Renal allograft survival in transplant recipients with focal segmental glomerulosclerosis


 Introduction: The frequency that idiopathic focal segmental glomerulosclerosis (FSGS) recurs in renal allografts is reportedly 20-50%, but the epidemiology of secondary FSGS in this setting has scarcely been addressed. Objectives: The aim of this study was to examine the incidence, etiology, and subtypes of FSGS in renal allograft recipients and allograft survival in recipients with FSGS. Patients and Methods: As a retrospective review, we examined medical records of 359 consecutive renal allograft recipients (living donors, 329; cadaveric donors, 30). In 121 of these patients, allograft dysfunction or proteinuria prompted biopsies. We compared allograft survival in recipients with and without FSGS. We then determined histologic subtypes of FSGS using the Columbia classification and categorized FSGS as recurrent or de novo, and idiopathic or secondary. Results: Of 121 subjects who were biopsied, six with inadequate specimens (<10 glomeruli) were excluded. Only 17 of those remaining (n=115) were diagnosed as secondary FSGS. Renal allograft survival did not differ significantly in patients with or without FSGS (P=0.953). Subtypes of FSGS were as follows; not otherwise specified (NOS; n=8), collapsing (n=5), cellular (n=2), and perihilar (n=2). Conclusion: Secondary FSGS was observed in 14.5% of biopsies of renal allograft recipients and seemed no significant impact on allograft survival.


Objectives
The present efforts were focused on the following; 1) incidence and subtypes of FSGS in renal allograft recipients, 2) allograft survival in recipients with FSGS, and 3) nature of FSGS (recurrent or de novo, idiopathic or secondary). ) (36). Urinary protein excretion was assessed by protein-to-Cr ratios (g/g Cr) of spot urine samples. Banff criteria were the benchmarks for rejection (37).

Ethical approval
Informed consent was obtained from each patient enrolled in this study. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki. This research was approved by the ethical committee of Jichi Medical University Hospital (IRB approval number RINDAI 16-066).

Statistical analysis
All data were expressed accordingly as mean ± SD or median (range). Chi-square test was applied to categorical variables, using Student's t-test or Mann-Whitney U test to assess continuous variables. Renal allograft survival was analyzed by Kaplan-Meier method, with log-rank test. The impact of FSGS on death-censored graft survival was gauged via Cox proportional hazards model, adjusting for baseline imbalances in recipient groups with or without FSGS. EZR freeware (v1.35; R Foundation for Statistical Computing, Vienna, Austria) (39) was invoked for all computations, setting significance at P<0.05.

Results
Of renal allograft recipients (n=121) who were biopsied, six with inadequate specimens (<10 glomeruli) were excluded. However, changes of FSGS were absent in all six. In the remaining 115 patients, a diagnosis of FSGS was established for 17.
Characteristics of allograft recipient groups, with or without FSGS at biopsy, are shown in Table 1. Although urinary protein excretion at biopsy and transplant-tobiopsy interval were significantly greater in patients with (vs without) FSGS (P=0.00146 and P=0.00151, respectively), the presence or absence of FSGS had no significant impact on renal function at biopsy (P=0.287) or death-censored graft survival (P=0.953) (Figure 1). Once adjusted for transplant-to-biopsy interval and urinary protein excretion (in Cox proportional hazards analysis), death-censored graft survival proved similar, regardless of FSGS status (adjusted hazard ratio for deathcensored graft loss in recipients with FSGS=3.70, 95% confidence interval: 0.733-18.7; P=0.113).

Discussion
During the course of this study, FSGS was identified in 14.5% of renal allograft recipients who required biopsies.
As the leading cause of secondary FSGS herein, CNI toxicity may inflict hyperfiltration injury and subsequent arteriolar hyalinosis, with global glomerulosclerosis (40) or glomerular ischemia (17,41). Indeed, severe arteriolar hyalinosis was visible in all 10 of our patients with overt CNI toxicity. Others (33,34) have also reported FSGS following rejection, although the inherent mechanism is still unclear. Immunologic injury to endothelium and podocytes may be involved. Obesity may contribute to glomerular hyperfiltration, heightening filtration pressures of proximal glomerular capillaries to result in sclerosis near    (11,42). Changes of FSGS have similarly been noted in many (101/128) cases of IgAN, again linked to podocyte injury (29). FSGS in reflux nephropathy likely results from nephron loss, imposing hyperfiltration on those left intact (10). Unilateral kidney recipients seem prone to glomerular hyperfiltration as well. A critical factor may be the duration of these conditions, because transplant-to-biopsy intervals proved significantly longer in our patients with FSGS.
There are data to indicate that graft survival is significantly worse in recipients with (vs without) de novo FSGS (43). Unfortunately, further categorization as idiopathic or secondary is lacking at the source, therefore the cited outcomes may in part reflect idiopathic de novo FSGS, the prognosis of which is poor. In our patients, FSGS was largely presumed to be secondary and whether present or not had no significant impact on renal allograft survival. Hence, the prognosis of renal allograft recipients is seemingly unaltered by secondary FSGS.

Conclusion
According to our data, only 14.5% of renal allograft recipients undergoing biopsies for allograft dysfunction or proteinuria showed evidence of FSGS which was considered secondary in all instances. Secondary FSGS was seemed to have no significant impact on allograft survival.

Limitation of the study
This study has several acknowledged limitations. The status of native kidneys in a segment of allograft recipients was unknown, prohibiting FSGS designation as recurrent or de novo. In addition, our method of separating idiopathic and secondary FSGS (based pathologic changes or clinical features) was not foolproof. Finally, biopsies were not obtained from every patient with renal allograft dysfunction or proteinuria, therefore the incidence of FSGS we have determined may be inaccurate.

Authors' contribution
TaS participated in research design, performance of the research, and writing the paper. KN participated in research design, performance of the research, and writing the paper. YK participated in research design, performance of the research, and writing the paper. TK participated in research design, performance of the research, and writing the paper. ToS participated in research design, performance of the research, and writing the paper. TY participated in research design, performance of the research, and writing the paper.

Conflicts of interest
The authors have declared that no conflict of interest exists.

Ethical considerations
Ethical issues have been completely observed by the authors.

Funding/Support
None.