Malnutrition and immune cell subsets in children undergoing kidney transplantation

Abstract

Background: Malnutrition, including obesity and undernutrition, among children is increasing in prevalence and is common among children on renal replacement therapy. The effect of malnutrition on the pre-transplant immune system and how the pediatric immune system responds to the insult of both immunosuppression and allotransplantation is unknown. We examined the relationship of nutritional status with post-transplant outcomes and characterized the peripheral immune cell phenotypes of children from the Immune Development of Pediatric Transplant (IMPACT) study.

Methods: Ninety-eight patients from the IMPACT study were classified as having obesity, undernutrition, or normal nutrition-based pre-transplant measurements. Incidence of infectious and alloimmune outcomes at 1-year post-transplantation was compared between nutritional groups using Gray's test and Fine-Gray subdistribution hazards model. Event-free survival was estimated by Kaplan-Meier method and compared between groups. Differences in immune cell subsets between nutritional groups over time were determined using generalized estimating equations accounting for the correlation between repeated measurements.

Results: We did not observe that nutritional status was associated with infectious or alloimmune events or event-free survival post-transplant. We demonstrated that children with obesity had distinct T-and B-cell signatures relative to those with undernutrition and normal nutrition, even when controlling for immunosuppression. Children with obesity had a lower frequency of CD8 Tnaive cells 9-month post-transplant (p < .001), a higher frequency of CD4 CD57 + PD1- T cells, and lower frequencies of CD57-PD1+ CD8 and CD57-PD1- CD8 T cells at 12-month transplant (p < .05 for all).

Conclusions: Children with obesity have distinct immunophenotypes that may influence the tailoring of immunosuppression.

Keywords: immunosuppression; immunosuppressive treatment; induction; kidney.

Figure 1:. Frequencies of CD8 Tnaive are decreased and CD8 Temra are increased among patients with obesity after kidney transplantation.

(A) A significant interaction effect of time and nutritional status was detected (p=0.007), with patients with obesity having a lower frequency of CD8+ Tnaive at at 9-months post-transplant compared to normal nutritionpatients (95% CI: −38.18% to −12.98%, p<0.0001). (B) No significant interaction with time was noted (p=0.186) and no differences between nutritional status groups observed for CD8 Tem (p=0.736). (C) A significant interaction between CD8 Temra cells and time was observed (p=0.042) and compared to normal nutritionpatients, patients with obesity on average had 14% higher in Temra cell frequency at 6-months post-transplant (95% CI: 1.02% to 26.98%, p=0.035) and 31.4% higher in mean Temra cell frequency at 9-months (95% CI: 18.57% to 44.22%, p<0.0001). (D) No significant interaction with time was noted (p=0.480) and no differences between nutritional status groups observed for CD8 Tem (p=0.841).

Figure 2:. Markers of senescence among CD4 T cells are associated with nutritional status among pediatric transplant recipients.

(A-B) No significant interaction between nutritional status and CD4+ CD57-PD1+ (p=0.948), or CD4+ CD57+PD1+ (p=0.082) T lymphocytes. (C) A significant interaction effect of time and nutritional status was detected for CD4 CD57+PD1- (p=0.0004). Compared to normal patients, patients with obesity on average had 1.82% higher in CD4 CD57+PD1- frequency at 12-month post-transplant (95% CI: 0.46% to 3.17%, p=0.0086). (D) No significant interaction between nutritional status and CD4+CD57-PD1- T lymphocytes was detected (p=0.504).

Figure 3:. Markers of senescence among CD8 T cells are associated with nutritional status among pediatric transplant recipients.

(A) A significant interaction of time and nutritional status was detected for CD8+CD57-PD1+ T cells (p=0.004). Compared to normal patients, patients with obesity on average had 4.7% lower in CD8+CD57-PD1+ frequency at 12-month post-transplant (95% CI: −8.46% to −0.95%, p=0.014). (B) No significant interaction with time was found (p=0.520). On average, frequency of CD8+CD57+PD1+ T cell was higher for patients with obesity compared to both normal growth (95% CI: 0.13% to 7.39%, p=0.0403) and undernourished patients (95% CI: 1.18% to 8.85%, p=0.010). (C) No significant interaction with time was found (p=0.059). On average, frequency of CD8+ CD57+PD1- T cells was higher among patients with obesity compared to normal (95% CI: 2.89% to 20.11%, p=0.0089) and under-nourished patients (95% CI: 1.14% to 19.25%, p=0.027). (D) A significant interaction of time and nutritional status was detected for CD8+CD57-PD1- T cells (p=0.0035). Compared to normal patients, patients with obesity on average had 34.03% lower in CD8+ CD57-PD1- T cell frequency at 9-month post-transplant (95% CI: −46.21% to −21.84%, p<0.0001) and −20.55% lower at 12-month post-transplant (95% CI: −35.97% to −5.13%, p=0.009).

Figure 4:. Nutritional status is associated with naïve B cell frequency

(A) A significant interaction between time and naïve B cell frequency was found (p=0.009). Compared to normal growth patients, patients with obesity on average had a higher (8.19%) naïve B cell frequency at baseline (95% CI: 1.68% to 14.70%, p=0.014), 7.23% higher at 1-month (95% CI: 1.35% to 13.11%, p=0.016), and 4.9% higher at 3-month post-transplant (95% CI: 0.32% to 9.51%, p=0.036). (B & C) No significant interaction between frequency and time was found for either Plasma cells or Transitional B cells (p=0.716 and p=0.378, respectively). After removing the interaction term, we still did not detect a significant effect of nutritional status on plasma B cell frequency (p=0.455) nor transitional B cell frequency (p=0.189).