Steroid-Free Immunosuppression Since 1999: 129 Pediatric Renal Transplants with Sustained Graft and Patient Benefits

Despite early promising patient and graft outcomes with steroid-free (SF) immunosuppression in pediatric kidney transplant recipients, data on long-term safety and efficacy results are lacking. We present our single-center experience with 129 consecutive pediatric kidney transplant recipients on SF immunosuppression, with a mean follow-up of 5 years. Outcomes are compared against a matched cohort of 57 concurrent recipients treated with steroid-based (SB) immunosuppression. In the SF group, 87% of kidney recipients with functioning grafts remain corticosteroid - free. Actual intent-to-treat SF (ITT-SF) and still-on-protocol SF patient survivals are 96% and 96%, respectively, actual graft survivals for both groups are 93% and 96%, respectively and actual death-censored graft survivals for both groups are 97% and 99%, respectively. Unprecedented catch-up growth is observed in SF recipients below 12 years of age. Continued low rates of acute rejection, posttransplant diabetes mellitus (PTDM), hypertension and hyperlipidemia are seen in SF patients, with sustained benefits for graft function. In conclusion, extended enrollment and longer experience with SF immunosuppression for renal transplantation in low-risk children confirms protocol safety, continued benefits for growth and graft function, low acute rejection rates and reduced cardiovascular morbidity.     

Donor Age and Renal P-Glycoprotein Expression Associate with Chronic Histological Damage in Renal Allografts

The contributions of donor kidney quality (partially determined by donor age), allograft rejection, and calcineurin inhibitor nephrotoxicity on the progression of histologic damage of renal allografts are not completely defined. Moreover, the determinants of individual susceptibility to calcineurin inhibitor nephrotoxicity are not known but may include variability in drug transport and metabolism. In a prospective cohort of 252 adult renal allograft recipients treated with a combination of tacrolimus, mycophenolate mofetil, and corticosteroids, we studied 744 renal allograft biopsies obtained regularly from time of transplantation for 3 yr. We assessed determinants of histologic evolution, including tacrolimus exposure, renal P-glycoprotein (ABCB1) expression, and polymorphisms in the CYP3A4, CYP3A5, and ABCB1 genes. Within the first 3 yr after transplantation, we noted a progressive increase in interstitial fibrosis, tubular atrophy, glomerulosclerosis, and vascular intimal thickening. Older donor age, absence of P-glycoprotein expression at the apical membrane of tubular epithelial cells, and combined donor–recipient homozygosity for the C3435T variant in ABCB1 significantly associated with increased susceptibility to chronic allograft damage independent of graft quality at implantation. Changes in graft function over time reflected these associations with donor age and ABCB1 polymorphisms, but it was acute T cell-mediated and antibody-mediated rejection that determined early graft survival. In conclusion, the effects of older donor age reach beyond the quality of the allograft at implantation and continue to be important for histologic evolution in the posttransplantation period. In addition, ABCB1 genotype and expression of P-glycoprotein in renal tubular epithelial cells determine susceptibility to chronic tubulointerstitial damage of transplanted kidneys.Progressive renal allograft dysfunction resulting from cumulative histologic damage to the allograft is the major cause of late renal allograft loss after recipient death with a functioning graft.^1,2 The evolution of renal allograft histology therefore can be regarded as a valuable surrogate marker for long-term graft outcome.³ This evolution has been described in detail by Nankivell et al. using renal allograft biopsies obtained at preset time points after transplantation in kidneys of pristine quality at implantation.⁴ In this study, the kidneys were recovered from a selected group of relatively young donors, and the majority of recipients (kidney–pancreas transplants in all but 1) were treated with a combination of the older formulation of cyclosporine in combination with azathioprine and corticosteroids.⁴However, with the increasing use of kidneys from older or extended criteria donors for transplantation, poor graft quality at implantation emerges as an important determinant of long-term outcome.^5,6 Therefore, the experience of Nankivell et al. may no longer be representative for current clinical practice. In addition, immunosuppressive drug combinations have improved over the past few decades,^7,8 and this has an impact on both histologic and functional evolution of allografts.^9–11 On one hand, although the newer immunosuppressive protocols have reduced the incidence of acute cellular rejection, rejection phenomena continue to play a major role in this histologic evolution. On the other hand, immunosuppressive drugs can elicit direct (e.g., nephrotoxicity of calcineurin inhibitors) and indirect (diabetes mellitus, hyperlipidemia, and hypertension) side effects, which also contribute to renal allograft injury.^12,13The complementary impact of these phenomena (donor kidney quality, allograft rejection, and calcineurin inhibitor nephrotoxicity) on the progression of histologic allograft damage has not been studied in patients treated with the current powerful immunosuppressive protocols nor within the wide range of donor graft quality. Moreover, the determinants of individual susceptibility to calcineurin inhibitor nephrotoxicity are not well known. Previous animal and human studies have suggested a role of decreased P-glycoprotein (ABCB1 or MDR1, the multidrug efflux transporter involved in tacrolimus transport¹⁴) expression^15–17 or activity¹⁸ and genetic polymorphisms in ABCB1^19,20 in the development of calcineurin inhibitor nephrotoxicity.The current study was undertaken to assess the determinants of the histologic evolution of renal allografts in the first years after transplantation in 252 patients treated with a combination of tacrolimus, mycophenolate mofetil, and corticosteroids against a background of varying degrees of pre-existing histologic damage in the donor kidney at implantation.^8,11 In addition, the determinants of individual susceptibility to calcineurin inhibitor nephrotoxicity were evaluated, including extensive tacrolimus exposure data, P-glycoprotein expression, and polymorphisms in ABCB1, CYP3A4, and CYP3A5 of both donor and recipients. Finally, this study examined the features that predict lower MDRD glomerular filtration rate during follow-up and assessed the main determinants of early graft survival.     

Ester prodrugs of cyclic 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine: synthesis and antiviral activity

Reaction of 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (1) with dicyclohexylcarbodiimide and N,N,-dicyclohexyl-4-morpholinocarboxamidine in dimethylformamide at elevated temperature afforded the corresponding cyclic phosphonate 2, that is, 1-{[(5S)-2-hydroxy-2-oxido-1,4,2-dioxaphosphinan-5-yl]methyl}-5-azacytosine. Compound 2 exerts strong in vitro activity against DNA viruses, comparable with activity of parent compound 1. Transformation of 2 to its tetrabutylammonium salt followed by reaction with alkyl or acyloxyalkyl halogenides enabled us to prepare a series of structurally diverse ester prodrugs: alkyl (octadecyl), alkenyl (erucyl), alkoxyalkyl (hexadecyloxyethyl), and acyloxyalkyl (pivaloyloxymethyl) (3-6). The introduction of an alkyl, alkoxyalkyl, or acyloxyalkyl ester group to the molecule resulted in an increase of antiviral activity; the most active compound was found to be the hexadecyloxyethyl ester 5. The relative configuration of the diastereoisomer trans-6 was determined using H,H-NOESY NMR.     

Tacrolimus Exposure and Evolution of Renal Allograft Histology in the First Year After Transplantation

Tacrolimus has a narrow therapeutic window and is characterized by a large inter-individual variability in bioavailability. The impact of tacrolimus exposure on subclinical evolution of graft histology has not been studied in renal recipients. This analysis included 239 protocol biopsies (obtained at implantation, 3 and 12 months) of 120 consecutive kidney recipients treated with tacrolimus, mycophenolate mofetil (MMF) and corticosteroids. Biopsies were scored according to the Banff 2001 criteria and a chronicity score was calculated. Prospective pharmacokinetic data were included in the analysis (5544 tacrolimus predose blood concentrations and tacrolimus AUC(0-12) at 3 and 12 months). Higher donor age and higher number of human leukocyte antigen-DR (HLA-DR) mismatches were independent predictors of subclinical acute rejection at 3 months, present in 8.7% of patients. The number of HLA-DR mismatches was independently associated with biopsy-proven clinical acute rejection. Biopsy-proven acute rejection episodes and low mean tacrolimus exposure were independently associated with higher increase in chronicity scores between 3 and 12 months after transplantation. This observational study suggests that rejection phenomena and immune-mediated mechanisms remain important in the early progression of chronic allograft pathology. Tacrolimus doses or systemic exposure were not associated with lesions of calcineurin inhibitor nephrotoxicity, suggesting that other factors determine susceptibility to tacrolimus nephrotoxicity.     

Resolution of diffuse skin and systemic Kaposi's sarcoma in a renal transplant recipient after introduction of everolimus: a case report

We present a case report of a patient with diffuse skin and systemic Kaposi's sarcoma (KS), 1 year after renal transplantation. A concomitant Pyrenochaeta romeroi granuloma of the right hallux was diagnosed and illustrated an important immunodysfunction in our patient. Four months after reduction in immunosuppression and switch to everolimus, a total regression of the KS was observed. Reduction in the immunosuppression and treatment with terbinafine cleared the P. romeroi infection, while lowering immunosuppression and changing the type of immunosuppressive therapy were important steps in the successful management of the KS. In recent years, evidence of the antitumor effects of everolimus is increasing: total regression of KS in combination with renal function preservation in renal graft recipients is possible with mammalian target of rapamycin (mTOR) inhibitor‐based regimens. In addition, with increasing numbers of human immunodeficiency virus‐positive transplant recipients, mTOR inhibitors may play a more crucial role in the management of KS.     

Tertiary ''Hyperphosphatoninism'' Accentuates Hypophosphatemia and Suppresses Calcitriol Levels in Renal Transplant Recipients

Hypophosphatemia and inappropriately low calcitriol levels are frequently observed following successful renal transplantation. Fibroblast growth factor-23 (FGF-23) is a recently characterized phosphaturic hormone that inhibits renal 1 alpha-hydroxylase activity and may be involved in the pathogenesis of both phenomena. The following hypotheses were tested: pretransplant FGF-23 predicts posttransplant FGF-23, FGF-23 predicts posttransplant hypophosphatemia and FGF-23 is associated with decreased calcitriol levels independent of renal and parathyroid function. Serum biointact parathyroid hormone (PTH), calcidiol, calcitriol, full-length FGF-23, calcium and phosphate were monitored in 41 renal transplant recipients at the time of transplantation (pre) and 3 months thereafter (post). In addition, serum phosphate nadir in each individual patient was identified and urinary fractional excretion of phosphate (FE(PO4)) at month 3 was calculated. High FGF-23(post) levels were independently associated with high FGF-23(pre), low calcitriol(post) and high calcium(post) levels. FGF-23, but none of the other mineral metabolism indices, was an independent predictor of the phosphate nadir in the early posttransplant period. A high FGF-23(post) level was independently associated with a high FE(PO4). High FGF-23(post) and creatinine levels and low PTH(post) levels were independently associated with low calcitriol(post) levels. In conclusion, our data indicate that persistence of FGF-23 contributes to hypophosphatemia and suboptimal calcitriol levels in renal transplant recipients.