The Role of the Gut Microbiome on Chronic Kidney Disease.

Chronic kidney disease (CKD) is estimated to affect nearly 500 million people worldwide and cardiovascular (CV) disease is a major cause of death in this population. However, therapeutic interventions targeting traditional CV risks are not effective at lowering the incidence of CV events or at delaying the progression of the disease in CKD patients. In recent years, disturbances of normal gut microbiome were recognized in the pathogenesis of diverse chronic diseases. Gut dysbiosis is being unraveled in CKD and pointed as a nontraditional risk factor for CV risk and CKD progression. The most often reported changes in gut microbiome in CKD are related to the lower levels of Bifidobacteriaceae and Lactobacillaceae and to higher levels of Enterobacteriaceae. Although metagenomics brought us an amplified vision on the microbial world that inhabits the human host, it still lacks the sensitivity to characterize the microbiome up to species level, not revealing alterations that occur within specific genus. Here, we review the current state-of-the-art concerning gut dysbiosis in CKD and its role in pathophysiological mechanisms in CKD, particularly in relation with CV risk. Also, the strategies towards prevention and treatment of gut dysbiosis in CKD progression will be discussed.

Combined C4d and CD3 immunostaining predicts immunoglobulin (Ig)A nephropathy progression.

A number of molecules have been shown recently to be involved in the pathogenesis and progression of immunoglobulin (Ig)A nephropathy (IgAN). Among these, we have selected C4d (complement lectin pathway involvement), CD3 (T cell marker, traducing interstitial inflammation), transglutaminase 2 (TGase-2, involved in tissue fibrosis development) and p-extracelluar-regulated kinase (ERK)1/2 (protein kinase intracellular signaling molecule) to perform a panel of immunohistological biomarkers and assess its predictive value for disease progression. Immunohistochemical staining of these biomarkers was performed in paraffin sections from 74 renal biopsy cases with the clinical diagnosis of IgAN. Association between score analysis of these parameters and disease course was assessed through univariate and multivariate analysis, including baseline clinical and histological data. Univariate analysis showed that glomerular C4d, tubulointerstitial TGase2 and CD3 scores were associated with baseline proteinuria and disease progression. Multivariate analysis showed that only baseline estimated glomerular filtration rate (eGFR), C4d and CD3 were associated independently with progressive kidney disease (decline of at least 50% in the eGFR or progression to end-stage renal disease (ESRD) during the follow-up period). Establishing an accurate prediction model for IgAN progression is still a matter of research in clinical nephrology. The complement system, particularly lectin pathway activation, and T cell activation, have been shown previously to be potential modifiers of the disease course. Here we show that the combination of two histological biomarkers (C4d and CD3) can be a powerful predictor of IgAN progression and a potential useful tool for the clinical approach of this disease.

Collagen type IV-related nephropathies in Portugal: pathogenic COL4A3 and COL4A4 mutations and clinical characterization of 25 families.

Pathogenic mutations in genes COL4A3/COL4A4 are responsible for autosomal Alport syndrome (AS) and thin basement membrane nephropathy (TBMN). We used Sanger sequencing to analyze all exons and splice site regions of COL4A3/COL4A4, in 40 unrelated Portuguese probands with clinical suspicion of AS/TBMN. To assess genotype-phenotype correlations, we compared clinically relevant phenotypes/outcomes between homozygous/compound heterozygous and apparently heterozygous patients. Seventeen novel and four reportedly pathogenic COL4A3/COL4A4 mutations were identified in 62.5% (25/40) of the probands. Regardless of the mutated gene, all patients with ARAS manifested chronic renal failure (CRF) and hearing loss, whereas a minority of the apparently heterozygous patients had CRF or extrarenal symptoms. CRF was diagnosed at a significantly younger age in patients with ARAS. In our families, the occurrence of COL4A3/COL4A4 mutations was higher, while the prevalence of XLAS was lower than expected. Overall, a pathogenic COL4A3/COL4A4/COL4A5 mutation was identified in >50% of patients with fewer than three of the standard diagnostic criteria of AS. With such a population background, simultaneous next-generation sequencing of all three genes may be recommended as the most expedite approach to diagnose collagen IV-related glomerular basement membrane nephropathies.

Collagen type IV-related nephropathies in Portugal: pathogenic COL4A5 mutations and clinical characterization of 22 families.

Alport syndrome (AS) is caused by pathogenic mutations in the genes encoding α3, α4 or α5 chains of collagen IV (COL4A3/COL4A4/COL4A5), resulting in hematuria, chronic renal failure (CRF), sensorineural hearing loss (SNHL) and ocular abnormalities. Mutations in the X-linked COL4A5 gene have been identified in 85% of the families (XLAS). In this study, 22 of 60 probands (37%) of unrelated Portuguese families, with clinical diagnosis of AS and no evidence of autosomal inheritance, had pathogenic COL4A5 mutations detected by Sanger sequencing and/or multiplex-ligation probe amplification, of which 12 (57%) are novel. Males had more severe and earlier renal and extrarenal complications, but microscopic hematuria was a constant finding irrespective of gender. Nonsense and splice site mutations, as well as small and large deletions, were associated with younger age of onset of SNHL in males, and with higher risk of CRF and SNHL in females. Pathogenic COL4A3 or COL4A4 mutations were subsequently identified in more than half of the families without a pathogenic mutation in COL4A5. The lower than expected prevalence of XLAS in Portuguese families warrants the use of next-generation sequencing for simultaneous COL4A3/COL4A4/COL4A5 analysis, as first-tier approach to the genetic diagnosis of collagen type IV-related nephropathies.

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.

Floristic survey of aquatic macrophytes in eastern Maranhão, Brazil: richness, biological forms and three new records.

The aim of this study was to carry out a floristic survey of aquatic macrophytes in the municipality of Chapadinha, eastern Maranhão, and classify their biological forms. The study was done between September 2021 and September 2022. A total of 31 families, 49 genera and 72 species of aquatic macrophytes were catalogued, of which 65 are angiosperms. Among them, Bacopa stricta (Plantaginaceae), Staurogyne diantheroides (Acanthaceae), and Xanthosoma aristeguietae (Araceae) are new records for the flora of Maranhão, with the last two new records for Northeast Brazil. The richest family was Cyperaceae, with 11 species, followed by Plantaginaceae (seven taxa), Fabaceae (five taxa) and Lentibulariaceae (five taxa). Six biological forms were recorded, amphibious (27 taxa) and emergent (26 taxa) being the most common. The aquatic environments of Chapadinha are home to a considerable number of species, families, and life forms of macrophytes. The results show that due to the lack of surveys, evidenced by the new records presented, the state aquatic flora is still underestimated. Further studies in poorly explored areas are suggested, especially in the eastern part of the state, to improve understanding of species richness.

First record of the aquatic plant Echinodorus scaber Rataj (Alismataceae) for the State of Maranhão, Northeastern Brazil.

Echinodorus is the second largest genus of the aquatic plant family Alismataceae, comprising 28 species, of which 24 occur in Brazil. This study represents the first record of Echinodorus scaber Rataj for the State of Maranhão, based on material collected in the Municipality of Brejo, eastern Maranhão. Echinodorus scaber shares morphological similarities with E. macrophyllus (Kunth) Micheli, but it can be distinguished by (I) a highly branched inflorescence, (II) scabrous peduncles and petioles covered by stellate trichomes, and (II) small flowers with reflexed petals. This new record of E. scaber contributes to a better understanding of this genus' diversity and distribution in Maranhão and underscores the necessity to broaden collection efforts for a better comprehension of the state's flooded zones. Comprehensive collection efforts, with a special focus on aquatic plants and in locations far from the state's main urban center, São Luís, may result in a significant knowledge increase of the flora, especially of the genus Echinodorus, which needs a broad taxonomic study. These recommendations may result in new records, range extensions, and species descriptions, contributing to the conservation of the aquatic environments of Maranhão.

Periodontal inflammation in renal transplant recipients receiving everolimus or tacrolimus - preliminary results.

OBJECTIVE: To compare oral health status between renal transplant recipients (RTRs) receiving tacrolimus (Tac) or everolimus (ERL) as immunosuppressive therapy. DESIGN: This study is a cross-sectional study. METHODS: Thirty-six RTRs receiving Tac and 22 RTRs receiving ERL were included in the study. Age, gender, time since transplant and pharmacological data were recorded for both groups. Oral health status was assessed through the evaluation of teeth, periodontal parameters as well as saliva flow rate and pH. RESULTS: RTRs receiving ERL were older than those receiving Tac. No differences were found between groups concerning oral hygiene habits, oral symptoms, smoking habits, unstimulated and stimulated saliva flow rate and pH, clinical attachment level or the number of decayed, missing and filled teeth. However, RTRs receiving ERL presented lower visible plaque index and lower values for bleeding on probing when compared to RTRs receiving Tac. In addition, RTRs receiving ERL presented a gingival index varying from normal to moderate inflammation whereas RTRs receiving Tac presented a gingival index varying from mild to severe inflammation. CONCLUSIONS: RTRs receiving ERL have lower periodontal inflammation when compared to RTRs receiving Tac.

Dupilumab for atopic dermatitis: a real-world Portuguese multicenter retrospective study.

INTRODUCTION: Atopic dermatitis (AD) is a difficult-to-treat inflammatory skin disease with a high impact on patients' quality of life. Dupilumab, an IL-4 and IL-13 inhibitor, was the first monoclonal antibody approved for the treatment of moderate-to-severe AD and is currently approved in patients aged 6 or older. METHODS: This is a nationwide, multicenter, retrospective, 48-week study designed by the Portuguese Group of AD to assess real-world efficacy and safety of dupilumab for the treatment of AD. RESULTS: A total of 169 patients were enrolled, with a mean disease duration of 22.75 (±11.98) years. The percentage of patients achieving an improvement of at least 75% in Eczema Area and Severity Index (EASI) compared to baseline (EASI75 response) at weeks 12 and 48 was 67.6% and 74.1%, respectively. In the same timepoints, 25.0% and 44.1% achieved an EASI90 response. Patient-reported outcome measures also improved throughout the study period. Regarding safety, 32.0% of the patients developed adverse events, with conjunctivitis (26.6%), persistent facial erythema (4.7%), and arthritis/arthralgia (3.6%) as the more frequently reported. CONCLUSION: Data from real-world populations are crucial to guide clinicians in their daily decisions. This study provides data demonstrating that dupilumab is an effective and safe therapeutic option for AD.

Early-onset of disseminated cryptococcal infection in two renal transplant recipients.

Cryptococcosis is the third most common invasive fungal infection in organ transplant recipients after candidiasis and aspergillosis. Newly acquired and reactivation of latent infection are the major causes of infection, with typical later-onset and mainly as disseminated infection. The type and intensity of immunosuppression, diabetes mellitus and other co-morbidities as well as uremia seem to be important determinants on clinical presentation and outcome. Moreover, the diagnosis is not always apparent since it usually presents subacutely, as well as mimicking bacterial infections, which may be responsible for a delay in the diagnosis. Thus, a high degree of suspicion and need of invasive procedures for microbiological and histological evaluation are critical for definitive diagnosis and prompt institution of adequate treatment. We report two cases of disseminated cryptococcosis with different presentations and with an early-onset after renal transplantation.

Cerebral coccidioidomycosis after renal transplantation in a non-endemic area.

Coccidioidomycosis is a fungal infection caused by Coccidioides species endemic to the desert south western United States. In healthy people, manifestations range mainly from asymptomatic to mild influenza-like syndrome. In immunosuppressed patients, extrapulmonary dissemination is common. We report the case of a patient with a parenchymal central nervous system lesion. This presentation is considered very rare. The highest risk of infection after solid organ transplantation occurs during the first year. Risk factors include treatment of acute rejection. In the reported case, the infection was probably donor-derived, as our patient had no history of traveling to endemic areas. Mortality is high among transplanted recipients with coccidioidomycosis, particularly those with disseminated infection.

Rituximab for steroid-dependent nephrotic syndrome.

Minimal change disease (MCD) is characterized by marked sensitivity to glucocorticoid therapy. However, in 40 - 50% of all cases the disease presents with frequent relapses and needs repeated courses of steroids as well as additional immunosuppressive therapy including azathioprine, cyclophosphamide or cyclosporine. Because such regimens are associated with significant toxicity, the therapeutic challenge of this disease is to identify the treatment with the highest probability of producing a sustained remission with the lowest risk of toxicity. There is increasing evidence that rituximab may play an important role in the treatment of idiopathic nephrotic syndrome. Here, we present an adult patient with steroid-sensitive but high-dose steroid-dependent MCD beginning in childhood with a heavy history of multiple immunosuppressive therapy that was brought into 1 year sustained remission of proteinuria with two infusions of rituximab (375 mg/m2).

Therapeutic implications of heparin-induced thrombocytopenia complicating acute hemodialysis.

Although patients undergoing acute hemodialysis (HD) constitute a group at risk for heparin-induced thrombocytopenia (HIT), the optimal therapeutic strategy remains undefined. We describe a case of HIT complicated with right subclavian vein thrombosis in a patient with chronic renal insufficiency undergoing acute HD for oligoanuria and pulmonary edema. Circulating anti-heparin-PF4 complex antibodies were detected. Past medical history was relevant for an otherwise unexplained self-limited episode of thrombocytopenia following acute HD one year earlier after an anterior STEMI. All sources of heparin were discontinued and alternative anticoagulation was initiated with argatroban, a direct-thrombin inhibitor with hepatic clearance, followed by transition to warfarin. Prevention of tunneled HD catheter obstruction was accomplished with low-dose alteplase catheter locking solution. No bleeding occurred with argatroban anticoagulation. Platelet count recovered and no further thrombotic complications were observed. The present report illustrates the diagnostic and therapeutic challenges of HIT complicating acute HD.