Intrarenal resistive index after renal transplantation.

BACKGROUND: The intrarenal resistive index is routinely measured in many renal-transplantation centers for assessment of renal-allograft status, although the value of the resistive index remains unclear. METHODS: In a single-center, prospective study involving 321 renal-allograft recipients, we measured the resistive index at baseline, at the time of protocol-specified renal-allograft biopsies (3, 12, and 24 months after transplantation), and at the time of biopsies performed because of graft dysfunction. A total of 1124 renal-allograft resistive-index measurements were included in the analysis. All patients were followed for at least 4.5 years after transplantation. RESULTS: Allograft recipients with a resistive index of at least 0.80 had higher mortality than those with a resistive index of less than 0.80 at 3, 12, and 24 months after transplantation (hazard ratio, 5.20 [95% confidence interval {CI}, 2.14 to 12.64; P<0.001]; 3.46 [95% CI, 1.39 to 8.56; P=0.007]; and 4.12 [95% CI, 1.26 to 13.45; P=0.02], respectively). The need for dialysis did not differ significantly between patients with a resistive index of at least 0.80 and those with a resistive index of less than 0.80 at 3, 12, and 24 months after transplantation (hazard ratio, 1.95 [95% CI, 0.39 to 9.82; P=0.42]; 0.44 [95% CI, 0.05 to 3.72; P=0.45]; and 1.34 [95% CI, 0.20 to 8.82; P=0.76], respectively). At protocol-specified biopsy time points, the resistive index was not associated with renal-allograft histologic features. Older recipient age was the strongest determinant of a higher resistive index (P<0.001). At the time of biopsies performed because of graft dysfunction, antibody-mediated rejection or acute tubular necrosis, as compared with normal biopsy results, was associated with a higher resistive index (0.87 ± 0.12 vs. 0.78 ± 0.14 [P=0.05], and 0.86 ± 0.09 vs. 0.78 ± 0.14 [P=0.007], respectively). CONCLUSIONS: The resistive index, routinely measured at predefined time points after transplantation, reflects characteristics of the recipient but not those of the graft. (ClinicalTrials.gov number, NCT01879124 .).

Human skin carcinoma arising from kidney transplant-derived tumor cells.

Tumor cells with donor genotype have been identified in human skin cancer after allogeneic transplantation; however, the donor contribution to the malignant epithelium has not been established. Kidney transplant recipients have an increased risk of invasive skin squamous cell carcinoma (SCC), which is associated with accumulation of the tumor suppressor p53 and TP53 mutations. In 21 skin SCCs from kidney transplant recipients, we systematically assessed p53 expression and donor/recipient origin in laser-microdissected p53+ tumor cells. In one patient, molecular analyses demonstrated that skin tumor cells had the donor genotype and harbored a TP53 mutation in codon 175. In a kidney graft biopsy performed 7 years before the skin SCC diagnosis, we found p53+ cells in the renal tubules. We identified the same TP53 mutation in these p53+ epithelial cells from the kidney transplant. These findings provide evidence for a donor epithelial cell contribution to the malignant skin epithelium in the recipient in the setting of allogeneic kidney transplantation. This finding has theoretical implications for cancer initiation and progression and clinical implications in the context of prolonged immunosuppression and longer survival of kidney transplant patients.

Extrarenal factors influencing resistance index in stable kidney transplant recipients.

BACKGROUND: Increased intrarenal resistance index (RI) has been associated with decreased long-term allograft and patient survival in kidney transplant recipients. Taking into account the potential role of endothelial dysfunction, systemic inflammation, arteriosclerotic lesions, and left ventricle remodeling, we performed a cross-sectional study that aimed to evaluate extrarenal factors that may have influence on kidney graft RI in a large cohort of stable kidney transplant recipients. METHODS: One hundred seventy-four kidney transplant recipients were enrolled into the study. Mean time after transplantation was 8.4±1.8 years. Echocardiography, carotid ultrasound (intima-media thickness), pulse wave velocity, and Doppler examination of kidney graft were performed. The inflammatory markers, adhesion molecules, and plasma N-terminal prohormone of brain natriuretic peptide concentrations were also measured. Patients were divided into quartile subgroups based on RI value (Q1: RI≤0.68, Q2: RI=0.69-0.72, Q3: RI=0.73-0.76, and Q4: RI≥0.77). RESULTS: The analyzed subgroups were comparable with respect to demographics (except age) and anthropometric parameters as well as comorbidities. The values of age, serum phosphate, pulse wave velocity, left ventricular mass (LVM), and LVM index (LVMI) increased in subsequent RI quartile subgroups. The strongest correlation was found between RI and age, LVM, LVMI, and plasma parathormone concentration and was negative with estimated glomerular filtration rate. In backward stepwise multivariate regression analysis, the RI variability was explained by age, LVMI, and serum phosphate concentration. CONCLUSION: Arterial stiffness and left ventricular hypertrophy may significantly influence the intrarenal vascular resistance measured using Doppler sonography in stable kidney transplant recipients.

Genomic biomarkers correlate with HLA-identical renal transplant tolerance.

The ability to achieve immunologic tolerance after transplantation is a therapeutic goal. Here, we report interim results from an ongoing trial of tolerance in HLA-identical sibling renal transplantation. The immunosuppressive regimen included alemtuzumab induction, donor hematopoietic stem cells, tacrolimus/mycophenolate immunosuppression converted to sirolimus, and complete drug withdrawal by 24 months post-transplantation. Recipients were considered tolerant if they had normal biopsies and renal function after an additional 12 months without immunosuppression. Of the 20 recipients enrolled, 10 had at least 36 months of follow-up after transplantation. Five of these 10 recipients had immunosuppression successfully withdrawn for 16-36 months (tolerant), 2 had disease recurrence, and 3 had subclinical rejection in protocol biopsies (nontolerant). Microchimerism disappeared after 1 year, and CD4(+)CD25(high)CD127(-)FOXP3(+) regulatory T cells and CD19(+)IgD/M(+)CD27(-) B cells were increased through 5 years post-transplantation in both tolerant and nontolerant recipients. Immune/inflammatory gene expression pathways in the peripheral blood and urine, however, were differentially downregulated between tolerant and nontolerant recipients. In summary, interim results from this trial of tolerance in HLA-identical renal transplantation suggest that predictive genomic biomarkers, but not immunoregulatory phenotyping, may be able to discriminate tolerant from nontolerant patients.

Comparison of pharmacokinetics and pathology for low-dose tacrolimus once-daily and twice-daily in living kidney transplantation: prospective trial in once-daily versus twice-daily tacrolimus.

BACKGROUND: A prolonged-release formulation of tacrolimus (Tacrolimus QD) was developed to allow once-daily dosing and to have similar safety and efficacy profiles to twice-daily tacrolimus (Tacrolimus BID). This study compared the pharmacokinetics (PK) and renal pathology by protocol biopsy in de novo living kidney transplant recipients treated with either low-dose Tacrolimus QD or Tacrolimus BID. METHODS: Between November 2009 and January 2011, 102 consecutive adult patients were randomized to receive either low-dose Tacrolimus QD or Tacrolimus BID. All patients underwent PK study and protocol biopsy on postoperative day 14. Additional protocol biopsies were performed between 6 and 12 months after renal transplantation. RESULTS: During the 1-year follow up, the incidence of biopsy-proven acute rejection and toxic tubulopathy was low and similar in both groups. Twenty-four hours area under the curve (AUC0-24) was not different in both groups (285 ± 78.7 and 281 ± 62.4 ng hr/mL in Tacrolimus QD and Tacrolimus BID, respectively). C0 was well correlated with AUC0-24 in both groups and AUC0-24 between 260 and 280 in the Tacrolimus QD group was achieved by 6 to 8 ng/mL of C0. Acute nephrotoxicity was less than 10% in both groups without any clinical manifestation. CONCLUSION: Clinical efficacy, safety, and PK profile of Tacrolimus QD is same as those of Tacrolimus BID.

Cryptic B cell response to renal transplantation.

Transplantation reliably evokes allo-specific B cell and T cell responses in mice. Yet, human recipients of kidney transplants with normal function usually exhibit little or no antibody specific for the transplant donor during the early weeks and months after transplantation. Indeed, the absence of antidonor antibodies is taken to reflect effective immunosuppressive therapy and to predict a favorable outcome. Whether the absence of donor-specific antibodies reflects absence of a B cell response to the donor, tolerance to the donor or immunity masked by binding of donor-specific antibodies to the graft is not known. To distinguish between these possibilities, we devised a novel ELISPOT, using cultured donor, recipient and third-party fibroblasts as targets. We enumerated donor-specific antibody-secreting cells in the blood of nine renal allograft recipients with normal kidney function before and after transplantation. Although none of the nine subjects had detectable donor-specific antibodies before or after transplantation, all exhibited increases in the frequency of donor-specific antibody-secreting cells eight weeks after transplantation. The responses were directed against the donor HLA-class I antigens. The increase in frequency of donor-specific antibody-secreting cells after renal transplantation indicates that B cells respond specifically to the transplant donor more often than previously thought.

Pathology of recurrent diseases in kidney allografts: membranous nephropathy and focal segmental glomerulosclerosis.

PURPOSE OF REVIEW: Glomerulonephritis is the leading cause of end-stage renal failure in renal transplant recipients. Recurrence of diseases in kidney allograft provides a unique opportunity to study the mechanisms of kidney disorders leading to the underlying native organ failure. There have been new advances in the understanding of the mechanisms of membranous nephropathy and focal segmental glomerulosclerosis (FSGS). RECENT FINDINGS: Recent studies of recurrent membranous nephropathy provide evidence of the presence of circulating recipient factor that targets the donor kidney and put forward the evidence of antiphospholipase A2 receptor antibody pathogenicity in some cases, point to a different pathogenesis of recurrent and de-novo membranous nephropathy, and stress the importance of early morphologic recognition of recurrent membranous nephropathy. New advances in understanding the FSGS include identification of soluble podocyte urokinase receptor as a circulating factor leading to the development and recurrence of FSGS after transplantation, imply that podocyte injury may be a reversible lesion, and suggest a dual role of activated parietal epithelial cells in sclerosing glomerular injury as well as in regeneration and repair. SUMMARY: Several new mechanisms of glomerular injury have been implicated in the development of recurrent kidney diseases. When further confirmed, some of these might result in early diagnosis and development of better therapy of the respective disorders.

Renal allograft pathology in the sensitized patient.

PURPOSE OF REVIEW: Patterns of renal allograft injury associated with alloantibody have been increasingly recognized over the past 2 decades. The use of more sensitive serum testing has brought to light the range of alloantibody-associated changes on biopsy at different time points posttransplant. There is likely to be an increasing number of patients with preformed alloantibody undergoing kidney transplantation, and so alloantibody-associated injury will become more prevalent. RECENT FINDINGS: Acute antibody-mediated rejection (AMR) is a major complication in kidney transplant patients with preformed donor-specific antibody (DSA), particularly in the early posttransplant period. Acute AMR is characterized by acute tissue injury and is likely to be antibody mediated and complement mediated. A recent study showed a decreased risk of acute AMR with terminal complement pathway inhibition. Other studies have shown endothelialitis, a vascular lesion traditionally associated with acute cellular rejection, in AMR. Features of chronic AMR are common and include transplant glomerulopathy, peritubular capillary basement membrane multilamination, and accelerated arteriosclerosis. Although previously a diagnosis of humoral rejection usually required complement factor C4d deposition in the graft, we now recognize chronic features because of DSA even in the absence of C4d deposition. SUMMARY: Acute and chronic AMR are major contributors to renal allograft dysfunction and loss. Recognition of tissue injury patterns associated with alloantibody can lead to treatment strategies in patients with DSA and can aid in interpreting biopsies in patients who are receiving new therapies.

Genomic meta-analysis of growth factor and integrin pathways in chronic kidney transplant injury.

BACKGROUND: Chronic Allograft Nephropathy (CAN) is a clinical entity of progressive kidney transplant injury. The defining histology is tubular atrophy with interstitial fibrosis (IFTA). Using a meta-analysis of microarrays from 84 kidney transplant biopsies, we revealed growth factor and integrin adhesion molecule pathways differentially expressed and correlated with histological progression. A bioinformatics approach mining independent datasets leverages new and existing data to identify correlative changes in integrin and growth factor signaling pathways. RESULTS: Analysis of CAN/IFTA Banff grades showed that hepatocyte growth factor (HGF), and epidermal growth factor (EGF) pathways are significantly differentially expressed in all classes of CAN/IFTA. MAPK-dependent pathways were also significant. However, the TGFß pathways, albeit present, failed to differentiate CAN/IFTA progression. The integrin subunits ß8, αv, αµ and ß5 are differentially expressed, but ß1, ß6 and α6 specifically correlate with progression of chronic injury. Results were validated using our published proteomic profiling of CAN/IFTA. CONCLUSIONS: CAN/IFTA with chronic kidney injury is characterized by expression of distinct growth factors and specific integrin adhesion molecules as well as their canonical signaling pathways. Drug target mapping suggests several novel candidates for the next generation of therapeutics to prevent or treat progressive transplant dysfunction with interstitial fibrosis.

Effect of conversion from ciclosporin to tacrolimus on endothelial progenitor cells in stable long-term kidney transplant recipients.

BACKGROUND: Endothelial progenitor cell (EPC) counts are proposed surrogate markers for vascular function and cardiovascular risk. The effect of tacrolimus (TAC) on EPC is unknown. METHODS: In this randomized controlled trial, we assigned 148 stable long-term kidney transplant recipients (KTR) to maintaining ciclosporin (CSA) or to commencing TAC-based immunosuppression at a 2:1 ratio. EPC counts (CD34/KDR) after 24 months were defined as primary endpoint. RESULTS: The intent-to-treat analysis included 141 KTR (estimated glomerular filtration rate, 46.7 [40.1-61.8] mL/min per 1.73 m). Median (interquartile range [IQR]) EPC counts at baseline and month 24 were 6 (2-9) and 3 (1-9) cells and 4 (2-8) and 2 (0-5) cells per 5×10 mononuclear cells in CSA and TAC, respectively. Median (IQR) circulating angiogenic cells at baseline and month 24 were 28 (10.7-57) and 44.33 (14.6-59.8) cells and 22 (10.8-41) and 21 (9.7-49.5) cells per high-power field in CSA and TAC, respectively. Median (IQR) endothelial cell colony-forming units count per well at baseline and month 24 were 10.5 (3.3-34.3) and 4.38 (1.7-26.5) in CSA and significantly declined from 9.31 (1.8-29.3) to 4.13 (1.1-9.5) in TAC (P=0.003). There were no cardiovascular events in either group. CONCLUSION: Although late conversion from CSA to TAC appears safe in KTR, conversion to TAC has no favorable effect on EPC. Low EPC levels are associated with a higher risk of subsequent cardiovascular events and are therefore of prognostic value. Their trend to decline over time deserves further examination.

Transvenous Renal Transplant Biopsy via a Transfemoral Approach.

Percutaneous renal biopsy (PRB) of kidney transplants might be prevented by an elevated risk of bleeding or limited access to the allograft. In the following, we describe our initial experience with 71 transvenous renal transplant biopsies in 53 consecutive patients with unexplained reduced graft function who were considered unsuitable candidates for PRB (4.2% of all renal transplant biopsies at our institution). Biopsies were performed via the ipsilateral femoral vein with a renal biopsy set designed for transjugular renal biopsy (TJRB) of native kidneys. Positioning of the biopsy system within the transplant vein was achievable in 58 of 71 (81.7%) procedures. The specimen contained a median of 10 glomeruli (range 0-38). Tissue was considered as adequate for diagnosis in 56 of 57 (98.2%) biopsies. With respect to BANFF 50.9% of the specimen were adequate (>10 glomeruli), 47.4% marginally adequate (1-9 glomeruli) and 1.8% inadequate (no glomeruli). After implementation of real-time assessment all specimen contained glomeruli. One of the fifty-eight (1.8%) procedure-related major complications occurred (hydronephrosis requiring nephrostomy due to gross hematuria). Transfemoral renal transplant biopsy (TFRTB) is feasible and appears to be safe compared to PRB. It offers a useful new alternative for histological evaluation of graft dysfunction in selected patients with contraindications to PRB.

Pathology of C4d-negative antibody-mediated rejection in renal allografts.

PURPOSE OF REVIEW: To summarize current evidence supporting the existence of C4d-negative antibody-mediated rejection (AMR) in renal allografts, its potential to cause chronic graft injury, and whether histopathologic features of C4d-negative AMR differ from those of C4d-positive AMR. RECENT FINDINGS: Recently published molecular, clinicopathologic, and ultrastructural studies provide strong evidence that microvascular injury in the presence of donor-specific alloantibodies (DSA) has the potential to cause interstitial fibrosis/tubular atrophy, transplant glomerulopathy, and graft loss, whether or not peritubular capillary (PTC) C4d is present. Although C4d-positive AMR may represent a more severe form of AMR, recent studies have found that in patients with DSA, microvascular injury (glomerulitis, peritubular capillaritis) is more strongly associated with graft loss than C4d deposition. Our data suggest that C4d-positive and C4d-negative AMR show similar degrees of glomerulitis and peritubular capillaritis, similar frequencies of concurrent cell-mediated rejection, and that both may occur early or late posttransplantation. SUMMARY: In renal allografts, microvascular injury in the presence of DSA but with negative C4d staining in PTC nonetheless is indicative of humorally mediated graft injury that has the potential to cause tubular atrophy/interstitial fibrosis, transplant glomerulopathy, and graft loss. Prompt treatment for AMR may prevent or at least delay subsequent development of transplant glomerulopathy.