D313Y variant in two related end-stage renal disease patients – Pathogenic or not yet? / Dos pacientes con enfermedad renal terminal con la variante de significado incierto D313Y: ¿patógena o aún no?

Fabry disease is a multisystem lysosomal storage disorder caused by mutations in the GLA gene that result in a deficient or absent activity of alpha-galactosidase A. There is a wide spectrum of GLA gene variants, some of which are described as non-pathogenic. The clinical importance of the D313Y variant is still under debate, although in recent years it has been considered as a variant of unknown significance or a benign variant. Despite this prevailing notion, there are multiple case reports of patients with D313Y variant that presented signs and symptoms consistent with FD without any other etiological explanation. In this article, we present two family members with an important renal phenotype and other typical manifestations of FD (white matter lesions and left ventricular hypertrophy) that only had the D313Y variant. These cases suggest that this variant of unknown significance may contribute to the development of common features of FD and should not be undervalued. (AU)

La enfermedad de Fabry (EF) es un trastorno de almacenamiento lisosómico multisistémico causado por mutaciones en el gen GLA que tienen como resultado una actividad deficiente o ausente de alfa-galactosidasa A. Existe un amplio espectro de variantes del gen GLA, algunas de las cuales se describen como no patógenas. La importancia clínica de la variante D313Y aún está en debate, aunque en los últimos años se ha considerado una variante de significado incierto o una variante benigna. A pesar de esta noción predominante, existen múltiples reportes de casos de pacientes con variante D313Y que presentaron signos y síntomas consistentes con EF sin ninguna otra explicación etiológica. En este artículo presentamos 2 familiares con un importante fenotipo renal y otras manifestaciones típicas de la EF (lesiones de la sustancia blanca e hipertrofia ventricular izquierda) que solo presentaban la variante D313Y. Estos casos indican que esta variante de significado incierto puede contribuir al desarrollo de características comunes de la EF y no debe subestimarse. (AU)

Etelcalcetide controls secondary hyperparathyroidism and raises sclerostin levels in hemodialysis patients previously uncontrolled with cinacalcet / Etelcalcetida controla el hiperparatiroidismo secundario y eleva los niveles de esclerostina en pacientes en hemodiálisis previamente no controlados con cinacalcet

Introduction: There is scarce clinical experience with etelcalcetide in patients with secondary hyperparathyroidism uncontrolled with cinacalcet. The effect of etelcalcetide on serum sclerostin levels remains to be clarified. Materials and methods: Prospective cohort study in prevalent hemodialysis patients with uncontrolled sHPT under cinacalcet for at least 3 months, mean parathyroid hormone (PTH)>800pg/mL and calcium (Ca)>8.3mg/dL. Etelcalcetide 5mg IV/HD was initiated after cinacalcet washout. Levels of PTH, Ca, and phosphorus (Pi) followed monthly for 6 months. Plasma sclerostin levels measured before etelcalcetide treatment and after 6 months. Results: Thirty-four patients were enrolled, 19 (55.9%) male gender. Mean age 60.7 (± 12.3) years; median time on HD 82.5 (7–296) months and median cinacalcet dose was 180mg/week (Interquartile Range: 180–270). Serum Ca, Pi and PTH levels showed a significant reduction after etelcalcetide treatment from 8.8mg/dL, 5.4mg/dL and 1005pg/mL to 8.1mg/dL (p=0.08), 4.9mg/dL (p=0.01) and 702pg/mL (p<0.001), respectively. Median etelcalcetide dose remained at 5mg/HD. Plasma sclerostin concentration increased from 35.66pmol/L (IQR11.94–54.58) to 71.05pmol/L (IQR54.43–84.91) (p<0.0001). Conclusion: Etelcalcetide improved sHPT control in this group of patients, previously under cinacalcet treatment, and significantly increased plasma sclerostin concentration. The impact of etelcalcetide treatment on sclerostin levels is a novel finding. (AU)

Introducción: Existe escasa experiencia clínica sobre el uso de etelcalcetida en pacientes con hiperparatiroidismo secundario no controlado con cinacalcet. Asimismo, el efecto de la etelcalcetida sobre los niveles de esclerostina aún no ha sido aclarado. Materiales y métodos: Realizamos un estudio de cohorte prospectivo en pacientes en hemodiálisis (HD) con hiperparatiroidismo secundario no controlado con cinacalcet durante al menos 3 meses, hormona paratiroidea media> 800 pg/ml y calcio (Ca)> 8,3mg/dl. Tras un periodo de lavado, se inició administración intravenosa de etelcalcetida 5mg/HD y se realizó un seguimiento mensual de los niveles de hormona paratiroidea, Ca y fósforo (Pi) durante 6 meses. Además, los niveles de esclerostina plasmática fueron medidos antes del tratamiento con etelcalcetida y después de 6 meses. Resultados: Se incluyeron 34 pacientes, 19 (55,9%) de sexo masculino. Edad media 60,7±12,3 años; la mediana de tiempo en HD fue 82,5 (7-296) meses y la mediana de la dosis de cinacalcet fue de 180mg/semana (rango intercuartílico 180-270). Los niveles séricos de Ca, Pi y hormona paratiroidea mostraron una reducción significativa después del tratamiento con etelcalcetida desde 8,8mg/dl, 5,4mg/dl y 1005 pg/ml hasta 8,1mg/dl (p=0,08), 4,9mg/dl (p=0,01) y 702 pg/mL (p<0,001) respectivamente. La dosis media de etelcalcetida se mantuvo en 5mg/HD. La concentración de esclerostina plasmática aumentó de 35,66pmol/L (rango intercuartílico 11,94-54,58) a 71,05pmol/L (rango intercuartílico 54,43-84,91; p <0,0001). Conclusión: En este grupo de pacientes previamente en tratamiento con cinacalcet, la etelcalcetida mejoró el control de hiperparatiroidismo secundario y resultó en un aumento de la concentración plasmática de esclerostina. El efecto del tratamiento con etelcalcetida sobre los niveles de esclerostina es un hallazgo novedoso. (AU)

Peritoneal Dialysis Exit-Site Care Protocols in Portugal and Its Association with Catheter-Related Infections.

INTRODUCTION: Exit-site infection (ESi) prevention is a key factor in lowering the risk of peritonitis. This study aimed to evaluate the associations between exit-site (ES) care protocols and the annual incidence rates of ESi and peritonitis in Portugal. METHODS: We performed a national survey using two questionnaires: one about the incidence of catheter-related infections and the other characterizing patients' education and ES care protocols. RESULTS: In 2017 and 2018, 14 Portuguese units followed 764 and 689 patients. ESi incidence rate was 0.41 episodes/year, and the peritonitis incidence rate was 0.37. All units monitor catheter-related infections on a yearly basis, use antibiotic prophylaxis at the time of catheter placement, and treat nasal carriage of S. aureus, although with different approaches. Screening for nasal carriage of S. aureus is performed by 12 units, and daily topical antibiotic cream is recommended by 6 out of 14 of the units. We did not find statistical differences in ESi/peritonitis, comparing these practices. The rate of ESis was lower with nonocclusive dressing immediately after catheter insertion, bathing without ES dressing, with the use of colostomy bags in beach baths and was higher with the use of bath sponge. The peritonitis rate was lower with bathing without ES dressing and if shaving of the external cuff was performed in the presence of chronic ESi. CONCLUSIONS: We found potential proceedings associated with ESi and peritonitis. A regular national audit of peritoneal dialysis units is an important tool for clarifying the best procedures for reduction of catheter-related infections.

D313Y variant in two related end-stage renal disease patients - Pathogenic or not yet?

Fabry disease is a multisystem lysosomal storage disorder caused by mutations in the GLA gene that result in a deficient or absent activity of alpha-galactosidase A. There is a wide spectrum of GLA gene variants, some of which are described as non-pathogenic. The clinical importance of the D313Y variant is still under debate, although in recent years it has been considered as a variant of unknown significance or a benign variant. Despite this prevailing notion, there are multiple case reports of patients with D313Y variant that presented signs and symptoms consistent with FD without any other etiological explanation. In this article, we present two family members with an important renal phenotype and other typical manifestations of FD (white matter lesions and left ventricular hypertrophy) that only had the D313Y variant. These cases suggest that this variant of unknown significance may contribute to the development of common features of FD and should not be undervalued.

Etelcalcetide controls secondary hyperparathyroidism and raises sclerostin levels in hemodialysis patients previously uncontrolled with cinacalcet.

INTRODUCTION: There is scarce clinical experience with etelcalcetide in patients with secondary hyperparathyroidism uncontrolled with cinacalcet. The effect of etelcalcetide on serum sclerostin levels remains to be clarified. MATERIALS AND METHODS: Prospective cohort study in prevalent hemodialysis patients with uncontrolled sHPT under cinacalcet for at least 3 months, mean parathyroid hormone (PTH)>800pg/mL and calcium (Ca)>8.3mg/dL. Etelcalcetide 5mg IV/HD was initiated after cinacalcet washout. Levels of PTH, Ca, and phosphorus (Pi) followed monthly for 6 months. Plasma sclerostin levels measured before etelcalcetide treatment and after 6 months. RESULTS: Thirty-four patients were enrolled, 19 (55.9%) male gender. Mean age 60.7 (± 12.3) years; median time on HD 82.5 (7-296) months and median cinacalcet dose was 180mg/week (Interquartile Range: 180-270). Serum Ca, Pi and PTH levels showed a significant reduction after etelcalcetide treatment from 8.8mg/dL, 5.4mg/dL and 1005pg/mL to 8.1mg/dL (p=0.08), 4.9mg/dL (p=0.01) and 702pg/mL (p<0.001), respectively. Median etelcalcetide dose remained at 5mg/HD. Plasma sclerostin concentration increased from 35.66pmol/L (IQR11.94-54.58) to 71.05pmol/L (IQR54.43-84.91) (p<0.0001). CONCLUSION: Etelcalcetide improved sHPT control in this group of patients, previously under cinacalcet treatment, and significantly increased plasma sclerostin concentration. The impact of etelcalcetide treatment on sclerostin levels is a novel finding.

Lupus-like nephritis with positive anti-neutrophil cytoplasmic antibodies and negative antinuclear antibodies / Nefrite semelhante à lúpica com anticorpos citoplasmáticos antineutrófilos positivos e anticorpos antinucleares negativos

Abstract Antineutrophil cytoplasmic antibodies (ANCAs) are associated with small vessel vasculitis but their prevalence is not rare in other immune diseases. In lupus nephritis (LN), their pathological role and clinical relevance have been the target of controversial views. We present a case of acute kidney injury and nephrotic syndrome in a young woman with diffuse global proliferative and membranous nephritis on her kidney biopsy, showing a full-house immunofluorescence pattern, very allusive of class IV + V LN, but lacking associated clinical criteria and laboratory findings to support the diagnosis of systemic lupus erythematosus (SLE). Furthermore, the patient presented with high titers of ANCA, steadily decreasing alongside the renal function and proteinuria improvements, with mycophenolate mofetil (MMF) and steroid treatment. The authors believe this is a case of lupus-like nephritis, in which ANCAs are immunological markers, although they are not directly involved in the pathogenesis.

Resumo Os anticorpos anticitoplasma de neutrófilos (ANCAs) estão associados à vasculite de pequenos vasos, no entanto, a sua prevalência não é rara em outras doenças imunológicas. Na nefrite lúpica (LN), o seu papel patológico e relevância clínica têm sido alvo de pontos de vista controversos. Apresentamos um caso de lesão renal aguda e síndrome nefrótica em uma jovem com nefrite proliferativa difusa e membranosa em sua biópsia renal, muito alusivo a NL classe IV + V, com um padrão full house na imunofluorescência, mas sem critérios clínicos e achados laboratoriais para corroborar o diagnóstico de lúpus eritematoso sistêmico (LES). Não obstante, a paciente apresentou títulos elevados de ANCA, que diminuiram progressivamente com a melhoria da função renal e da proteinúria, após tratamento com micofenolato de mofetil (MMF) e esteróide. Os autores acreditam que se trata de um caso de nefrite semelhante à nefrite lúpica, em que os ANCAs são marcadores imunológicos, embora não estejam diretamente envolvidos na patogênese.

Lupus-like nephritis with positive anti-neutrophil cytoplasmic antibodies and negative antinuclear antibodies.

Antineutrophil cytoplasmic antibodies (ANCAs) are associated with small vessel vasculitis but their prevalence is not rare in other immune diseases. In lupus nephritis (LN), their pathological role and clinical relevance have been the target of controversial views. We present a case of acute kidney injury and nephrotic syndrome in a young woman with diffuse global proliferative and membranous nephritis on her kidney biopsy, showing a full-house immunofluorescence pattern, very allusive of class IV + V LN, but lacking associated clinical criteria and laboratory findings to support the diagnosis of systemic lupus erythematosus (SLE). Furthermore, the patient presented with high titers of ANCA, steadily decreasing alongside the renal function and proteinuria improvements, with mycophenolate mofetil (MMF) and steroid treatment. The authors believe this is a case of lupus-like nephritis, in which ANCAs are immunological markers, although they are not directly involved in the pathogenesis.

Rituximab use in adult glomerulopathies and its rationale / Uso do rituximabe em glomerulopatias em adultos e justificativas

Abstract Glomerulopathies are one of the leading causes of end-stage renal disease. In the last years, clinical research has made significant contributions to the understanding of such conditions. Recently, rituximab (RTX) has appeared as a reasonably safe treatment. The Kidney Disease: Improving Global Outcomes guidelines (KDIGO) recommended RTX only as initial treatment in antineutrophil cytoplasm antibody associated vasculitis (AAV) and in non-responders patients with lupus nephritis (LN), but these guidelines have not been updated since 2012. Nowadays, RTX seems to be at least as effective as other immunosuppressive regimens in idiopathic membranous nephropathy (IMN). In minimal-change disease, (MCD) this drug might allow a long-lasting remission period in steroid-dependent or frequently relapsing patients. Preliminary results support the use of RTX in patients with pure membranous LN and immunoglobulin-mediated membranoproliferative glomerulonephritis (MPGN), but not in patients with class III/IV LN or complement-mediated MPGN. No conclusion can be drawn in idiopathic focal segmental glomerulosclerosis (FSGS) and anti-glomerular basement membrane antibody glomerulonephritis (anti-GBM GN) because studies are small, heterogeneous, and scarce. Lastly, immunosuppression including RTX is not particularly useful in IgA nephropathy. This review presents the general background, outcomes, and safety for RTX treatment in different glomerulopathies. In this regard, we describe randomized controlled trials (RCTs) performed in adults, whenever possible. A literature search was performed using clinicaltrials.gov and PubMed.

Resumo As glomerulopatias figuram entre as principais causas de doença renal terminal. Nos últimos anos, a pesquisa clínica efetuou contribuições significativas para a compreensão desse grupo de patologias. Recentemente, o rituximabe (RTX) surgiu como um tratamento razoavelmente seguro. As diretrizes do Kidney Disease: Improving Global Outcomes (KDIGO) recomendam o RTX apenas como tratamento inicial na vasculite associada ao ANCA (VAA) e em pacientes não respondedores com nefrite lúpica (NL), embora não sejam atualizadas desde 2012. Atualmente, o RTX parece ser pelo menos tão eficaz quanto outros esquemas imunossupressores na nefropatia membranosa idiopática (NMI). Na doença por lesão mínima (DLM), o medicamento pode proporcionar um período de remissão duradouro em pacientes córtico-dependentes ou com recidivas frequentes. Resultados preliminares corroboram o uso de RTX em pacientes com NL membranosa pura e glomerulonefrite membranoproliferativa (GNMP) mediada por imunoglobulina, mas não em pacientes com NL classe III/IV ou GNMP mediada por complemento. Os achados a respeito de glomeruloesclerose segmentar e focal (GESF) idiopática e doença por anticorpo antimembrana basal glomerular (anti-MBG) não são conclusivos em função do pequeno número, porte e heterogeneidade dos estudos publicados até o presente momento. Por fim, a imunossupressão com RTX não é particularmente útil na nefropatia por IgA. A presente revisão apresenta o racional da prescrição de RTX nas diferentes glomerulopatias, desfechos e segurança. Nesse sentido, foram incluídos ensaios clínicos randomizados (ECRs) realizados em adultos, sempre que possível. Pesquisas bibliográficas foram realizadas nas bases de dados do clinictrials.gov e no PubMed.

Rituximab use in adult glomerulopathies and its rationale.

Glomerulopathies are one of the leading causes of end-stage renal disease. In the last years, clinical research has made significant contributions to the understanding of such conditions. Recently, rituximab (RTX) has appeared as a reasonably safe treatment. The Kidney Disease: Improving Global Outcomes guidelines (KDIGO) recommended RTX only as initial treatment in antineutrophil cytoplasm antibody associated vasculitis (AAV) and in non-responders patients with lupus nephritis (LN), but these guidelines have not been updated since 2012. Nowadays, RTX seems to be at least as effective as other immunosuppressive regimens in idiopathic membranous nephropathy (IMN). In minimal-change disease, (MCD) this drug might allow a long-lasting remission period in steroid-dependent or frequently relapsing patients. Preliminary results support the use of RTX in patients with pure membranous LN and immunoglobulin-mediated membranoproliferative glomerulonephritis (MPGN), but not in patients with class III/IV LN or complement-mediated MPGN. No conclusion can be drawn in idiopathic focal segmental glomerulosclerosis (FSGS) and anti-glomerular basement membrane antibody glomerulonephritis (anti-GBM GN) because studies are small, heterogeneous, and scarce. Lastly, immunosuppression including RTX is not particularly useful in IgA nephropathy. This review presents the general background, outcomes, and safety for RTX treatment in different glomerulopathies. In this regard, we describe randomized controlled trials (RCTs) performed in adults, whenever possible. A literature search was performed using clinicaltrials.gov and PubMed.

[Contrast-induced nephropathy]. / Nefropatia de contraste.

Contrast-induced nephropathy (CIN) is an iatrogenic disorder, resulting from procedures requiring the intravascular administration of iodinated contrast media. It has an association with increased morbidity and mortality, increased costs and it remains the third most common cause of hospital-acquired kidney failure. CIN is usually defined as an increase in serum creatinine by either at least 0.5 mg/dl or by 25% from baseline within the first 48 hours after contrast administration, in the absence of other causes of renal function impairment. In its pathogenesis have been implicated 2 main mechanisms: renal vasoconstriction resulting in medullary hypoxia and direct cytotoxic effects of the contrast agents. There are several risk factors for radiocontrast nephrotoxicity but patients with underlying renal insufficiency or diabetic nephropathy with renal insufficiency have the greatest risk. Other classic risk factors include: advanced age, peri-procedural intravascular depletion, congestive heart failure. Finally, toxicity also depends on the volume, type of contrast administered and concomitant use of other nephrotoxic drugs. Since there is no specific treatment for CIN and it is limited to supportive measures, prevention is the best way to deal with this condition. In this setting it is important to use lower doses of a low or iso-osmolal agent and avoid volume depletion. Nowadays it is recommended to do volume expansion prior to and continued for several hours after the procedure. Randomized controlled trials suggest that isotonic intravenous fluids, particularly isotonic bicarbonate, confer better protection. Several pharmacologic approaches have been tested to decrease the risk of CIN in patients with preexisting renal disease, based in the mechanisms by which contrast medium is believed to cause nephrotoxicity. However, with the exception of some antioxidant agents, few of those adjunctive therapies have shown any consistent benefit. N-Acetylcysteine is the most widely studied of all prophylactic strategies and despite conflicting data it is advised to do an elevated dosage orally twice daily, the day before and the day of the procedure, based upon its potential for benefit, low toxicity and cost. This article pretends to review CIN pathogenesis, risk factors, clinical course, treatment and prevention. The authors propose themselves a prevention protocol for risk patients based on the latest clinical evidence.