Focal segmental glomerulosclerosis (FSGS) is the second leading cause of end-stage renal disease (ESRD) in children. At our center, we have seen an increasing number of cases of FSGS in children progressing to ESRD and requiring a kidney transplant. Unfortunately, FSGS may recur aggressively after transplantation and FSGS recurrence is an important cause of graft failure. Published studies have shown an increased risk of recurrence among recipients of living donor (LD) kidneys compared with recipients of deceased donor (DD) kidneys (1). In addition, graft loss caused by recurrent FSGS has been shown to be increased in LD kidneys (2). Thus, there has been enough concern about this possibility that some transplant centers avoid living-related donation, especially among siblings (3–5). Additional risk factors for recurrence have been reviewed elsewhere and include young age, white race, mesangial proliferation on biopsy, and low albumin levels pretransplantation (6). Furthermore, younger, Caucasian children are both more likely to recur and receive a LD kidney (7–9). Therefore, it is important to systematically analyze FSGS recurrence risk in a way that accounts for these confounders.
In this study, we used 20 years of comprehensive data collected by the United Network for Organ Sharing (UNOS) to look at national trends in FSGS leading to pediatric kidney transplantation and analyze risk factors for disease recurrence.
FSGS was reported as the cause of ESRD in 2157 pediatric transplantations over 20 years. Trend analysis of absolute number of kidney transplantations for FSGS over time showed a risk ratio of 1.058 or an increase in cases of 5.8% per year or 209% over 20 years (P<0.0001). There were no differences in risk ratio based on UNOS region or gender. Hispanic race and age range of 11 to 17 years were associated with disproportionate increases in cases during the study period. Hispanic children demonstrated an increase of 10.6% per year, whereas 11- to 17-year-old children increased 7.8% per year. As shown in Figure 1, the incidence of FSGS showed an increase even when adjusted for the overall increase in pediatric kidney transplantations. FSGS recurrence rate also increased over time, from 12% between 1988 and 1997 to 17% from 1998 to 2008 (Fig. 2).
Recurrence was reported in 327 (15%) cases overall and more often in younger pediatric age groups, occurring in 19% of children 10 years and younger compared with 14% in those 11 years and older (P=0.003). Recurrence occurred significantly more in whites than in all other races combined (19% vs. 12%; P<0.001), whereas gender and human leukocyte antigen (HLA) matching were not significant. Last, donor type was significant, with recurrence in 17% of LD recipients compared with 14% of children who received DDs (Table 1). In the multivariable analysis, age of 1 to 10 years and white race were associated with recurrence (Table 2). Children who received LD kidneys did not demonstrate a significant association with disease recurrence (odds ratio [OR], 1.22; P=0.11). When excluding the small number of patients who received a living unrelated donation (n=76), living-related kidney donation remained insignificant (OR, 1.16; P=0.23).
This study confirms our suspicion that FSGS as a cause of ESRD for incident pediatric kidney transplantations is increasing on a national scale. Moreover, the rate of FSGS recurrence among transplanted children is also on the rise. We demonstrated that young age and white race were risk factors for posttransplantation FSGS recurrence, whereas donor type was not independently associated with disease recurrence.
FSGS is the most common form of pediatric glomerular disease leading to ESRD and has significant risk of disease recurrence, with reported center-specific values ranging from 30% to 50% in children receiving a kidney transplantation (4, 10–14). Among children with FSGS, recurrence was a cause of graft failure in 20% of transplant recipients in a multicenter European study (15). A review of the North American Pediatric Renal Trials and Collaborative Studies database of 127 transplanted children for FSGS demonstrated a 20.5% recurrence rate (16). In this nationwide study of FSGS recurrence, we report a total recurrence incidence of 15%, which is less than previous estimates. African Americans comprised a large percentage of our cohort (34%) and represent a demographic at lower risk for recurrence, which may account for this finding.
Generally, LD kidneys have a graft survival advantage over DD kidneys. However, when Baum et al. reviewed North American Pediatric Renal Trials and Collaborative Studies data on FSGS, they found loss of the typical renal allograft survival advantage of LD kidneys and more recurrence in LD kidneys. However, this study did not differentiate the effect of recipient race on donor type (17). A stratified analysis by race and donor type done on UNOS data (1987–1997) showed that, for non-black children with FSGS, LD transplantations have a graft survival advantage over DD transplantations (18). A review of the U.S. Renal Data System database for graft loss of all kidney transplantations performed for FSGS between 1987 and 1996 in both children and adults showed that recurrence was a more frequent cause of graft loss in LD compared with DD kidneys (3.9% vs. 2.1%). However, in multivariate analysis, donor type was not associated with graft loss due to disease recurrence. Furthermore, this study found that LD kidneys had improved graft survival when controlled for other factors, including age and race (19). Therefore, the inferior outcomes demonstrated by Baum et al. in LD kidneys may be explained by the higher frequency of LD transplantations in whites and younger children; demographic risk factors for recurrence that were confirmed in this study. Furthermore, our results demonstrate that donor type and HLA mismatches are not independently associated with disease recurrence, suggesting that a well-matched kidney (such as a sibling kidney) does not confer an increased risk of recurrence in children.
We suggest that living donation for children with FSGS awaiting transplantation should not be discouraged. Potential benefits of living donation include decreased waiting time and higher feasibility of carefully planned peritransplantation plasmapheresis to possibly reduce recurrence risk as suggested by recent retrospective analyses (20). Hickson et al. reported reduced postoperative acute tubular necrosis as a result of fulminant FSGS recurrence when patients received preemptive plasmapheresis (21). The limited experience at our center, which has transitioned to preemptive plasmapheresis on all LD transplant patients with FSGS considered at high risk for recurrence, corroborates this. Our data presented here may help select high-risk patients for preemptive plasmapheresis.
Recurrent FSGS may often respond to plasma exchange, suggesting that there is a putative circulating factor involved in the disease’s pathophysiology, and Savin et al. have indeed hypothesized that a “permeability factor” with a molecular weight of approximately 50 kDa is playing a central role (22). The group has also shown that this molecule’s activity is disabled by galactose in vitro and in one patient who had already progressed to ESRD (23). However, their observations have not been reproduced on a larger scale. Savin’s group has also developed a bioassay for testing patient serum for this permeability factor, but this did not reliably predict recurrence in a cohort of Italian children (13). In addition, Wei et al. have isolated soluble urokinase receptor as a putative “culprit” in human FSGS and have replicated this finding in a mouse model (24). These reports and efforts related to potential drivers of and putative risk factors for recurrent FSGS are exciting steps forward but continue to await confirmation, including in children with FSGS proceeding to transplantation.
This study shows that the diagnosis of FSGS as a cause of childhood ESRD progressing to kidney transplantation is increasing on a national scale. The strength of this study is that, theoretically, UNOS captures all kidney transplantations done that are paid for by Medicare (i.e., essentially all transplantations in this country), thus allowing a broad review of data. The database also contains a large number of patients, which makes it possible to assess confounding variables in a multivariate model. The observed increase in pediatric ESRD caused by FSGS, paired with the substantial additional care “burden” that comes with peritransplantation pheresis regimens and posttransplantation disease recurrence, may also inform cost-related discussions between transplant centers and insurance providers going forward.
Limitations of our study include potential misclassification of reported disease. FSGS may be particularly vulnerable to this problem, because it is a pathologic diagnosis and therefore dependent on the performance of a renal biopsy with adequate tissue sampling. For example, FSGS could be characterized as “chronic glomerulosclerosis not otherwise specified,” but numbers reported to UNOS for this diagnosis are relatively small and have had minimal changes over the same time period. In contrast, the “other” category for classifying underlying disease appears to be used more frequently, but despite this increase we found more FSGS cases being reported. Our study is also limited by the information that UNOS collects, which would not include information such as nadir albumin levels and details of biopsy findings. An important limitation is lack of standardization regarding definition and reporting for FSGS recurrence. Currently, recurrence is noted as an adverse event by the transplant center; therefore, UNOS data are dependent on accurate reporting by each center. In addition, there may be a time lag between the adverse event and its reporting by individual centers. We accordingly recommend that a standard definition for FSGS recurrence be applied and reported.
Nonetheless, the nearly threefold increase of FSGS leading to kidney transplantation over 20 years in children is noteworthy. Although there may be more transplantations being done for this diagnosis despite the recurrence risk, the large increase found by us raises concerns regarding the true rise in the incidence of this disease over time. Unfortunately, baseline data ascertaining the overall incidence of FSGS in the United States over time are not available. Some cases of FSGS are secondary to obesity, and as our nation becomes more obese, this may explain a portion of the increased FSGS incidence. Obesity-associated FSGS is an epidemic that has grown 10-fold over 15 years based on a single-center pathology review from 2001 (25). However, obesity-induced FSGS usually has a more indolent course than non-obesity related FSGS and theoretically should be less likely to progress to ESRD in childhood. Another possible explanation for our findings may be more or earlier biopsy diagnoses (which could mean that some of the earlier ESRD patients were misclassified). However, there has been disturbing evidence as early as 1999 indicating that the histopathology of idiopathic nephrotic syndrome in children is changing, with more biopsy-proven FSGS being found (26, 27). We also do not know if practice changes in pediatric nephrology may have affected progression to ESRD: the use of calcineurin inhibitors and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, while standard of care in FSGS, can contribute to renal dysfunction secondary to drug-related nephrotoxicity. There are no large-scale studies to show the effect of these medications on disease progression in children.
We found a disproportionate increase in cases of FSGS in Hispanic children and in children ages 11 to 17. The number of transplantations done for Hispanic children tripled in the studied time period, also out of proportion to the overall increase in pediatric kidney transplantation (28). Thus, the growing population of Hispanics in the United States likely accounts for this finding, and it should not be inferred that Hispanic race is a risk factor for FSGS. Increased prevalence of secondary forms of FSGS, including obesity-related disease, may account for the increase in cases among adolescent children.
In summary, our study confirms our local suspicion that FSGS as a cause of ESRD for incident pediatric kidney transplantations is increasing nationally. It also demonstrates that white race and young age are associated with a higher likelihood of posttransplantation recurrence, whereas receiving a LD kidney is not independently associated with recurrence of FSGS in children.
MATERIALS AND METHODS
Data from the UNOS from 1988 to 2008 were analyzed for the number of transplantations for a primary diagnosis of FSGS in first kidney transplant recipients 1 to 20 years old. Ages up to and including 20 years were evaluated to be consistent with standard pediatric nephrology practice, whereas recipients less than 1 year of age were excluded. All data were provided by UNOS. Statistical analysis was performed using SAS 9.3 statistical software (Cary, NC). PROC GENMOD was used to perform trend analysis by Poisson regression. Differences in trends were examined by age group, gender, race, and UNOS region. To account for increasing numbers of children undergoing kidney transplantation, we examined changes in FSGS incidence per 1000 pediatric kidney transplantations using Mantel–Haenzel chi-square statistics. Risk factors for disease recurrence including gender, race, age group, HLA mismatches, and donor type were evaluated. All variables were categorical and compared in univariate analysis by chi-square testing. Using PROC LOGISTIC, a multivariate logistic regression was performed with initial inclusion of all covariates. Backward elimination was then used to optimize the model by removing all variables with P values greater than 0.05 while forcing donor type into the model. ORs along with 95% confidence intervals (CI; both adjusted and unadjusted) were reported for donor type and each independent predictor of disease recurrence.
Prior approval was not required from our institutional review board, as this study was conducted using a deidentified database.
Special thanks to Katarina Linden of UNOS.
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