Isabel Tavares

Compared to mycophenolate mofetil, rapamycin induces significant changes on growth factors and growth factor receptors in the early days post-kidney transplantation.

BACKGROUND The new immunosuppressive drug Rapamycin (Rapa) is endowed with a mechanism of action that is distinct from that of calcineurin inhibitors. It has been claimed that Rapa does not significantly modulate either the cytokine expression or the transcription of several growth factors in mitogen-activated T cells. Previously, we reported that fine-needle aspiration biopsy (FNAB) sample cultures synthesize a large array of cytokines, and some of them may be powerful predictors of acute rejection in renal transplants. We hypothesized that Rapa may induce significant changes on cytokine production by FNAB sample cultures and on serum cytokine receptors when compared to other immunosuppressive drugs. METHODS Kidney transplants treated with CsA-Rapa-Pred (Rapa group) were compared with transplants treated with CsA-mycophenolate mofetil-Pred (MMF group). They were studied on day 7 posttransplantation, and they remained rejection free for at least the first 6 months. FNAB samples were cultured and the supernatants were collected at 48 hr of incubation and analyzed by ELISA for interleukin 1 receptor antagonist (IL-1ra), IL-2, IL-6, IL-10, IL-18, monocyte chemotactic protein 1 (MCP-1), soluble tumor necrosis factor I, and transforming growth factor (TGF)-beta(1). The soluble receptors for IL-1, IL-2, IL-6, and tumor necrosis factor alpha, together with IL-2 and IL-18 were also measured in serum. RESULTS Significant differences were observed when comparing Rapa with the MMF group. IL-18 and TGF-beta(1) synthesis were up-regulated, whereas IL-6 and MCP-1 were down-regulated in FNAB sample cultures. The Rapa group showed a significant down-regulation of each cytokine receptor and of IL-2 in serum. CONCLUSIONS Rapa was associated with a decreased synthesis of primarily monocyte-derived cytokines and enhanced production of TGF-beta(1), which in an appropriate cytokine milieu may promote allograft tolerance. The down-regulation of cytokine receptors and IL-2 may be associated with a depressed immune response towards the kidney allograft.

The synthesis by fine-needle aspiration biopsy cultures of IL-7, IL-16 and IL-18 is significantly associated with acute rejection in kidney transplants.

Background: T-cell activation, the key event in the development of acute allograft rejection, depends on co-stimulatory signals delivered by antigen-presenting cells (APC). APC-derived cytokines may provide co-stimulation and modulate alloimmune reaction. We have studied cytokine synthesis by fine-needle aspiration biopsy (FNAB) culture and we found significant differences for interleukin (IL)-2, IL-6, IL-10, M-CSF and IL-1ra on comparing acute rejection versus stable kidney transplant patients. We report our findings on FNAB cultures synthesis of IL-7, IL-15, IL-16, IL-17, IL-18 and RANTES (regulated upon activation, normal T-cell expressed and secreted), all potential modulators of anti-graft reaction. Patients and Methods: Kidney transplants (KTX) treated with CsA-AZA-Pred from the beginning, were divided into four groups. Group I: day 7 post-KTX, stable; II: day 7 post-KTX, 6.5 ± 5.5 days before acute rejection; III: first day of acute rejection; IV: day 14 post-KTX, stable. Patients from I and IV remained rejection-free for the first 6 months, at least. All rejection episodes were confirmed by classical core renal biopsy. FNAB samples were cultured according to our published methodology and culture supernatants were collected at 48 h and analysed by ELISA for IL-7, IL-15, IL-16, IL-17, IL-18 and RANTES. Results: Group III synthesized significantly higher amounts of IL-7, IL-16 and IL-18 than stable patients (groups I and IV). RANTES production did not show significant differences among the four groups. We did not find any trace of IL-15. Conclusions: IL-18 may play the activation role that has been attributed to IL-12 which previously, we did not find to correlate significantly with acute rejection in KTX. IL-16 seems to play an activation role rather than an inhibition of anti-graft reaction. We confirm that RANTES is not significantly associated with acute rejection in KTX.

Body composition assessed by impedance changes very early with declining renal graft function.

Background: Kidney transplant (Tx) restores renal filtration, although it does not achieve the function of two native kidneys, and with time it may variably involute back to chronic renal failure. We hypothesized that bioelectrical impedance analysis (BIA) might highlight differences for body compartments among Tx with different filtration rates, and we compared them with healthy controls. Methods: 38 Tx patients (25 males, 13 females) were studied at 75.9 ± 37.8 months postsurgery and divided into three groups: good creatinine clearance (CrCl, ml/min/1.73 m2; > 65.0), borderline (35.0 < CrCl < 60.0) and bad (CrCl < 35.0). BIA was assessed three times in a year. Total body water, extracellular water (ECW), intracellular water (ICW), Na:K exchange rate (Nae:Ke) and phase angle were studied. Healthy (n = 11) and hemodialysis (n = 11) groups were also studied. Results: BIA showed no differences between healthy controls and good Tx while both borderline and bad Tx presented a significantly higher ECW and lower ICW than either good Tx or normal controls. Only good CrCl was different from predialysis. Conclusions: A good kidney graft manages to restore and maintain normal body composition, even with potential disturbances brought about by steroids and cyclosporine. With mild renal dysfunction a change in body compartments was observed, moving towards the composition of that with chronic renal failure patients.

Homozygosity for the E526V Mutation in Fibrinogen A Alpha-Chain Amyloidosis: The First Report

Systemic hereditary amyloidoses are autosomal dominant diseases associated with mutations in genes encoding ten different proteins. The clinical phenotype has implications on therapeutic approach, but it is commonly variable and largely dependent on the type of mutation. Except for rare cases involving gelsolin or transthyretin, patients are heterozygous for the amyloidogenic variants. Here we describe the first patient identified worldwide as homozygous for a nephropathic amyloidosis, involving the fibrinogen variant associated with the fibrinogen alpha-chain E526V (p.Glu545Val) mutation. In 1989, a 44-year-old woman presented with hypertension, hepatosplenomegaly, nephrotic syndrome, and renal failure. She started hemodialysis in 1990 and 6 years later underwent isolated kidney transplantation from a deceased donor. Graft function and clinical status were unremarkable for 16 years, despite progressively increased left ventricular mass on echocardiography. In 2012, 4 months before death, she deteriorated rapidly with severe heart failure, precipitated by Clostridium difficile colitis and urosepsis. Affected family members developed nephropathy, on average, nearly three decades later, which may be explained by the gene dosage effects on the phenotype of E526V (p.Glu545Val) fibrinogen A alpha-chain amyloidosis.

Long-term follow-up of patients with hereditary fibrinogen A alpha-chain amyloidosis

: Fibrinogen A alpha-chain amyloidosis (AFib) is an autosomal dominant condition with variable penetrance, usually of late onset. Progression to stage V chronic kidney disease is a consiste...

Sequential body composition analysis by bioimpedance early post-kidney transplantation

Background: While chronic renal failure patients present disturbed body water composition, few studies have been done on its behavior following kidney grafting (Tx). We report the changes associated with a successful Tx on body composition evaluated by bioelectrical impedance analysis (BIA). Methods: Twelve Tx (seven males, five females) were studied. The BIA was assessed before Tx, at month 1 and at month 3 post‐Tx. Total body water (TBW), extracellular water (ECW), intracellular water (ICW), Na:K exchange rate (Nae:Ke) and phase angle (PA) were studied. An healthy group and a HD group were evaluated three times in a year interval. Results: Comparing before Tx with month 1 post‐Tx, TBW, ECW and Nae:Ke increased, while ICW and PA decreased significantly. Comparing month 1 with month 3 post‐Tx, ECW decreased, while ICW and PA increased. On comparing month 1 post‐Tx with the healthy group, Nae:Ke was greater and PA was lower at month 1. Conclusions: The BIA showed that the different body water compartments of Tx recipients quickly match the constitution of normal individuals, overcoming drug therapy side effects.

Bacteremia due to Campylobacter in renal transplantation: a case report and review of literature.

Campylobacter species are the leading cause of acute bacterial diarrhea in industrialized countries. However, bacteremia is detected in <1% of patients with Campylobacter enteritis and is most likely to occur in patients who are immunocompromised or of older age. To our knowledge, only 2 cases of Campylobacter jejuni bacteremia have been reported in renal transplant recipients (RTRs). We present a case of an RTR with C. jejuni bacteremia presenting as self‐limiting diarrhea followed by fever and cellulitis. The patient was successfully treated with a 2‐week course of imipenem and developed no other complications. We review all cases of Campylobacter bacteremia in RTRs, and discuss clinical presentation and treatment of this potentially fatal disease.

Reactivation of Hepatitis B virus in kidney transplant recipients with previous clinically resolved infection: A single-center experience

BACKGROUND Hepatitis B virus (HBV) reactivation in kidney transplant recipients (KTR) involves important morbidity and mortality. Despite being more common in patients who are HBsAg-positive, it may occur in patients with clinically resolved infection (HBsAg-negative and anti-HBc-positive), in whom the presence of the protective anti-HB antibody is thought to decrease the risk of reactivation. Data regarding reactivation rates in this population are scarce. OBJECTIVE To retrospectively evaluate the risk of HBV reactivation in KTR with previously resolved infection. MATERIAL AND METHODS Retrospective cohort study including patients who underwent a kidney transplant between January 1994 and December 2014 with resolved HBV infection at the time of transplantation (anti-HBc seropositivity without detectable HBsAg, with or without anti-HB-positive antibodies and normal liver enzymes). RESULTS Out of 966 patients, 95 patients with evidence of resolved HBV infection were analyzed, of which 86 had a titer of anti-HBs >10mIU/ml. Mean follow-up time was 93 months; 12 patients had lost anti-HBs. Two patients showed evidence of reactivation. Risk factors associated with loss of anti-HBs were elderly age (>60) and occurrence of acute graft rejection (p<0.05). CONCLUSION The risk of HBV reactivation in KTR with previously resolved infection is not negligible at 2%. Elderly age and acute rejection were associated with loss of anti-HBs, and these patients may benefit from closer monitoring of HBV DNA levels. Routine serology and/or HBV viral load monitoring in HBsAg-negative, anti-HBc-positive patients is recommended and should be emphasized in these patients.

Unrecognized Fibrinogen A α-Chain Amyloidosis: Results From Targeted Genetic Testing

BACKGROUND Fibrinogen A α-chain (AFib) amyloidosis results from autosomal-dominant mutations in the gene encoding AFib (FGA). Patients with this disorder typically present with proteinuria. Isolated cases of AFib amyloidosis, carrying the FGA p.Glu545Val variant, were identified in the district of Braga, in northwest Portugal. This observation led us to hypothesize that this disorder might be an unrecognized cause of kidney disease in that region and prompted us to carry out targeted genetic testing for the p.Glu545Val variant in the local hemodialysis population and family members of identified cases. STUDY DESIGN Case series. SETTING & PARTICIPANTS 3 groups of participants: (1) kidney biopsy registry, n=4; (2) hemodialysis facility, n=122 of 267 patients; and (3) genetically at-risk individuals; n=69 of 167 family members. OUTCOMES Kidney disease, kidney disease progression, and survival. RESULTS The p.Glu545Val variant was identified in all 4 patients of the biopsy registry, 12 of 122 (9.8%) hemodialysis patients tested, and 34 of 69 (49%) relatives tested. These 50 cases belonged to 13 unrelated families with kidney disease or amyloidosis identified in 61% of probands. 35 individuals presented with hypertension at a mean of 51.0±10.4 years. Of these, 30 developed kidney disease at a mean of 56.7±12.0 years, and 21 initiated dialysis therapy at a mean of 61.4±11.3 years. Heart, liver, spleen, colon, and ileum were involved along the progression of the disease. Kidney disease was formerly attributed to hypertension in 25% of patients with AFib amyloidosis undergoing hemodialysis. LIMITATIONS Retrospective data collection for patients with amyloidosis previously diagnosed. CONCLUSIONS AFib amyloidosis appears to be an under-recognized disorder in Braga, Portugal, where we found a high frequency of the FGA p.Glu545Val variant. Due to the nonspecific nature of its major clinical features, the diagnosis of AFib amyloidosis should have a high index of suspicion, particularly in populations in which hypertension is prevalent.

Ganciclovir-resistant cytomegalovirus infection in renal transplantation

Cytomegalovirus (CMV) infection is an important cause of morbidity in renal transplant recipients, due to both direct and indirect effects of the virus on the graft and patient [1]. Ganciclovir (GCV) remains the most common first-line therapy, but its low oral bioavailability was identified as a risk factor for the emergence of resistant strains [1], and intravenous (IV) administration is inconvenient for use in prophylactic or pre-emptive therapy. Valganciclovir (VGCV) is a prodrug of GCV with a much higher oral bioavailability, which makes it very useful for prophylaxis and pre-emptive therapy, as well as for treatment in selected patients [2–4]. Although initially associated with a negligible risk of drug resistance [5], subsequent papers identified patients with GCV-resistant CMV infection after VGCV prophylaxis and treatment [6, 7]. Patients with drug-resistant CMV strains often have more tissue-invasive disease and unfavourable clinical outcomes [8, 9], but there is some heterogeneity, and reports of asymptomatic infection, particularly in non-lung transplant recipients, suggest that some mutations are less pathogenic than others [10]. The therapeutic approach is a challenge and must balance the severity of the infection against the risks of drug toxicity and reduction of immunosuppression. We report two cases of GCV-resistant CMV from our unit: the first is a case of invasive CMV disease in a low-risk renal transplant recipient while on therapy with VGCV, and the second is a high-risk patient who developed GCV-resistant CMV infection while on VGCV prophylaxis.