Impact on grafted kidney function of rocuronium-sugammadex vs cisatracurium-neostigmine strategy for neuromuscular block management. An Italian single-center, 2014-2017 retrospective cohort case-control study.

BACKGROUND: The impact of sugammadex in patients with end-stage renal disease undergoing kidney transplantation is still far from being defined. The aim of the study is to compare sugammadex to neostigmine for reversal of rocuronium- and cisatracurium-induced neuromuscular block (NMB), respectively, in patients undergoing kidney transplantation. METHODS: A single-center, 2014-2017 retrospective cohort case-control study was performed. A total of 350 patients undergoing kidney transplantation, equally divided between a sugammadex group (175 patients) and a neostigmine group (175 patients), were considered. Postoperative kidney function, evaluated by monitoring of serum creatinine and urea and estimated glomerular filtration rate (eGFR), was the endpoint. Other endpoints were anesthetic and surgical times, post-anesthesia care unit length of stay, postoperative intensive care unit admission, and recurrent NMB or complications. RESULTS: No significant differences in patient or, with the exception of drugs involved in NMB management, anesthetic, and surgical characteristics, were observed between the two groups. Serum creatinine (median [interquartile range]: 596.0 [478.0-749.0] vs 639.0 [527.7-870.0] µmol/L, p = 0.0128) and serum urea (14.9 [10.8-21.6] vs 17.1 [13.1-22.0] mmol/L, p = 0.0486) were lower, while eGFR (8.0 [6.0-11.0] vs 8.0 [6.0-10.0], p = 0.0473) was higher in the sugammadex group than in the neostigmine group after surgery. The sugammadex group showed significantly lower incidence of postoperative severe hypoxemia (0.6% vs 6.3%, p = 0.006), shorter PACU stay (70 [60-90] min vs 90 [60-105] min, p < 0.001), and reduced ICU admissions (0.6% vs 8.0%, p = 0.001). CONCLUSIONS: Compared to cisatracurium-neostigmine, the rocuronium-sugammadex strategy for reversal of NMB showed a better recovery profile in patients undergoing kidney transplantation.

Technical aspects of unilateral dual kidney transplantation from expanded criteria donors: experience of 100 patients.

One option for using organs from donors with a suboptimal nephron mass, e.g. expanded criteria donors (ECD) kidneys, is dual kidney transplantation (DKT). In adult recipients, DKT can be carried out by several techniques, but the unilateral placement of both kidneys (UDKT) offers the advantages of single surgical access and shorter operating time. One hundred UDKT were performed using kidneys from ECD donors with a mean age of 72 years (Group 1). The technique consists of transplanting both kidneys extraperitoneally in the same iliac fossa. The results were compared with a cohort of single kidney transplants (SKT) performed with the same selection criteria in the same study period (Group 2, n = 73). Ninety-five percent of UDKTs were positioned in the right iliac fossa, lengthening the right renal vein with an inferior vena cava patch. In 69% of cases, all anastomoses were to the external iliac vessels end-to-side. Surgical complications were comparable in both groups. At 3-year follow-up, patient and graft survival rates were 95.6 and 90.9% in Group 1, respectively. UDKT can be carried out with comparable surgical complication rates as SKT, leaving the contralateral iliac fossa untouched and giving elderly recipients a better chance of receiving a transplant, with optimal results up to 3-years follow-up.

Absence of interaction between rivaroxaban, tacrolimus and everolimus in renal transplant recipients with deep vein thrombosis or atrial fibrillation.

No data are available on rivaroxaban use in renal transplant recipients and on its surmised interaction with immunosuppressants. The aim was to investigate potential interactions between rivaroxaban and immunosuppressants in this setting. Renal transplant recipients with a stable renal function treated with rivaroxaban and tacrolimus with or without everolimus were investigated. All drugs and creatinine concentrations were determined daily for 2 weeks after the start of anticoagulation. Blood samples were drawn at 8.00 am and 3-4 h later for trough and peak concentrations, respectively. Bleeding and thrombotic events were recorded during a minimum follow-up of 6 months. In 8 renal transplant patients, rivaroxaban levels showed a predictable pharmacokinetic trend, both at Ctrough (30-61 µg/L) and at Cpeak (143-449 µg/L), with limited variability in the 25th-75th percentile range. Tacrolimus (Ctrough 3-13 µg/L; Cpeak 3-16 µg/L), everolimus (Ctrough 3-11 µg/L; Cpeak 5-17 µg/L) and creatinine concentrations were stable as well. Immunosuppressors variability before and after rivaroxaban were 30% and 30% for tacrolimus, 27% and 29% for everolimus, respectively, as well as 14% and 3% for creatinine. For rivaroxaban monitoring, the reference change value better performed in identifying significant variations of its concentration. No patient had bleeding or thrombotic events, worsening of renal graft function, and signs of immunosuppressants toxicity during a mean follow-up of 23 (9-28) months. In conclusion, rivaroxaban does not seem to interact with tacrolimus and everolimus in renal transplant recipients. Both anticoagulant and immunosuppressive effects seem warranted, without major bleeding complications and effect on the graft function.

Acute rejection features in dual kidney transplant recipients from elderly donors: comparison of calcineurin inhibitor-based and calcineurin inhibitor-free immunosuppressive protocols.

Features of acute rejection in dual kidney transplant have not been studied. The aim of this study is to compare acute rejections in dual kidney transplant recipients from elderly donors on different immunosuppressive protocols. Sixty-nine patients were evaluated: 28 received calcineurin inhibitor-based (group 1) and 41 received calcineurin inhibitor-free immunosuppression (group 2). Histology of all donor kidneys was evaluated before implantation. All rejections showed tubulitis in both groups, and were classified as T-cell mediated acute rejections. Incidence and Banff grade of rejections in the two groups were not significantly different. Late rejections however, were observed in group 1 (P < 0.01) whereas steroid-resistant rejections occurred in group 2 (P < 0.03). C4d deposition was only observed in group 2. Occurrence of acute rejection was significantly associated with graft loss due to interstitial fibrosis/tubular atrophy in both groups. In group 1 mean serum creatinine levels of patients with rejections at six months and one year were higher than those of patients without rejections (P < 0.03 and P < 0.009, respectively). In group 2 they were higher at six months (P < 0.01) but not at one year. In addition, graft loss due to interstitial fibrosis/tubular atrophy occurred in 3/28 patients in group 1 (10.7%, OR= 1.95, 95%CI 1.02-3.71), and in 1/41 patients in group 2 (2.4%, OR= 0.41, 95%CI 0.07-2.24). Taken together these results suggest better renal function in patients on calcineurin inhibitor-free immunosuppression. In conclusion, acute rejections were detrimental irrespective of the type of immunosuppression, but different features were observed with each therapy. A tailored approach should be advantageous for prevention and treatment of acute rejections.

[Living donor kidney transplant: the surgical procedure]. / Trapianto di rene da donatore vivente: la procedura chirurgica.

The ideal nephrectomy technique for living donors should preserve donor safety and maximize graft quality for the recipient. The laparoscopic technique performs as well as the traditional open technique and has become the procedure of choice in up to 70% of the transplant centers in the US. Since November 2001, 70 living donor kidney transplants have been performed at the Transplant Center of Padua: 42 of the donors underwent laparoscopic left nephrectomy, 28 standard open nephrectomy. Donor and recipient results were analyzed retrospectively. After a mean follow-up of 38+/-26 months (laparoscopic group) and 40+/-27 months (open nephrectomy group) no deaths had occurred among the donors. Only one minor surgical complication was registered (hernia at the port site in a laparoscopic donor). Renal function was optimal in both groups of recipients, without significant differences in the incidence of delayed graft function and acute rejection. Minimally invasive approaches to donor nephrectomy are as safe and effective as the traditional open technique, minimizing postoperative pain and disability, and providing a better cosmetic result.

[A case of Kaposi's sarcoma in the rapamycin era]. / Un caso di sarcoma di Kaposi nell'era della Rapamicina.

We report a case of Kaposi's sarcoma in a patient who received a double kidney transplant in 2005. Immunosuppression was induced with rapamycin and antilymphocyte serum while maintenance therapy consisted of rapamycin, corticosteroids and mycophenolic acid. The patient developed delayed graft function but no rejection. In November 2006 and March 2007 two graft biopsies were taken because of a significant rise in serum creatinine; they revealed chronic allograft nephropathy and polyomavirus infection. Meanwhile a skin biopsy of the leg was performed to determine the nature of a discolored lesion. The morphohistological diagnosis was Kaposi's sarcoma. For this reason rapamycin was stopped and steroid treatment gradually reduced. Specific therapy with doxorubicin was started; radiological and endoscopic examination excluded disseminated disease while serological tests were positive for antibodies to HHV-8, a virus known to cause Kaposi's sarcoma. Unfortunately, withdrawal of antirejection therapy caused loss of the graft, so the patient had to start dialysis. In this report we stress the possible development of malignancy in transplanted patients who are given rapamycin. Rapamycin is known to be an antirejection drug and to have antineoplastic activity; the major risk of malignancy is probably related to immunosuppression rather than the type of drugs used to obtain it.

Laparoscopic live donor nephrectomy: single center experience.

AIMS: The aim of this study was a retrospective assessment of the safety of laparoscopic live donor nephrectomy (LLDN) and the outcome of these renal transplantations. METHODS: From November 2001 to October 2006, we performed 30 LLDN (all left nephrectomies) after excluding any renal vascular anomalies in the donor. All laparoscopic procedures were performed by a team consisting of an expert laparoscopic surgeon and a transplant surgeon. The donor mean age was 48.9 +/- 7.6 years (range 22 to 69), 33% of the donors were men and their mean Body Mass Index was 24.7 +/- 3.8 kg/m(2). The recipients were a 32 +/- 14 years old (range 6 to 64), with 66% of them men, and their mean time on dialysis, 33 +/- 49 months (range 0 to 120). RESULTS: After a mean follow-up of 39 +/- 14 months, all donors and recipients are alive. The mean operative time was 272 +/- 41 min (range 225-360) and the mean warm ischemia time, 161 +/- 35 seconds (range 107 to 240). Surgical complications in the donors were one incisional hernia and two cases of pneumonia. The donor's mean hospital stay was 5.3 +/- 1.7 days (range 3 to 12) and their mean serum creatinine at discharge was 111 +/- 21 micromol/L. There was one surgical complication-a hematoma-among the recipients, and all transplants functioned immediately except for one case. CONCLUSIONS: LLDN was confirmed to be safe and effective, with no negative impact on transplants success. Expertise in laparoscopic surgery is needed to minimize the side effects for the transplant donor and for the recipient.

Histological markers of humoral rejection in renal transplant patients.

Diagnosis of "suspicious humoral rejection" can be formulated in the presence of peritubular capillary (PTC) C4d deposition and one of the following tissue changes: (1) acute tubular necrosis, (2) glomerulitis or presence of polymophonuclear leukocytes or monocytes in PTC, or (3) arteritis. From January 2004 to October 2006, we performed immunohistochemical staining with anti-C4d antibody on 54 renal biopsies from 39 renal transplant patients. In 25 biopsies we observed diffuse (n = 13) or focal (n = 12) C4d deposition. Based on C4d-positivity, patients were divided into three groups: group 1 included 19 C4d-negative patients; group 2, 10 patients with diffuse C4d-positivity; and group 3, 10 patients with focal C4d-positivity. Panel-reaction antibody-positive tests were associated with diffuse C4d-positivity: 50% of group 2 patients showed a positive test, while no group 1 or 3 patients had a positive test (P < .001). Glomerulitis was observed in six biopsies and associated with diffuse C4d staining. Graft loss occurred in 3/10 group 2 patients (30%); 2/19 group 1 patients (10.5%), and 1/10 group 3 patients (10%). Viral infections were experienced in the year of the biopsy by 50% of group 1 patients 80% of group 2 patients, and 100% of group 3 patients (P < .025), indicating a significantly greater number of infections among patients with C4d-positive biopsies. In eight cases, anti-thymocyte globulin was administered less than 21 days before the biopsy: four had diffuse and four had focal C4d positivity.

Combined liver and kidney transplantation: analysis of Padova experience.

BACKGROUND/AIM: The main indications for combined liver and kidney transplantation (CLKT) are as follows: (1) cirrhosis with renal damage dependent or not upon liver disease, (2) renal failure with dialysis and concomitant liver end-stage disease, (3) congenital diseases, and (4) enzymatic liver deficiency with concomitant renal failure. The aim of this study was to evaluate our results with CLKT both in adult and pediatric patients. METHODS: From September 1995 to September 2006, 15 CLKT (2.8%) among 541 liver transplantations included 4 pediatric patients (27%). The main indications for CLKT were hepatitis C virus (HCV) and polycystic diseases in adult patients, and primary hyperoxaluria in pediatric patients. RESULTS: The double transplantation was performed from the same donor in all cases. All adult patients received whole liver grafts, whereas 3 split transplants and 1 whole liver graft were transplanted in the pediatric patients. Median liver and kidney cold ischemia times were 468 and 675 minutes, respectively. After a median follow-up of 36 months (range, 1-125), the overall survival rate was 80%. Five-year patient and graft survival rates were 100% for adult CLKT, whereas they were 50% for pediatric patients. We observed only 2 cases (18%) of delayed renal function, requiring temporary hemodialysis with progressive graft improvement. There was only 1 case of kidney retransplantation due to early graft nonfunction in a pediatric patient. CONCLUSION: Although CLKT is related to major surgical risks, results after transplantation are satisfactory with an evident immunological advantage.

Balance impairment in kidney transplant recipients without concurrent peripheral neuropathy.

Kidney transplant recipients (KTRs) present with compromised functional capacity, low levels of physical activity, muscle atrophy, and peripheral nerve dysfunction that may result in high postural instability. This study aimed to compare the static balance control of 19 KTRs with 19 healthy adults (HA). All participants completed the Romberg test on a stabilometric platform with eyes open (EO), eyes closed (EC) and during a dual task (DT) condition. Centre of pressure (COP) measures (COP velocity (COPv) and sway area (SA)), as well as position-based outcomes such as anterior-posterior (AP) and medio-lateral (ML) ranges of COP displacements were recorded. Independent ANCOVA revealed an overall lower performance of KTRs compared to HA (p<0.05) with the EC condition exhibiting the worst relative performance for KTRs, suggesting a poorer capacity of relying on proprioceptive information when maintaining the upright posture. The addition of a cognitive task did not further worsen balance performance in KTRs. As impaired postural control is one of the main predictors of falls in elderly subjects, these data might also indicate that this constitutes an equivalent risk factor for falling in middle-aged KTRs.

Coronary Microvascular Dysfunction Predicts Long-Term Outcome in Simultaneous Pancreas-Kidney Transplantation.

BACKGROUND: Patients with diabetes are at increased cardiovascular risk. Simultaneous pancreas-kidney transplantation (SPKT) is the treatment of choice in patients with type 1 diabetes mellitus and diabetic nephropathy. We assessed coronary flow reserve (CFR) by transthoracic echocardiography as a marker of major adverse cardiac events (MACE) in SPKT patients. METHODS: We studied 48 consecutive SPKT patients (28 male, age at SPKT 54 ± 8 years). Time from transplantation was 8.5 ± 3 years. Follow-up was 4.6 ± 1.8 years. Coronary flow velocity in the left anterior descending coronary artery was detected by Doppler echocardiography at rest and during adenosine infusion. CFR was the ratio of hyperemic diastolic flow velocity (DFV) to resting DFV. A CFR ≤ 2 was considered abnormal and a sign of coronary microvascular dysfunction. MACE were cardiac death, myocardial infarction, and heart failure. RESULTS: CFR was 2.55 ± 0.8. CFR was ≤2 in 13 (27%) patients. CFR was lower in SPKT patients with MACE (2.1 ± 0.7 vs 2.7 ± 0.8, P = .03) and patients with MACE had a higher incidence of CFR ≤ 2 (P = .03). Time from transplantation was shorter in patients with MACE (P < .0001). Patients with CFR ≤ 2 had a lower MACE-free survival (P = .03). CFR ≤ 2 predicted the risk of MACE (P = .007) independently from coronary artery disease and metabolic control. However, this predicted role is lost when adjusted for the time from transplantation, which plays a protective role (P = .001). CONCLUSIONS: In SPKT, CFR ≤ 2 may be a reliable marker for MACE, independent of coronary artery disease diagnosis. However, this role seems to be reduced over time. This finding suggests a gradual reduction of cardiovascular risk in SPKT patients.

Deuterium nuclear magnetic resonance for evaluating the metabolic status of livers subjected to warm ischemia.

BACKGROUND: The development of reliable methods for assessing the viability of currently available livers is expected to increase the number of successful transplantations. METHODS: 2 H nuclear magnetic resonance (NMR) was used to search for metabolic markers of ischemia in explanted rat livers. Deuterium oxide (2 H2O) was used as a source of 2 H. A total of 10-80% v/v 2 H2O was added to homogenates obtained from a liver biopsy and the formation of 2 H-labeled metabolites was monitored. RESULTS: Some well-resolved 2 H resonances were found in the homogenates from biopsies of warm ischemic liver. Two of these were identified as [3-2 H] lactate and [2-2 H] lactate, and a linear relationship was found between the ratio of [[2-2 H] lactate] to [[3-2 H] lactate] and the warm ischemia time. The deuterium incorporation into lactate was explained on the basis of the metabolic events occurring under hypoxic conditions. CONCLUSIONS: The experimental results support the application of 2 H NMR for a reliable evaluation of the metabolic status of a liver harvested from non-heart-beating donors.

Mycophenolate mofetil (MMF) versus azathioprine (AZA) in pancreas transplantation: a single-center experience.

AIM: Advances in immunosuppression and careful monitoring for rejection are largely responsible for improved results in pancreas transplantation. We conducted a retrospective study to establish the effectiveness of immunosuppressive therapy with mycophenolate mofetil (MMF) instead of azatioprine (AZA) in pancreas transplantation and to assess adverse effects in the two different immunosuppressive regimes. SUBJECTS AND METHODS: Since 1991, 27 pancreas transplantations were performed in 25 patients at our Institute. For induction therapy, immunosuppressant protocol consisted of quadruple immunosuppressive therapy with cyclosporine, steroids, antilymphocyte globulin and AZA in 13 patients or MMF in 12 patients respectively. RESULTS: Acute rejection occurred in 76% of patients in the AZA group compared with 53% in the MMF group. Steroid-resistant rejection was observed in 7% in the MMF group compared to 38% of patients on AZA (p < 0.01). Two kidney grafts were lost due to acute rejection in the AZA group, one pancreas was lost due to acute rejection and one to chronic rejection in the MMF group. There were no significant differences in CMV infection. Severe fungal infections were noted in 2 patients treated with MMF. Malignancy occurred in 1 patient (pancreas graft lymphoma) in MMF. CONCLUSIONS: In conclusion, patients treated with MMF required less frequent and less intensive treatment for acute rejection. However, its short- and long-term side effects should be further investigated.

Application of cyclosporine in renal transplantation: experience at the University of Padua.

Cyclosporine (CsA) therapy has evolved considerably since its introduction as the primary immunosuppressant drug in the early 1980s and its use in renal transplantation continues to expand globally. In the last 20 years, there have been significant advances in formulation design, therapeutic drug monitoring guidelines, and the emerging role of CsA-based combination therapies that have resulted in a substantial improvement in clinical outcomes in renal transplant recipients. The aim of this work is to review developments in the application of CsA in kidney transplantation at our Center in Padua and to evaluate the clinical outcome of our patients in the last 15 years in relation to the new trends in CsA management strategies.

Desensitization with plasmapheresis and anti-Cd20 for ABO incompatible kidney transplantation from living donor: experience of a single center in Italy.

OBJECTIVE: Blood group incompatibility in kidney transplants from a living donor can be successfully overcome by using various desensitization protocols: intravenous immunoglobulin, plasmapheresis (PP), immunoadsorption, and double filtration PP. PATIENTS AND METHODS: From July 2010 to October 2013, we performed 10 ABO incompatible kidney transplantation (KT) procedures from a living donor. The desensitization protocol was based on rituximab and PP+cytomegalovirus immune globulin. All patients received induction with basiliximab, except 1 case treated with Thymoglobuline® (ATG) for the simultaneous presence of donor-specific antibody. Tacrolimus and mycophenolate mofetil were initiated at the time of desensitization and continued after the transplant. RESULTS: After a mean follow-up of 11.6±10.4 months, all patients are alive with a functioning graft. The mean serum creatinine concentration at 1 month, 3 months, 6 months, and 1 year was 1.48±0.29, 1.47±0.18, 1.47±0.27, and 1.5±0.27 mg/dl. Three episodes of acute cellular rejection occurred in 2 patients. There was only 1 case of BK virus infection, treated with reduction of immunosuppressive therapy. The protocol biopsy specimens at 1, 3, and 6 months were C4d positive in the absence of acute rejection. CONCLUSIONS: Desensitization with rituximab, PP, and anti-cytomegalovirus immune globulin allowed us to perform transplants from living donors to ABO incompatible recipients with excellent results and reduced costs.

Everolimus associated with low-dose calcineurin inhibitors, an option in kidney transplant recipients of very old donors.

BACKGROUND: Despite potential renal and cardiovascular advantages of proliferation signal inhibitors, their de novo use in kidney transplantation (KT) from elderly donors (ED) is poorly documented. We retrospectively analyzed two consecutive cohorts of KT from ED: low-dose extended-release tacrolimus (Tac) was used from 2010 to 2012 and cyclosporine (Csa) was used from 2008 to 2010. METHODS: Associated maintenance drugs were everolimus (Eve) and steroids. Outcomes were compared between groups over a 12-month follow-up. Fifty-six patients were analyzed in the Tac-Eve group and 54 in the Csa-Eve group. RESULTS: There were no significant differences at baseline with the exception of older donors age in the Tac-Eve cohort (74 vs 71 years, P = .002). There were no deaths, primary non functions, or graft losses. Eight (14%) Tac-Eve and 15 (28%) Csa-Eve patients had delayed graft function (P = .10). Renal function was fairly stable over time (median cGFR 36-49 mL/min and 51-55 mL/min in single kidney transplantation and dual kidney transplantation patients, respectively) with no significant differences between groups at month 12. Surgical complications were infrequent and observed mostly in dual kidney transplantation recipients. Thirty-nine (70%) and 30 (56%) patients remained under their initial Tac-Eve or Csa-Eve regimen, respectively. CONCLUSIONS: Induction with Thymoglobuline and maintenance with Eve and low-dose extended-release Tac and steroids is safe and effective in renal transplant from ED.

Organ donors with small renal cancer: report of 3 cases.

Transmission of donor malignancies has been reported since the early days of clinical transplantation. Up to 1995, the Transplant Tumor Registry created by Penn included 155 cadaver and 29 living donor affected by tumors. The most common, excluding brain tumor, was renal cell carcinoma (RCC). RCC represents 2% of adult cancers, an incidence that increases with advancing age. The expansion of the criteria that define a suitable organ donor has as a consequence included donors that are older than in the past. Small RCCs are found during renal recovery from a cadaveric donor in ∼1% of cases. The use of such donors is a matter of debate; it has been suggested that donor kidneys with small RCC Fuhrman grade I/II may be transplanted after appropriate surgical excision. We report our experience with 3 donors with clear cell RCC: 2 contralateral kidneys were transplanted in 2 recipient and a third recipient received an affected kidney after a wide tumor excision. All of the patients we alive and free from recurrence at 14-48 months (mean 35 mo). In the third case, immunosuppression was achieved with a mammalian target of rapamycin inhibitor, which is currently used not only as an immunosuppressant to prevent rejection, but also as treatment for renal cancer. Our data confirmed that donors with small renal tumors may be used, because the risk of tumor recurrence is small and the benefits of a kidney transplantation are great.

Refinement of a macaque transplantation model: application of a subcutaneous port as a means for long-term enteral drug administration and nutritional supplementation.

A new application of a device enabling the long-term enteral administration of drugs or nutritional supplementation was developed for implementing in research entailing the use of macaques (Macaca fascicularis). After implanting a subcutaneous port, a surgically-placed gastrostomy (SPG) was completed to afford access to the gastric lumen and enable the administration of substances. In this study, the device was left in place for a period ranging between two and 12 months in macaques (n= 16). In five cases, the SPG was used successfully for 8-12 months, until the experimental endpoint was reached. In six cases, the SPG had to be removed earlier due to local infection at the implant site, which promptly regressed after the SPG was removed and antibiotic treatment was administered. One SPG-implanted macaque was euthanized for reasons unrelated to the SPG or the xenotransplantation procedure. In four cases, the SPG was implanted without any complications but has yet to be used to administer substances to the animals. From an ethical standpoint, the SPG device described here minimizes the forced handling of macaques otherwise needed for the oral administration of viscous or unpalatable substances by gavage. The device thus represents an effective refinement that fully complies with the tenet of the '3 Rs' that should be considered by primate centres exposing non-human primates to the long-term daily administration of substances by oral gavage.

Glomerular c4d immunoreactivity in acute rejection biopsies of renal transplant patients.

In renal transplant patients, glomerulitis may be present in all types of acute rejection, often accompanied by diffuse C4d staining of peritubular capillaries: C4d3 positivity in more than 50% of peritubular capillaries. It may progress to chronic transplant glomerulopathy, characterized by capillary basement membrane multilayering, proteinuria, and progressive loss of renal function. While C4d3 is a recognized marker of an antibody-mediated reaction, the significance of glomerular C4d (GlC4d) staining is unknown. The aim of this study was to evaluate GlC4d immunoreactivity and its correlation with C4d3 in acute rejection biopsies. Paraffin-embedded acute rejection biopsies from 90 renal transplant patients were evaluated according to the Banff classification. Biopsies showing C4d-positive endothelial cells in more than 50% of glomeruli were considered GlC4d-positive. C4d3-positive staining prevalence was 23%. GlC4d-positive staining showed an 89% concordance rate (r = 0.81, P < .0001; Cohen's k = 0.80, P < .0001). GlC4d detection sensitivity was 0.80 and specificity 0.97. C4d3 and GlC4d immunoreactivity was significantly associated with glomerulitis (P < .006 and P < .03, respectively) and with proteinuria at the time of biopsy (P < .03 and P < .01, respectively). Interestingly, GlC4d positivity correlated better than C4d3 positivity with the presence of posttransplant circulating anti-human leukocyte antigen alloantibodies (P < .04 and P = .7, respectively). Patients with C4d3- or GlC4d-positive acute rejections underwent graft loss due to interstitial fibrosis and tubular atrophy more frequently than those with C4d0- or GlC4d-negative rejections (P < .0001 and P < .005, respectively), whereas no differences were observed in graft loss due to death. In conclusion, C4d3 and GlC4d stains showed a high correlation rate. Compared with C4d3, GlC4d staining demonstrated good sensitivity and excellent specificity. Our results suggested that GlC4d staining may indicate glomerular endothelial damage and be of prognostic value.

C4d-positive renal allograft rejection biopsies in cyclosporine-treated patients: single-center incidence and outcome.

T cell-mediated acute rejection (ATCMR) in renal transplant patients can have an antibody-mediated component. The aim of this study was to evaluate the incidence of renal biopsies showing ATCMR with C4d immunoreactivity and the correlation between C4d-positive ATCMRs and graft outcomes. We studied 216 renal transplant patients receiving cyclosporine-based immunosuppression (mean follow-up = 203.5 +/- 42.5 months). Of these, 79 experienced biopsy-proven ATCMR (group 1), whereas 137 did not show clinical or laboratory evidence of ATCMR (group 2). Mean serum creatinine levels were evaluated at 6 months, as well as 2 and 5 years after transplantation. The number of graft losses due to interstitial fibrosis and tubular atrophy (IF/TA) was greater in group 1 than in group 2 (P < .001 and P < .02, respectively), while graft survival was lower (P < .03). Staining with anti-C4d antibody was performed in 61/77 type I ATCMR biopsies: seven cases showed diffuse C4d positivity with CD68(+) monocytes in peritubular capillaries observed in all cases. Three cases showed focal C4d positivity. Two ATCMRs were steroid, resistant. Graft loss due to IF/TA occurred in 4/7 patients (57.1%) who had previously experienced ATCMRs with diffuse C4d positivity; whereas it occurred in 5/51 patients (9.8%) with previous C4d negative ATCMRs (P < .001). Patients with focal C4d positivity did not undergo graft loss due to IF/TA. In conclusion, at our center the diffuse C4d positivity that occurred in 11.4% of type I ATCMRs was associated with a poor prognosis.