Chronic Transplant Dysfunction Research Articles

Prevention of Triglyceridemia by (Non-)Anticoagulant Heparin(oids) Does Not Preclude Transplant Vasculopathy and Glomerulosclerosis.

Background: In renal transplantation, chronic transplant dysfunction (CTD) is associated with increased PCSK9 and dyslipidemia. PCSK9 is an enzyme that increases plasma cholesterol levels by downregulating LDLR expression. We recently showed increased PCSK9–syndecan-1 interaction in conditions of proteinuria and renal function loss. Treatment with heparin(oids) might be a therapeutic option to improve dyslipidemia and CTD. We investigated the effects of (non-)anticoagulant heparin(oids) on serum lipids, syndecan-1 and PCSK9 levels, and CTD development. Methods: Kidney allotransplantation was performed from female Dark Agouti to male Wistar Furth recipients. Transplanted rats received daily subcutaneous injections of saline, unfractionated heparin, and RO-heparin or NAc-heparin (2 mg heparin(oid)/kg BW) until sacrifice after 9 weeks of treatment. Results: Saline-treated recipients developed hypertension, proteinuria, and loss of creatinine clearance (all p < 0.05 compared to baseline), along with glomerulosclerosis and arterial neo-intima formation. Saline-treated recipients showed significant increase in plasma triglycerides (p < 0.05), borderline increase in non-HDLc/HDLc (p = 0.051), and ∼10-fold increase in serum syndecan-1 (p < 0.05), without significant increase in serum PCSK9 at 8 weeks compared to baseline. Heparin and non-anticoagulant RO-heparin administration in transplanted rats completely prevented an increase in triglycerides compared to saline-treated recipients at 8 weeks (both p < 0.05). Heparin(oids) treatment did not influence serum total cholesterol (TC), plasma syndecan-1 and PCSK9 levels, creatinine clearance, proteinuria, glomerulosclerosis, and arterial neo-intima formation, 8 weeks after transplantation. Combining all groups, increased syndecan-1 shedding was associated with TC (r = 0.5; p = 0.03) and glomerulosclerosis (r = 0.53; p = 0.021), whereas the non-HDLc/HDLc ratio was associated with the neo-intimal score in the transplanted kidneys (r = 0.65; p < 0.001). Conclusion: Prevention of triglyceridemia by (non-)anticoagulant heparin(oids) neither influenced PCSK9/syndecan-1 nor precluded CTD, which however did associate with the shedding of lipoprotein clearance receptor syndecan-1 and the unfavorable cholesterol profile.

Will advances in functional renal magnetic resonance imaging translate to the nephrology clinic?

Characterizing structural and tissue abnormalities of the kidney is fundamental to understanding kidney disease. Functional multi-parametric renal magnetic resonance imaging (MRI) is a noninvasive imaging strategy whereby several sequences are employed within a single session to quantify renal perfusion, tissue oxygenation, fibrosis, inflammation, and oedema without using ionizing radiation. In this review, we discuss evidence surrounding its use in several clinical settings including acute kidney injury, chronic kidney disease, hypertension, polycystic kidney disease and around renal transplantation. Kidney size on MRI is already a validated measure for making therapeutic decisions in the setting of polycystic kidney disease. Functional MRI sequences, T1 mapping and apparent diffusion coefficient, can non-invasively quantify interstitial fibrosis and so may have a near-future role in the nephrology clinic to stratify the risk of progressive chronic kidney disease or transplant dysfunction. Beyond this, multi-parametric MRI may be used diagnostically, for example differentiating inflammatory versus ischaemic causes of renal dysfunction, but this remains to be proven. Changes in MRI properties of kidney parenchyma may be useful surrogate markers to use as end points in clinical trials to assess if drugs prevent renal fibrosis or alter kidney perfusion. Large, multi-centre studies of functional renal MRI are ongoing which aim to provide definitive answers as to its role in the management of patients with renal dysfunction.

Renal transplant evaluation: multimodality imaging of post-transplant complications.

With advancements in surgical techniques and immuno-suppression, renal transplantation is established as the most effective treatment option in patients with end-stage renal disease. Early detection of renal allograft complications is important for long-term graft survival. Late clinical presentation often causes diagnostic delays till the time allograft failure is advanced and irreversible. Imaging plays a key role in routine surveillance and in management of acute or chronic transplant dysfunction. Multimodality imaging approach is important with ultrasound-Doppler as the first-line imaging study in immediate, early and late post-transplant periods. Additional imaging studies are often required depending on clinical settings and initial ultrasound. Renal functional MRI is a rapidly growing field that has huge potential for early diagnosis of transplant dysfunction. Multiparametric MRI may be integrated in clinical practice as a noninvasive and comprehensive "one-stop" modality for early diagnosis and longitudinal monitoring of renal allograft dysfunctions, which is essential for guiding appropriate interventions to delay or prevent irreversible renal damage. With rapidly increasing numbers of renal transplantation along with improved patient survival, it is necessary for radiologists in all practice settings to be familiar with the normal appearances and imaging spectrum of anatomical and functional complications in a transplant kidney. Radiologist"s role as an integral part of multidisciplinary transplantation team continues to grow with increasing numbers of successful renal transplantation programs across the globe.

Death after lung transplantation: improving long term survival despite perilous early postoperative years.

Many centers showed that since they started a lung transplantation program overall survival improved every 5 or 10 year cohort. This is also seen in combined international data (1). Many changes in donor selection, organ preservation and perioperative management improved short term survival despite usage of extended criteria donors. In parallel, also long term survival improved, likely due to gained experience and better anticipation on developing diseases after transplantation.

Increased migration of antigen presenting cells to newly-formed lymphatic vessels in transplanted kidneys by glycol-split heparin.

BackgroundChronic renal transplant dysfunction is characterized by loss of renal function and tissue remodeling, including chronic inflammation and lymph vessel formation. Proteoglycans are known for their chemokine presenting capacity. We hypothesize that interruption of the lymphatic chemokine–proteoglycan interaction interferes with the lymphatic outflow of leukocytes from the renal graft and might decrease the anti-graft allo-immune response.MethodsIn a rat renal chronic transplant dysfunction model (female Dark-Agouti to male Wistar Furth), chemokines were profiled by qRT-PCR in microdissected tubulo-interstitial tissue. Disruption of lymphatic chemokine–proteoglycan interaction was studied by (non-anticoagulant) heparin-derived polysaccharides in vitro and in renal allografts. The renal allograft function was assessed by rise in plasma creatinine and urea.ResultsWithin newly-formed lymph vessels of transplanted kidneys, numerous CD45+ leukocytes were found, mainly MHCII+, ED-1-, IDO-, HIS14-, CD103- antigen presenting cells, most likely representing a subset of dendritic cells. Treatment of transplanted rats with regular heparin and two different (non-)anticoagulant heparin derivatives revealed worsening of kidney function only in the glycol-split heparin treated group despite a two-fold reduction of tubulo-interstitial leukocytes (p<0.02). Quantitative digital image analysis however revealed increased numbers of intra-lymphatic antigen-presenting cells only in the glycol-split heparin group (p<0.01). The number of intra-lymphatic leukocytes significantly correlates with plasma creatinine and urea, and inversely with creatinine clearance.ConclusionsTreatment of transplanted rats with glycol-split heparin significantly increases the number of intra-lymphatic antigen presenting cells, by increased renal diffusion of lymphatic chemokines, thereby increasing the activation and recruitment of antigen presenting cells towards the lymph vessel. This effect is unwanted in the transplantation setting, but might be advantageous in e.g., dendritic cell vaccination.

Human Cytomegalovirus-Encoded Receptor US28 Is Expressed in Renal Allografts and Facilitates Viral Spreading In Vitro.

Renal transplantation is the preferred treatment for patients with end-stage renal disease. Human cytomegalovirus (HCMV) activation is associated with decreased renal graft function and survival. Human cytomegalovirus encodes several immune modulatory proteins, including the G protein-coupled receptor US28, which scavenges human chemokines and modulates intracellular signaling. Our aim was to identify the expression and localization of US28 in renal allograft biopsies by immunohistochemistry and determine its role in viral spreading in vitro. Immunohistochemistry revealed US28 in 31 of 34 renal transplant biopsies from HCMV-seropositive donors. Expression was independent of HCMV viremia or IgG serostatus. US28 was predominantly expressed in the cytoplasm of vascular smooth muscle cells (VSMCs) and tubular epithelial cells, with a median positivity of 20% and 40%, respectively. Also, US28-positive cells were present within arterial neointima. In contrast to US28, HCMV-encoded immediate early antigen was detected in less than 5% of VSMCs, tubular epithelial cells, interstitial endothelium, interstitial inflammatory infiltrates, and glomerular cells.Primary VSMCs were infected with green fluorescent protein-tagged wild type or US28-deficient HCMV. The viral spreading of US28-deficient HCMV, via culture medium or cell-to-cell transmission, was significantly impeded as shown by green fluorescent protein (ie, infected) cell quantification and quantitative real-time polymerase chain reaction. Additionally, the number and size of foci was smaller. In summary, HCMV-encoded US28 was detected in renal allografts from HCMV-positive donors independent of viremia and serostatus. Also, US28 facilitates HCMV spreading in VSMCs in vitro. Because the vasculature is affected in chronic renal transplant dysfunction, US28 may provide a potential target for therapeutic intervention.

Erratum: Local gene therapy with indoleamine 2,3-dioxygenase protects against development of transplant vasculopathy in chronic kidney transplant dysfunction

Correction to: Gene Therapy advance online publication 4 August 2016; doi:10.1038/gt.2016.59 Following the online publication of this article, noted that the article title contained errors. The complete and correct title appears above.

Local gene therapy with indoleamine 2,3-dioxygenase protects against development of transplant vasculopathy in chronic kidney transplant dysfunction.

Chronic transplant dysfunction (CTD) is the primary cause of late allograft loss in kidney transplantation. Indoleamine 2,3-dioxygenase (IDO) is involved in fetomaternal tolerance and IDO gene therapy inhibits acute rejection following kidney transplantation. The aim of this study is to investigate whether gene therapy with IDO is able to attenuate CTD. Transplantation was performed in a rat Dark-Agouti to Wistar-Furth CTD model. Donor kidneys were incubated either with an adenovirus carrying IDO gene, a control adenovirus or saline. During the first 10 days recipients received low-dose cyclosporine. Body weight, blood pressure, serum creatinine and proteinuria were measured every 2 weeks. Rats were killed after 12 weeks. IDO had a striking beneficial effect on transplant vasculopathy at week 12. It also significantly improved body weight gain; it reduced blood pressure and decreased proteinuria during the follow-up. However, it did not affect the kidney function. In addition, IDO therapy significantly decreased the number of graft-infiltrating macrophages at week 12. The messenger RNA levels of forkhead box p3 and transforming grow factor-β were elevated in the IDO treated group at week 12. Here we show for first time a clear beneficial effect of local IDO gene therapy especially on transplant vasculopathy in a rat model of renal CTD.

Thrombotic Microangiopathy as a Cause of Chronic Kidney Transplant Dysfunction: Case Report Demonstrating Successful Treatment with Eculizumab

Atypical hemolytic uremic syndrome is a rare disease associated with genetic or acquired defects in complement regulation which frequently leads to renal failure. Disease often recurs early after kidney transplantation, leading to a rapid irreversible loss of function. Extrarenal features, such as hemolysis and thrombocytopenia, may not always occur, and diagnosis is made by demonstrating the classic features of thrombotic microangiopathy on renal biopsy. Eculizumab, a terminal complement inhibitor, has been used successfully to treat fulminant early recurrent disease after transplantation. We describe a case of disease recurrence presenting in the second year after transplantation with a gradual decline in function and the first report of eculizumab treatment for chronic thrombotic microangiopathy in a transplanted kidney. The resultant diagnostic challenges and successful response to eculizumab in this setting are discussed.

Early Posttransplant Tryptophan Metabolism Predicts Long-term Outcome of Human Kidney Transplantation.

Chronic transplant dysfunction (CTD) is the leading cause of long-term loss of the renal allograft. So far, no single test is available to reliably predict the risk for CTD. Monitoring of tryptophan (trp) metabolism through indoleamine 2.3-dioxygenase (IDO) has been previously proposed to predict acute rejection of human kidney transplants. Here, we investigate the potential of IDO/trp degradation along the kynurenine (kyn) pathway to predict the long-term outcome of human kidney transplantation. During the 2-year follow-up blood, urine, and kidney biopsies were collected from 48 renal transplant patients. Concentrations of kyn and trp in serum and urine were measured at 2 weeks, 6 months, and 2 years after transplantation. Kynurenine to tryptophan ratio was calculated as an estimate of trp degradation. To evaluate the histological changes and IDO expression, respectively, periodic acid schiff staining and immunohistochemistry for IDO were performed on biopsies taken at 6 months and 2 years. Two years after transplantation, kyn/trp was increased in urine and decreased in serum as compared to 2-week values. In 2-year biopsies, IDO expression was mainly found in infiltrating inflammatory cells and in the glomeruli. The urine level of trp 2 weeks after transplantation predicted the serum creatinine 6 months and the estimated creatinine clearance 2 years after transplantation. Additionally, serum level of kyn 6 months after transplantation predicted the serum creatinine 2 years after transplantation. Early serum and urine levels of trp and kyn may offer a novel route for early detection of patients at risk for developing CTD.

E22. A Case of Rhabdomyolysis Induced by Febuxostat Therapy in a Patient with Hyperuricaemia and Chronic Renal Transplant Dysfunction

E22. A Case of Rhabdomyolysis Induced by Febuxostat Therapy in a Patient with Hyperuricaemia and Chronic Renal Transplant Dysfunction

CD16+ monocytes with smooth muscle cell characteristics are reduced in human renal chronic transplant dysfunction

In chronic transplant dysfunction (CTD), persistent (allo)immune-mediated inflammation eventually leads to tissue remodeling including neointima formation in intragraft arteries. We previously showed that recipient-derived neointimal α-SMA+ smooth muscle-like cells are present in human renal allografts with CTD. Human PBMC contain myeloid cells capable of differentiating into α-SMA+ cells in vitro; the phenotype of the ancestral subset is as yet unknown. This study aimed to investigate whether monocyte subsets contain cells with smooth muscle-like cell differentiation capacity and whether CTD in renal transplant recipients is associated with a shift in these monocyte subsets. To accomplish this goal, monocyte subsets from healthy controls were sorted based on CD14 and CD16 expression to investigate gene expression levels of mesenchymal markers α-SMA and SM22α. CD14+/CD16++ monocytes displayed increased α-SMA and SM22α mRNA expression compared with CD14++/CD16− monocytes, suggesting increased differentiation potential toward smooth muscle-like cells. Flow cytometry revealed that in non-CTD transplant recipients the percentage of CD14+/CD16++ monocytes was reduced, with an even further reduction in patients with CTD. To determine a potential correlation between CD14+/CD16++ monocytes and α-SMA+ cell outgrowth potential in vitro, PBMC of healthy controls and transplant recipients with and without CTD were cultured under fibrotic culture conditions, and indeed a significant correlation (p=0.0002, r=0.62) was observed. Finally, double staining for α-SMA and CD16 revealed presence of α-SMA+CD16+ cells in kidney explants from CTD patients, albeit at very low numbers.Our data represent evidence that, compared to CD14++CD16− monocytes, CD14+CD16++ monocytes have an increased expression of smooth muscle cell-associated genes. This monocyte subpopulation is reduced in renal transplant patients with CTD, possibly due to selective migration into the allograft.

Lymphangiogenesis in renal diseases: passive bystander or active participant?

Lymphatic vessels (LVs) are involved in a number of physiological and pathophysiological processes such as fluid homoeostasis, immune surveillance, and resolution of inflammation and wound healing. Lymphangiogenesis, the outgrowth of existing LVs and the formation of new ones, has received increasing attention over the past decade on account of its prominence in organ physiology and pathology, which has been enabled by the development of specific tools to study lymph vessel functions. Several studies have been devoted to renal lymphatic vasculature and lymphangiogenesis in kidney diseases, such as chronic renal transplant dysfunction, primary renal fibrotic disorders, proteinuria, diabetic nephropathy and renal inflammation. This review describes the most recent findings on lymphangiogenesis, with a specific focus on renal lymphangiogenesis and its impact on renal diseases. We suggest renal lymphatics as a possible target for therapeutic interventions in renal medicine to dampen tubulointerstitial tissue remodelling and improve renal functioning.

Renal Heparan Sulfate Proteoglycans Modulate Fibroblast Growth Factor 2 Signaling in Experimental Chronic Transplant Dysfunction

Depending on the glycan structure, proteoglycans can act as coreceptors for growth factors. We hypothesized that proteoglycans and their growth factor ligands orchestrate tissue remodeling in chronic transplant dysfunction. We have previously shown perlecan to be selectively up-regulated in the glomeruli and arteries in a rat renal transplantation model. Using the same model, here we present quantitative RT-PCR profiling data on proteoglycans and growth factors from laser-microdissected glomeruli, arterial tunicae mediae, and neointimae at 12 weeks after transplantation. In glomeruli and neointimae of allografts, selective induction of the matrix heparan sulfate proteoglycan perlecan was observed, along with massive accumulation of fibroblast growth factor 2 (FGF2). Profiling the heparan sulfate polysaccharide side chains revealed conversion from a non-FGF2-binding heparan sulfate phenotype in control and isografted kidneys toward a FGF2-binding phenotype in allografts. In vitro experiments with perlecan-positive rat mesangial cells showed that FGF2-induced proliferation is dependent on sulfation and can be inhibited by exogenously added heparan sulfate. These findings indicate that matrix proteoglycans such as perlecan serve as functional docking platforms for FGF2 in chronic transplant dysfunction. We speculate that heparin-like glycomimetics could be a promising intervention to retard development of glomerulosclerosis and neointima formation in chronic transplant dysfunction.

Nonesterified Fatty Acids and Development of Graft Failure in Renal Transplant Recipients

Chronic transplant dysfunction is the most common cause of graft failure on the long term. Proteinuria is one of the cardinal clinical signs of chronic transplant dysfunction. Albumin-bound fatty acids (FA) have been hypothesized to be instrumental in the etiology of renal damage induced by proteinuria. We therefore questioned whether high circulating FA could be associated with an increased risk for future development of graft failure in renal transplant recipients (RTR). To this end, we prospectively investigated the association of fasting concentrations of circulating nonesterified FA (NEFA) with the development of graft failure in RTR. Baseline measurements were performed between 2001 and 2003 in outpatient RTR with a functioning graft of more than 1 year. Follow-up was recorded until May 19, 2009. Graft failure was defined as return to dialysis or retransplantation. We included 461 RTR at a median (interquartile range [IQR]) of 6.1 (3.3-11.3) years after transplantation. Median (IQR) fasting concentrations of NEFA were 373 (270-521) μM/L. Median (IQR) follow-up for graft failure beyond baseline was 7.1 (6.1-7.5) years. Graft failure occurred in 23 (15%), 14 (9%), and 9 (6%) of RTR across increasing gender-specific tertiles of NEFA (P=0.04). In a gender-adjusted Cox-regression analysis, log-transformed NEFA level was inversely associated with the development of graft failure (hazard ratio, 0.61; 95% confidence interval, 0.47-0.81; P<0.001). In this prospective cohort study in RTR, we found an inverse association between fasting NEFA concentrations and risk for development of graft failure. This association suggests a renoprotective rather than a tubulotoxic effect of NEFA. Further studies on the role of different types of NEFA in the progression of renal disease are warranted.

Low-Dose Rapamycin Treatment Increases the Ability of Human Regulatory T Cells to Inhibit Transplant Arteriosclerosis In Vivo

Regulatory T cells (Treg) are currently being tested in clinical trials as a potential therapy in cell and solid organ transplantation. The immunosuppressive drug rapamycin has been shown to preferentially promote Treg expansion. Here, we hypothesized that adjunctive rapamycin therapy might potentiate the ability of ex vivo expanded human Treg to inhibit vascular allograft rejection in a humanized mouse model of arterial transplantation. We studied the influence of combined treatment with low-dose rapamycin and subtherapeutic Treg numbers on the development of transplant arteriosclerosis (TA) in human arterial grafts transplanted into immunodeficient BALB/cRag2−/−Il2rg−/− mice reconstituted with allogeneic human peripheral blood mononuclear cell. In addition, we assessed the effects of the treatment on the proliferation and apoptosis of naïve/effector T cells. The combined therapy efficiently suppressed T-cell proliferation in vivo and in vitro. Neointima formation in the human arterial allografts was potently inhibited compared with each treatment alone. Interestingly, CD4+ but not CD8+ T lymphocytes were sensitive to Treg and rapamycin-induced apoptosis in vitro. Our data support the concept that rapamycin can be used as an adjunctive therapy to improve efficacy of Treg-based immunosuppressive protocols in clinical practice. By inhibiting TA, Treg and rapamycin may prevent chronic transplant dysfunction and improve long-term allograft survival

Do Intraoperative Hemodynamic Factors of the Recipient Influence Renal Graft Function?

PurposeTo assess the importance of intraoperative management of recipient hemodynamics for immediate versus delayed graft function. MethodsThe retrospective study of 1966 consecutive renal transplants performed in our department between June 1980 and December 2009 analyzed several perioperative hemodynamic factors: central venous pressure (CVP), mean arterial pressure (MAP) as well as volumes of fluids, fresh frozen plasma (FFP), albumin, and whole blood transfusions. We examined their influence on renal graft function parameters: immediate diuresis, serum creatinine levels, acute rejection, chronic transplant dysfunction, and graft survival. ResultsMean CVP was 9.23 ± 2.65 mm Hg and its variations showed no impact on graft function. We verified a twofold greater risk of chronic allograft dysfunction among patients with CVP ≥ 11 mm Hg (P < .001). Mean MAP was 93.74 ± 13.6 mm Hg; graft survivals among subjects with MAP ≥ 93 mm Hg were greater than those of patients with MAP < 93 mm Hg (P = .04). On average, 2303.6 ± 957.4 mL of saline solutions were infused during surgery. Patients who received whole blood transfusions (48%) showed a greater incidence of acute rejection episodes (ARE) (P = .049) and chronic graft dysfunction (P < .001). Patients who received FFP (55.7%), showed a higher incidence of ARE (P < .001). Only 4.6% of patients (n = 91) received human albumin with a lower incidence of ARE (P = .045) and chronic graft dysfunction (P = .024). Logistic binary regression analysis revealed that plasma administration was an independent risk factor for ARE (P < .001) and chronic dysfunction (P = .028). Volume administration (≥2500 mL) was also an independent risk factor for chronic allograft dysfunction (P = .016). Using Cox regression, we verified volume administration ≥ 2500 mL to be the only independent risk factor for graft failure (P < .001). ConclusionMAP ≥ 93 mm Hg and perioperative fluid administration <2500 mL were associated with greater graft survival. Albumin infusion seemed to be a protective factor, while CVP ≥ 11 mm Hg, whole blood, and FFP transfusions were associated with higher rates of ARE and chronic graft dysfunction.

Plasma bilirubin and late graft failure in renal transplant recipients

Exogenous bilirubin has been shown to protect against oxidative stress in ischemia-reperfusion injury. Oxidative stress has been implicated in the pathophysiology of chronic transplant dysfunction leading to late graft failure after renal transplantation. We prospectively investigated whether high endogenous bilirubin is protective against development of late graft failure in renal transplant recipients (RTR). Baseline data were collected between August 2001 and July 2003 in nonicteric outpatient RTR with a functioning graft for >1 year. At baseline, bilirubin and liver enzymes were measured using routine assays on a Merck Mega analyzer. Graft failure was prospectively recorded until May 19 2009. During follow-up for 7.1 [6.2-7.2] years, 55 RTR developed graft failure. We found that circulating levels of bilirubin are inversely associated with late graft failure in RTR (HR = 0.29 [95% CI: 0.16-0.52], P < 0.001). This association was independent of potential confounders, including creatinine clearance, urinary protein excretion, calcineurin inhibitors, and gender (HR = 0.31 [95% CI: 0.15-0.62] P = 0.001). Our findings are consistent with a protective effect of increased endogenous bilirubin against development of late graft failure in RTR. If our findings are confirmed by other studies, intervention with endogenous or exogenous bilirubin may be of interest for long-term preservation of renal function in RTR.

Immunosuppressive Regimen and Interstitial Fibrosis and Tubules Atrophy at 12 Months Postrenal Transplant

Chronic renal transplant dysfunction is histopathologically characterized by interstitial fibrosis and tubular atrophy. This study investigated the relative contribution of baseline donor, recipient, and transplant characteristics to interstitial fibrosis and tubular atrophy score at month 12 after renal transplantation. This retrospective study includes all 109 consecutive recipients with adequate implantation and month 12 biopsies transplanted between April of 2003 and February of 2007. Immunosuppression regimen was tacrolimus and steroids (10 days) plus either sirolimus or mycophenolate mofetil. Average interstitial fibrosis and tubular atrophy score increased from 0.70 to 1.65 (P<0.001). In an adjusted multiple linear regression analysis, interstitial fibrosis and tubular atrophy score at month 12 was significantly related to donor type (donors after cardiac death versus living donor had interstitial fibrosis and tubular atrophy score+0.41, 95% confidence interval=0.05-0.76, P=0.02), baseline interstitial fibrosis and tubular atrophy, and immunosuppression regimen. Because of interaction between the latter two variables (P=0.002), results are given separately: recipients with a baseline interstitial fibrosis and tubular atrophy score of zero had a 0.60 higher score at month 12 (95% confidence interval=0.09-1.10, P=0.02) when mycophenolate mofetil-treated, whereas recipients with a baseline interstitial fibrosis and tubular atrophy score more than zero had a 0.38 higher score at month 12 (95% confidence interval=0.01-0.74, P=0.04) when sirolimus-treated. A higher score at month 12 correlated with a lower estimated GFR (ρ=-0.45, P<0.001). These findings suggest that histologic assessment of a preimplantation biopsy may guide choice of immunosuppresion to maximize transplant survival and its interaction with type of immunosuppression.

Early Loss of Peritubular Capillaries after Kidney Transplantation

Inflammation, interstitial fibrosis (IF), and tubular atrophy (TA) precede chronic transplant dysfunction, which is a major cause of renal allograft loss. There is an association between IF/TA and loss of peritubular capillaries (PTCs) in advanced renal disease, but whether PTC loss occurs in an early stage of chronic transplant dysfunction is unknown. Here, we studied PTC number, IF/TA, inflammation, and renal function in 48 patients who underwent protocol biopsies. Compared with before transplantation, there was a statistically significant loss of PTCs by 3 months after transplantation. Fewer PTCs in the 3-month biopsy correlated with high IF/TA and inflammation scores and predicted lower renal function at 1 year. Predictors of PTC loss during the first 3 months after transplantation included donor type, rejection, donor age, and the number of PTCs at the time of implantation. In conclusion, PTC loss occurs during the first 3 months after renal transplantation, associates with increased IF and TA, and predicts reduced renal function.