Ana Cristina Carvalho de Matos

Early detection of heart transplant patients with increased risk of ciclosporin nephrotoxicity

Chronic nephrotoxic effects from ciclosporin are a common clinical complication after heart transplantation and frequently lead to progressive renal failure. There is no laboratory test to predict development of chronic renal failure in heart transplant patients. We analysed urinary retinol-binding protein (uRBP) concentration, to assess proximal tubular dysfunction, in 36 clinically stable heart transplant patients. We detected a subgroup of 13 patients who had high concentrations of uRBP, good renal function, and a high risk of developing progressive renal failure compared with patients with normal uRBP (relative risk 3.87, p=0.003).

Functional and morphologic evaluation of kidney proximal tubuli and correlation with renal allograft prognosis.

Renal transplant patients with stable graft function and proximal tubular dysfunction (PTD) have an increased risk for chronic allograft nephropathy (CAN). In this study, we investigated the histologic pattern associated with PTD and its correlation with graft outcome. Forty‐nine transplant patients with stable graft function were submitted to a biopsy. Simultaneously, urinary retinol‐binding protein (uRBP) was measured and creatinine clearance was also determined. Banff’s score and semi‐quantitative histologic analyses were performed to assess tubulointerstitial alterations. Patients were followed for 24.0 ± 7.8 months. At biopsy time, mean serum creatinine was 1.43 ± 0.33 mg/dl. Twelve patients (24.5%) had uRBP ≥1 mg/l, indicating PTD and 67% of biopsies had some degree of tubulointerstitial injury. At the end of the study period, 18 (36.7%) patients had lost renal function. uRBP levels were not associated with morphologic findings of interstitial fibrosis and tubular atrophy (IF/TA), interstitial fibrosis measured by Sirius red or tubulointerstitial damage. However, in multivariate analysis, the only variable associated with the loss of renal function was uRBP level ≥1 mg/l, determining a risk of 5.290 of loss of renal function (P = 0.003). Renal transplant patients who present PTD have functional alteration, which is not associated with morphologic alteration. This functional alteration is associated to progressive decrease in renal function.

Comparison of Long-Term Effect of Thymoglobulin Treatment in Patients With a High Risk of Delayed Graft Function

BACKGROUND T-lymphocyte depletion is a strategy to reverse the impact of ischemia-reperfusion injury (IRI) in progression to chronic allograft dysfunction, especially among patients at high risk for delayed graft function (DGF). METHODS The present work assessed the effect of thymoglobulin among a population with a high incidence of DGF. We analyzed 209 transplanted patients: 97 in the thymoglobulin and 112 in the control group. RESULTS The main complication was DGF (59.3%), with a similar incidence in both groups (63.9% vs. 55.3%; P = .36). Acute rejection episodes (ARE) were decreased with thymoglobulin (8.2% vs. 28.5%; P < .001), but cytomegalovirus viremia was 3.4-fold more frequent (58.3% vs. 17.1%; P < .001). One-year graft function was significantly better in the thymoglobulin group (59.2 ± 17.2 vs. 51.8 ± 15.3 mL/min; P = .004), even when censored by ARE (59.7 ± 17.5 vs. 53.3 ± 14.4; P = .023). The same difference was observed at the 2-year follow-up (P = .024), even when censored for ARE (P = .045). A multivariate analysis showed thymoglobulin to be a factor strongly associated with protection of graft function (P = .039). CONCLUSION Despite not reducing the incidence of DGF, thymoglobulin induction significantly reduced the incidence of ARE and showed a long-term profile of protection of renal graft function, independent of the reduction in ARE.

Cytomegalovirus infection in renal transplantation: clinical aspects, management and the perspectives

Cytomegalovirus infection is one of most frequent infectious complications after renal transplantation, and can be classified as primo-infection, when the transmission occurs through the graft, or reactivation, when the recipient is cytomegalovirus seropositive. After transplantation, cytomegalovirus can appear as an infection, when the patient presents with evidence of viral replication without symptoms or disease, which has two clinical spectra: typical viral syndrome or invasive disease, which is a less common form. Their effects can be classified as direct, while the disease is developed, or indirect, with an increase of acute rejection and chronic allograft dysfunction risks. Diagnosis must be made based on viremia by one of the standardized methods: antigenemia or PCR, which is more sensitive. The risk factors related to infection after transplantation are the serologic matching (positive donor and negative recipient) and anti-lymphocyte antibody drugs. One of the strategies to reduce risk of disease should be chosen for patients at high risk: preemptive treatment or universal prophylaxis. Recent clinical research has described ganciclovir resistance as an emergent problem in management of cytomegalovirus infection. Two types of mutation that cause resistance were described: UL97 (most frequent) and UL54. Today, sophisticated methods of immunologic monitoring to detect specific T-cell clones against cytomegalovirus are used in clinical practice to improve the management of high-risk patients after renal transplantation.

Labile Plasma Iron Generation After Intravenous Iron is Time-dependent and Transitory in Patients Undergoing Chronic Hemodialysis

Iron supplementation in hemodialysis patients is fundamental to erythropoiesis, but may cause harmful effects. We measured oxidative stress using labile plasma iron (LPI) after parenteral iron replacement in chronic hemodialysis patients. Intravenous iron saccharate (100 mg) was administered in patients undergoing chronic hemodialysis (N = 20). LPI was measured by an oxidant‐sensitive fluorescent probe at the beginning of dialysis session (T0), at 10 min (T1), 20 min (T2), and 30 min (T3) after the infusion of iron and at the subsequent session; P < 0.05 was significant. The LPI values were significantly raised according to the time of administration and were transitory: −0.02 ± 0.20 µmol/L at the beginning of the first session, 0.01 ± 0.26 µmol/L at T0, 0.03 ± 0.23 µmol/L at T1, 0.09 ± 0.28 µmol/L at T2, 0.18 ± 0.52 µmol/L at T3, and −0.02 ± 0.16 µmol/L (P = 0.001 to 0.041) at the beginning of the second session. The LPI level in patients without iron supplementation was −0.06 ± 0.16 µmol/L. Correlations of LPI according to time were T1, T2, and T3 vs. serum iron (P = 0.01, P = 0.007, and P = 0.0025, respectively), and T2 and T3 vs. transferrin saturation (P = 0.001 and P = 0.0003, respectively). LPI generation after intravenous saccharate administration is time‐dependent and transitorily detected during hemodialysis. The LPI increment had a positive correlation to iron and transferrin saturation.

Hospital Admission following Acute Kidney Injury in Kidney Transplant Recipients Is Associated with a Negative Impact on Graft Function after 1-Year

The incidence and outcomes of acute kidney injury (AKI) in kidney transplantation are poorly known. Retrospective cohort analysis was performed on the data of all patients (≥3 months after transplantation and ≥16 years of age) admitted to the hospital due to medical or surgical complications from 2007 to 2010. We analyzed 458 kidney transplant recipients, 55.2% men, median age 49 (IQR, 36–58) years, median of 12.5 (IQR, 3–35) months after kidney transplantation; admitted to the hospital due to medical or surgical complications. Most of the patients received a kidney from a deceased donor (62.2%), the primary cause for hospital admission was infection (60.7%) and 57 (12.4%) individuals were diagnosed with acute rejection (AR). The incidence of AKI was 82.3%: 31.9% stage 1, 29.3% stage 2 and 21.2% stage 3. Intensive care unit (ICU) admission (OR 8.90, 95% CI: 1.77–44.56 p = 0.008), infection (OR 5.73, 95% CI: 2.61–12.56, p<0.001) and the use of contrast media (OR 9.34, 95% CI: 2.04–42.70, p = 0.004) were the independent risk factors for AKI development. The mortality rate was 2.1% and all patients who died were diagnosed with AKI. Even after the exclusion of AR cases, at the end of 12 months, the individuals with AKI exhibited higher percent changes in creatinine values when compared with individuals without AKI (9.1% vs. -4.3%; p<0.001). According to KDIGO system, we found a high incidence of AKI among the complications of renal transplantation. As in other scenarios, AKI was associated with renal function loss at 1-year after the hospital discharge.

Expanding the pool of kidney donors: use of kidneys with acute renal dysfunction

ABSTRACT Given the shortage of organs transplantation, some strategies have been adopted by the transplant community to increase the supply of organs. One strategy is the use of expanded criteria for donors, that is, donors aged >60 years or 50 and 59 years, and meeting two or more of the following criteria: history of hypertension, terminal serum creatinine >1.5mg/dL, and stroke as the donor´s cause of death. In this review, emphasis was placed on the use of donors with acute renal failure, a condition considered by many as a contraindication for organ acceptance and therefore one of the main causes for kidney discard. Since these are well-selected donors and with no chronic diseases, such as hypertension, renal disease, or diabetes, many studies showed that the use of donors with acute renal failure should be encouraged, because, in general, acute renal dysfunction is reversible. Although most studies demonstrated these grafts have more delayed function, the results of graft and patient survival after transplant are very similar to those with the use of standard donors. Clinical and morphological findings of donors, the use of machine perfusion, and analysis of its parameters, especially intrarenal resistance, are important tools to support decision-making when considering the supply of organs with renal dysfunction.

Presence of arteriolar hyalinosis in post-reperfusion biopsies represents an additional risk to ischaemic injury in renal transplant.

The role of post‐reperfusion biopsy findings as a predictor of early and long‐term graft function and survival is still a target of research.

Impact of Machine Perfusion after Long Static Cold Storage on Delayed Graft Function Incidence and Duration and Time to Hospital Discharge

Delayed graft function (DGF) is very high in our center (70%‐80%), and we usually receive a kidney for transplant after more than 22 hours of static cold ischemia time (CIT). Also, there is an inadequate care of the donors, contributing to a high rate of DGF. We decided to test whether machine perfusion (MP) after a CIT improved the outcome of our transplant patients. We analyzed the incidence of DGF, its duration, and the length of hospital stay (LOS) in patients who received a kidney preserved with MP after a CIT (hybrid perfusion—HP). We included 54 deceased donors kidneys preserved with HP transplanted from Feb/13 to Jul/14, and compared them to 101 kidney transplants preserved by static cold storage (CS) from Nov/08 to May/12. The median pumping time was 11 hours. DGF incidence was 61.1% vs 79.2% (P = .02), median DGF duration was 5 vs 11 days (P < .001), and median LOS was 13 vs 18 days (P < .011), for the HP compared to CS group. The observed reduction of DGF with machine perfusion did not occur in donors over 50 years old. In the multivariate analysis, risk factors for DGF, adjusted for CIT, were donor age (OR, 1.04; P = .005) and the absence of use of MP (OR, 1.54; P = .051). In conclusion, the use of HP contributed to faster recovery of renal function and to a shorter length of hospital stay.

Deficient of Megalin in Stable Renal Transplanted Patients with Proximal Tubular Dysfunction

Introduction: Renal-transplant patients with stable graft function and proximal tubular dysfunction (PTD) have an increased risk for IF/TA. The morphological features associated with this dysfunction are unknown. Material and methods: 54 renal transplant patients with normal and stable renal function were submitted to a biopsy and had urinary retinol binding protein (uRBP) and renal function assessment. Patients were divided according to uRBP levels: 1, these findings had no association with uRBP levels. Megalin expression was observed at BB of PTC, 13.7% of bxs presented its expression in less than 50% of tubules, 56.8% had in more than 50% of tubules but with discontinuity over the BB and in 29.5% megalin expressed in more than 50% of tubules continuouslly over the BB. Patients who presented uRBP > 0.6 mg/L had lower amount of megalin expression in their biopsies, p=0.007. Cellular RBP expression was observed diffusely over the cytoplasma of PTC, with different intensities. No correlation was found between tubular megalin expression and uRBP values with CRBP expression. Conclusions: Half of renal transplant patients with normal renal function had PTD. The deficiency of megalin expression could be the subjacent functional alteration found in patients with PTD.