Inflammatory biomarkers in staging of chronic kidney disease: elevated TNFR2 levels accompanies renal function decline.

BACKGROUND: Inflammation is a common feature in the pathogenesis of chronic kidney disease (CKD), regardless of the disease cause. Our aim was to evaluate the potential of several inflammatory biomarkers in CKD diagnosis and staging. METHODS: A total of 24 healthy controls and 92 pre-dialysis CKD patients with diverse etiologies, were enrolled in this study and grouped according to their CKD stage. We analysed the circulating levels of inflammatory molecules, C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), tumor necrosis factor receptor 2 (TNFR2), pentraxin 3 (PTX3) and leptin, as well as the hemogram. We studied their association with parameters of kidney function and kidney injury, to evaluate their potential as early markers of the disease and/or of its worsening, as well as their interplay. RESULTS: Compared to controls, patients in CKD stages 1-2 presented significantly higher IL-6 and TNFR2 levels, and higher neutrophil-to-lymphocyte ratio. All inflammatory cytokines and acute-phase proteins showed a trend to increase up to stage 3, stabilizing or declining thereafter, save for TNFR2, which steadily increased from stage to stage. All inflammatory molecules, apart from PTX3, were negatively and significantly correlated with eGFR, with a remarkable value for TNFR2 (r = - 0.732, p < 0.001). CONCLUSION: TNFR2 might be useful for an early detection of CKD, as well as for disease staging/worsening. Still, the potential value of this biomarker in disease progression warrants further investigation.

Kidney graft function before pregnancy as a predictor of graft, maternal and fetal outcomes in pregnant renal transplant recipients.

OBJECTIVES: Maternal and fetal complications can occur in pregnant kidney transplant recipients. Since these are high-risk pregnancies, they require a multidisciplinary follow-up to prematurely detect adverse events. Identifying factors that would affect fetal, maternal and graft outcomes is essential to further stratify the risk of pregnant kidney transplant recipients. METHODS: All pregnancies in kidney transplant recipients followed in a single center for 30 years were included. Data included previous transplant information and blood and urine tests performed before pregnancy. Impact of graft function on fetal, maternal and graft outcomes was evaluated. RESULTS: There were 41 pregnancies among 34 patients. Mean gestational age of 35 ± 3 weeks. Caesarean section was performed in 69.4% of patients. Five pregnancies were unsuccessful (12.2%). Four patients suffered an acute graft dysfunction (9.8%) and 12 (29.3%) had a serious maternal hypertensive disorder (preeclampsia, eclampsia or HELLP syndrome). Graft function before pregnancy showed significant correlation with adverse outcomes. CONCLUSIONS: A proteinuria >669 mg/g, serum creatinine >1.75 mg/dL and glomerular filtration rate <36.2 mL/min/1.73 m2 before pregnancy were correlated to graft dysfunction during pregnancy. Similar values of proteinuria were also associated with a risk of maternal hypertensive disorders and pregnancy failure. Therefore, in patients with proteinuria and graft dysfunction, follow-up should be stricter to quickly detect complications.

Acute kidney injury: a strong risk factor for hypoglycaemia in hospitalized patients with type 2 diabetes.

AIMS: Acute kidney injury (AKI) is highly prevalent during hospitalization of patients with type 2 diabetes (T2D). We aimed to assess the impact of AKI and its severity and duration on the risk of hypoglycaemia in hospitalized patients with T2D. METHODS: Retrospective cohort analysis of patients with T2D, admitted at a University Hospital in 2018-2019. AKI was defined as an increase in serum creatinine by ≥ 0.3 mg/dl (48 h) or ≥ 1.5 times baseline (7 days), and hypoglycaemia as blood glucose concentration < 70 mg/dl. Patients with chronic kidney disease stage ≥ 4 were excluded. We registered 239 hospitalizations with AKI and randomly selected 239 without AKI (control). Multiple logistic regression was used to adjust for confounding factors and ROC curve analysis to determine a cutoff for AKI duration. RESULTS: The risk of hypoglycaemia was higher in the AKI group (crude OR 3.6, 95%CI 1.8-9.6), even after adjusting for covariates (OR 4.2, 95%CI 1.8-9.6). Each day of AKI duration was associated with a 14% increase in the risk of hypoglycaemia (95%CI 1.1-1.2), and a cutoff of 5.5 days of AKI duration was obtained for increased risk of hypoglycaemia and mortality. AKI severity was also associated with mortality, but showed no significant association with hypoglycaemia. Patients with hypoglycaemia had 4.4 times greater risk of mortality (95%CI 2.4-8.2). CONCLUSIONS: AKI increased the risk of hypoglycaemia during hospitalization of patients with T2D, and its duration was the main risk factor. These results highlight the need for specific protocols to avoid hypoglycaemia and its burden in patients with AKI.

Immunoglobulin a (IgA) Vasculitis in the Elderly.

IgA vasculitis is a small vessel vasculitis mediated by the deposition of IgA immune complexes. It mostly occurs in children and is rare in adults, with increased severity and mortality in the latter. Its aetiology remains largely unknown, and its prognosis depends primarily on the extent of renal involvement. We present the case of a 71-year-old woman with purpuric lesions in both lower and upper limbs associated with fever, abdominal pain, vomiting and blood in her stools for the past month. The patient was diagnosed with IgA vasculitis and the full systemic involvement (renal, dermatological, intestinal, and cerebral) of the disease was identified with excellent response to parenteral corticotherapy.

Host-derived mannose glycans trigger a pathogenic γδ T cell/IL-17a axis in autoimmunity.

Autoimmune diseases are life-threatening disorders that cause increasing disability over time. Systemic lupus erythematosus (SLE) and other autoimmune diseases arise when immune stimuli override mechanisms of self-tolerance. Accumulating evidence has demonstrated that protein glycosylation is substantially altered in autoimmune disease development, but the mechanisms by which glycans trigger these autoreactive immune responses are still largely unclear. In this study, we found that presence of microbial-associated mannose structures at the surface of the kidney triggers the recognition of DC-SIGN-expressing γδ T cells, inducing a pathogenic interleukin-17a (IL-17a)-mediated autoimmune response. Mice lacking Mgat5, which have a higher abundance of mannose structures in the kidney, displayed increased γδ T cell infiltration into the kidney that was associated with spontaneous development of lupus in older mice. N-acetylglucosamine supplementation, which promoted biosynthesis of tolerogenic branched N-glycans in the kidney, was found to inhibit γδ T cell infiltration and control disease development. Together, this work reveals a mannose-γδ T cell-IL-17a axis in SLE immunopathogenesis and highlights glycometabolic reprogramming as a therapeutic strategy for autoimmune disease treatment.

Tacrolimus Trough Intravariability in Patients Treated With the Prolonged-Release Formulation Is a Risk Factor for Acute Graft Rejection.

OBJECTIVES: Tacrolimus has a narrow therapeutic window, and lack of adherence to the therapeutic regimen is a main risk factor for acute graft rejection; hence, the prolonged-release formulation was created. A high intrapatient variability for tacrolimus trough levels has been associated with worse graft outcomes; therefore, we investigated the correlation between the tacrolimus variation coefficient and the development of biopsy-proven acute graft rejection in kidney transplant patients with typical maintenance immunosuppression versus the prolonged-release formulation. MATERIALS AND METHODS: This was a single-center observational retrospective study that included all adult kidney transplants from deceased donors between January 2011 and December 2014 for which the transplant recipients were given maintenance therapy with tacrolimus prolonged-release formulation (Advagraf). The overall tacrolimus variation coefficient was calculated for the follow-up period from transplant until December 2019. Biopsy-proven acute graft rejection results were collected throughout follow-up. Statistical analysis was performed with SPSS software. RESULTS: The study was composed of 147 patients with a mean follow-up time of 60.4 ± 15 months. The mean age of the patients was 47.5 ± 11.9 years and 67.3% were men. Of these 147 patients, 29 had at least 1 episode of acute graft rejection during follow-up. There was a significant correlation between patients with a higher tacrolimus variation coefficient and the presence of biopsy-proven acute graft rejection. Receiver operating characteristic curves were used to determine an intrapatient variability cutoff point of 28.3% for tacrolimus. Younger patients were also more likely than older patients to develop acute graft rejection in our sample. CONCLUSIONS: High intrapatient variability of tacrolimus trough levels is a risk factor for acute graft rejection in kidney transplant patients.

A Case of Acute Interstitial Nephritis After Two Doses of the BNT162b2 SARS-CoV-2 Vaccine.

BACKGROUND: The development of vaccines to prevent COVID-19 breakouts came with highly positive results but some unexpected side effects. Rare side effects have been seen with the BNT162b2 SARS-CoV 2 vaccine. CASE PRESENTATION: We present the case of a 45-year-old female patient who developed an acute kidney injury needing urgent hemodialysis one week after the second administration of the BNT162b2 SARS-CoV 2 vaccine. She developed a macular rash on her lower limbs and palms as well. A kidney biopsy was performed 10 days after vaccine inoculation, diagnosing acute interstitial nephritis and acute tubular necrosis with cellular casts. The patient was treated with three corticosteroid pulses followed by daily prednisolone. We witnessed clinical improvement 4 days after the initial corticosteroid treatment with progressive recovery of kidney function and hemodialysis withdrawal. After 2 weeks, the patient had recovered her kidney function. Immunophenotyping was performed, diagnosing a hypersensitivity to the vaccine and the polyethylene glycol excipient. CONCLUSION: Patients may develop acute reactions to vaccines. In this case, symptoms seem to correlate significantly with its inoculation and, although this case had a favourable outcome, these side effects must be made aware for clinicians and patients.

Borderline Changes in Renal Transplantation: Are We Aware of the Real Impact in Graft Survival?

BACKGROUND: Borderline changes suspicious for acute T-cell-mediated rejection (BC) are frequently seen on biopsy specimens, but their clinical significance and clinical management are still controversial. Our goal was to compare clinical outcomes of kidney transplant recipients with biopsy-proven BC vs acute T-cell-mediated rejection (aTCMR) and the influence of treating BC on graft outcomes. METHODS: A retrospective cohort study was performed in all kidney transplant recipients with biopsy-proven BC and aTCMR between January 2012 and December 2018, according to Banff 2017 criteria; patients with concomitant antibody-mediated rejection were excluded. RESULTS: We included 85 patients, 30 with BC (35.3%) and 55 with aTCMR (64.7%). There was no difference between groups regarding demographics, HLA matching and sensitization, immunosuppression, or time of transplant. Treatment with steroids was started in 15 patients with BC (50%) and in all patients with aTCMR, with 4 of the latter additionally receiving thymoglobulin (7.2%). At 1 year post biopsy, overall graft survival was 71%, and despite presenting better estimated glomerular filtration rate (eGFR) at biopsy (33.3 ± 23.4 vs 19.9 ± 13.2 mL/min/1.73 m2, P = .008), patients in the BC group presented the same graft survival as the aTCMR group according to Kaplan-Meyer survival curves. When analyzing the BC group (n = 30) and comparing the patients who were treated (n = 15) vs a conservative approach (n = 15), graft survival at 1 year was 87% for treated patients and 73% for nontreated patients (P = .651), with no difference in eGFR for patients with functioning graft. However, at longer follow-up, survival curves showed a trend for better graft survival in treated patients (70.2 ± 9.2 vs 38.4 ± 8.4 months, P = .087). CONCLUSION: Our study showed that patients with BC did not present better graft survival or graft function at 1 year after biopsy or at follow-up compared with the aTCMR group, despite better eGFR at diagnosis. We found a trend for better graft survival in patients with BC treated with steroids compared with a conservative approach. These results reinforce the importance of borderline changes in graft outcomes and that the decision to treat can influence long-term outcomes.

Hemodialysis Reliable Outflow graft: A valid option in patients with central venous stenosis.

INTRODUCTION: Central venous stenosis can be the main obstacle to the creation of an autologous vascular access in the upper limbs. The Hemodialysis Reliable Outflow graft was developed to provide an upper limb vascular access option to such patients, avoiding alternative, less advantageous options, such as lower limb vascular accesses or central venous catheters. Its advantages include catheter avoidance and, in case of lower limbs accesses, reduction of the ischemic risk and iliac vein thrombosis, potentially compromising a future kidney transplant. PATIENTS AND METHODS: Revision of the clinical files of the four patients who were placed a Hemodialysis Reliable Outflow device in our Center, including demographic variables, implantation technique characteristics, surgical complications, episodes of infection and thrombosis of the access, and need to place a transitory central venous catheter to undergo hemodialysis treatment. RESULTS: Four Hemodialysis Reliable Outflow grafts were placed, which resulted in a significant improvement in the dialysis efficacy in all patients, with a median raise in the Kt/V of 36.7%. Two cases needed thrombectomy, one of which was unsuccessful. The actual time of patency varies between 3 and 28 months. CONCLUSION: Our experience with the Hemodialysis Reliable Outflow device showed that it was a safe option for patients with central venous stenosis and was associated with good clinical and analytic outcomes.

Atypical haemolytic uremic syndrome from multiple missenses to a full-blown disease.

A 72-year-old woman was admitted to the hospital because of dorsal, lumbar and lower abdomen pain that had started 4 days before. She had a history of age-related macular degeneration (treated with intraocular bevacizumab). Blood tests showed anaemia, thrombocytopaenia, acute kidney injury, elevated liver enzymes and total bilirubin (mainly because of the indirect fraction). Viral serologies and ADAMTS13 activity levels were normal, and stool testing was negative for Escherichia coli-producing Shiga toxins. E. coli was isolated in urine. Atypical haemolytic uremic syndrome triggered by a urinary tract infection or by the vascular endothelial growth factor-inhibitor bevacizumab were the most likely hypothesis. The patient started urgent plasmapheresis and dialysis that lasted for a total of 18 days. There was complete remission and recovery of kidney function allowing for treatment discontinuation, and she was discharged home. After 6 months of follow-up, she shows no signs of relapse.

Parvoviral infection with systemic impact and renal consequences.

Parvovirus infection is usually asymptomatic especially in immunocompetent adults. When symptomatic it can range from mild to life threatening depending on the patient's age and comorbidities. We report a case of a 40-year-old male patient with parvovirus infection who presented a purpuric rash in distal extremities, acute kidney injury, type II mixed cryoglobulinaemia and hypocomplementaemia. His renal biopsy showed a mesangioproliferative glomerulonephritis with positive immunoreactivity to C3, IgM and C1q. Parvovirus B19 was detected in the biopsy tissue by PCR. He was treated with prednisolone with total remission after 1 month. We discuss the diagnosis of kidney lesion due to parvovirus in an immunocompetent person, which is a very rare condition and its association with the cryoglobulinaemia diagnosis.

Multiple complications of a 14-year-old hemodialysis catheter.

INTRODUCTION: Vascular access for hemodialysis is a key factor in every patient dependent on this treatment. Maintaining a central venous catheter can be a good choice when all the other options have been exhausted, but unwanted and rare complications may arise from longer catheter dwell time. CASE REPORT: We describe a case of a 65-year-old woman undergoing hemodialysis treatment since 1986 after a bilateral nephrectomy due to complicated nephrolithiasis. Her last access, two Tesio® tunneled cuffed catheters implanted via the right internal jugular vein functioned correctly for 14 years without complications, and so, was not replaced in the meantime. She was referred to our hospital due to a rupture in a catheter lumen, which was corrected conservatively by creating a more proximal tunnel and excising the affected area. A few weeks later, a new rupture in the same lumen was identified, so the catheter was replaced with angiographic control. The catheter was frail, so upon its removal, the tip fractured and remained in the right ventricle, being swiftly removed by an endovascular snare without complications. DISCUSSION: This case reports two rare complications associated with catheter handling and identifies a possible technique for conservative resolution of a lumen rupture.

Adherence to a Mediterranean diet, lifestyle and age-related macular degeneration: the Coimbra Eye Study - report 3.

PURPOSE: To characterize the lifestyle and nutritional risk profile associated with the Mediterranean diet in a Portuguese population with and without age-related macular degeneration (AMD). METHODS: Nested case-control study (n = 883) within the Coimbra Eye Study, including 434 subjects with AMD and 449 age- and sex-matched subjects without AMD. All enrolled subjects underwent a full risk assessment, including lifestyle-related risk factors and a thorough food frequency questionnaire. This allowed us to build an adherence score to the Mediterranean diet (mediSCORE, range 0-9) constructed from individual food intakes. Food intake was also further analysed by conversion to micronutrient consumption. RESULTS: Our results suggest that physical activity has a protective role in AMD [p = 0.018 after multivariate adjustment, OR: 0.69 (0.51-0.93)]. High (mediSCORE ≥6) was also found to be protective [p = 0.041, OR: 0.62 (95% CI: 0.38-0.97)]. Food group analysis unveiled a specific protective role for increased fruits consumption (p = 0.029). Finally, micronutrient analysis revealed a protective role associated with increased consumption of caffeine, fibres, beta-carotene, vitamin C and vitamin E (p < 0.05). CONCLUSION: High mediSCORE appears to confer protection against the development of AMD in a Mediterranean population. This effect is driven by increased consumption of fruits and some antioxidant micronutrients, which emerged as statistically significant protective factors. Further studies are required to establish dietary recommendations with clinical application.

Switch to Aflibercept in Diabetic Macular Edema Patients Unresponsive to Previous Anti-VEGF Therapy.

Purpose. The aim was to evaluate the efficacy of aflibercept in patients with diabetic macular edema (DME) unresponsive to prior anti-VEGF therapy. Methods. Retrospective review of DME unresponsive to previous anti-VEGF switched to aflibercept with 3 months of follow-up. Changes in best correct visual acuity (BCVA), central retinal thickness (CRT), and frequency of injections were analyzed. The percentage of subjects who had ≥20/40 (logMAR equivalent 0.3) and ≤20/200 (logMAR equivalent 1) was evaluated. Results. A total of 32 eyes from 26 patients were included. Mean age was 65 ± 10 years old. The mean number of previous anti-VEGF injections was 5.34 ± 2.38, and the mean number of aflibercept injections at the end of the study was 2.00 ± 0.00. The CRT at baseline was 501.47 ± 150.51 µm and 367.97 ± 124.61 µm at 3 months of follow-up (P < 0.001). The logMAR BCVA at baseline was 0.71 ± 0.36 and 0.65 ± 0.33 at the end of the follow-up (P = 0.037). At baseline, 12.5% of patients had ≥20/40 compared with 25% at the end of follow-up. At baseline, 28.13% of patients had 20/200 or inferior vision compared with 15.63% at the end of the follow-up. Conclusions. DME patients unresponsive to previous multiple ranibizumab injections demonstrate a significant anatomical and functional improvement with the switch to aflibercept.

Real-World Outcomes of Anti-VEGF Treatment for Retinal Vein Occlusion in Portugal.

PURPOSE: Retinal vein occlusion (RVO) is an important cause of visual disability in the modern world. We aim to evaluate the real-world outcomes of patients with RVO treated with anti-vascular endothelial growth factor (VEGF) in Portugal. METHODS: We performed a retrospective, observational, multicenter study including 8 centers across Portugal and 200 patients treated with either ranibizumab or bevacizumab. Data were collected at 3 time points: time of diagnosis (0 time point) and 6 and 12 months after initiating treatment. Demographic and clinical data were collected. RESULTS: Median visual acuity (VA) and central macular thickness (CMT) improved in the branch RVO (BRVO), central RVO (CRVO), bevacizumab, and ranibizumab groups at 6 and 12 months compared to baseline, with CMT improving further only in the CRVO and ranibizumab groups between 6 and 12 months (p = 0.002 and p = 0.001, respectively). The CMT was lower in the ranibizumab group compared to the bevacizumab group both at 6 and 12 months (p<0.02). Median CMT improved in both the good and poor baseline VA groups at 6 and 12 months compared to baseline (p<0.001). Median VA only improved for the group with poor baseline VA at 6 and 12 months of follow-up (p<0.001). Regression analysis identified several baseline variables as predictors of visual outcomes at 6 and 12 months, with different results depending on the analyzed group. CONCLUSIONS: Both treatments were effective, although less effective than results reported in clinical trials. The morphologic response was better with ranibizumab compared to bevacizumab, although functionally there were no differences.