Growth following solid organ transplantation in childhood.

One of the ultimate goals of successful transplantation in pediatric solid organ transplant recipients is the attainment of optimal final adult height. This manuscript will discuss the attainment of height following solid organ transplantation in pediatric recipients of kidney, liver, heart, lung, and small bowel transplantation. Age is a primary factor with younger recipients exhibiting the greatest immediate catch up growth. Graft function is a significant contributory factor with a reduction in glomerular filtration rate correlating with poor growth in kidney recipients and the need for re-transplantation with impaired growth in liver recipients. The known adverse impact of steroids on growth has led to modification of steroid dosage and even to steroid withdrawal and steroid avoidance. In kidney and liver recipients, this has been associated with the development on occasion of acute rejection episodes. In infant heart transplantation, avoidance of maintenance corticosteroid immunosuppression is associated with normal growth velocity in the majority of patients. With marked improvement in patient and graft survival rates in pediatric organ graft recipients, it is timely that the quality of life issues, such as normal adult height, receive paramount attention. In general, normal growth post-transplantation should be an achievable goal that results in normal adult height for many solid organ transplantation recipients.

Adherence to the immunosuppressive regimen in pediatric kidney transplant recipients: a systematic review.

As most prior reviews on NA focus on adult transplant patients, there is a need for a comprehensive overview on adherence to the immunosuppressive regimen in pediatric kidney transplant patients. This systematic review searched for English-language papers (1990-2008) addressing the prevalence of NA to the immunosuppressive regimen, its consequences, determinants, and interventions in pediatric kidney transplant patients (< age 21 yr). We found 36 papers, showing a prevalence of NA (weighted mean) of 31.8% with adolescents being more at risk compared to younger patients. About 44% of all graft losses and 23% of late acute rejection episodes are associated with NA. Most studies investigated socio-economic, condition-related or treatment-related determinants. Only one educational intervention has been tested but yielded inconclusive results. NA to the immunosuppressive regimen is prevalent with serious clinical consequences in pediatric kidney transplant patients, but the economic consequences have not yet been explored. More studies on determinants of NA are needed. The literature currently lacks fully powered RCTs testing adherence-enhancing interventions. The results of this systematic review identify the gaps in the present evidence-based information regarding NA and can be used as a tool to pursue future adherence research in pediatric populations.

Nonadherence consensus conference summary report.

This report is a summary of a 'Consensus Conference' on nonadherence (NA) to immunosuppressants. Its aims were: (1) to discuss the state-of-the-art on the definition, prevalence and measurement of NA, its risk factors and impact on clinical and economical outcomes and interventions and (2) to provide recommendations for future studies. A two-day meeting was held in Florida in January 2008, inviting 66 medical and allied health adherence transplant and nontransplant experts. A scientific committee prepared the meeting. Consensus was reached using plenary and interactive presentations and discussions in small break-out groups. Plenary presenters prepared a summary beforehand. Break-out group leaders initiated discussion between the group members prior to the meeting using conference calls and e-mail and provided a summary afterward. Conclusions were that NA: (a) is more prevalent than we assume; (b) is hard to measure accurately; (c) tends to confer worse outcomes; (d) happens for a number of reasons, and system-related factors including the patient's culture, the healthcare provider and the setting and (e) it is not currently known how to improve adherence. This consensus report provided some roadmaps for future studies on this complicated, multifaceted problem.

Somatomedin activity and inorganic sulfate in children undergoing hemodialysis.

Bioassayable serum somatomedin activity could be estimated in uremic subjects only after appropriate correction for increased circulating inorganic sulfate. Somatomedin activity increased after hemodialysis in six of ten patients, possibly due to removal of somatomedin inhibitors.

Nutritional status of children undergoing continuous ambulatory peritoneal dialysis.

Nutritional status was assessed in 24 clinically stable children, aged 9.68 +/- 4.31 (SD) yr, who underwent CAPD for 6.6 +/- 4.4 months. Energy intake tended to be more suppressed than protein intake. Several nutritional parameters were more abnormal in children less than 10 yr old as compared to children 10 yr of age or older. In comparison to normals of the same chronological age and sex, both groups of patients displayed reduced height, weight, midarm, and midarm muscle circumference, and, in the younger children, triceps skinfold; height retardation was particularly severe. Compared to height/age, anthropometry was not reduced in older children while triceps skinfold and midarm circumference were decreased in children younger than 10 yr. In both groups, serum total protein, albumin, transferrin, and many plasma amino acids were decreased, and serum triglycerides and cholesterol were elevated. Serum total protein decreased during treatment with continuous ambulatory peritoneal dialysis. These observations suggest decreased stature and poor nutritional status in children undergoing continuous ambulatory peritoneal dialysis. Low protein and energy intake and dialysate protein losses may contribute to these abnormalities.

Autolymphocytotoxic antibodies in patients on dialysis awaiting renal transplantation.

Two-hundred eighty sera from 78 dialysis patients were examined for autolymphocytotoxic antibodies (ALCAs). Thirty-five (12%) sera in 18 (23%) patients had ALCAs. Eight patients had ALCAs in multiple sera. Two patients had ALCAs against both T and B lymphocytes, 2 against T lymphocytes, and 14 against B lymphocytes. In those sera with ALCAs against both B and T lymphocytes, broad thermal reactivity was present. In sera with ALCAs against only B lymphocytes, the majority were reactive at 5 C. Sixteen (89%) patients with ALCAs had some form of glomerulonephritis; five had rapidly progressive glomerulonephritis (RPGN) and three had systemic lupus erythematosis (SLE). Nine of 10 sera with a positive crossmatch against B lymphocytes from a renal transplant donor did not have ALCAs against autologous B lymphocytes; three sera with ALCAs against B lymphocytes and two with ALCAs against T lymphocytes had negative crossmatches against transplant donor lymphocytes. Positive crossmatches against donor B and T lymphocytes attributable solely to ALCAs were therefore uncommon in our patients. Nevertheless, patients at risk to develop ALCA, including those with SLE and RPGN, should be identified and their sera tested for ALCAs. Once identified, studies can be carried out to distinguish a positive crossmatch attributable to ALCAs from that attributable to HLA alloantibody.

Cadaver renal transplant outcome in recipients with autolymphocytotoxic antibodies.

The major impact of autolymphocytotoxic antibodies (ALCA) on renal transplantation has been in the interpretation of the pretransplant crossmatch as a cause of false-positive results. Less attention has been paid to the direct affects of ALCA on renal allografts. We have examined the sera of 38 recipients of 41 cadaver renal allografts for the presence of ALCA. There were 9 patients with ALCA who received 10 allografts. In these allografts with ALCA, actuarial graft survival was significantly improved (P less than 0.05) over that of 31 transplants without ALCA. In recipients with ALCA, graft survival was 90% at six months and 60% at one and two years; in recipients without ALCA, graft survival was 48% at six months, 35% at one year and 24% at two years. ALCA may be exerting graft-enhancing properties by means of an autoregulatory effect upon the recipient's immunologic system.

Pretransplant dialysis status and outcome of renal transplantation in North American children: a NAPRTCS Study. North American Pediatric Renal Transplant Cooperative Study.

BACKGROUND: There are no large studies of the effect of pretransplant dialysis status on the outcome of renal transplantation (Tx) in children. This study evaluated the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) registry data for the outcome of Tx in pediatric patients who either (1) received their transplants preemptively or (2) were maintained on dialysis before receiving their transplants. METHODS: We compared graft survival and patient survival rates, incidence of acute tubular necrosis (ATN), acute rejection episodes, and causes of graft failure in peritoneal dialysis (PD) patients with those maintained on hemodialysis (HD) and those undergoing preemptive Tx (PTx). RESULTS: Primary Tx was performed in 2495 children (59% male; 61% Caucasian; 1090 PD, 780 HD, 625 PTx) between 1/1/1992 and 12/31/1996. The overall graft survival rates of the PD and HD groups were similar, but were less than that of the PTx group (3-year: 82% PD and HD, 89% PTx, overall P = 0.0003). Improved graft survival in the PTx group was present only in recipients of grafts from living donors. There was no difference in the overall patient survival rate at 3 years, or in time to first acute-rejection episodes in the three groups. The incidence of ATN in the first 7 days post-Tx was higher in PD and HD patients than in PTx patients (11% PD and 12% HD vs. 2% PTx, P<0.001; HD vs. PD, P = NS). The major single cause of graft failure in each group was: PD, vascular thrombosis (200%); HD, chronic rejection (27%); PTx, acute and chronic rejection (21% each). CONCLUSION: NAPRTCS data show that graft survival is improved in patients receiving PTx, compared with those receiving PD and HD. Graft loss resulting from vascular thrombosis is more common in children who receive PD than in those receiving HD.

Outcome after transplantation of young patients with systemic lupus erythematosus: a report of the North American pediatric renal transplant cooperative study.

BACKGROUND: The risk of progressing to end-stage renal disease in children with lupus glomerulonephritis is 18% to 50%. Published reports of transplantation secondary to end-stage renal failure in adult patients with systemic lupus erythematosus (SLE) demonstrate equivalent patient and graft survival. The purpose of this analysis is to compare patient and graft outcomes of pediatric SLE renal transplant recipients with an age-, race-, and gender-matched control group. METHODS: A retrospective analysis of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database identified 100 renal transplants performed in 94 young SLE patients. A control group of 470 children having received 501 renal transplants was identified. RESULTS: The SLE cohort was primarily female (82%), non-Caucasian (61%), adolescents and differed from the control group in being less likely to be preemptively transplanted, in receiving longer pretransplant dialysis, and in being likely to have received more than five pretransplant transfusions. After transplantation, there were no differences seen in patient survival at 3 years (89% vs. 95%, SLE vs. control) or in overall graft failure rates (31% vs. 29%, SLE vs. control). There was a trend toward poorer graft survival in non-white SLE patients receiving living donor grafts compared with white SLE patients. An increased graft failure rate was seen among those SLE cadaveric transplant recipients receiving peritoneal dialysis before transplant compared with controls and compared with SLE patients receiving hemodialysis. No differences were seen in rates of acute tubular necrosis or overall acute rejection incidence, although there was a significant increase in the percentage of living donor SLE patients who experienced greater than four rejection episodes. There were nonsignificant trends toward increased graft loss due to patient death with a functioning graft as well as increased mortality secondary to infection in the SLE patients. CONCLUSIONS: The results of renal transplantation in young SLE patients are comparable to those seen in an age-, race- and gender-matched control group. The similar patient and graft survival is seen despite the SLE patients having an underlying disease with multiorgan involvement and despite receiving immunosuppression for potentially prolonged periods before transplantation. No outcome differences were seen except for an unexplained increase in the incidence of recurrent rejections (> or =4) in the living donor SLE patients as well as increased graft failure rate in those patients receiving cadaveric renal transplants after a period of peritoneal dialysis. The nonsignificant trends toward increased graft failures in non-white SLE patients receiving living donor grafts, increased graft loss secondary to death with a functioning graft, as well as the increased mortality due to infection deserve recognition and further study.

Acute renal allograft rejection. Comparative value of ultrasound versus magnetic resonance imaging.

Both magnetic resonance imaging (MRI) and ultrasound (US) have been reported to be useful in differentiating between acute allograft rejection and other causes of graft dysfunction in renal transplantation. The aim of this study was to evaluate the comparative usefulness of these techniques in the assessment of patients with acutely rising serum creatinine levels. Seventeen patients with 19 episodes of acute serum creatinine elevations were evaluated for the presence of acute rejection. The ultimate diagnoses of acute rejection were based on either renal pathological findings, or the response to standard antirejection therapy. Clinical, US and MRI diagnoses were assessed independently, without knowledge of the results of the other evaluation techniques. We found that US alone was useful in diagnosing acute rejection (x2 = 4.95, P less than 0.05), and when taken in the clinical setting was an added advantage (x2 = 6.68, P less than 0.01). MRI did not increase the diagnostic accuracy significantly.

Determination of antiidiotypic antibodies to anti-HLA IgG following blood transfusions.

Blood transfusions (BT) administered prior to renal allograft transplantation are known to enhance allograft survival. One proposed mechanism for this effect is through the induction of antiidiotypic antibodies that modify the immune response to subsequently presented graft antigens. In an attempt to determine if antiidiotypic antibodies are generated post-BT, we studied sera from post-BT patients for the presence of antiidiotypic antibodies to anti-HLA class I IgG (i.e., anti-anti-HLA). Anti-HLA antiidiotypes were demonstrated by idiotype-specific inhibition of an enzyme immunoassay (EIA) for anti-HLA antibodies. Using this inhibition technique, test sera from 8 of 16 post-BT patients showed significant inhibition of the anti-HLA target sera (P less than 0.05). Sera from normal individuals showed no inhibition of the target sera, and test sera did not inhibit other antigen-antibody systems. Protein A absorption of test sera eliminated the inhibitory effect, suggesting that the antiidiotypic activity was limited to the IgG fraction of the sera. The EIA binding activity of F(ab')2 fragments of anti-HLA IgG was suppressed by sera from patients post-BT but not by sera from normal volunteers. Studies of serially obtained sera from a post-BT patient showed that anti-HLA antiidiotype levels fluctuate with time and transfusion status. These studies demonstrate that anti-HLA antiidiotypic antibodies are generated post-BT. Their importance in mediating the known allograft-enhancing effect of pretransplant BT remains to be clarified.

Long-term cadaver allograft survival in the recipient with a positive B lymphocyte crossmatch.

Over a 2 1/2-year period, prospective standard, T, and B lymphocyte crossmatches were performed in 45 cadaver renal transplants using the microlymphocytotoxicity technique. Twenty-three of the 45 recipients had a positive B lymphocyte crossmatch. Cumulative graft survival rates did not differ between recipients with a positive and negative B lymphocyte crossmatch. High levels of presensitization in routine lymphocytotoxic antibody screening or transplant number did not adversely affect graft survival in recipients with a positive B lymphocyte crossmatch. Five recipients had moderately positive standard crossmatches which were attributable to anti-B lymphocytotoxicity. Four of these five grafts are presently functioning with normal serum creatinine levels 9 to 14 months post-transplant. A positive B lymphocyte crossmatch is compatible with good long-term cadaveric renal allograft survival. In addition, a weakly positive standard crossmatch is not a contraindication to transplantation when the positive crossmatch is attributable to anti-B lymphocyte antibody.

Serial decrease in glomerular filtration rate in long-term pediatric liver transplantation survivors treated with cyclosporine.

Serial calculations of glomerular filtration rate were made in 31 pediatric liver transplant recipients surviving more than 1 year. GFR was computed from the Schwartz formula, (cGFR = KL/S Cr), before orthotopic liver transplantation, and at 3-6 monthly intervals thereafter. At the same time points, CsA dose/kg, CsA level, blood pressure, and liver functions were recorded. The mean difference between the pre-OLT cGFR and the most-current cGFR for all patients was -50 ml/min/1.73 m2 (P = less than 0.005). In 17/31 (55%), the current cGFR was less than 80 ml/min/1.73 m2, indicative of renal impairment. The cGFR continued to decrease in 24 patients followed beyond 1 year (26.8 ml/min/1.73 m2 per year decrease, P less than 0.005). More patients with a cGFR less than 80 ml/min/1.73 m2 had outpatient hypertension. There was no correlation of cGFR with CsA levels, CsA dose, or liver function. We conclude that a significant decrease in cGFR is seen in children treated with CsA for more than 1 year, which is progressive in the majority.

Spontaneous anti-tubular-basement-membrane antibody production by lymphocytes isolated from a rejected allograft.

The immunological events mediated by, and antigen specificity of, allograft-bound lymphocytes (ABLs) are poorly understood. To further define the role of antibody-mediated rejection, a rejected allograft from a patient with primary anti-TBM disease was sterilely minced and pressed through a microscreen. The ABLs were isolated by density gradient centrifugation. Using this technique, 8.5 X 10(6) ABLs were isolated. Then 1 X 10(6) washed ABLs/ml were suspended in RPMI 1640 with 20% fetal calf serum and cultured in microtiter plates with media only, or with pokeweed mitogen (PWM) (100 micrograms/culture). The cells were incubated for 7 days and supernatants were collected and assayed for total IgG and IgM by a solid-phase enzyme immunoassay (EIA) and reactivity with normal human kidney targets by indirect immunofluorescence (IF) and immunoperoxidase (IP) techniques. Total IgG production was 500 ng/ml for both spontaneous and PWM stimulated cells. No IgM production was detected. IF and IP studies demonstrated IgG-anti-TBM antibodies in the spontaneous supernatants only. IgG antibodies reactive with peritubular capillaries (anti-PTC) were also noted. IgG-anti-TBM anti-bodies and antibodies reactive with arterioles were subsequently demonstrated by direct immunofluorescence techniques in the rejected allograft. Analysis of serum samples obtained at the time of allograft rejection showed no IF or IP reactivity with the kidney targets. Subsequent analysis of anti-TBM production by the patient's peripheral blood mononuclear cells (PBMs) showed IgM-anti-TBM only. These studies suggest that the IgG-anti-TBM and IgG-anti-PTC antibodies reactive with the allograft resulted from in situ antibody production by ABLs; the role of anti-TBM antibodies in mediating the AR is unclear, but their presence suggests recurrence of the original disease in the allograft. Anti-PTC antibodies could be important in mediation of the vascular AR.

Plasma exchange for recurrent nephrotic syndrome following renal transplantation.

Patients with steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis (FGS) who develop end-stage renal disease are at risk for recurrence of the disease following renal transplantation. Recurrence of the nephrotic syndrome in renal allografts of two children with primary FGS was successfully controlled by plasma exchange. This report suggests that plasma exchange instituted early in the course of recurrent nephrotic syndrome may be beneficial in some patients with steroid-resistant nephrotic syndrome and FGS.

Antibodies to donor B lymphocytes and mixed lymphocyte culture blocking in cadaveric renal transplantation.

In 33 renal allograft recipient-donor pairs, B and T lymphocyte complement-dependent cytotoxicity crossmatches and mixed lymphocyte culture (MLC) blocking experiments were performed and the results were correlated with graft outcome. MLC blocking particularly in the unidirectional culture against donor-stimulating cells, was highly correlated with the presence of complement-dependent cytotoxicity antibodies against donor B lymphocytes. Grafts in both MLC blocking and B lymphocyte crossmatch-positive groups fared equally as well as those without positive tests. No difference in graft outcome was noted when the presence or absence of MLC blocking was examined in relationship to positive or negative B lymphocyte complement-dependent cytotoxicity crossmatching.

Use of antithymocyte globulin (dose by rosette protocol) in pediatric renal allograft recipients.

Total rosette-forming cells (TRFCs) and percentage of rosette-forming cell (RFC) levels were measured in patients undergoing dialysis and in recipients following renal transplantation. The percentage of RFCs of the dialysis patients was not different from the percentage of RFCs of normal subjects, whereas the TRFCs were significantly lower in the dialysis patients. After transplantation, the percentage of RFCs and TRFCs was significantly lower in recipients treated with antithymocyte globulin (ATG) than in those of the control group; however, there was no difference in allograft survival between the ATG-treated and control recipients when using ATG in the dose by rosette protocol.

Circulating immune complexes in pediatric renal allograft rejection.

Previous reports on the generation and nephritogenic capacity of post-transplant circulating immune complexes (CICs) are conflicting. To assess the pathogenicity of CICs in acute rejection (AR), 784 CIC determinations were performed on 392 serum samples from 27 pediatric renal allograft recipients using the C1q-solid phase assay (C1q-SPA) and the Raji cell radioimmunoassay (Raji-RIA). Serum samples from transplant recipients not undergoing rejection episodes and from normal subjects served as controls. Of the 784 CIC determinations, 723 (92.3%) were negative in both assays. CICs were present at some point post-transplant in eight (19.6%) recipients. Correlation of CIC levels with allograft rejection was found in only two patients with CIC levels responding to antirejection therapy; however, statistical analysis of data by chi 2 analysis failed to reveal a significant correlation of CICs with AR episodes. Allograft histology in three recipients demonstrated characteristic signs of AR. Immunofluorescent studies did not reveal significant deposition of immunoglobulin or complement. Sucrose density gradient ultracentrifugation studies confirmed the immune complex nature of materials reactive with the CIC assays. There was no immunological evidence supporting antithymocyte globulin (ATG) as an immunogen in patients demonstrating CICs post-transplant. CICs do not appear to be an important mediator of AR. Statistical analysis of data using the chi 2 test failed to reveal a positive correlation of CIC levels with AR or ultimate allograft outcome.

Prediction of the progression of chronic renal failure in children: are current models accurate?

Mathematical models have been used since 1976 in an attempt to predict the progression of chronic renal failure. These models have used the serum creatinine level as either a reciprocal or logarithmic plot against time. The accuracy of such predictions are characterized by either a correlation coefficient (r value) or prediction error (time at which dialysis was predicted minus time at which dialysis actually occurred). Retrospectively, we analyzed 37 children who progressed to end-stage renal disease, grouped them by their respective primary diseases, and calculated both r values and prediction error for each individual and group. Although r values for each group (with the exception of patients less than 1 year of age) were comparable, prediction errors were widely disparate among the various groupings. Individuals within each of the groups had disparate values even though identical r values were present. These observations indicate that predictive models using serum creatinine levels are of limited clinical use and are least useful for patients younger than 1 year of age.

Noncompliance in children with renal transplants.

Fourteen patients (13 of them adolescents) interrupted immunosuppressive treatment following renal transplantation. Twelve were girls and two were boys. Six subsequently lost their allografts and eight had impaired renal function. Noncompliance was suspected when diminution in cushingoid features, unexplained weight loss, or changes in renal function occurred. Noncompliance was comfirmed by interview with psychosocial staff. Available psychosocial data from family interview and personality test obtained earlier as part of systematic follow-up study were analyzed to explore the reasons for noncompliance. Non compliant patient families had lower incomes, more fatherless households, and comunication difficulties within the family and with the medical establishment. Using a stepwise discriminant analysis, a discriminant function was derived which selected 13 of 14 noncompliant patients. Noncompliance may be a preventable cause of allograft failure. These data can aid in identifying high-risk patients and planning intervention programs.