Unravelling the connections between donor specific antibodies and renal allograft pathology.

The imperfections of early technologies for assessment of human leukocyte antigen (HLA) antibody specificity have been resolved by solid phase micro bead assays, but this has revealed new uncertainties. The relationship between presence of antibody specific for a donor HLA molecule to graft damage and outcomes has had to be re-evaluated. Studies of protocol biopsies have identified a correlation between donor specific antibody and electron microscopy (EM) changes at three months, which do not predict chronic antibody mediated rejection, but that are predicted by EM changes seen on 12-month protocol biopsies. These intriguing results point to the plasticity of the renal endothelium in the earlier post-transplant months, as well as to the reality that the immune system interaction with the endothelium changes with time.

Transcriptome changes of chronic tubulointerstitial damage in early kidney transplantation.

BACKGROUND: Tubulointerstitial damage (TID) is a key feature of chronic kidney transplant failure; however, the associated gene expression changes are poorly defined. METHODS: This pilot study used RNA from 59 protocol kidney transplant biopsies at implantation, 1, 3, and 12 months (n=18 patients), processed into cDNA and hybridized to 8K human cDNA microarrays. Gene expression was correlated with graft histology categorized by the Banff schema. RESULTS: Gene and pathway expression were differentially activated according to the time after transplantation. Immune pathway activity peaked at 1 month, fibrotic expression at 3 months, wound healing-remodelling and cell proliferation-repair processes were activated between 3 and 12 months, whereas macrophage-related gene expression occurred late by 12 months. Forty percent of genes and 50% pathways initially activated persisted to 3 months. Biopsies with TID displayed 262 differentially expressed genes (P<0.001, B>2 compared with implantation), dominated by upregulated fibrogenic and immune-related genes reflecting unique immune (10% to 15% of genes) and fibrotic (15% vs. 4% in normal) pathway activation. Profibrotic genes were expressed before interstitial fibrosis was observed by sequential microscopic analysis. Kidneys progressing to TID by 3 months demonstrated 30 unique genes (B>1, P<0.05) versus nonprogressors with 95 genes (B>1, P<0.009). Fourteen of these progressor genes also occurred in the top decile from an independent validation set. CONCLUSIONS: Allografts display predictable immune and fibrotic gene expression profiles, with patterns of expression gradually varying by time after transplantation. The pathology reflects differential activation of intrinsic pathways. Gene expression predated histologic damage, suggesting its possible use in early diagnostic testing.

Individualization of immunosuppression: concepts and rationale.

PURPOSE OF REVIEW: New immunosuppressive agents have decreased the incidence of acute rejection rates without improvement in long-term outcomes. Drug toxicity due to a narrow therapeutic index and individual variations in pharmacokinetics and pharmacodynamics significantly contributes to the inferior outcomes. This review focuses on advances in individualization of immunosuppression therapy using therapeutic drug monitoring and pharmacogenetics/pharmacogenomics as a strategy to minimize toxicity. RECENT FINDINGS: Although therapeutic drug monitoring for calcineurin inhibitors and mammalian targets of rapamycin inhibitors is well established, its utility in mycophenolate mofetil dosage adjustments is still the subject of ongoing debate. However, there is potential for optimizing mycophenolate mofetil therapy based on polymorphisms in genes that encode metabolizing and target enzymes. Single-nucleotide polymorphisms in cytochrome P450 genes have an effect on tacrolimus response. Donor genotype could have an effect on drug metabolism. SUMMARY: Therapeutic drug monitoring remains the most widely used method for individualizing immunotherapy. Improvements in molecular technology have enabled identification of several polymorphisms in genes that encode for drug-metabolizing enzymes, drug transporters, and their targets, which have an effect on individual response to therapy. Prospective studies are needed to explore this field and improve utility of donor and recipient genotype testing in managing immunosuppression therapy.

Epithelial-to-mesenchymal transition in early transplant tubulointerstitial damage.

It is unknown whether epithelial-to-mesenchymal transition (EMT) leads to tubulointerstitial fibrosis in renal transplants. In this study, interstitial fibrosis and markers of EMT were followed in protocol transplant biopsies in 24 patients. Tubulointerstitial damage (TID) increased from 34 to 54% between 1 and 3 mo after transplantation. Detection of EMT depended on the marker used; low levels of alpha-smooth muscle actin were found in 61% of biopsies, but the less specific marker S100 calcium binding protein-A4 (also known as Fsp1) suggested a higher incidence of EMT. The presence or development of TID did not correlate with EMT but instead significantly correlated with subclinical immune activity (P < 0.05). Among biopsies showing TID, microarray analysis revealed differential regulation of 127 genes at 1 mo and 67 genes at 3 mo compared with baseline; these genes were predominantly associated with fibrosis, tissue remodeling, and immune response. Of the 173 EMT-associated genes interrogated, however, only 8.1% showed an expression pattern consistent with EMT at 1 mo and 6.3% at 3 mo. The remainder were not differentially altered, or their changes in expression were opposite those expected to promote EMT. Quantitative reverse transcriptase-PCR revealed that the expression pattern of 12 EMT-associated genes was inconsistent over time, opposite that expected, or consistent with subclinical rejection or inflammation. In conclusion, EMT does not seem to play a significant role in the development of early allograft fibrosis.

The need for early nephrology referral.

The incidence of end-stage renal disease is increasing. Progression to end stage can be slowed if kidney damage is detected at an early stage. Prognosis and outcomes in patients with chronic kidney disease have been related to the quality of predialysis care and the timing of referral. Many patients with chronic kidney disease are referred to a nephrologist close to commencement of renal replacement therapy. This leads to suboptimal management of complications of chronic renal insufficiency, and increased morbidity and mortality of patients on renal replacement therapy. This article addresses the evidence that examines the view that patients need to be referred early in order to avoid complications of chronic renal insufficiency. Early referral can be achieved through improved communication between primary health care givers and nephrology services. A multidisciplinary approach has a significant impact on outcomes. In the face of rising incidence of chronic kidney disease, early referral of all patients is not possible. Therefore, identification of patients at risk for rapid deterioration of renal function is important in order to rationalize and reduce health care expenditure.