Ana Maria Manzione

Outcomes of Pregnancies after Kidney Transplantation: Lessons Learned from CKD. A Comparison of Transplanted, Nontransplanted Chronic Kidney Disease Patients and Low-Risk Pregnancies: A Multicenter Nationwide Analysis

Background Kidney transplantation (KT) may restore fertility in chronic kidney disease (CKD). The reasons why maternofetal outcomes are still inferior to the overall population are only partially known. Comparison with the CKD population may offer some useful insights for management and counselling. Aim of this study was to analyse the outcomes of pregnancy after KT, compared with a large population of nontransplanted CKD patients and with low-risk control pregnancies, observed in Italy the new millennium. Methods We selected 121 live-born singletons after KT (Italian study group of kidney in pregnancy, national coverage about 75%), 610 live-born singletons in CKD, and 1418 low-risk controls recruited in 2 large Italian Units in the same period (2000-2014). The following outcomes were considered: maternal and fetal death; malformations; preterm delivery; small for gestational age (SGA) baby; need for the neonatal intensive care unit; doubling of serum creatinine or increase in CKD stage. Data were analyzed according to kidney diseases, renal function (staging according to CKD-epidemiology collaboration), hypertension, maternal age, parity, ethnicity. Results Maternofetal outcomes are less favourable in CKD and KT as compared with the low-risk population. CKD stage and hypertension are important determinants of results. Kidney transplantation patients with estimated glomerular filtration rate greater than 90 have worse outcomes compared with CKD stage 1 patients; the differences level off when only CKD patients affected by glomerulonephritis or systemic diseases (“progressive CKD”) are compared with KT. In the multivariate analysis, risk for preterm and early-preterm delivery was linked to CKD stage (2-5 vs 1: relative risk 3.42 and 3.78) and hypertension (RR 3.68 and 3.16) while no difference was associated with being a KT or a CKD patient. Conclusions The maternofetal outcomes in patients with kidney transplantation are comparable with those of nontransplanted CKD patients with similar levels of kidney function impairment and progressive and/or immunologic kidney disease.

Neutrophil Gelatinase Associated Lipocalin Is an Early and Accurate Biomarker of Graft Function and Tissue Regeneration in Kidney Transplantation from Extended Criteria Donors

Background Delayed graft function (DGF) is an early complication of kidney transplantation (KT) associated with increased risk of early loss of graft function. DGF increases using kidneys from extended criteria donors (ECD). NGAL is a 25KDa protein proposed as biomarker of acute kidney injury. The aim of this study was to investigate the role of NGAL as an early and accurate indicator of DGF and Tacrolimus (Tac) toxicity and as a mediator of tissue regeneration in KT from ECD. Methods We evaluated plasma levels of NGAL in 50 KT patients from ECD in the first 4 days after surgery or after Tac introduction. Results Plasma levels of NGAL at day 1 were significantly higher in DGF group. In the non DGF group, NGAL discriminated between slow or immediate graft function and decreased more rapidly than serum creatinine. NGAL increased after Tac introduction, suggesting a role as marker of drug toxicity. In vitro, hypoxia and Tac induced NGAL release from tubular epithelial cells (TEC) favoring an autocrine loop that sustains proliferation and inhibits apoptosis (decrease of caspases and Bax/Bcl-2 ratio). Conclusions NGAL is an early and accurate biomarker of graft function in KT from ECD favoring TEC regeneration after ischemic and nephrotoxic injury.

Assessment of Platelet Function Analyzer (PFA-100) in Kidney Transplant Patients Before Renal Allograft Biopsy: A Retrospective Single-Center Analysis

BACKGROUND Kidney biopsy (KB) represents the criterion standard to obtain information on diagnosis and prognosis of renal allograft dysfunctions. However, it can be associated with bleeding complications (BCs). Bleeding time test (BTT), the best predictive indicator of post-biopsy BCs, is not a very reproducible test and is invasive. Therefore, the aim of this study was to evaluate whether the platelet function analyzer (PFA-100), a very reliable test to investigate primary hemostasis, could be useful in predicting the risk of bleeding complications in transplant patients undergoing KB. METHODS We carried out a retrospective analysis of PFA-100 collagen-epinephrine (C-EPI) and collagen-adenosine diphosphate (C-ADP) closure times in 119 patients undergoing KB in our center. Data regarding BTT, age, sex, blood pressure, number of renal allograft punctures for each biopsy procedure, thromboplastin time, prothrombin time, complete blood count, and prophylactic therapy with desmopressin were also collected. Major (need for blood transfusion) or minor (no need for any intervention) BCs (hematoma and hematuria) were recorded. RESULTS Indications for KB were: delayed graft function (n=23), allograft dysfunction (n=40), proteinuria (n=27), allograft dysfunction plus proteinuria (n=19), and protocol biopsy (n=10). Nine of the 119 patients (7.5%) developed minor BCs (6 macrohematuria, 3 hematoma), major BCs did not develop. No significant differences were found in any of the clinical and laboratory data, including BTT and PFA-100 (C-EPI and C-ADP) between patients who developed BCs compared with those who did not. In addition, there was no correlation between PFA-100 test (C-EPI and C-ADP) values and BTT data [R2=0.002; P=.6]. CONCLUSIONS The PFA-100 test was not useful in predicting the risk of BCs in kidney transplant patients undergoing renal allograft biopsy.

A newly identified mutation in the complement factor I gene not associated with early post-transplant recurrence of atypical hemolytic-uremic syndrome: a case report.

Atypical hemolytic uremic syndrome (aHUS), which can recur after renal transplantation, is associated with poor graft outcomes. The underlying genetic defect, namely, mutations in genes coding for the complement factor H, I (CFI), or membrane cofactor protein, greatly impacts the risk of aHUS recurrence. We report here the case of a patient with chronic renal failure due to aHUS in which screening for complement mutations, performed before wait-listing for kidney transplantation, showed a never described previously heterozygous mutation in the exon II of the CFI gene. Specifically, this mutation leads to a substitution of cytosine for guanosine at nucleotide 148, resulting in the change at amino acid 50 from arginine to proline. Subsequently, he received a renal allograft from deceased donor. Good graft function was established immediately, without clinical features of aHUS. Due to a lack of data on this mutation, we avoided prophylactic treatment for aHUS but closely monitored biochemical markers of aHUS to treat a possible recurrence. Immunosuppressive treatment was based on basiliximab, tacrolimus, steroids, and mycophenolic acid. At the time of discharge the serum creatinine was 1.4 mg/dL. Ten months after transplantation the patient is doing well without evidence of aHUS. Our case suggested that a heterozygous mutation in exon II of the CFI gene was not associated with a risk of early post-transplant aHUs recurrence adding new knowledge on complement mutations implicated in aHUS post-transplant recurrences.

Bullous pemphigoid in a renal transplant recipient

Bullous pemphigoid (BP) is a subepidermal autoimmune bullous disease mediated by autoantibodies directed toward antigens (BPAg1-230, BPAg2-180) located in hemidesmosomes and the lamina lucida of the dermal-epidermal junction. BP is usually idiopathic but multiple etiological agents (drugs, physical stimulation, cancers and immune abnormalities) have been identified [1]. We report a 59 year-old kidney-transplant recipient who developed an itchy rash with lichenoid features on the trunk and back nine [...]

Immunosuppression in pregnant women with renal disease: review of the latest evidence in the biologics era

Care of pregnant woman, including fertility and procreation counseling, has become a significant part of the nephrological practice in the last years. In this context, the management of immunosuppression assumes a primary role both for autoimmune diseases and for post-transplant follow up. The present review analyzes the latest evidence on immunosuppressive drugs of current use in nephrology and kidney transplantation. Although the placenta inactivates prednisone and prednisolone, it is advisable to limit the dose to the minimal effective one, to prevent side effects. Azathioprine is generally the immunosuppressive of choice in many high-risk pregnancies in autoimmune diseases because of the safety profile and its steroid-sparing property. In lupus nephropathy, hydroxychloroquine is a current indication in the prevention of flares. Cyclosporine and tacrolimus can also be used as steroid-sparing agents as well as in post-transplant maintenance therapy. Experience on mammalian target of rapamycin inhibitors is limited and its use during pregnancy is still controversial even if initial positive data are emerging. Intravenous immunoglobulins are safe and represent an important option for relapses of lupus and vasculitis. Mycophenolate mofetil and cyclophosphamide are to avoid. An important part is reserved to biologic agents, which are having a huge impact on therapy protocols for several pathologies. Data on the utilization of these molecules during pregnancy, however, are still scant and therefore they do not yet allow a definitive evaluation of their safety profile.

Plasma NGAL Is An Early Biomarker of Graft Function, Calcineurin Inhibitor Nephrotoxicity and Tubular Regeneration in Kidney Transplantation from Extended Criteria Donors: 902

Delayed graft function (DGF) is an early complication of kidney transplantation (KT) usually defined as the need for dialysis in the first week after the procedure. The main cause of DGF is ischemiareperfusion injury and the incidence of DGF has been increasing in the last years for the use of kidneys from extended criteria donors (ECD). Moreover, DGF is associated with an increased risk of acute rejection due to enhanced tissue immunogenicity and to a premature loss of kidney graft function. Plasma Neutrophil Gelatinase Associated Lipocalin (NGAL) is a 25 kDa protein belonging to the lipocalin family secreted by leukocytes and different epithelia including renal tubular epithelial cells. NGAL has been proposed as early biomarker of ischemic and toxic acute kidney injury and of DGF in kidney graft. The aims of this study were to evaluate: 1) plasma NGAL in 50 patients in the first 24h after KT from ECD; 2) the relationship between plasma NGAL and DGF, slow graft function (SGF) and immediate graft function (IGF); 3) the trend of serum creatinine (sCr) and plasma NGAL in the first 5 days after KT; 4) plasma NGAL before and after the introduction of calcineurin inhibitors (CNI, tacrolimus or cyclosporine); 5) the in vitro role of NGAL in tubular regeneration after ischemic injury. Fifty patients were enrolled in the study (immunosuppression with basiliximab, MMF and steroids: CNI introduced when sCr < 2.5 mg/dl). Patients were divided in 3 groups: DGF, SGF (sCr >3 mg/dl at day 6 after KT) and IGF (sCr < 3 mg/dl at day 6 after KT). Plasma NGAL levels were measured by a fluorimetric method (Alere, San Diego, CA). Protein and mRNA NGAL levels, proliferation and apoptosis were evaluated in isolated human tubular cells cultured under hypoxia or with therapeutic doses of tacrolimus/cyclosporine. Patients‘ demographics and characteristics were: male 67%, recipient age 57.65 yr, donor age 65 yr, cold ischemia time 16.8 h, HLA mismatches 3.46, recipient BMI 24.2, donor hypertension 64.4%, donor eGFR 88.66 ml/min. The incidence of DGF was 28%: in the 72% of patients without DGF, SGF occurred in 55%, IGF in 45%. Plasma NGAL levels (< 24h after KT) were significantly higher in DGF than in SGF and IGF groups (DGF 654.94 ng/ml; SGF 439.75 ng/ml; IGF 357.37 ng/ml). A decline of plasma NGAL but not of sCr was detectable at day 2 after KT with a further decrease at day 3, 4 and 5. By contrast, NGAL increased after 24 hr from CN