1976–2000 1968–2001 1990–2003 NA 1982–2004 1985–2004 1985–2005 1989–2006 1977–2007 1987–2006 1972–2005 1998–2007 1984–2009 1998–2007

1975 1982 1983 1983 1983 1983 1984 1987 1988 1990 1990 1991 1991 1992 1993 1995 1996 1997 1998 1998 1998 1998 1998 2000 2000 2003 2003 2005 2005 2005 2006 2008 2008 2009 2010 2010 2011 2012 2012

56 6 18 12 3 8 8 15 32 18 8 28 16 40 10 64 80 9 4 44 60 97 45 1162 14 50 23 13 20 33 5 26 23 177 6850 44 1785 32 3161

1992–2010 1986–2013 1999–2014 2005–2013 2000–2013 1998–2012

2012 2014 2016 2016 2016 2016

14 40 19 27 12 176

0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 2 (13%) 0 (0%) 0 (0%) 0 (0%) 1 (4%) 1 (6%) 1 (3%) 0 (0%) 0 (0%) 2 (3%) 0 (0%) 2 (50%) 2 (4.5%) 1 (1.3%) 6 (6.2%) 4 (9%) 0.2 (%) 2 (14%) 15 (30%) 1 (4%) 0 (0%) 0 (0%) 3 (9%) 3 (60%) 2 (8%) 1 (4%) 20 (11%) 167 (2.4%) 22 (50%) 0.5–4.3% 6 (19&) 2.8–5.3% at 10 years 0 (0%) 1 (3%) 1 (5%) 1 (4%) 6 (50%) 4 (2%)

NA NA NA NA NA NA NA NA NA NA NA NA 0.6 8 NA NA NA NA (4.4, 11) NA NA 3.1 (0–9.3) 1.8 ± 1.1 (0.5–3.2) NA (0.2, 2) 4.3 ± 4.7 (0–15.3) 5.1 NA NA (0.5–7) NA NA NA 4.5 ± 3.7 4.3 (0–15.3) 8 ± 4 (3–15) NA (0.2–11.6) NA

Rio de Janeiro, Brazil [183] Barcelona, Spain [61] Gdansk, Poland [184] Medellín, Colombia [185] Izmir, Turkey [186] ANZDATA registry, Australia and New Zealand [118] Cali, Colombia [187] USRDS/UNOS, US [117] Madrid, Spain [188] Daegu, Korea [189] Mexico city, Mexico [190] Seoul, Republic of Korea [191] Estado de México, México [192]

2 (mean) NA 2.9 (1.0–11.5) NA NA NA NA NA 7.1 ± 4.6 (NA – 16.6) 4.8 (2.8–7.3) 2.6 (0.3–7.4) 3.6 ± 3.8 4.8 ± 2.1 NA NA NA 3.0 ± 3.1 NA NA NA 4.8 (mean) NA 4.9 (cadaveric); 5.3 (living -related) NA 6.8 ± 4.9 (0.3–20) 6.2 ± 6.1 5 (mean), (0.5–13.8) 3.0 ± 2.9 (0.1–10) 7.6 ± 4.9 NA 6.6 ± 5.1 7.3 ± 3.3 7.1 ± 5.5 (0.3–26.8) 4.95 ± 3.94 7 (2–27) NA 10.2 ± 7.2 4 groups (5.5 ± 1.8, 5.9 ± 1.7, 6.5 ± 1.7, 6.4 ± 1.7) NA 6.0 ± 3.4 (0.1–10.5) NA 4.8 (1.1–10.6) 3.8 [1.6–8.3]

1996–2014 1996–2011 1980–2014 1982–2007 1979–2015 2005–2016 1991–2014

2017 2017 2018 2018 2018 2018 2019

65 5884 43 8 74 19 25

7.2 [3.2–11.7] 4.7 [2.0–8.3] 8.1 [3.0–19.1] 8.6 ± 6.8 11.3 ± 5.6 5.8 ± 2.7 2.8 [2.3]

2 (3.1%) 67 (1.1%) 0 (0%) 0 (0%) 6 (8%) 0 (0%) 2 (8%)

0.6 and 0.1 NA NA NA 5.0 (0.3–11) NA NA

*1

NA NA NA NA*2 0.67 (0.1–2.8) 4.6

*1 Time to recurrence was shown as median (range), median [interquartile range], or mean ± SD. *2 NA: not available.

ethnicity difference can be attributed to the susceptibility and severity of lupus nephritis. African Americans develop lupus nephritis more frequently than Caucasians [130]. Also, African Americans displayed a more aggressive disease and a less favorable response to treatment. Renal survival was significantly worse in African Americans compared with Caucasians [130]. Racial differences in renal outcome were independent of age, duration of lupus, history of hypertension, hypertension control during therapy, and activity or chronicity indices on renal biopsy [130]. Consistent with this, Contreras et al. indicated that non-Hispanic black race, female and younger age (below 33) independently are increased risk of recurrent lupus nephritis [119]. Younger lupus patients were shown to have a higher frequency of nephritis, which requires a higher amount of glucocorticoid and other

immunosuppressants [131]. The risk factors of recurrent lupus nephritis are quite matched to those of more frequent and severe lupus nephritis of native kidneys. [132]. Low complement after transplantation is the most relevant factor for recurrence of lupus nephritis [132,133]. Antiphospholipid antibody syndrome (APS) is often associated with SLE, and increases the risk of post-transplant thrombosis in the renal transplantation [134,129,135]. 3.3. Impact of recurrent lupus nephritis on long-term outcomes According to a surveillance-biopsy based study [122], the majority of the patients of biopsy-proven recurrent lupus nephritis had subclinical class I or II (17 of 22), while 3 of 22 had class III or IV. The 8

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clinical significance of this subclinical class I and II recurrence is not clear since there are no studies with longitudinal biopsy follow-up in patients with SLE with transplants. Besides pathological recurrence, the clinical recurrence of lupus nephritis is relatively uncommon, but affect the outcome of the graft. Clinically manifesting recurrent glomerulonephritis is an essential cause of deteriorating the renal function of the renal transplants in general and in lupus nephritis [136 128]. Still, the most common cause of allograft loss in patients with lupus nephritis is rejection and chronic allograft nephropathy [119]. From this point of view, some researchers insist that the impact of recurrent lupus nephritis on graft outcome is negligible [137].

[12] [13] [14] [15] [16]

4. Future perspectives [17]

There is an urgent need to prevent recurrence of autoimmune diseases in the graft to avoid retransplantation, especially because the shortage of donor organ is a major issue for patients awaiting transplantation worldwide [138]. Furthermore, risk factors associated with an increased frequency of recurrence of autoimmune diseases are not clearly defined and robust approaches for prevention are not available. Large-scale and multicenter studies with prospective cohorts of patients after transplantation are needed to draw conclusive results, under the auspices of international collaborative consortia. Furthermore, these prospective cohorts would be valuable resources for further understanding of disease etiological mechanisms. While autoimmune diseases patients are largely diagnosed when the disease has already progressed, those at the very beginning stage of disease onset can be followed longitudinally for an extended period with protocol (or even event-driven) biopsy and blood sampling at pre- and post-transplant to access disease recurrence and perhaps biomarkers identification. Again, the establishment of well-designed and organized prospective registries with clinical information as well as clinical samples are critical not only to improve the outcomes of posttransplant patients, but also to unveil the etiological myth of autoimmune diseases.

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