Peter D. Yorgin

Promising early outcomes with a novel, complete steroid avoidance immunosuppression protocol in pediatric renal transplantation.

Background. Corticosteroids have been a cornerstone of immunosuppression for four decades despite their adverse side effects. Past attempts at steroid withdrawal in pediatric renal transplantation have had little success. This study tests the hypothesis that a complete steroid-free immunosuppressive protocol avoids steroid dependency for suppression of the immune response with its accompanying risk of acute rejection on steroid withdrawal. Methods. An open labeled prospective study of complete steroid avoidance immunosuppressive protocol was undertaken in 10 unsensitized pediatric recipients (ages 5–21 years; mean 14.4 years) of first renal allografts. Steroids were substituted with extended daclizumab use, in combination with tacrolimus and mycophenolate mofetil. Protocol biopsies were performed in the steroid-free group at 0, 1, 3, 6, and 12 months posttransplantation. Clinical outcomes were compared to a steroid-based group of 37 matched historical controls. Results. Graft and patient survival was 100% in both groups. Clinical acute rejection was absent in the steroid-free group at a mean follow-up time of 9 months (range 3–13.7 months). Protocol biopsies in the steroid-free group (includes 10 patients at 3 months, 7 at 6 months, and 4 at 12 months) revealed only two instances of mild (Banff 1A) subclinical rejection (reversed by only a nominal increase in immunosuppression) and no chronic rejection. At 6 months the steroid-free group had no hypertension requiring treatment (P =0.003), no hypercholesterolemia (P =0.007), and essentially no body disfigurement (P =0.0001). Serum creatinines, Schwartz GFR, and mean delta height Z scores trended better in the steroid-free group. In the steroid-free group, one patient had cytomegalovirus disease at 1 month and three had easily treated herpes simplex stomatitis, but with no significant increase in bacterial infections or rehospitalizations over the steroid-based group. The steroid-free group was more anemic early posttransplantation (P =0.004), suggesting an early role of steroids in erythrogenesis; erythropoietin use normalized hematocrits by 6 months. Conclusions. Complete steroid-free immunosuppression is efficacious and safe in this selected group of children with no early clinical acute rejection episodes. This protocol avoids the morbid side effects of steroids without increasing infection, and may play a future critical role in avoiding noncompliance, although optimizing renal function and growth.

Treatment of steroid-resistant focal segmental glomerulosclerosis with pulse methylprednisolone and alkylating agents

In children, steroid-resistant nephrotic syndrome due to focal segmental glomerulosclerosis (FSGS) is frequently a progressive condition resulting in end-stage renal disease. There have been no reports of effective treatment for this condition. For the past several years, the Pediatric Nephrology services at the University of California, San Diego and Stanford University Schools of Medicine have treated these patients with a protocol involving infusions of high doses of methylprednisolone, often in combination with oral alkylating agents. Twenty-three children have been treated in this manner with a follow-up of 46±5 months. Twelve of these children are in complete remission. Six have minimal to moderate proteinuria. Four children remain nephrotic. Each of these children has a normal glomerular filtration rate. One child developed chronic renal failure and subsequently died while on dialysis. These results appear significantly better than previous series of children with FSGS. A controlled, multi-center trial of this protocol has been proposed.

Late Post-transplant Anemia in Adult Renal Transplant Recipients. An Under-recognized Problem?

Post‐transplant anemia (PTA), a frequent complication during the first 3–6 months after transplant, is thought to be uncommon during the late post‐transplant period. A study population of adults (> 18 years) transplanted during 1995 at Stanford University (n = 88) and University of North Carolina (n = 40) was selected. Data‐collection points were 0, 1, 2, 3, 4 and 5 years post transplant. Anemia was defined as a hematocrit < 33 volume percentage. Thirty percent of patients were anemic at some time during the post‐transplant period. The prevalence of PTA increased over time; by 5 years post transplant, 26% of the patients were anemic. Anemia occurred in 62.5% of patients converted from azathioprine to mycophenolate mofetil. A multivariate logistic regression model demonstrated a correlation between anemia and serum total CO2 (p = 0.002), BUN (p = 0.04), and creatinine (p = 0.045) at 1 year post transplant. At 5 years post transplant, only serum total CO2 (p = 0.0004) correlated with anemia. Thus, diminished renal excretory function and metabolic acidosis appear to be the most important correlates of late PTA. These findings should be interpreted in view of the fact that the newer immunosuppressive agents may have an even more profound effect on anemia and its recovery after transplantation.

Effects of Geldanamycin, a Heat-Shock Protein 90-Binding Agent, on T Cell Function and T Cell Nonreceptor Protein Tyrosine Kinases

The benzoquinoid ansamycins geldanamycin (GA), herbimycin, and their derivatives are emerging as novel therapeutic agents that act by inhibiting the 90-kDa heat-shock protein hsp90. We report that GA inhibits the proliferation of mitogen-activated T cells. GA is actively toxic to both resting and activated T cells; activated T cells appear to be especially vulnerable. The mechanism by which GA acts is reflected by its effects on an essential hsp90-dependent protein, the T cell-specific nonreceptor tyrosine kinase lck. GA treatment depletes lck levels in cultured T cells by a kinetically slow dose-dependent process. Pulse-chase analyses indicate that GA induces the very rapid degradation of newly synthesized lck molecules. GA also induces a slower degradation of mature lck populations. These results correlate with global losses in protein tyrosine kinase activity and an inability to respond to TCR stimuli, but the activity of mature lck is not immediately compromised. Although the specific proteasome inhibitor lactacystin provides marginal protection against GA-induced lck depletion, proteasome inhibition also induces changes in lck detergent solubility independent of GA application. There is no other evidence for the involvement of the proteosome. Lysosome inhibition provides quantitatively superior protection against degradation. These results indicate that pharmacologic inhibition of hsp90 chaperone function may represent a novel immunosuppressant strategy, and elaborate on the appropriate context in which to interpret losses of lck as a reporter for the pharmacology of GA in whole organisms.

Anemia in children after transplantation: etiology and the effect of immunosuppressive therapy on erythropoiesis

Abstract: Anemia in children after renal transplantation is more common than previously appreciated. Multiple factors appear to play roles in the development of post‐transplant anemia, the most common of which is absolute and/or functional iron deficiency anemia. Most experts recommend that iron limited anemias in transplant patients should be diagnosed using the same criteria as for chronic renal failure patients. Serum erythropoietin (EPO) levels are expected to normalize after a successful renal transplantation with a normal kidney function, yet both EPO deficiency and resistance have been reported. While no large controlled trials comparing the effect of different immunosuppressive agents on erythropoiesis after transplantation have been performed, generalized bone marrow suppression attributable to azathioprine (AZA), mycophenolate mofetil (MMF), tacrolimus, antithymocyte preparations has been reported. Pure red cell aplasia (PRCA) occurs rarely after transplantation and is characterized by the selective suppression of erythroid cells in the bone marrow. PRCA has been reported with the use of AZA, MMF, tacrolimus, angiotensin converting enzyme inhibitors (ACEI), but not with cyclosporine (CSA) use. Post‐transplant hemolytic uremic syndrome has been reported with orthoclone anti T‐cell antibody (OKT3), CSA and tacrolimus therapy. Viral infections including cytomegalovirus, Epstein–Barr virus and human parvovirus B19 have been reported to cause generalized marrow suppression. Management of severe anemia associated with immunosuppressive drugs generally requires lowering the dose, drug substitution or, when possible, discontinuation of the drug. Because this topic has been incompletely studied, our recommendation as to the best immunosuppressive protocol after renal transplantation remains largely dependent on the clinical response of the individual patient.

Pulse methylprednisolone treatment of idiopathic steroid-resistant nephrotic syndrome

Abstract Although much of the interest in pulse methylprednisolone therapy (PMT) has centered around its use in children with focal segmental glomerulosclerosis, PMT has also been shown to be effective in the treatment of other proteinuric renal diseases. We hypothesized that a PMT-based treatment protocol, derived from the Tune-Mendoza protocol, would effectively induce a more rapid remission in young children with idiopathic steroid-resistant nephrotic syndrome (SRNS). A retrospective analysis was conducted of 11 consecutive SRNS patients (mean age 3.6±1.5 years) that received PMT between 1 August 1992 and 1 May 1998. The initial mean urinary protein/urinary creatinine ratio (UP/UC, mg/mg) was 8.3±9.7 and mean estimated creatinine clearance (CCr) 137.7±47.0 ml/min per 1.73 m2. An average of 24.8±10.5 PMT doses were given. The mean duration of PMT therapy until remission was 23.4±29.9 days (median 12 days). Cyclosporine and cyclophosphamide were used to maintain and extend remissions in 5 and 4 patients, respectively. At the conclusion of the study, the mean UP/UC was 0.12±0.22 and mean CCr 151.8± 39.8 ml/min per 1.73 m2 (no CCr≤100 ml/min per 1.73 m2). Of the 11 patients, 9 attained complete remission. Adverse effects were mild and infrequent. This PMT protocol appears to safely and effectively induce remission in young children with SRNS. A future prospective trial that evaluates the efficacy of PMT in young children with SRNS is warranted.

Long-term plasmapheresis and protein A column treatment of recurrent FSGS

Abstract. Transient or intermittent plasmapheresis with concurrent immunosuppressive therapy is thought to be beneficial in the treatment of recurrent focal segmental glomerulosclerosis (FSGS) in the early post-transplant period. The results of long-term (6-year) plasmapheresis therapy, in a 9-year-old female with an immediate recurrence of FSGS [urinary protein/urinary creatinine (UP/UC)=17.7] after cadaveric renal transplant, are presented. A 4-week plasmapheresis course induced a decline in the proteinuria, but a relapse occurred after cessation of plasmapheresis. Addition of protein A column therapy led to a further decrease in the proteinuria, to a non-nephrotic range. Long-term control of the nephrotic syndrome was established using a chronic treatment regimen consisting of a single-volume plasmapheresis, followed by a protein A column treatment, performed on sequential days every 3–4 weeks. Mean UP/UC values decreased to 1.15±0.9. A course of cyclophosphamide was successfully used to control a worsening of proteinuria 4 years post transplant. Although sequential renal biopsies demonstrated progressive glomerular sclerosis, the patient’s mean calculated creatinine clearance only modestly declined from 78.3 ml/min per 1.73 m2, at the time of transplantation, to 62.7 ml/min per 1.73 m2, 6 years later. This patient demonstrated dependence on plasmapheresis/protein A column therapy to maintain a clinical remission of her FSGS recurrence. While long-term plasmapheresis and protein A column therapy in combination with immunosuppressive therapy reversed the effects of uncontrolled nephrosis and possibly facilitated long-term renal allograft survival, the glomerular sclerosis continued to progress.

The use of art therapy to detect depression and post‐traumatic stress disorder in pediatric and young adult renal transplant recipients

Abstract:  Pediatric and young adult renal transplant recipients may experience feelings of depression and emotional trauma. A study was conducted to (1) determine the prevalence of depression and emotional trauma and (2) assess the utility of the Formal Elements of Art Therapy Scale (FEATS). Sixty‐four renal transplant recipients, 6–21 yr of age, were evaluated using self‐report measures (CDI and Davidson) and art‐based assessments. Subject art was analyzed by art therapists using seven of the 14 elements of the (FEATS), to assess depression. Unlike CDI and Davidson self‐report testing, all patients were able to complete the art‐based directives. When self‐report measures and art‐based assessments were combined, 36% of the study population had testing results consistent with depression and/or post‐traumatic stress. The FEATS assessments identified a subset of patients who were not identified using the self‐report measures. There was a correlation between CDI and Davidson scores (p < 0.0001), Davidson scores correlated with hospital days (p = 0.05), and FEATS correlated with height Z score (p = 0.04) and donor type (p = 0.01). Patients who required psychological interventions including antidepressant therapy, psychological counseling and psychiatric hospitalization during the year after the study were identified as depressed. Sensitivity for FEATS and CDI were 22 and 50% respectively. The results suggest that while art therapy may be of utility in the identification of pediatric and young adult transplant recipients who are suffering from depression, FEATS analysis appears to lack sufficient sensitivity to warrant its use in this population. Study of other quantitative art‐based assessment techniques may be warranted.

Limited surgical interventions in children with posterior urethral valves can lead to better outcomes following renal transplantation

Abstract: There is currently no consensus as to the most appropriate means by which children with posterior urethral valves (PUV) are to be managed prior to transplantation. We compared (i) renal allograft survival and function in patients with PUV vs. those with non‐obstructive causes of ESRD and (ii) graft outcomes in children who had limited interventions (Group 1) vs. those with more extensive urologic surgeries to decompress the urinary tract (Group 2). Twenty‐six pediatric renal transplant recipients had ESRD due to PUV (Group 1, n = 16; Group 2, n = 10). The study group was compared to 23 matched controls with ESRD due to non‐obstructive causes. Five yr patient and graft survival was similar in all patients with PUV (Groups 1 and 2) when compared to all other kidney recipients in the transplant program, 96.2% vs. 98.0% and 87.5% vs. 87.0%, respectively. Although calculated creatinine clearance (Ccr), was similar between the PUV group and controls for the first 4 yr, the 5 yr graft function was significantly lower in the PUV group. (53.7 ± 15.7 vs. 70.2 ± 21.0 mL/min/1.73 m2; p = 0.03). When the two PUV groups were compared, graft survival was equivalent, but graft function was significantly better at 5 yr in Group 1(60.4 ± 10.8 vs. 33.8 ± 9.3 mL/min/1.73 m2; p = 0.02). Thus, patients with PUV managed by a limited intervention approach of vesicostomy with delayed valve ablation or primary valve ablation, had better outcomes. When ESRD is virtually certain, additional pre‐transplant surgeries affecting the urinary tract should be avoided.

Comparison of outcomes with low-dose anti-thymocyte globulin, basiliximab or no induction therapy in pediatric kidney transplant recipients: a retrospective study.

Abstract: It is unclear which induction therapy yields the best outcomes in pediatric kidney transplantation. Retrospective data of 88 children receiving a renal allograft between November 1996 and October 2003 were analyzed. Patients received ATGI (n = 12), BI (n = 29), or NAI (n = 47). The mean ATG dose was 5.1 ± 2.1 mg/kg. At 12 months, graft survival rates were 91.7%, 100%, and 97.9% for ATGI, BI, and NAI groups, respectively. Acute rejection rates at 12 months were 0 (ATGI), 20.6% (BI), and 10.7% (NAI). The mean GFR for ATGI (42.4 ± 25.9 mL/min) was lower than for BI (78.3 ± 27.2 mL/min), and NAI (66 ± 28.3 mL/min) at 12 months (p < 0.05). One ATGI patient developed CMV pneumonia but none developed post‐transplant lymphoproliferative disorder. Although there was no renal allograft survival benefit with either ATGI or BI, relative to NAI, the absence of acute rejection and equivalent rates of viral infections in the higher‐risk ATGI recipient group suggests that the treatment strategy is promising. A large prospective study is needed to better define the role of ATGI in pediatric kidney transplantation.