Noninvasive assessment of early kidney allograft dysfunction by blood oxygen level-dependent magnetic resonance imaging

BACKGROUND: Blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) is a noninvasive method to assess tissue oxygen bioavailability, using deoxyhemoglobin as an endogenous contrast agent. We hypothesized that BOLD-MRI could accurately discriminate different types of rejection early after kidney transplantation. METHODS: Twenty-three patients underwent imaging in the first four months posttransplant. Five had normal functioning transplants and 18 had biopsy-proven acute allograft dysfunction (acute tubular necrosis [ATN, n=5] and acute rejection [n=13] including borderline rejection: n=3; IA rejection: n=4; IIA rejection: n=6: C4d(+) rejection: n=9). RESULTS: Mean medullary R2* (MR2*) levels (a measure directly proportional to tissue deoxyhemoglobin levels) were significantly higher in normal functioning allografts (R2*=24.3/s+/-2.3) versus acute rejection (R2*=16.6/s+/-2.1) and ATN (R2*=20.9/s+/-1.8) (P<0.05). The lowest MR2* levels were observed in acute rejection episodes with vascular injury i.e. IIA and C4d (+). Similarly, the lowest medullary to cortical R2* ratios (MCR2*) were present in allografts with IIA (1.24+/-0.05) and C4d(+) rejection (1.26+/-0.06). ROC curve analyses suggested that MR2* and MCR2* values could accurately discriminate acute rejection in the early posttransplant period. CONCLUSIONS: BOLD-MRI demonstrated significant changes in medullary oxygen bioavailability in allografts with biopsy-proven ATN and acute rejection, suggesting that there may be a role for this noninvasive tool to evaluate kidney function early after transplantation.     

Utility of protocol biopsy for the early diagnosis of transplanted kidney dysfunction

Abstract:  We performed protocol kidney biopsies for the early diagnosis of asymptomatic histopathological acute rejection (AR), commonly defined as subclinical rejection and drug nephrotoxicity. Forty-seven kidney recipients that had asymptomatic and stable kidney function underwent protocol biopsies both one month and one yr after kidney transplantation. The protocol biopsies one month after transplantation revealed borderline change in 13 of 47 cases (27.6%). AR 1a was observed in eight cases (17.2%) and AR 1b was observed in three cases (6.4%). The AR 1a and AR 1b groups were treated with methyl prednisolone pulse and deoxyspergualin. Toxic tubulopathy was found in four cases (8.5%). In the cases of nephrotoxicity, cyclosporine or tacrolimus was reduced. The borderline change group was observed without any additional treatment. Every case diagnosed with acute rejection one month after transplantation improved histopathologically one yr after transplantation, and the borderline change group partially remained borderline change and partially improved histopathologically one yr after transplantation. The nephrotoxicity group improved histopathologically one yr after transplantation. In our institution, protocol biopsies one month and one yr after kidney transplantation proved useful in screening for subclinical rejection and toxic tubulopathy and subsequently effective in improving long-term graft survival.     

Interstitial expression of alpha-SMA: an early marker of chronic renal allograft dysfunction.

BACKGROUND: Renal myofibroblast infiltration has been shown to be strongly associated with renal function decline in several chronic renal diseases. The purpose of the present study was to investigate whether early detection of myofibroblast infiltration using alpha-smooth-muscle actin (alpha-SMA) expression in time-zero biopsies predicts renal allograft dysfunction. METHODS: We studied renal tissue from 38 renal transplant patients from whom biopsies had been taken after vascular anastomosis during transplantation to ascertain whether myofibroblasts infiltration predicts renal graft survival. Immunohistochemistry was performed on time-zero biopsies to determine alpha-SMA expression, and this was compared to annual glomerular filtration rate (GFR) variation and other parameters including cold ischaemic time (CIT), donor and recipient age, number of acute rejections, and delayed graft function (DGF). GFR was measured by inulin clearance during of 3 years of follow-up after the transplantation. Progressors were defined as patients with an annual GFR decline >5 ml/min/year. RESULTS: We found a significant correlation between interstitial alpha-SMA expression in time-zero biopsies and GFR evolution during the post-transplantation course (r=0.60, P<0.001). Although progressors had greater interstitial alpha-SMA expression than non progressors (7.9+/-0.7 vs 4.3+/-0.4%), they showed only a tendency towards higher glomerular alpha-SMA expression. In addition, progressors had more interstitial fibrosis in time-zero biopsies than non-progressors. There was no relationship between alpha-SMA expression and CIT, donor and recipient ages, number of acute rejections, and occurrence of DGF. CONCLUSION: This study suggests that alpha-SMA evaluation in time-zero biopsies, especially the combination of alpha-SMA expression and interstitial fibrosis, can strongly predict chronic renal allograft dysfunctions.     

The contribution of adhesion molecule expression in donor kidney biopsies to early allograft dysfunction.

BACKGROUND: Renal allograft rejection is associated with the expression of adhesion molecules on vascular endothelial and tubular epithelial cells. METHODS: To assess whether the number of cell adhesion molecules expressed in donor kidneys can predict early rejection or delayed graft function, kidney biopsies from 20 living and 53 cadaveric kidney donors were obtained before engraftment into the recipients and the expression of the cell adhesion molecules intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and endothelial leukocyte adhesion molecule (E-selectin) were determined by immunohistochemistry. RESULTS: All biopsies from living donors showed significantly lower expression of ICAM-1 and VCAM-1 compared to biopsies from cadaveric donors. There was no difference in the expression of adhesion molecules on tubular cells between transplants with primary function compared to allografts with early rejection in living donated kidneys (ICAM-1: 2+/-8 vs. 3+/-8%; VCAM-1: 9+/-7 vs. 1+/-1%), as well as in cadaveric kidneys (ICAM-1: 38+/-29 vs. 39+/-38%; VCAM-1: 55+/-27 vs. 48+/-29%). The expression of ICAM-1 molecules on tubular cells was determined to be a predictor for the occurrence of delayed graft function in cadaveric kidneys (ICAM-1: 65+/-24* vs. 38+/-29% delayed graft versus primary graft function). No delayed graft function occurred in recipients of living donated kidneys. CONCLUSIONS: These data suggest that adhesion molecule expression in donor biopsies is not a predictor for early allograft rejection, but can be used as a marker for the development of postischemic acute renal allograft failure.     

Late perfusion. A simple remedy for renal allograft primary nonfunction

Primary nonfunction in renal allografts makes the diagnosis of allograft dysfunction more difficult and may effect long-term graft survival. The prevention of primary nonfunction by a reperfusion technique has been assessed in a prospective analysis of 145 consecutive renal transplants performed in a single center. All kidneys were retrieved using an in situ perfusion method, and all but 13 recipients received a standardized immunosuppressive protocol with cyclosporine. The first 106 transplants were performed without the benefit of any additional perfusion, and the incidence of primary nonfunction was 57.5% in these patients. The last 39 kidneys received additional perfusion with kidney perfusion fluid immediately prior to implantation (late perfusion). In the latter group, the incidence of primary nonfunction was 30.8% (P = 0.007). Using logistic regression analysis, only three factors were found to be associated with primary nonfunction: immunosuppression with cyclosporine (P = 0.01), a second warm ischemia time of greater than 35 min (P = 0.002), and late perfusion (P = 0.003). In this study, the use of late perfusion alone has reduced the incidence of primary nonfunction by almost one half. The technique is simple, safe, inexpensive, and effective. Its routine use is now advocated in all renal transplants.     

Angiography in the diagnosis of renal allograft dysfunction.

We reviewed retrospectively 75 renal transplant arteriograms done during a 7-year period. Acute rejection and vasomotor nephropathy were not differentiated. Generalized cortical ischemia was diagnosed correctly in 23 of 30 cases but there were 7 falsely negative results. Renal artery stenosis was found in 7 of 17 cases in which the main indication for arteriography was hypertension. We conclude that the major role of transplant arteriography is in the diagnosis of larger vessel disease.     

Practical tests for clinical diagnosis of kidney allograft dysfunction

Abstract:  Graft dysfunction after renal transplant occurs due to a variety of causes. Graft biopsy is a mainstay in the diagnosis of graft dysfunction, including rejection, infection, glomerulonephritis and drug toxicity. Clinical tests including regular laboratory tests, antibody tests and imaging studies, however, are also important in the process of diagnosis. The possible causes of graft dysfunction are different depending on the period after transplantation. Pre-transplant donor factors may also affect the early graft function. Perioperative graft dysfunction is mainly related to hemodynamic factors and surgical complications. Early acute rejection may occur in immunologically high-risk cases. Later graft dysfunction may be related to infection, acute and chronic rejection or drug toxicity. Clinical tests to differentiate these factors are discussed in this paper.     

Significance of subclinical rejection in early renal allograft biopsies for chronic allograft dysfunction

To determine the significance of early subclinical rejection of renal allografts, we reviewed 127 biopsy specimens obtained soon after transplantation. Histological finding was categorized according to a modification of the Banff scheme as: acute rejection (AR), borderline changes (BL); non-specific inflammatory changes, (NI) and no rejection (NR). Subclinical rejection was defined as AR, BL or NI. Patients with BL or NI were divided into two groups; one was treated with high-dose methylprednisolone (MP), the other remained untreated. Freedom from chronic allograft dysfunction (defined as non-doubling of serum creatinine 5 yr after transplantation) was significantly more frequent in the NR group (89%) than in the BL (70%) and AR (64%) groups. At 1 yr after transplantation, mean serum creatinine had increased significantly only in the untreated group (p < 0.05), and re-biopsy showed that interstitial fibrosis had developed to a significantly greater extent in the untreated group than in the treated group (p < 0.01). Subclinical rejection in the early protocol biopsies correlated closely with subsequent allograft dysfunction. High-dose MP treatment for early subclinical rejection may be effective in suppressing the development of interstitial fibrosis at 1 yr after transplantation.