A review and recommendations for oral chaperone therapy in adult patients with Fabry disease.

Fabry disease (FD) is a rare, X-linked lysosomal storage disorder affecting both males and females caused by genetic abnormalities in the gene encoding the enzyme α-galactosidase A. FD-affected patients represent a highly variable clinical course with first symptoms already appearing in young age. The disease causes a progressive multiple organ dysfunction affecting mostly the heart, kidneys and nervous system, eventually leading to premature death. Disease-specific management of FD includes enzyme replacement therapy with agalsidase α and ß or pharmacological oral chaperone migalastat. Migalastat is a low-molecular-mass iminosugar, that reversibly binds to active site of amenable enzyme variants, stabilizing their molecular structure and improving trafficking to the lysosome. Migalastat was approved in the EU in 2016 and is an effective therapy in the estimated 35-50% of all patients with FD with amenable GLA gene variants. This position statement is the first comprehensive review in Central and Eastern Europe of the current role of migalastat in the treatment of FD. The statement provides an overview of the pharmacology of migalastat and summarizes the current evidence from the clinical trial program regarding the safety and efficacy of the drug and its effects on organs typically involved in FD. The position paper also includes a practical guide for clinicians on the optimal selection of patients with FD who will benefit from migalastat treatment, recommendations on the optimal selection of diagnostic tests and the use of tools to identify patients with amenable GLA mutations. Areas for future migalastat clinical research have also been identified.

First two years of reimbursed enzyme replacement therapy in the treatment of Fabry disease in Poland.

Fabry disease (FD) is an ultra-rare genetic lysosomal storage disease caused by pathologic gene variants resulting in insufficient expression of α-galactosidase A. This enzyme deficiency leads to accumulation of globotriaosylceramide and globotriaosylsphingosine in plasma and in different cells throughout the body, causing major cardiovascular, renal, and nervous system complications. Until 2018, reimbursed enzyme replacement therapy (ERT) for FD was available in all European Union countries except Poland.             We present the preliminary results of the first two years of reimbursed ERT in Poland. We obtained data from the seven largest academic centers in Katowice, Kraków, Wroclaw, Poznan, Gdansk, Warszawa, and Lódz. The questionnaire included the following data: number of patients treated, number of patients qualified for ERT, and patient characteristics.             All centers returned completed questionnaires that included data for a total of 71 patients (28 men and 43 women) as of June 2021. Thirty-five patients with the diagnosis of FD confirmed by genetic testing (22 men and 13 women) had already qualified for reimbursed ERT. Mean (SD) age at the commencement of the ERT program was 39.6 (15.5) years (range 18-79 years). Mean time from the first clinical symptoms reported by the patients to the FD diagnosis was 21.1 (8.9) years, and the mean time from the final diagnosis of FD to the beginning of ERT was 4.7 (4.6) years.             FD is still underdiagnosed in Poland. To identify undiagnosed FD patients and to ensure that patients in Poland benefit fully from ERT, implementation of an effective nationwide screening strategy and close cooperation with a network of rare disease centers is advised.

Recurrence of Cryoglobulinemia Secondary to Hepatitis C in a Patient with HCV RNA (-) Negative in the Serum.

Hepatitis C virus infection is associated with many extrahepatic manifestations such as mixed cryoglobulinemia (MC). Renal manifestation of HCV infection might present as cryo-positive membranoproliferative glomerulonephritis (MPGN). First-line therapy includes antiviral treatment as the underlying infection leads to formation of immune complexes. After introducing direct-acting antiviral agents (DAAs) cure rates of HCV infection increased. Sustained virologic response (SVR) is defined as the absence of HCV RNA in serum by a sensitive test performed 12 or 24 weeks after the end of antiviral treatment. Although HCV RNA is undetectable in the serum, it may be present in hepatocytes and peripheral blood mononuclear cells (occult HCV infection). However, the impact of DAA treatment on occult HCV infection is not clear. We report a case of recurrence of MC with MPGN and development of lymphoproliferative disorder 2 years after achieving SVR.

An unexpected diagnosis of intravascular loss of guidewire after central venous catheterization - a case report.

Hemodialysis is the dominant method of renal replacement therapy. The condition of its effectiveness is obtaining adequate vascular access, among others, central catheters. Central venous catheterization is a routine procedure, but it carries a risk of complications. An extremely rare but completely avoidable complication is the loss of the guidewire during the central venous catheterization procedure. A CASE REPORT: A 79-year-old patient, chronically hemodialyzed was admitted to the hospital to create vascular access. Previous vascular access, femoral central venous catheter was removed due to thrombosis. During hospitalization, angio-CT scan was performed, which showed the presence of a foreign body in the venous system, from the inguinal canal to the brachiocephalic vein. This structure turned out to be a guide, remaining after vein catheterization in the past. Complications during the procedure have never been reported. While bending her torso, the patient has been complaining of nonspecific pains in the neck area for 2 years. Part of the guide was extravascular in the upper mediastinum. The patient was consulted by a vascular surgeon, who due to the presence of the guidewire for a long time, recommended conservative treatment and regular follow-ups. CONCLUSIONS: An extremely rare complication, which is the loss of the guide during insertion of a vascular catheter, can be avoided by strict adherence to procedures, mindfulness, occupational hygiene and by appropriate supervision of specialists over young doctors. The presented case of the patient proves that the guidewire left in the venous system may remain unnoticed for several years. In the described case, removal of a foreign body would be associated with extensive surgery and a high risk of vascular damage, therefore conservative treatment and regular check-ups were recommended.

Tunnelled haemodialysis catheter insertion into the persistent left superior vena cava.

Persistent left superior vena cava is an uncommon abnormality of the venous system. Most commonly, it is diagnosed incidentally during central vein catheterisation on the left side or pacemaker implantation. We present the case of a patient with persistent left superior vena cava, which was diagnosed after the attempted insertion of tunnelled haemodialysis catheter through the left internal jugular vein. The presence of the persistent left superior vena cava was confirmed by cardiac echography and angio-computed tomography scan. The 19-cm long tunnelled haemodialysis catheter was inserted into persistent left superior vena cava through the left internal jugular vein with good long-term function.

Kidney disease in the elderly: biopsy based data from 14 renal centers in Poland.

BACKGROUND: Longer life expectancy is associated with an increasing prevalence of kidney disease. Aging itself may cause renal damage, but the spectrum of kidney disorders that affect elderly patients is diverse. Few studies, mostly form US, Asia and West Europe found differences in the prevalence of some types of kidney diseases between elderly and younger patients based on renal biopsy findings, with varied proportion between glomerulopathies and arterionephrosclerosis as a dominant injury found. Here, for the first time in Eastern Europe we analyzed native kidney biopsy findings and their relationship to clinical characteristics at the time of biopsy in elderly individuals (aged ≥65) in comparison to younger adults (aged 18-64). METHODS: Biopsy and clinical data from 352 patients aged ≥65 were retrospectively identified, analyzed and compared with a control group of 2214 individuals aged 18-64. All kidney biopsies studied were examined at Medical University of Warsaw in years 2009-14. RESULTS: In elderly patients the leading indication for biopsy was nephrotic range proteinuria without hematuria (34.2%) and the most prevalent pathologic diagnoses were: membranous glomerulonephritis (MGN) (18.2%), focal segmental glomerulosclerosis (FSGS) (17.3%) amyloidosis (13.9%) and pauci immune glomerulonephritis (12.8%). Hypertension and age-related lesions very rarely were found an exclusive or dominant finding in a kidney biopsy (1.7%) and a cause of proteinuria (1.1%) in elderly individuals. There were 18.2% diabetics among elderly individuals, and as much as 75% of them had no morphologic signs of diabetic kidney disease in the renal biopsy. Amyloidosis, MGN, pauci immune GN, crescentic GN and light and/or heavy chain deposition disease (LCDD/HCDD) were more frequent whereas IgA nephropathy (IgAN), lupus nephritis (LN) and thin basement membrane disease (TBMD) were less common among elderly than in younger patients. CONCLUSIONS: Proteinuria, a dominating manifestation in elderly patients subjected to kidney biopsy was most commonly related to glomerulopathies. The relatively high prevalence of potentially curative kidney diseases in elderly individuals implicates the importance of renal biopsy in these patients.

Survival of tunneled hemodialysis catheters after percutaneous placement.

BACKGROUND: Tunneled catheters are becoming increasingly used as a permanent dialysis access. Easy way of insertion and good long-term patency make them competitive to fistulas in some groups of patients. METHODS: Late complications and survival of 180 tunneled catheters inserted from June 2010 to December 2013 in 171 unselected hemodialysis patients were analyzed. RESULTS: The cumulative time of observation was 2103.5 patient-months and median observation was 9 months (range of 0.5-45 months). Only 19 out of 180 catheters were removed due to complications (12 for infections, 4 due to malfunction and 3 because of mechanical damage). Majority of catheters were removed electively: 27 after maturation of arterio-venous fistula (AVF), 4 after kidney transplant, 5 after transfer to peritoneal dialysis and 3 due to the recovery of renal function. At the end of the observation, 58 catheters were still in use and 64 patients had died with functioning catheter. When censored for elective catheter removal and patient death, 88.2% of catheters survived for 1 year. Catheter survival was significantly better in older patients (over 65 years, in comparison to patients < 65 years, p = 0.046). CONCLUSIONS: Nearly 90% of all inserted catheters gave reliable dialysis access as long as it was needed. Among them, over 30% of the inserted catheters were in use at the end of the observation period, and over 30% of patients had died with a functioning catheter. The results of tunneled catheters survival are encouraging and they should be taken into consideration during decision-making on vascular access, especially in the older patients.

Catheter tip malposition after percutaneous placement of tunneled hemodialysis catheters.

The percutaneous catheterization of central veins is increasingly used in nephrological practice as a temporary or permanent vascular access. The aim of our study was to present and to analyze episodes of catheter tip malposition during percutaneous tunneled hemodialysis catheter insertion in the large, unselected group of patients. All patients who underwent the procedure of catheter insertion in our department during year 2012 were analyzed retrospectively. One hundred four tunneled hemodialysis catheters were inserted in 101 patients. In 58 patients, the catheter was inserted at the initiation of hemodialysis therapy as the first access and in 46 the catheter was placed because of the failure of the existing one. In 68 patients, the catheter was inserted into the right internal jugular vein and in 20 patients into the left internal jugular vein (LIJV). Subclavian veins were used in five cases and femoral veins in 11 cases. Malposition of the catheter tips occurred in six patients. In all cases, the LIJV was cannulated. In two cases, the catheter tip malposition was in the right innominate vein and in four cases in the azygos vein. Our data demonstrate that with the blind insertion of tunneled hemodialysis catheters, the risk of catheter tip malposition is significantly higher with the left side insertion. As catheter insertion through the LIJV holds very high (30%) risk of the tip malposition, it should always be performed under the fluoroscopic control.

Prolonged renal failure in the course of atypical ethylene glycol intoxication.

Ethylene glycol poisoning is not an uncommon cause of an acute renal injury. In this paper we present case of prolonged renal failure in the course of ethylene glycol intoxication. Due to the low dose of ingested ethylene glycol and concomitant ethanol consumption, the neurodepressive phase of the intoxication was rather mild and patient presented to the hospital on the ninth day after poisoning with established renal failure. The diagnosis of the specific cause of renal injury was facilitated by the renal biopsy.

Transforming growth factor ß1 protein and mRNA levels in inflammatory bowel diseases: towards solving the contradictions by longitudinal assessment of the protein and mRNA amounts.

Previously published studies on levels of the transforming growth factor-ß1 (TGF-ß1) protein and mRNA of the corresponding gene in patients suffering from inflammatory bowel diseases (IBD) gave varying results, leading to contradictory conclusions. To solve the contradictions, we aimed to assess longitudinally TGF-ß1 protein and mRNA levels at different stages of the disease in children suffering from IBD. The study group consisted of 19 pediatric patients with IBD at the age between 3.5 and 18.4 years. The control group consisted of 42 children aged between 2.0 and 18.0 years. The plasma TGF-ß1 concentration was measured with ELISA. mRNA levels of the TGF-ß1 gene isolated from samples of the intestinal tissue were assessed by reverse transcription and real-time PCR. Levels of TGF-ß1 protein in plasma and corresponding mRNA in intestinal tissue were significantly higher in IBD patients than in controls. TGF-ß1 and corresponding transcripts were also more abundant in plasma and intestinal tissue, respectively, in patients at the active stage of the disease than during remission. In every single IBD patient, plasma TGF-ß1 level and mRNA level in intestinal tissue was higher at the active stage of the disease than during remission. Levels of TGF-ß1 and corresponding mRNA are elevated during the active stage of IBD but not during the remission. Longitudinal assessment of this cytokine in a single patient may help to monitor the clinical course of IBD.

The mRNA level of the transforming growth factor ß1 gene, but not the amount of the gene product, can be considered as a potential prognostic parameter in inflammatory bowel diseases in children.

PURPOSE: Transforming growth factor ß1 (TGF-ß1) plays a role in cell proliferation and differentiation, and it can modulate immune response. In this work, we asked whether levels of either TGF-ß1 or mRNA of the corresponding gene in plasma or tissue can be useful in diagnosing and/or monitoring of the clinical course of inflammatory bowel diseases (IBD). METHODS: The study group consisted of 104 pediatric patients with IBD: 36 with Crohn's disease (CD) and 68 with ulcerative colitis (UC); 42 children represented the control group. TGF-ß1 levels in plasma and intestinal mucosa were estimated by ELISA and immunohistochemistry (IHC), respectively. Levels of TGF-ß1 mRNA were determined by reverse transcription and real-time PCR. RESULTS: In patients with IBD, and in subgroups with CD and UC, no significant differences in the TGF-ß1 level in plasma and tissue were found relative to the control group. These variables were not dependent on the stage of the disease, its activity or severity of endoscopic and histopathological findings. TGF-ß1 mRNA levels were significantly higher in tissue samples withdrawn during the relapse of the disease than in those taken during the remission or in the control group. However, no correlation between TGF-ß1 plasma levels and TGF-ß1 mRNA amount in the intestinal mucosa was observed. CONCLUSIONS: The TGF-ß1 mRNA level, but not the amount of the gene product, was significantly increased in the pathologically changed tissue during the relapse of IBD. We suggest that this parameter might be considered as a potential prognostic value when assessing IBD in children.

Clinical parameters of inflammatory bowel disease in children do not correlate with four common polymorphisms of the transforming growth factor ß1 gene.

Transforming growth factor ß1 (TGF-ß1) is a cytokine affecting cell proliferation and development, which also has an immunomodulatory activity. Correlations between polymorphisms of the TGF-ß1 gene and clinical parameters of inflammatory bowel disease (IBD) were reported previously in adults. Here, we tested whether such correlations occur in pediatric patients suffering from IBD. One hundred and four pediatric IBD patients were involved in this study. Among them, 36 were diagnosed with Crohn's Disease (CD) and 68 were diagnosed with ulcerative colitis (UC). The control group consisted of 103 children, in which IBD was excluded. TGF-ß1 levels were determined in plasma and intestinal mucosa samples. The presence of the TGF ß1 protein and the amount of TGF ß1 mRNA were estimated in intestinal mucosa by immunohistochemistry and reverse transcription Real-Time PCR, respectively. Four common polymorphisms of the TGF-ß1 gene were investigated: -800G/A, -509C/T, 869T/C and 915G/C. No significant correlation between TGF-ß1 genotypes and (i) TGF-ß1 levels in plasma and tissue samples, (ii) TGF-ß1 gene expression efficiency in intestinal mucosa, (iii) IBD clinical parameters and (iv) inflammatory activity could be detected in children suffering from IBD. We conclude that, contrary to previous suggestions, the four common polymorphisms of the TGF-ß1 gene do not influence the susceptibility to or clinical parameters of IBD in the tested population of children.

When to initiate dialysis--is early start always better?

The question when to initiate dialysis is attracting increasing attention. In recent years, there has been a tendency to initiate dialysis earlier in terms of estimated glomerular filtration rate (eGFR) in an attempt to achieve better patient outcomes. However, several observational studies and one randomized controlled trial have found no benefit for early dialysis initiation. On the contrary, they have found that starting dialysis with a higher eGFR is associated with increased mortality. These studies need to be carefully interpreted in light of their reliance on eGFR to estimate kidney function at dialysis initiation. The decision to start dialysis should not be based solely on a predefined eGFR value, but more importantly on a careful clinical assessment of the individual patient.

Expression of Hsp72 protein in chronic kidney disease patients.

OBJECTIVE: Expression of heat shock protein (Hsp) 72 is one of the major mechanisms acting against cellular injury. It displays a plethora of functions, including a considerable impact on inflammation. The aim of this study was to investigate Hsp72 expression in blood monocytes of patients with chronic kidney disease (CKD). MATERIAL AND METHODS: Hsp72 protein level was assessed by flow cytometry in blood monocytes of predialysis, haemodialysis (HD) and continuous peritoneal dialysis patients, and controls. It was followed by evaluation of Hsp72 gene expression in the same cohorts by reverse transcription-polymerase chain reaction. RESULTS: The level of Hsp72 protein was significantly lower in the predialysis (359+/-83 AU) and HD groups (293+/-62 AU) than in controls (405+/-51 AU) (p<0.01 and p<0.001, respectively). The amount of mRNA was significantly lower only in the HD group, compared with controls (0.39+/-0.10 vs 0.48+/-0.10, p<0.01). In the predialysis group, there were negative correlations between Hsp72 protein level and serum creatinine concentration, blood urea nitrogen and C-reactive protein. CONCLUSIONS: This study demonstrates that uraemic toxicity decreases expression of Hsp72. Attenuation of Hsp 72 expression in uraemia, found in the present study, could contribute to the inflammatory state, a common complication in CKD patients.

Therapy outcome in peritoneal dialysis patients transferred from haemodialysis.

BACKGROUND: Haemodialysis (HD) and peritoneal dialysis (PD) should be regarded as complementary methods of renal replacement therapy. Approximately 10-20% of patients on PD are transferred annually to HD due to technique failure. Much smaller proportion of patients changes modality from HD to PD, predominantly due to vascular access problems, cardiac disease or patient preference. The effects of these transfers on therapy outcome, patient and technique survival have not been studied, with research focusing on outcome measures within the single modality and comparisons between the two methods. METHODS: We have analysed retrospectively a cohort of 264 patients treated with PD in a single PD centre during 1994-2006. Patient characteristics, therapy measures and outcome of patients were compared between patients for whom PD was the initial method of renal replacement therapy (group 1, n = 197) and those transferred to PD from haemodialysis because of complications (group 2, n = 67). The Kaplan-Meier method and Cox proportional hazards multiple regression analysis were used to assess patient and technique survival. RESULTS: In patients transferred from HD, significantly less had diabetes (11.9% versus 38.1%, P < 0.0001) and there were also significantly more females (57% versus 42.2%, P < 0.05). Baseline Kt/V was significantly higher in the primary PD therapy group (2.46 +/- 0.57 versus 2.11 +/- 0.48, P < 0.001), due to lower residual renal function in patients transferred from HD. Group 2 had also significantly higher peritonitis rate (0.86 versus 0.62 episode/year, P < 0.05). During the time of observation, 71 patients have died, in 100 patients kidney transplantation was performed, 56 were transferred to HD, renal function recovered in 5 and 32 were still on PD at the end of the study. No significant differences were observed in unadjusted patient survival, but technique survival was significantly lower in group 2 (P < 0.05). In the Cox multiple regression model, diabetes status, age and albumin level significantly influenced survival. Relative risk of death was not increased significantly in patients transferred from HD. CONCLUSIONS: Our data suggest that outcome of patients transferred from HD is similar to that achieved in patients in whom PD is the first choice therapy. Thus, this option should be strongly considered in patients experiencing complications on HD, mainly vascular access problems, heart failure or intradialytic hypotension.

[Role of transforming growth factor beta1 (TGF-beta1) in the pathogenesis and clinical course of chronic hepatitis in children]. / Rola transformujacego czynnika wzrostu beta1 (TGF-beta1) w etiopatogenezie i przebiegu klinicznym przewleklych zapalen watroby u dzieci.

UNLABELLED: Transforming growth factor-beta1 (TGF-beta1) is known to play a key role in processes of cell proliferation and differentiation. It also plays an important role in modulation of the immune response. Various diseases may arise both from excessive and insufficient activity of this cytokine. THE AIM OF THE STUDY was to evaluate the role of TGF-beta1 in the pathogenesis of chronic hepatitis (Ch.h.) and to assess whether TGF-beta1 level in plasma or its tissue expression can be useful in diagnosing and monitoring of clinical course of this disease. PATIENTS AND METHODS: Twenty-one children with chronic hepatitis were included in the study and 42 healthy children constituted the control group. Liver function tests and TGF-beta1 plasma levels measured by ELISA method were evaluated in both groups of patients. In liver tissue obtained by needle biopsy, the histopathological grading and staging of hepatitis was evaluated, TGF-beta1 protein was assessed by immunohistochemical methods and TGF-beta1 gene expression was measured by reverse transcription and real-time polymerase chain reaction. RESULTS: In chronic hepatitis group of patients the plasma TGF-beta1 level did not differ from the control group and did not correlate with grading and staging of the liver tissue while positive correlation was observed with gamma-glutamyl transpeptidase activity in the serum. There was no correlation between tissue TGF-beta1 expression and TGF-beta1 plasma level and staging or grading in liver tissue. TGF-beta1 gene expression correlated positively with ESR and ALAT activity but no correlation with TGF-beta1 plasma level, TGF-beta1 gene or protein expression, grading or staging in liver tissue were observed. CONCLUSION: 1. In children with chronic hepatitis, TGF-beta1 plasma level is not related to grading or staging in the liver tissue. This finding may be due to low level of fibrosis observed in the studied children. 2. It appears that local expression of TGF-beta1 in liver tissue should not be used as a sole marker in differentiating and monitoring the course of chronic hepatitis. 3. In children with chronic hepatitis assessment of liver TGF-beta1 gene expression is not helpful in the evaluation of pathological changes in liver tissue. 4. Due to the relatively low number of patients in the analysed groups it seems advisable to perform similar complex studies in larger groups of children with chronic hepatitis.