Incidence and risk factors for recurrent focal segmental glomerulosclerosis after kidney transplantation: a meta-analysis

Abstract

Aims

To systematically review the incidence and risk factors for recurrent FSGS after kidney transplantation.

Methods

We searched PubMed, Embase, Medline, Web of Science, the Cochrane Library, CNKI, CBMdisc, Wanfang, and Weipu for case-control studies related to recurrent FSGS from the establishment until October 2022. The protocol was registered on PROSPERO (CRD42022315448). Data were analyzed using Stata 12.0, with odds ratios (counting data) and standardized mean difference (continuous data) being considered as effect sizes. If the I² value was greater than 50%, the random-effects model was used; otherwise, a fixed-effects model was used. A meta-analysis on the incidence and risk factors for recurrent FSGS after kidney transplantation was performed.

Results

A total of 22 studies with 966 patients and 12 factors were included in the meta-analysis. There were 358 patients with recurrent FSGS and 608 patients without FSGS after kidney transplantation. The results showed that the recurrence rate of FSGS after kidney transplantation was 38% (95% CI: 31%–44%). Age at transplantation (SMD = −0.47, 95% CI −0.73 to −0.20, p = .001), age at onset (SMD = −0.31, 95% CI −0.54 to −0.08, p = .008), time from diagnosis to kidney failure (SMD = −0.24, 95% CI −0.43 to −0.04, p = .018), proteinuria before KT (SMD = 2.04, 95% CI 0.91 − 3.17, p < .001), related donor (OR 1.99, 95% CI 1.20 − 3.30, p = .007) and nephrectomy of native kidneys (OR 6.53, 95% CI 2.68 − 15.92, p < .001) were associated with recurrent FSGS, whereas HLA mismatches, duration of dialysis before KT, sex, living donor, tacrolimus use and previous transplantation were not associated with recurrent FSGS after kidney transplantation.

Conclusions

The recurrence of FSGS after kidney transplantation remains high. Clinical decision-making should warrant further consideration of these factors, including age, original disease progression, proteinuria, related donor, and nephrectomy of native kidneys.

Keywords:

• Meta-analysis
• focal segmental glomerulosclerosis
• kidney transplantation
• incidence
• risk factors

1. Introduction

Recurrent focal segmental glomerulosclerosis (FSGS) refers to a diagnosis of FSGS after a successful kidney transplant in patients who had FSGS prior to surgery. The mechanism of podocyte damage leading to recurrent FSGS is thought to involve a circulating factor, the identity of which is still unclear. Anti-CD40 antibody, serum urine-type plasminogen activator receptor (suPAR), cardiotrophin-like cytokine factor 1, and apoA1b (an isoform of ApoA [1]) were reviewed as prospective candidates for the recurring FSGS component [2–5]. The cytoskeleton of cultured podocytes is adversely affected by recurrent FSGS patients’ plasma, including promoting cell mobility by phosphorylating vasodilator-stimulated phosphoprotein and breaking up focal adhesion complexes [6,7].

No curative therapies exist for the treatment of FSGS, and a significant proportion (40–70%) of patients with FSGS advance to kidney failure within 10–20 years after diagnosis, making FSGS one of the most common primary glomerular diseases leading to kidney failure requiring dialysis, along with diseases such as diabetic nephropathy and hypertensive nephrosclerosis [8,9]. In cases of kidney failure, kidney transplantation is usually the therapy of choice. However, primary FSGS recurrence occurs in 40%–60% of patients after kidney transplantation and varies widely depending on the study population, diagnostic criteria, and follow-up duration [10]. Patients with FSGS recurrence have a 52 percent 5-year graft survival rate compared to 83 percent in patients without FSGS recurrence, which significantly impairs the quality of life and places a heavy burden on families [10].

Published studies failed to provide consistent evidence for recurrence rate and risk factors due to a variety of reasons, such as small sample sizes, inconsistent diagnostic criteria, and different methodologies. The reported rates of recurrence ranged widely, from 9% to 15% in registry-based research to 17%–55% in smaller investigations [11]. Age, disease course, living donor, native kidney nephrectomy, and choice of immunosuppression have been demonstrated to influence the occurrence and progression of recurrent FSGS following kidney transplantation [12], whereas some of these factors remain controversial. The accurate identification of risk factors associated with recurrent FSGS after kidney transplantation is key to select transplant candidates and might help to improve the long-term survival rate of patients. Meanwhile, developing effective preventive and therapeutic strategies for recurrent FSGS continues to be an active field of research [13,14]. Therefore, we performed a meta-analysis to explore the recurrence rate and risk factors of recurrent FSGS after kidney transplantation.

2. Materials and methods

2.1. Search strategy

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used to conduct this meta-analysis. The protocol was registered on PROSPERO (CRD42022315448). English and Chinese databases, including PubMed, Embase, Medline, Web of Science, Cochrane Library, CNKI, CBMdisc, Wanfang, and Weipu (VIP), were utilized to search relevant studies. The retrieval period of each database was from the establishment until 24 October 2022. The relevant papers were identified using Medical Subject Headings (MeSH) terms: ‘Kidney Transplantation’, ‘Transplantation, Kidney’, ‘Grafting, Kidney’, ‘Glomerulonephritis’, ‘Glomerulonephritides’, ‘Kidney Scarring’ and free words. The idiographic search strategy retrieval was shown in Supplementary Material 1.

2.2. Inclusion criteria and exclusion criteria

The following were the criteria for inclusion: (i) type of study: published case-control studies containing clinical data from the recurrence and nonrecurrence groups; (ii) the full text was available on the internet (iii) exposure factors: risk factors for recurrent FSGS in kidney transplant recipients and (iv) outcome indicators: recurrent FSGS after kidney transplantation, diagnosed according to the biopsy.

The following were the criteria for exclusion: (i) repeated publications; (ii) insufficient full text, partial data, inconvertible data, or no control group; (iii) no biopsy and patients replaced by a number of grafts.

2.3. Literature selection and bias assessment

All literature selection and necessary data extraction were performed by two independent reviewers (YW and JC). If there were disagreements, the reviewers discussed them, and a third researcher adjudicated them (CH, blinded to the authors and institute of studies). When selecting articles, titles, and abstracts were read, and obviously unrelated articles were excluded first. Then, we downloaded and reviewed the full-text articles. The following data were extracted: (i) basic information, such as author, publication year, and type of study. (ii) baseline characteristics of patients, such as study samples and risk factors. (iii) the number of patients in the recurrence group and nonrecurrence group and (iv) key information on the risk of bias. Newcastle–Ottawa Scale (NOS) is a scale for assessing the quality of published non-randomized studies, which contains eight items, categorized into three dimensions including selection, comparability, and exposure. The study quality is evaluated semi-quantitatively using a star system, with a NOS ranging from zero to nine [15]. Two investigators assessed the quality of the selected studies independently on the NOS. In the case of disagreements, a third researcher adjudicated.

2.4. Statistical analyses

Stata 12.0 was used to conduct the meta-analysis. The odds ratio (OR) is an indicator evaluating the association between exposure and disease in controlled studies, and the standard mean difference (SMD) is obtained by dividing the difference of the two estimated means by the average standard deviation. When different studies record the same outcome variable in different units of measurement, SMD should be used as a measure of effect size [16]. Continuous data used the SMD, and categorical variables adopted OR for analyzing the effect size in this study. Effect quantities are presented with a 95% confidence interval (95% CI). The kappa statistic was applied to evaluate the level of agreement in study selection between two reviewers. The heterogeneity across studies was quantified using the inconsistency statistic. If the I² value was greater than 50%, significant heterogeneity was expected. In the case of statistical heterogeneity, the random-effects model was used; otherwise, a fixed-effects model was used. The meta-analysis was performed at a significance level set as α = 0.05. To examine publication bias, a funnel plot, and Egger’s test were used. The graphs were created using R 3.6.3.

3. Results

3.1. Study characteristics

A total of 1124 articles identified in the preliminary examination. After screening the full-text, 22 articles remained [3,4,17–36]. This study included 966 patients, including 358 with recurrent FSGS and 608 without recurrent FSGS after kidney transplantation. An overview of the results and process of literature screening was shown in Figure 1. The kappa statistic was 0.78 (p < .001) following the full-text review, showing substantial consensus across reviewers. The details of data for kappa statistic were shown in Supplemental Materials 1. According to NOS, the risk of bias and quality were assessed (Table 1). The results of risk factors were presented in Table 2.

Figure 1. The process of the identification and inclusion of selected studies.

Table 1. Characteristics and Newcastle–Ottawa Scale quality score of included studies.

Ref no	Author	Year	Study type	NOS	Country	Recurrent FSGS (n)	Sample (n)	Period	Risk factors
1	Baskin [38]	2022	Case-control study	7	Turkey	5	34	2004–2019	Sex, Age at transplantation, Time from diagnosis to kidney failure, Duration of dialysis before KT, Living donor
2	Vallianou [35]	2021	Case-control study	7	Greece	26	46	1993–2019	Sex, Age at transplantation, Age at onset, Time from diagnosis to kidney failure, Living donor, HLA mismatches, Previous transplantation
3	Uffing [37]	2020	Case-control study	9	Unite States	57	176	2005–2015	Sex, Age at transplantation, Time from diagnosis to kidney failure, Duration of dialysis before KT, Previous transplantation, Nephrectomy of native kidneys, Living donor, Related donor, HLA mismatches, Tacrolimus use
4	Puig-Gay [17]	2019	Case-control study	8	Spain	15	37	2013–2015	Sex, Age at transplantation
5	Harel [18]	2019	Case-control study	7	Unite States	18	55	NA	Age at transplantation
6	Alasfar [19]	2018	Case-control study	7	Unite States	37	64	2008–2015	NA
7	Cormica [20]	2018	Case-control study	9	Irish	23	38	1982–2015	Sex, Age at transplantation, Time from diagnosis to kidney failure, Proteinuria before KT, Duration of dialysis before KT, Living donor, Tacrolimus use, HLA mismatches
8	Mujtaba [21]	2015	Case-control study	8	Unite states	12	28	NA	Sex, Age at transplantation, Previous transplantation, Living donor
9	Park [22]	2014	Case-control study	8	Korea	7	27	2000–2010	Sex, Age at transplantation, Time from diagnosis to kidney failure, Proteinuria before KT, Living donor, Related donor, HLA mismatches
10	Straatmann [23]	2014	Case-control study	8	Unite states	7	24	1995–2013	Age at transplantation, Living donor, Related donor, HLA mismatches, Nephrectomy of native kidneys
11	Delville [4]	2014	Case-control study	8	France	27	50	NA	Sex, Age at onset, Previous transplantation, Duration of dialysis before KT
12	Lopez-Hellin [3]	2013	Case-control study	7	Spain	14	74	NA	NA
13	Franco [26]	2013	Case-control study	7	Unite states	13	28	NA	Age at transplantation, Sex, Proteinuria before KT
14	Shishido [27]	2013	Case-control study	8	Japan	10	16	2000–2009	Age at transplantation, Age at onset, Duration of dialysis before KT
15	Maas [28]	2013	Case-control study	9	Netherlands	28	94	1968–2009	Sex, Age at transplantation, Age at onset, Time from diagnosis to kidney failure, Living donor, Related donor, HLA mismatches, Tacrolimus use
16	Sener [33]	2009	Case-control study	8	Canada	5	22	1996–2004	Sex, Age at transplantation, Nephrectomy of native kidneys, Living donor,Proteinuria before KT
17	Hickson [34]	2009	Case-control study	7	Unite States	14	30	2000–2006	Age at transplantation, Sex, Duration of dialysis before KT, Previous transplantation, Related donor, HLA mismatches, Nephrectomy of native kidneys
18	Pardon [36]	2006	Case-control study	8	France	12	35	1986–2001	Sex, Age at onset, Duration of dialysis before KT, Age at transplantation, HLA mismatches
19	Fujisawa [32]	2002	Case-control study	7	Japan	8	13	NA	Sex, Age at onset, Duration of dialysis before KT, HLA mismatches, Nephrectomy of native kidneys
20	Kim [31]	2001	Case-control study	7	Korea	9	22	1984–1999	Sex, Age at onset, Proteinuria before KT, Duration of dialysis before KT, Related donor, Living donor, HLA mismatches
21	Ingulli [29]	1991	Case-control study	8	Unite states	6	28	1974–1990	Previous transplantation
22	Pinto [30]	1981	Case-control study	8	UK	5	25	1967–1979	Age at onset

NA: not available; NOS: Newcastle–Ottawa Scale.

Table 2. Summary of meta-analysis results of risk factors for recurrent focal segmental glomerulosclerosis after renal transplantation.

Factors	No. study	Sample (n)	Heterogeneity test		OR/SMD (95% CI)	p-value	Egger’s test
			p	I^2			t	P
Age at transplantation	16	703	.003	56.7%	−0.47 (−0.73 to −0.20)	.001	−3.40	.004
Age at onset	9	331	.095	40.9%	−0.31(−0.54 to −0.08)	.008	1.60	.153
Time from diagnosis to kidney failure	9	486	.082	42.9%	−0.24 (−0.43 to −0.04)	.018	−2.11	.073
HLA mismatches	7	435	.194	30.6%	−0.17 (−0.37 to 0.04)	.107	−0.14	.898
Proteinuria before KT	6	167	<.001	87.3%	2.04 (0.91 − 3.17)	<.001	2.56	.063
Duration of dialysis before KT	10	441	.174	29.5%	−0.02 (−0.22 to 0.18)	.861	−0.32	.755
Sex	16	704	.262	16.7%	0.78 (0.56–1.07)	.127	−1.52	.150
Living donor	8	467	.546	0.00%	0.88 (0.57 − 1.38)	0.586	−1.10	.312
Related donor	6	373	.203	31.00%	1.99 (1.20 − 3.30)	.007	0.45	.673
Tacrolimus use	3	308	.514	0.00%	0.97 (0.54 − 1.72)	.911	−1.14	.458
Previous transplantation	5	328	.248	26.00%	1.16 (0.68 − 1.97)	.582	0.68	.548
Nephrectomy of native kidneys	3	230	.727	0.00%	6.53 (2.68 − 15.92)	<.001	10.24	.062

3.2. Incidence

The recurrence rate of FSGS after kidney transplantation was 38% (95% CI 31%−44%) (Figure 2). To investigate the potential regional impact on incidence, we performed subgroup analyses by country, and the results showed that the recurrence rate of FSGS was 38% (95% CI 30%−47%) in the United States, 29% (95% CI 8%−50%) in Spain, 32% (95% CI 18%−47%) in Korea, 45% (95% CI 25%−64%) in France and 62% (95% CI 44%−80%) in Japan (Figure 2). Subgroup analyses were also performed according to the number of samples in the studies. The results showed that the recurrence rate of FSGS was 39% (95% CI 31%−48%) in the group with a sample size greater than 30 and 35% (95% CI 26%−44%) in the group with a sample size less than 30 (Supplemental Materials 2).

Figure 2. The recurrence rate of FSGS by subgroup analysis of the country.

3.3. Risk factors

3.3.1. Age at transplantation

There were 16 studies included in the total, including 260 patients in the FSGS recurrent group and 443 patients in the non-recurrent group. As significant heterogeneity among studies was observed (p = .003, I² = 56.7%), the random effects model was applied for analysis, and age at transplantation was associated with a risk for recurrent FSGS after kidney transplantation (SMD = −0.47, 95% CI −0.73 to −0.20, p = .001; Figure 3).

Figure 3. SMD and the corresponding 95% CI for risk factors of recurrent FSGS. Young age at transplantation and age at onset, a short time from diagnosis to kidney failure, and high level of proteinuria before kidney transplantation were associated with recurrent FSGS after kidney transplantation, whereas HLA mismatches and duration of dialysis before kidney transplantation were not associated with recurrent FSGS.

We performed a sensitivity analysis to identify the sources of heterogeneity. The result showed that the study of Straatmann et al. was the main sources of heterogeneity, which had a major role in determining the pooled SMD of age at transplantation. After eliminating Straatmann et al. the pooled SMD was −0.38 (95% CI −0.62 to −0.14, p = .002; Figure 4(A)). The results remained stable.

Figure 4. (A) Sensitivity analysis for age at transplantation in the meta-analysis. (B) Trim and filling for age at transplantation in the meta-analysis.

3.3.2. Age at onset

There were 9 studies included in the total, including 139 patients in the FSGS recurrent group and 192 patients in the non-recurrent group. As no significant heterogeneity among studies was observed (p = .095, I² = 40.9%), the fixed effects model was applied for analysis, and age at onset was associated with a risk for recurrent FSGS after kidney transplantation (SMD = −0.31, 95% CI −0.54 to −0.08, p = .008; Figure 3).

3.3.3. Time from diagnosis to kidney failure

There were 9 studies included in the total, including 175 patients in the FSGS recurrent group and 311 patients in the non-recurrent group. As no significant heterogeneity among studies was observed (p = .082, I² = 42.9%), the fixed effects model was applied for analysis and time from diagnosis to kidney failure was associated with a risk for recurrent FSGS after kidney transplantation (SMD = −0.24, 95% CI −0.43 to −0.04, p = .018; Figure 3).

3.3.4. HLA mismatches

There were 7 studies included in the total, including 162 patients in the FSGS recurrent group and 273 patients in the non-recurrent group. As no significant heterogeneity among studies was observed (p = .194, I² = 30.6%), the fixed effects model was applied for analysis and HLA mismatches was not associated with a risk for recurrent FSGS after kidney transplantation (SMD = −0.17, 95% CI −0.37 to 0.04, p = .107; Figure 3).

3.3.5. Proteinuria before KT

There were 6 studies included in the total, including 71 patients in the FSGS recurrent group and 96 patients in the non-recurrent group. As significant heterogeneity among studies was observed (p < .001, I² = 87.3%), the random effects model was applied for analysis and proteinuria before KT was associated with a risk for recurrent FSGS after kidney transplantation (SMD = 2.04, 95% CI 0.91 − 3.17, p < .001; Figure 3).

We performed a sensitivity analysis to identify the sources of heterogeneity. The result showed that the study of Carlos et al. was the main sources of heterogeneity, which had a major role in determining the pooled SMD of proteinuria before KT. After eliminating Carlos et al. the pooled SMD was 1.56 (95% CI 0.58 − 2.54, p = .002) (Supplementary Material 2). The results remained stable.

3.3.6. Duration of dialysis before KT

There were 10 studies included in the total, including 172 patients in the FSGS recurrent group and 269 patients in the non-recurrent group. As no significant heterogeneity among studies was observed (p = .174, I² = 29.5%), the fixed effects model was applied for analysis and the duration of dialysis before KT was not associated with a risk for recurrent FSGS after kidney transplantation (SMD = −0.02, 95% CI −0.22 − 0.18, p = .861; Figure 3).

3.3.7. Sex

There were 16 studies included in the total, including 268 patients in the FSGS recurrent group and 436 patients in the non-recurrent group. As no significant heterogeneity among studies was observed (p = .262, I² = 16.7%), the fixed effects model was applied for analysis and sex was not associated with a risk for recurrent FSGS after kidney transplantation (OR 0.78, 95% CI 0.56 − 1.07, p = .127; Figure 5).

Figure 5. OR and the corresponding 95% CI for risk factors of recurrent FSGS. Related donor and nephrectomy of native kidneys were associated with recurrent FSGS after kidney transplantation, whereas sex, living donor, tacrolimus use, and previous transplantation were not associated with recurrent FSGS.

3.3.8. Living donor

There were 8 studies included in the total, including 165 patients in the FSGS recurrent group and 302 patients in the non-recurrent group. As no significant heterogeneity among studies was observed (p = .546, I² = 0.0%), the fixed effects model was applied for analysis and the living donor was not associated with a risk for recurrent FSGS after kidney transplantation (OR 0.88, 95% CI 0.57 − 1.38, p = .586; Figure 5).

3.3.9. Related donor

There were 6 studies included in the total, including 122 patients in the FSGS recurrent group and 251 patients in the non-recurrent group. As no significant heterogeneity among studies was observed (p = .203, I² = 31.0%), the fixed effects model was applied for analysis and the related donor was associated with a risk for recurrent FSGS after kidney transplantation (OR 1.99, 95% CI 1.20 − 3.30, p = .007; Figure 5).

3.3.10. Tacrolimus use

There were 3 studies included in the total, including 108 patients in the FSGS recurrent group and 200 patients in the non-recurrent group. As no significant heterogeneity among studies was observed (p = .514, I² = 0.0%), the fixed effects model was applied for analysis and tacrolimus use was not associated with a risk for recurrent FSGS after kidney transplantation (OR 0.97, 95% CI 0.54 − 1.72, p = .911; Figure 5).

3.3.11. Previous transplantation

There were 5 studies included in the total, including 128 patients in the FSGS recurrent group and 200 patients in the non-recurrent group. As no significant heterogeneity among studies was observed (p = .248, I² = 26.0%), the fixed effects model was applied for analysis, and previous transplantation was not associated with a risk for recurrent FSGS after kidney transplantation (OR 1.16, 95% CI 0.68 − 1.97, p = .582; Figure 5).

3.3.12. Nephrectomy of native kidneys

There were 3 studies included in the total, including 78 patients in the FSGS recurrent group and 152 patients in the non-recurrent group. As no significant heterogeneity among studies was observed (p = .727, I² = 0.0%), the fixed effects model was applied for analysis, and nephrectomy of native kidneys was associated with a risk for recurrent FSGS after kidney transplantation (OR 6.53, 95% CI 2.68 − 15.92, p < .001; Figure 5).

3.4. Publication bias

Using Egger’s test and funnel plots, we assessed publication bias. The funnel plots and Egger’s test (t = 1.91, p = .071) of recurrence rate did not demonstrate publication bias (Figure 6). Furthermore, Table 2 presented the results of the risk factor analysis with publication bias. As a result, age at onset (t = 1.60, p = .153), time from diagnosis to kidney failure (t = −2.11, p = .073), HLA mismatches (t = −0.14, p = .898), proteinuria before KT (t = 2.56, p = .063), duration of dialysis before KT (t = −0.32, p = .755), sex (t = −1.52, p = .150), living donor (t = −1.10, p = .312), related donor (t = 0.45, p = .673), tacrolimus use (t = −1.14, p = .458), previous transplantation (t = 0.68, p = .548) and nephrectomy of native kidneys (t = 10.24, p = .062) did not demonstrate publication bias.

Figure 6. Funnel chart results of recurrence rate.

The funnel plots (asymmetry) and Egger’s test (t = −3.40, p = .004) of age at transplantation indicated the existence of publication bias. The trim-and-fill analysis was used, and no potential ‘missing studies’ was found in age at transplantation. The adjustment for publication bias had no impact on the pooled estimate (Adjusted pooled SMD = −0.47, 95% CI −0.73 to −0.20, p = .001) (Figure 4(B)).

4. Discussion

This meta-analysis summarized 22 studies involving 358 patients with recurrent FSGS and 608 patients without recurrent FSGS after kidney transplantation. Overall, recurrent FSGS remains one of the most significant challenges of kidney transplantation, with a recurrence rate of 38% when data from the included studies were pooled. In addition, the disparities in the recurrence of FSGS patients in different populations and ethnic groups were observed by subgroup analysis. In a comparative study from the United States, the recurrence of FSGS was found to be more common in non-black races among those who had kidney transplants [37]. Compared to Caucasians, Hispanics, and Asians, African Americans showed a decreased rate of recurrence [38–40].

In this study, we found that age at transplantation, age at onset, time from diagnosis to kidney failure, proteinuria before KT, related donor, and nephrectomy of native kidneys were associated with recurrent FSGS. Younger age at transplantation and older age at onset were considered the most reliable predictors of recurrent FSGS [20]. The higher level of proteinuria before KT was associated with a risk factor for recurrence, which supported the widely held belief among clinicians that a more severe disease in FSGS patients was related to a higher risk of recurrence [26]. Additionally, patients with recurrent FSGS progressed to kidney failure more quickly, especially those who developed kidney failure within 3 years of diagnosis [41]. Our literature review identified the related donor as a risk factor for recurrent FSGS in kidney transplant patients, with an odds ratio of 1.99.

HLA mismatches, duration of dialysis before KT, sex, living donor, tacrolimus use, and previous transplantation were not associated with recurrent FSGS after kidney transplantation during this meta-analysis. Although the duration of dialysis preceding KT did not differ significantly between the two groups, it should be noted that kidney transplantation was linked with a significantly lower risk of mortality than dialysis, making patients who must wait longer for transplantation more likely to suffer a poorer overall prognosis [42]. Tacrolimus is a calcineurin inhibitor, often used as immune maintenance therapy after kidney transplantation. Consistent with previous studies, our results suggested that the use of tacrolimus was neither a protective factor nor a risk factor for recurrent FSGS after kidney transplantation. However, the short observation duration and low doses of tacrolimus used in certain studies might have an effect on the results.

Compared to the Cochrane Reviews by Ruospo M et al. which evaluated the efficacy and safety of phosphate binders for the treatment of hyperphosphatemia in chronic kidney disease patients, we searched databases for case-control studies and examined incidence and risk factors for recurrent FSGS [43,44]. Some systematic reviews with meta-analyses investigating recurrent FSGS have been published. Two existing reviews have looked into rituximab and plasmapheresis or plasma exchange to demonstrate the efficacy of combination or monotherapy for FSGS in transplanted kidneys [45,46]. The meta-analyses by M. A. Baum et al. have focused on living donor transplantation in children because of concerns about the increased risk of graft loss with recurrent FSGS, which has been controversial [47]. Essentially, the present meta-analyses was not consistent with the earlier reviews. We performed a meta-analysis to explore the risk factors (including but not limited to therapy and living donors) and evaluated the recurrence rate by a single-arm meta-analysis.

We conducted this review in accordance with a predetermined process and made use of a sensitive search strategy. Study selection, data management, and bias assessment was carried out independently by at least two authors, reducing the risk of mistakes in the determination of eligible studies and the determination of the certainty of the evidence. To assess the influence of study quality and other participant and study factors on the outcomes, we performed sensitivity analyses. Despite these processes, we acknowledged the limitations of our study. During this meta-analysis, only the full-text studies in Chinese and English were included. Because the number of studies on some factors was small, the relationship between these factors and the occurrence of FSGS was difficult to determine. It was necessary to conduct more multicenter studies to verify these factors. The results might be affected by the quality of the original research, such as the lack of adequate sample size in some included studies. Furthermore, our meta-analysis could not take into account the interrelationship of factors as a multivariate analysis. We further propose that research set up lengthy follow-up intervals in order to get more thorough and objective conclusions.

The existence of circulating permeability factors that likely contribute to podocyte injury and the emergence of proteinuria in recurrent FSGS has been supported by nephrectomy before KT as a risk factor. One hypothesis is that the native kidneys absorb any potentially harmful circulating component that might harm the transplanted kidney [4,32,35]. A well-matched kidney (such as a sibling kidney) conferred an elevated risk of recurrence since the related donor was associated with FSGS recurrence. We suggested that related donation for patients with FSGS awaiting transplantation should be discouraged. In addition, patients are typically not re-transplanted due to the high chance of recurrence in the replacement allograft when they lose their allograft because of recurrent FSGS [48,49]. Still, the previous transplantation did not increase the risk of recurrence in our meta-analysis, which should be fully considered in the decision to re-transplant based on multiple factors.

The strategies for recurrent FSGS multi-targeted treatment were plasmapheresis or immunoadsorption with concomitant high-dose steroids [13,14,50]. Given that approximately 40% of those affected did not respond to therapy with plasmapheresis as the sole therapeutic intervention, it was crucial to understand that in most series, administration of additional treatment modalities was required to achieve remission or a significant reduction in proteinuria [51,52]. Tacrolimus is a calcineurin inhibitor (CNI), often used as immune maintenance therapy after kidney transplantation. Our meta-analysis results suggested that the use of tacrolimus was neither a protective factor nor a risk factor for recurrent FSGS after kidney transplantation. With the continuous development and use of immunosuppressive agents, the short-term engraftment rate of transplanted kidneys has improved. However, the long-term survival rate of transplanted kidneys is still low, with the role of immunosuppressive therapy in the onset of recurrent FSGS yet to be clarified. Currently, there is no established medication for preventing post-transplant FSGS recurrence [46].

The evidence did not provide enough high-quality evidence for some risk factors, such as the use of immunosuppressive agents, with the limited sample size and inaccurate incidence estimates resulting in wide confidence ranges. Long-term and large-scale studies of the use of immunosuppressive agents, previous transplantation, and age should be conducted. Based on limitations in existing studies and a paucity of evidence for specific investigation at different ages of onset, the more pediatric patients in the recurrence group could reduce the level of age when compared to the non-recurrence group; a younger age of FSGS onset was therefore recommended as a recurrence risk factor in some studies [32,33]. In future research on specific age groups (children, older adults), whether the age of onset or age of transplant is a risk factor may lead to opposite conclusions. Standardization of study measures that prioritize patient-important risk factors will facilitate the comparability and design of future studies to assess meaningful risk factors.

5. Conclusion

In general, the recurrence rate of FSGS after kidney transplantation remained high. Our results indicated that young age at transplantation and age at onset, a short time from diagnosis to kidney failure, high level of proteinuria before KT, related donor, and nephrectomy of native kidneys were associated with recurrent FSGS in kidney transplant recipients. In the clinical setting, thorough research for modifiable risk factors should be performed in kidney transplant patients to adopt a comprehensive approach.

Authors contributions

J.B. and T.Z. designed the study. Y.W., Z.D., L.J. and J.C. screened the literature. J.B. and T.Z. analyzed the data, wrote the original draft. Q.G, C.H. and Y.Z. reviewed and edited the manuscript. All authors read and approved the final manuscript.

Ethics statement

Ethical approval was not required for this study in accordance with local/national guidelines. Written informed consent to participate in the study was not required in accordance with local/national guidelines. The protocol was registered on PROSPERO (CRD42022315448).

Acknowledgments

This manuscript does not include any non-author contributors to acknowledge.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by no grants.