Glomerular Parietal Epithelial Cells Infection Is Associated With Poor Graft Outcome in Kidney Transplant Recipients With BK Polyomavirus-Associated Nephropathy.

BACKGROUND: The purpose of this study was to investigate the effect of BK polyomavirus (BKPyV infection of glomerular parietal epithelial cells (GPECs) on graft outcome in kidney transplant recipients with BKPyV-associated nephropathy (BKPyVAN). METHODS: A total of 152 kidney transplant recipients with BKPyVAN were divided into 31 with (GPEC-positive group) and 121 without (GPEC-negative group) BKPyV-infected GPECs. Clinicopathological characteristics and allograft survival were compared between the groups. RESULTS: The GPEC-positive group had more patients with advanced-stage BKPyVAN than the GPEC-negative group (P < .001). At the last follow-up, the GPEC-positive group had a significantly higher serum creatinine level than the GPEC-negative group. The graft loss rate in the GPEC-positive group was higher than that in the GPEC-negative group (32.3% vs 12.4%; P = .008). Kaplan-Meier analysis showed that the graft survival rate in the GPEC-positive group was lower than that in the GPEC-negative group (log-rank test, P = .004). Multivariate Cox regression analysis demonstrated that BKPyV infection of GPECs was an independent risk factor for graft survival (hazard ratio, 3.54; 95% confidence interval, 1.43-8.76; P = .006). CONCLUSIONS: GPEC infection in patients with BKPyVAN indicates more-severe pathological damage and a rapid decline in renal function. BKPyV infection of GPECs is an independent risk factor for allograft loss.

Hemodynamics in Transplant Renal Artery Stenosis and its Alteration after Stent Implantation Based on a Patient-specific Computational Fluid Dynamics Model.

BACKGROUND: Accumulating studies on computational fluid dynamics (CFD) support the involvement of hemodynamic factors in artery stenosis. Based on a patient-specific CFD model, the present study aimed to investigate the hemodynamic characteristics of transplant renal artery stenosis (TRAS) and its alteration after stent treatment. METHODS: Computed tomography angiography (CTA) data of kidney transplant recipients in a single transplant center from April 2013 to November 2014 were reviewed. The three-dimensional geometry of transplant renal artery (TRA) was reconstructed from the qualified CTA images and categorized into three groups: the normal, stenotic, and stented groups. Hemodynamic parameters including pressure distribution, velocity, wall shear stress (WSS), and mass flow rate (MFR) were extracted. The data of hemodynamic parameters were expressed as median (interquartile range), and Mann-Whitney U-test was used for analysis. RESULTS: Totally, 6 normal, 12 stenotic, and 6 stented TRAs were included in the analysis. TRAS presented nonuniform pressure distribution, adverse pressure gradient across stenosis throat, flow vortex, and a separation zone at downstream stenosis. Stenotic arteries had higher maximal velocity and maximal WSS (2.94 [2.14, 3.30] vs. 1.06 [0.89, 1.15] m/s, 256.5 [149.8, 349.4] vs. 41.7 [37.8, 45.3] Pa at end diastole, P= 0.001; 3.25 [2.67, 3.56] vs. 1.65 [1.18, 1.72] m/s, 281.3 [184.3, 364.7] vs. 65.8 [61.2, 71.9] Pa at peak systole, P= 0.001) and lower minimal WSS and MFRs (0.07 [0.03, 0.13] vs. 0.52 [0.45, 0.67] Pa, 1.5 [1.0, 3.0] vs. 11.0 [8.0, 11.3] g/s at end diastole, P= 0.001; 0.08 [0.03, 0.19] vs. 0.70 [0.60, 0.81] Pa, 2.0 [1.3, 3.3] vs. 16.5 [13.0, 20.3] g/s at peak systole, P= 0.001) as compared to normal arteries. Stent implantation ameliorated all the alterations of the above hemodynamic factors except low WSS. CONCLUSIONS: Hemodynamic factors were significantly changed in severe TRAS. Stent implantation can restore or ameliorate deleterious change of hemodynamic factors except low WSS at stent regions.

Factors Influencing Graft Outcomes Following Diagnosis of Polyomavirus -Associated Nephropathy after Renal Transplantation.

BACKGROUND: Polyomavirus associated nephropathy (PVAN) is a significant cause of early allograft loss and the course is difficult to predict. The aim of this study is to identify factors influencing outcome for PVAN. METHODS: Between 2006 and 2014, we diagnosed PVAN in 48 (7.8%) of 615 patients monitored for BK virus every 1-4 weeks after modification of maintenance immunosuppression. Logistic or Cox regression analysis were performed to determine which risk factors independently affected clinical outcome and graft loss respectively. RESULTS: After 32.1±26.4 months follow-up, the frequencies of any graft functional decline at 1 year post-diagnosis, graft loss and any graft functional decline at the last available follow-up were 27.1% (13/48), 25.0% (12/48), and 33.3% (16/48), respectively. The 1, 3, 5 year graft survival rates were 100%, 80.5% and 69.1%, respectively. The mean level of serum creatinine at 1 year post-diagnosis and long-term graft survival rates were the worst in class C (p<0.05). Thirty-eight of 46 (82.6%) BKV DNAuria patients reduced viral load by 90% with a median time of 2.75 months (range, 0.25-34.0 months) and showed better graft survival rates than the 8 patients (17.4%) without viral load reduction (p<0.001). Multivariate logistic regression analysis showed that extensive interstitial inflammation (OR 20.2, p = 0.042) and delayed fall in urinary viral load (>2.75 months for >90% decrease) in urine (OR 16.7, p = 0.055) correlated with worse creatinine at 1 year post-diagnosis. Multivariate Cox regression analysis showed that extensive interstitial inflammation (HR 46988, p = 0.032) at diagnosis, and high PVAN stage (HR 162.2, p = 0.021) were associated with worse long-term graft survival rates. CONCLUSIONS: The extent of interstitial inflammation influences short and long-term graft outcomes in patients with PVAN. The degree of PVAN, rate of reduction in viral load, and viral clearance also can be used as prognostic markers in PVAN.

Monitoring of polyomavirus BK replication and impact of preemptive immunosuppression reduction in renal-transplant recipients in China: a 5-year single-center analysis.

This provides the long-term patient/graft survival and outcome of BK viremia and BK virus allograft nephropathy (BKVAN) in renal transplant recipients in the setting of intensive monitoring and preemptive of reduction of immunosuppression. Quantitative BKV DNA PCR and urinary cytology surveillance were performed regularly after transplantation in 229 kidney recipients. Patients with BK viremia and BKVAN were treated with 30-50% reduction in doses of tacrolimus and/or mycophenolate mofetil and were monitored for BKV every 3-6 months. All the patients were followed for 5 years. Overall 5-year patient and graft survival were 95.6% and 92.1%, respectively, and independent of presence of decoy cells, BK viruria, viremia, or BKVAN. After reduction of immunosuppression, BK viremia (n = 38) resolved in 100% of patients, without increased acute rejection. Recurrent BK viremia was not observed in viremic patients without BKVAN (n = 30). All BKVAN patients (n = 7, 3.1%) cleared viremia with a mean time of 5.9 months (range 1-15 months) and manifested no decline in estimated glomerular filtration rate from 1 month to 5 years after transplantation. Viral monitoring and preemptive reduction of immunosuppression resulted in the successful resolution of BK viremia and BKVAN with excellent graft survival and renal function at 5 years.

Noninvasive tool for the diagnosis of polyomavirus BK-associated nephropathy in renal transplant recipients.

Noninvasive methods can facilitate early diagnosis of BK virus (BKV) replication and guide the evaluation of BKV-associated nephropathy (BKVAN). We developed 3 noninvasive methods for BKVAN screening including quantitative polymerase chain reaction (PCR) assay for BKV DNA load in urine and plasma, and quantitative assay of urine cytology by light microscopy or electron microscopy, and used these assays concurrently with renal transplant biopsies for the evaluation of 338 patients. BKVAN was diagnosed in 24 (7.1%) of 338 renal recipients. The median level of the 3 methods was the highest in pattern B of BKVAN (P < 0.05). Using these 3 methods for pattern B of BKVAN yielded a high sensitivity of 100%. Using decoy cells without quantitation had a sensitivity of 95.8% and a specificity of 83.1% for BKVAN. The amount of decoy cells in urine samples was related to BKV DNAuria, BKV DNAemia, and the pattern of BKVAN. Using a decoy cell threshold of >5 per 10 high-power fields (HPF) had an ideal sensitivity and specificity for high-risk BKVAN and BKVAN. Using a decoy cell threshold of >20 per 10 HPF for BKVAN had a specificity of 99.7%. Quantitative assay of urine cytology is a very convenient and sensitive method for diagnosis of BKVAN, which can be deemed as an additional diagnostic method for quantitative PCR screening with increased accuracy.

[Clinical feature and analysis on the clinical related factors of BK virus associated nephropathy].

OBJECTIVE: To determine the incidence of BK virus associated nephropathy (BKVAN) in renal-transplantation recipients, observe its histological features. METHODS: A total of 137 renal allograft biopsy specimens collected at our hospital during December 1999 to January 2008 were analyzed by routine histologic examination, immunohistochemistry and transmission electron microscopy (TEM) to screen for BKV. The case records of involved recipients were accessed to know their clinical manifestations, diagnostic characteristic and treatment regimens at that time. And the 1-, 3-year graft survival rate were analyzed by Kaplan-Meier analysis. RESULTS: A total of 16 renal biopsy specimens (11.7%) were positive for BKV. Viral particales on the size of 35 - 40 nm were seen in the tubular epithelial cells of 3 biopsy specimens and 7 urinary sediment samples. The numbers of BKVAN recipients suffering acute rejection, using ALG/ATG/OKT3 and using FK506+MMF immunosuppressive protocol were 7, 7 and 10 respectively. In 14 cases of BKVAN, there was an elevated level of serum creatine concentrations. Four cases lost their grafts after using a large dose of immunosuppressives. And renal functions improved by a reduction of immunosuppression or a replacement of FK506 with CsA in 8 cases. And graft functions deteriorated or had already failed in the remaining 4 cases whose immunosuppressive protocol were not changed. The 1-, 3-year graft survival rates were 81.3% and 54.2% in BKVAN recipients respectively. CONCLUSION: The diagnosis of BKVAN should be considered in recipients when their graft functions are deteriorating, especially for those with the accompanied risk factors. The morphological hallmarks of BKVAN are similar to those of acute rejection. The differentiation may be made by either immunohistochemistry or TEM. A proper modification of maintenance immunosuppression is effective in slowing down the progression of BKVAN.

Prospective study of polyomavirus BK replication and nephropathy in renal transplant recipients in China: a single-center analysis of incidence, reduction in immunosuppression and clinical course.

BACKGROUND: BK virus (BKV)-associated nephropathy (BKVAN) in renal transplant recipients is an important cause of renal transplant dysfunction. Our aim was to determine the kinetics of BKV load within one yr after kidney transplantation under the impact of intensive monitoring and reduction in maintenance immunosuppression, the incidence of BKVAN, and the outcome of BKVAN treatment. METHODS: Urine and peripheral blood (PB) were taken from 90 renal transplant recipients for BKV cytological testing and real-time PCR for BKV DNA at one, three, six, nine, and 12 months after transplantation and treatment. Graft biopsies and urinary sediments of recipients with BKVAN were taken to monitor viral particles by conventional transmission electron microscopy (TEM). RESULTS: By one post-transplant year, urinary decoy cells (median, 8/10 HPF), BKV viruria (median, 2.60 × 10(5) copies/mL), viremia (median, 9.65 × 10(3) copies/mL), and BKVAN occurred in 42.2%, 45.6%, 22.2%, and 5.6% of patients, respectively. The incidence of BK infection was lower in patients who received cyclosporine A (CsA) (28.9%) compared to tacrolimus (FK506) (57.7%) (p = 0.007). An increased hazard of BK infection was associated with the use of FK506 (HR 2.6, p = 0.009) relative to CsA. After reduction in immunosuppression, viremia resolved in 95%, without increased acute rejection, allograft dysfunction, or graft loss. BKVAN was diagnosed in five patients (5.6%). The treatment of immunosuppression reduction was effective (i.e., decreased the viral load and number of decoy cells, and improved graft function) in our five patients with BKVAN. Quantitative count of decoy cells (e.g., >10 per 10 HPF) as a marker of viremia and BKVAN had increased positive predictive values of 85.7% and 57.1%, respectively. CONCLUSIONS: Choice of FK506 as immunosuppressive agent is an independent risk factor affecting BKV infection. Monitoring and pre-emptive of immunosuppression reduction were associated with resolution of viremia and showed effective in BKVAN recipients at the early stage without acute rejection or graft loss. Quantitative count of urine cytology is a very convenient, useful, and sensitive method for evaluating BKV infection in renal transplant recipients.

[Living-related kidney transplantation: report of 175 cases].

OBJECTIVE: To analyze the clinical characteristics of living-related kidney transplantation (LRKT). METHODS: From January, 2004 to December, 2008, 175 LRKT were performed including 63 cases (36%) of parent-child relations and 49 cases (28%) of sibling relations between the recipients and donors. Out of 175 donors, 52 were 50 years old or above, 4 had microscopic hematuria (including 2 with also hypertension), 2 had kidney stone, and 2 had high body mass index (BMI). Zero-point graft biopsy was performed in 59 donors, and abnormalities were found in 15 of them. The recipients were at the age of 33-/+10.5 years, and the primary diseases are mainly dominant glomerular nephritis (72.6%, 127/175), and with a few cases of diabetes (4%, 7/175) and hypertensive nephropathy (4%, 7/175). RESULTS: Serum creatinine of the donors was 102-/+22.5 micromol/L at 7 days postoperatively, and 92-/+19.1 micromol/L at one month. One recipient died of severe pulmonary infection. Two recipients underwent graft nephrectomy due to anastomotic stenosis with concomitant acute graft rejection and renal arterial embolism. The one-year survival rates of the patients and grafts were 99.3% and 98.2%, respectively. The incident rates of accelerated rejection and acute rejection were 1.1% and 14.9%, respectively. Other complications included impaired liver function (22.3%), infection (9.7%) and leucopenia (4.6%). The renal arterial stenosis occurred in 2.3% (4/175) of the recipients. CONCLUSIONS: The recipients of living-related and cadaveric kidney transplant have different primary kidney disease spectrums. Differential diagnosis and treatment of acute rejection and renal artery or anastomotic stenosis can be of vital importance. Marginal donor kidneys with appropriate inclusion criteria can be safely used for transplantation. With good short-term patient and graft survival, LRKT needs further study to evaluate its long-term effect.

[Anatomy character of renal artery and treatment of living-donor renal transplantation].

OBJECTIVE: To study the anatomy characters of renal artery and the treatment of multiple arteries in living donor renal grafts. METHODS: Records of 142 living donors were analyzed in our center. We analyzed the anatomic structure of renal arteries by DSA and CTA pre-transplantation. Thirty-one kidneys with multiple arteries were transplanted after reconstruction. Then clinical effects were compared between multiple-renal-arteries group (n=31) and single-renal-artery group (n=111). RESULTS: The incidence of multiple renal artery was 30.99%, and there was no difference between both sides (left kidney 22.54%, right kidney 22.13%). If the multiple artery occurred in left or right kidney, the incidence of the multiple artery occurred in the other side was 56.25% and 60.00%, respectively. The diameter of left main renal artery was more magnanimous (P=0.001) and the first branch was more closed to abdominal aorta (P=0.004). Operation time and warm/cool ischemia time were longer in the multiple-renal-arteries group. However, estimated blood loss, delayed graft function, acute rejection and flow rate of arcuate artery were similar in both groups, the same as serum creatinine and serum creatinine clearance rate on day 7, 1 month and 3 month post-operation. It was shown by repeated measures ANOVA that graft with multiple arteries didn't affect the tendency of renal function at early time post-operation. CONCLUSION: Comprehending the character of renal artery and accurate treatment of multiple artery anastomosis are critical for the effect of the living kidney transplantation.

Tuberculosis in southern Chinese renal-transplant recipients.

OBJECTIVES: To analyze the characteristics of tuberculosis (TB) in Southern Chinese renal transplant recipients, and summarize the corresponding experiences in diagnosis and management. METHOD: Retrospectively study 41 documented post-transplant TB cases out of the 2333 patients who received kidney transplantation in the First Affiliated Hospital of Sun Yat-sen University between Jan. 1991 and Apr. 2007. RESULTS: TB in the post-renal-transplant population in Southern China displayed the following characteristics: (i) high incidence within a short time after transplantation, the median interval between renal transplantation and diagnosis of TB was 8 months (range: 1-156 months) and 56.1% were diagnosed within the first year post-transplant; (ii) high prevalence (51.2%) of extra-pulmonary tuberculosis; (iii) high co-infection rate (19.5%), pathogens included candida albicans, pseudomonas aeruginosa, staphylococcus aureus, Acinetobacter haemolyticus and cytomegalovirus; (iv) fever (82.9%), cough (56.1%) and sputum (39.0%) are the most common clinical manifestations; (v) purified protein derivative of tuberculin (PPD) skin test had little diagnostic value in this group with a negative result in all 41 cases; (vi) acute rejection (29.3%) and liver function damage (17.1%) were the main adverse effects of anti-tuberculosis chemotherapy; (vii) mortality of patients with post-transplant tuberculosis reached up to 22.0%. CONCLUSIONS: Chinese renal transplant recipients face a high risk of TB because of their immuno-compromised state and epidemiological prevalence of the disease. Therefore, attention should be given to this differential diagnosis in clinical practice. Balancing the benefits and disadvantages of anti-tuberculosis chemotherapy is of importance for this specific population.

[Therapeutic effect of sirolimus against chronic allograft nephropathy in kidney transplant recipients].

OBJECTIVE: To investigate the efficacy and safety of sirolimus in management of chronic allograft nephropathy (CAN). METHODS: A retrospective study was conducted involving 31 CAN patients followed up since March 2002, who experienced a change from a calcineurin inhibitor (CNI)-based regimen to a SRL-based regimen. Serum creatinine (Cr) in these patients was compared before and after the regimen change, and the adverse events associated with SRL were analyzed. RESULTS: Till March 2007 when the study closed, 15 patients reached the primary endpoint for resuming dialysis, 8 had improved and 8 had stable renal function. In patients with high Cr(0)(> or =3 mg/L, n=12), 9 resumed dialysis and 2 had improved renal function, but one of the patients with renal improvement eventually died due to infection; in the patients with low Cr(0)(<3 mg/L, n=19), 5 resumed dialysis, 8 had stable renal function and 6 had improved renal function, showing significant difference between the 2 groups (P=0.003). Altogether 14 patients reached the secondary endpoint for ceasing SRL for severe infection (5 patients, of whom 4 resumed dialysis and 1 died of infection) or adverse events associated with SRL (9 patients, of whom 4 resumed dialysis, 2 had stable and 3 had improved renal function). Hyperlipidemia (51.6%), leukocytopenia (41.9%), mouth ulcer (29.0%) and liver function lesion (16.1%) were the commonest adverse events in these patients, and totalling 13 severe adverse events were recorded, including 2 fatal cerebral hemorrhage, 3 fatal infection episodes, and 8 pulmonary and urinary infections that require hospitalization. CONCLUSION: Conversion from a CNI-based to SRL-based regimen can be effective for some CAN cases, especially for those with Cr(0) below 3 mg/L. Attention must be given to adverse events like hyperlipidemia and leukocytopenia, as well as the related cerebral vascular accidents and infections.

[Effect of ulinastatin in promotion of graft recovery in early stage after kidney transplantation: a clinical study].

OBJECTIVE: To investigate the effects of ulinastatin (UTI), a urinary trypsin inhibitor, on the promotion of the function recovery of transplanted kidney, especially for those with acute tubular necrosis (ATN). METHODS: Thirty patients underwent general cadaver kidney transplantation were randomly allocated to 2 equal groups: Group A (UTI-treatment group) and Group B (control group). 40 patients whose allografts were presumed to be with acute tubular necrosis (ATN) were also divided into 2 equal groups: Group C (UTI-treatment group) and Group D (control group). Group A and C were given ulinastatin perioperatively. 1, 3, 7, and 10 days after the transplantation blood and urine samples were collected. The levels of urine and blood alpha1-microglobulin (MG) were detected by radioimmunoassay. Blood IL-8, IL-10, and serum creatine (sCr) were detected by ELISA. RESULTS: Within 10 days after the transplantation the urine volume of Group A significantly increased, especially the urine volumes of days 2, 6, 7, 9, and 10 were significant greater than those of Group B (all P < 0.05). The levels of blood IL-8 of Group A in days 1 and 3 were (93.75 +/- 31.5) ng/L and (41.98 +/- 24.01) ng/L respectively, significantly lower than those of Group B [(135.0 +/- 31.2) ng/L and (78.34 +/- 76.39) ng/L respectively, both P < 0.05]. The levels of urine alpha1-MG in days 1 and 3 were (69.89 +/- 32.60) mg/L and (35.33 +/- 34.54) mg/L respectively, both significantly lower than those of Group B [(91.15 +/- 28.39) mg/L and (65.84 +/- 33.38) mg/L respectively, both P < 0.05]. In group C, the levels of blood alpha1-MG in days 7 and 10 of Group C were (118.26 +/- 41.23) mg/L and (99.49 +/- 68.63) mg/L respectively, both significantly lower than those of Group D [(187.15 +/- 55.23) mg/L and (151.27 +/- 87.42) mg/L respectively, both P < 0.05]. The urine alpha1-MG in days 7 and 10 were (39.89 +/- 22.32) mg/L and (38.21 +/- 20.36) mg/L respectively, both significantly lower than those of Group D [(67.34 +/- 21.56) mg/L and (62.26 +/- 29.24) mg/L respectively, both P < 0.05]. Compared to Group D, the increasing tendency of blood IL-8 was better suppressed in Group C, and the diuretic phases appeared earlier. CONCLUSION: UTI significantly improves the microcirculation, protects the tubule of transplanted kidney, increases the volume of urine, inhibits the inflammatory response, and promotes the recovery of ATN during the perioperative period of kidney transplantation.

[Clinical diagnosis of BK virus infection in renal transplant recipients].

OBJECTIVE: To explore the clinical diagnosis of BK virus (BKV) infection in renal transplant recipients. METHODS: Urine and peripheral blood samples were taken from 234 renal transplant recipients for BKV detection with cytological test and real-time PCR. RESULTS: The occurrence rate of urine decoy cells, BKV viruria and viremia in these patients was 33.3 %, 33.3% and 16.2%, respectively, and the median level of urine decoy cells was 6/10 HPF, with the median level of urine and peripheral blood BKV of 7.62 x 10(3) copy/ml and 7.61 x 10(3) copy/ml, respectively. The positivity rate of BKV in the urine samples were significantly higher than that in peripheral blood samples (P=0.000). The amount of decoy cells was related to BKV load in the urine samples (gamma=0.59, P=0.000), but the BKV load in the urine samples was not related to that in peripheral blood samples (P=0.14). CONCLUSION: Renal transplantation is associated with increased BKV shedding, indicating the necessity of BKV monitoring in renal transplant recipients with urine cytology, which is convenient and sensitive and indicates renal histological changes indirectly. Urine and peripheral blood BKV DNA detection is of value in identifying BKV activation to prevent irreversible graft damage of BKV-associated nephropathy.

[Characteristics of neoplasm occurrence of renal allograft recipients and their prognosis].

BACKGROUND & OBJECTIVE: Renal allograft recipients are more likely to develop neoplasm than general population because of long-term immunosuppressive treatment and concurrent infections. This study was designed to analyze the clinical features of neoplasm occurrence of renal allograft recipients, and the effect of radical surgery (RS) on their prognosis. METHODS: Records of 2 160 renal allograft recipients treated in our center from Oct. 1987 to Apr. 2003 were retrospectively studied. The time to neoplasm development, pathologic type of tumor, patients' survival time were analyzed to explore the clinical features of neoplasm developing after kidney transplantation. Recipients developed neoplasms were divided into RS group and non-RS group according to their treatment pattern. The effect of RS on patients' survival was estimated. RESULTS: A total of 33 patients developed neoplasms after transplantation. Among them,11(33.3%) developed neoplasms in digestive system. The median survival time of RS group (10 patients) was 41.5 months, that of non-RS group (23 patients) was 6.0 months. The 20-month survival rate of RS group was 70.0%, while that of non-RS group was 13.0%. CONCLUSIONS: Renal allograft recipients are more likely to develop neoplasm than general population. Moreover, their main malignancies are liver cancer, skin cancer, lymphoma and thyroid carcinoma, which differ from those observed in general population. Early diagnosis and treatment, especially feasible RS, will improve short-term outcome, while long-term therapeutic effect needs to be further observed.