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Clinical Transplantation

DIFFERENCES IN ANTHROPOMETRIC PARAMETERS AND THE IGF-I-IGFBP3 AXIS BETWEEN LIVER AND RENAL TRANSPLANT CHILDREN1

Pasqualini, T.2; Ferraris, J. R.; Jasper, H.; Pennisi, P.; D’Agostino, D.

Author Information

Seccion Endocrinologia, Crecimiento y Desarrollo, Servicio de Nefrologia, Servicio de Hepatologia y Transplante Hepatico, Departamento de Pediatría, Hospital Italiano de Buenos Aires and Division de Endocrinología, Hospital “Ricardo Gutierrez,” Buenos Aires, Argentina

Received 3 November 1999.

Accepted 29 January 2000.

2 Address correspondence to: Titania Pasqualini, MD, Departamento de Pediatria, Seccion Endocrinologia, Crecimiento y Desarrollo, Hospital Italiano, Gascon 450, 1181, Buenos Aires, Argentina.

1 Supported by grants from Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET) and by Novartis SA, Buenos Aires, Argentina.

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Abstract

Chronic liver and renal disease in childhood often results in growth retardation. The success of transplantation (Tx) has led to prolonged survival in both end-stage liver and renal diseases. With the improvement of long-term survival, growth retardation has become one of the major problems. Both poor graft function and glucocorticoid therapy have been suggested as the major factors inhibiting growth after liver (1–4) and renal Tx (5–8). Moreover, age, diagnosis, height, and weight for height at Tx have been reported to influence growth (5–10). Furthermore, abnormalities have also been reported in the growth hormone/insulin-like growth factor-I (GH-IGF-I) axis. After liver Tx, normal GH secretion and serum IGF-I, and normal or elevated IGF-binding protein-3 (IGFBP3) levels were found (4, 11, 12). However, after renal Tx, reduced GH secretion, normal or low IGF-I associated with normal or high IGF-binding protein-3 (IGFBP3) levels were observed, probably related to altered graft function and immunosuppressive steroid therapy (13).

At our institution, growth seems to be more inhibited after renal Tx than after liver Tx, in contrast to what has been reported (3). To further characterize factors affecting growth, we compared graft function, immunosuppression, height, weight/height ratio, and IGF-I/IGFBP3 axis between liver and renal Tx children who were followed for 4–6 years.

MATERIALS AND METHODS

Patients

Liver and renal Tx.

All patients were prepubertal except one in each group who was at Tanner stage II. Only patients followed for at least 4 years post-Tx were included in the study.

Liver Tx.

Fifteen patients (6 boys and 9 girls) with a mean±SEM age at Tx of 5.68±1.1 years (range 1.24–13.2 years) were studied. The indications for liver Tx were biliary atresia n=10, Alagille syndrome n=1, Budd-Chiari syndrome n=1, fulminant acute hepatitis n=1, cryptogenetic cirrhosis n=1, sclerosing cholangitis n=1. Fifteen, 12, and 8 patients completed 4, 5, and 6 years of follow-up, respectively. The differences in patient numbers at the different time points were due to different time of follow-up since Tx; no grafts were lost. Acute rejection episodes were documented in 6/15 patients.

Renal Tx.

Seventeen (all boys) with a mean±SEM age at Tx of 7.45±1 years (range 1.64–15.56 years), P= NS versus liver Tx (Student’s t test), were studied. Thirteen patients required 21.5±4.4 (range 5–54) months of dialysis before Tx. The indications for renal Tx were hemolytic-uremic syndrome n=8, obstructive uropathy n=5, focal segmental glomerulosclerosis n=2, nephronoptisis n=1, renal dysplasia n=1. Seventeen, 15, and 10 patients completed 4, 5, and 6 years of follow-up, respectively. The differences in patient numbers at the different time points were due to different time of follow-up since Tx; no grafts were lost. One patient presented an acute rejection episode immediately after Tx and chronic rejection episodes were documented in another four patients.

Follow-up visits.

After Tx, the patients were seen regularly at the Pediatric Department of the Italian Hospital of Buenos Aires. Consent was obtained from the parents and the patients (where applicable). The following longitudinal data were obtained: prothrombin time, serum alanine aminotransferase (ALT), and creatinine clearance. Serum creatinine concentrations were determined by the picric acid method (14). Creatinine clearance was calculated by using the Schwartz formula (15). The same trained observers using a Harpenden stadiometer for height measurements performed weight and height determinations. Height standard deviation score (SDS) was calculated according to the following equation: height SDS=(observed value−mean value)/SD, with SD representing the SD for the normal population of the same chronological age and gender. The weight/height ratio was expressed by the percentage that the patient’s weight exceeds the 50th percentile of weight for patient height. Anthropometric measurements were matched against the Argentine National Growth Charts (16). The immunosuppressive protocol used was triple drug regimen of cyclosporine, azathioprine, and methylprednisone or deflazacort. When appropriate, glucocorticoid dosage was calculated by assuming the equivalence of 1 mg methylprednisone to 1.5 mg deflazacort as reported previously (17). At 3.7±0.4 years post-Tx serum IGF-I (radioimmunoassay) and IGFBP3 (IRMA) were measured by techniques reported previously (17, 18).

Statistical analysis.

All results are reported as mean±SEM. Changes over time were analyzed with analysis of variance for repeated measures and Student-Newman-Keuls test. Student’s t test was used to compare the means between the two different groups studied. Correlations were determined by Pearson’s correlation coefficient. P <0.05 were considered statistically significant.

RESULTS

Graft Function

Liver Tx.

Mean±SEM prothrombin time was 80.5±5.9, 86±3.5, 87±4.1, 85±2.5, 82±3.5, 80±2.9% (normal value 75–100%) and serum ALT was 18±3.2, 13.9±1.3, 16.7±2.7, 16±2.3, 23.5±11.4, 19±5.7 UI/liter (normal value 5–22 IU/liter) at Tx, and 1, 2, 3, 4, 5, and 6 years post-Tx, respectively. Both mean values remained normal during follow-up.

Liver and renal Tx.

Longitudinal mean±SEM creatinine clearance values are shown in Figure 1. Creatinine clearance did not change post-liver Tx. In renal recipients, mean creatinine clearance decreased from 98±7 to 69±8 ml/min/1.73 m2 after 6 years, P <0.001(analysis of variance for repeated measures and Student-Newman-Keuls test). Differences between the groups became statistically significant at and after the second year of follow-up (P <0.05, Student’s t test). Only 1/15 liver Tx patient presented a low creatinine clearance of 63 and 54 ml/min/1.73 m2 after 3 and 5 years of follow-up. In contrast, 3/17, 6/17, 8/17, 8/17, 7/15, and 7/10 renal Tx patients presented creatinine clearance lower than 75 ml/min/1.73 m2 during 1–6 years of follow-up. The lowest observed values were 49 at 4 years, 43 at 5 years, and 36 ml/min/1.73 m2 at 6 years.

F1-13
Figure 1:
Creatinine clearance post-liver and renal Tx. The creatinine clearance did not change post-liver Tx and decreased post renal Tx (analysis of variance for repeated measures and Student-Newman-Keuls test).

Age and Anthropometric Measurements at Tx

Liver and renal Tx.

At liver Tx, mean±SEM age, 5.68±1.1 years (range 1.24–13.2 years), was not significantly different from that at renal Tx, 7.45±1 years (range 1.64–15.56 years); 10/15 liver Tx patients and 7/17 renal Tx patients were <5 years. Mean height SDS was higher in liver than in renal Tx children (−1.1±0.31 vs. −2.4±0.36 SDS, P <0.02); 5/15 (33%) patients in the liver transplant group and 9/17 (53%) patients in the renal transplant group were at or <−2 SDS for height. There was no significant difference in the height SDS between the younger (<5 years old) and older (>5 years old) patients in each group (liver Tx patients −1.16±0.43 vs. −.96±0.42; renal Tx patients −2.52±0.7 vs. −2.34±0.41). Height SDS was correlated with length of time on dialysis in renal Tx patients, r=−0.73, P <0.001.

Anthropometric Measurements during Follow-Up

Liver and renal Tx.

Mean height SDS was significantly higher in liver Tx patients at and after 3 years of follow up (P <0.02). Mean±SEM height SDS improved significantly beyond the second year post-liver Tx (Fig. 2). The mean gain in height (2nd to 6th year) was 0.92±0.2 SDS reaching a mean height of −0.3±0.4 SDS at the 6th year of follow-up. In contrast, after renal Tx height remained low, and mean height SDS was −2.3±0.3 at the end of the study. At the 1st and 2nd year of follow-up height SDS was correlated with length of time on dialysis before Tx, r=−0.62, P <0.01 and r=−0.49, P <0.05, respectively.

F2-13
Figure 2:
Height SDS post-liver and renal Tx. Height SDS increased after the 2nd year of follow up in liver Tx patients and did not change post-renal Tx (analysis of variance for repeated measures and Student-Newman-Keuls test).

During the 6 years of follow-up, there was no significant difference in mean height SDS when renal patients were divided according to age at Tx in < or >5 years old (3rd year, −1.83±0.56, n=7 vs. −2.01±0.28, n=10; 6th year, −2.93±0.76, n=4 vs. −1.95±0.21, n=6).

At 3 and 6 years post-Tx, 13% (2/15) and 12.5% (1/8) of the liver Tx patients and 47% (8/17) and 50% (5/10) of the renal Tx patients, were at or below the normal range for height, respectively. At 5 years post-Tx, height SDS correlated with creatinine clearance, r=0.69, P <0.01, in renal Tx patients.

Weight for height index did not change after Tx in both groups. At Tx, 3 and 6 years post-Tx weight/height ratio were 9.8±2.8, 11.1±2.2, 1.8±3.0% in liver Tx patients and 5.1±3.4, 8.7±4.4, 21±9.4% in renal Tx patients. There was no statistically significant difference between the two groups of patients. No Tx patients (either liver or renal) presented a weight/height ratio suggestive of undernutrition (<15%). However, at 6 years of follow-up, 3/10 renal transplanted patients showed overweight with a weight/height ratio of 87, 57, and 24%; overweight was present since the 2nd, 3rd, and 4th year of follow-up, respectively.

Immunosuppressive Treatment

Liver and renal Tx.

Mean±SEM maintenance dosage of orally administered glucocorticoids, azathioprine, and cyclosporine are shown in Table 1. All patients in the renal Tx group received glucocorticoid therapy during the 6 years of follow-up. In contrast, steroids were more rapidly weaned and discontinued in the liver Tx group so that 14/15 and only 3/12 and 3/8 patients continued to receive glucocorticiods after 4, 5, and 6 years, respectively. Mean maintenance dosage decreased significantly through time (1 vs. 2 years post Tx, P <0.01; 1 vs. 3, 4 years, P <0.001, analysis of variance for repeated measures). There was no difference in cyclosporine dosage and serum cyclosporine concentration in both groups of patients.

T1-13
Table 1:
Mean±SEM longitudinal maintenance immunosuppressive doses of glucocorticoids, azathioprine and cyclosporine, and serum cyclosporine concentration in liver and renal Tx patients

Endocrine Function

Serum IGF-I and IGFBP3 were measured after 3.8±0.6 and after 3.7±0.4 years post- liver and renal Tx. Patients at that time were 9.4±1.2 and 11.1±1.0 years old (P= NS). Mean creatinine clearance was 108±5 and 79±5 ml/min/1.73 m2 (P <0.001); mean glucocorticoid dosage was 0.08±0.01 and 0.16±0.01 mg/kg/day (P <0.001) in liver and renal recipients, respectively.

Mean serum IGF-I level (0.5±0.2 vs. −0.7±0.4 SDS, P <0.02), was significantly higher in the liver Tx group; only 3/17 of the renal Tx patients presented values at or less than −2 SDS. In contrast, mean serum IGFBP3 level (0.3±0.3 vs. 1.3±0.2 SDS, P <0.01) was significantly higher in the renal Tx group; 5/17 renal Tx patients and 1/15 liver Tx patient presented values at or more than 2 SDS. IGF-I/IGFBP3 molar ratio (0.3±0.5 vs. −2.1±0.4 SDS, P <0.001) was significantly higher after liver Tx. There was correlation between IGFBP3 SDS and glucocorticoid dosage in liver Tx patients, r:0.65, P <0.01. No such correlation was found in renal Tx patients.

DISCUSSION

In this study we found that height SDS was higher at the moment of Tx in liver compared to renal recipients, and that in the former it increased significantly during follow-up.

In our liver Tx patients, graft survival was good and no grafts were lost due to acute rejection episodes; prothrombin time, serum ALT, and consequently liver function were normal. Creatinine clearance did not decrease in liver recipients but it decreased after renal Tx.

Growth was clearly more inhibited in the renal Tx group, and catch up growth was observed only after liver Tx where mean height SDS increased 0.92±0.2 SDS after the 2nd year of follow-up. It has been reported that although catch-up growth is expected after liver Tx, 15 to 59% of these children remain outside the normal range for height (9, 10). We found that 12.5% of our liver Tx children currently present height SDS <−2, although 50% of our renal Tx patients remain less than the normal range for height. However, Sarna et al. (3) found that 77% of the liver Tx and only 7% of the renal Tx patients were less than the normal range for height 3 years after Tx. The shorter follow-up cannot explain their results, because our liver Tx patients were always taller than renal Tx children, and the difference between our two groups was already significant at the 3rd year post-Tx.

The mean age of liver patients at Tx was less than that of the renal patients, but the difference was not statistically significant. Although in the pediatric renal transplant literature it is described that the most catch-up growth is seen in young patients (6, 7), when we divided our patients according to age at Tx in < or >5 years old there was no significant difference in mean height SDS during follow-up. Thus, our younger patients did not grow better than the older ones. However, it is interesting to note that the length of time on dialysis was inversely correlated with height SDS at Tx and only during the first and second year of follow-up and therefore it can be considered a marker for the degree of stunting only at these time points. Suggested causes for growth stunting post-Tx are malnutrition, high-dose steroids, altered graft function, and decreased glomerular filtration rate (17, 19–25).

Our weight for height data do not support the fact that undernutrition played a role during follow-up in both groups. However, the lack of a significant difference in weight for height ratio observed between liver and renal Tx patients at 6 years of follow-up is due to the wide range of values provided by the three overweight renal patients.

Glucocorticoids are one of the major factors responsible for altered growth (17, 22, 23, 24) and the possibility of weaning and discontinuing steroid therapy after liver Tx may be the major cause of better growth in our liver recipients. In this regard, Falkenstein and Dunn (22) also reported improvement in height SDS in liver Tx children on cyclosporine monotherapy.

IGF-I is a low molecular weight peptide that mediates at least in part, the action of growth hormone (26, 27). Although normal serum IGF-I levels have been reported in children after liver (3, 4, 11, 12, 23) and renal Tx (13) we found that our liver Tx patients presented higher mean IGF-I value than those in the renal Tx group. In serum, IGF-I is mostly bound by IGFBP3 (26, 27). Although serum IGFBP3 concentration correlates positively with height, growth hormone secretion, and serum IGF-I concentration, an excess of unsaturated IGFBP inhibits IGF-mediated mitogenic and metabolic events in many tissues and cell lines (26, 27). Mean IGFBP3 value was significantly higher in our renal Tx recipients. This finding may be related to their decreased creatinine clearance which has been suggested to cause accumulation of low molecular weight IGFBP3 fragments (which are recognized by the IRMA). Moreover, glucocorticoid dosage was higher in our renal recipients, and this also may induce higher serum IGFBP3 levels as suggested by Hokken-Koelega et al. (13). Furthermore, elevated serum IGFBP3 concentrations were found in some liver Tx children with normal renal function (3, 4) and methylprednisone-induced synthesis of IGFBP3 has been shown to occur in liver extracts (28). In this regard, in liver Tx patients we found a positive correlation between IGFBP3 levels and glucocorticoid dosage that was not present after renal Tx possibly because of the deterioration of graft function. In our renal Tx patients, the lower serum IGF-I with increased IGFBP3 levels led to a decreased bioavailable IGF-I concentration with significantly lower IGF-I/IGFBP3 ratio. Therefore, this also may explain in part, the difference in growth between liver and renal Tx recipients.

In conclusion, this study demonstrates that after liver Tx, the preserved graft function, the possibility of weaning and discontinuing steroids and the higher serum IGF-I levels and IGF-I/IGFBP3 molar ratio may explain the catch up growth of this group of children. In contrast, in our renal Tx patients growth inhibition was more often observed possibly due to the reduced graft function, higher glucocorticoid dosage, and lower serum IGF-I with increased IGFBP3 levels (which decrease bioavailable IGF-I concentration). Obtaining immunosuppression to allow stable allograft function and catch up growth continues to be a challenge in renal Tx patients. In the future our goal should reside in making it possible to substitute steroid therapy without altering graft function.

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