Case report: First diagnosis of Fabry disease in North Macedonia in a patient presenting with kidney failure on hemodialysis.

Introduction: Fabry disease is a rare X-linked lysosomal storage disorder caused by α-galactosidase A (α-Gal A) deficiency. Reduced or absent enzyme activity causes progressive lysosomal accumulation of globotriaosylceramide (Lyso-Gb3) in various cells throughout the body to trigger inflammation and fibrosis. Case description: We present the first familial case of Fabry Disease in North Macedonia identified based on clinical manifestations and confirmed through enzyme, biomarker, and genetic tests. The index case in the family was a 45-year-old male undergoing hemodialysis therapy. He has had chronic burning uncontrolled limb pain since childhood, intermittent abdominal cramps, anhidrosis, and hypertension. The constellation of clinical presentations accompanied by similar symptoms in close family members prompted the enzyme, biomarker, and genetic analyses for Fabry disease. Genetic testing identified a known pathogenic GLA missense variant c.443G>A or p.(Ser148Asn) in the hemizygous state. Subsequent family studies allowed identification of another hemizygous male and five heterozygous female carriers affected by this X-linked disorder. Conclusion: We report identification of the first familial case of Fabry disease in North Macedonia and describe the phenotype associated with the Ser148Asn GLA variant. Greater awareness of this rare disease linked to continuous medical education is crucial for timely diagnosis and treatment.

Pathohistomorphometric and Immuno-Histologic Changes in Early Arteriovenous Fistula Failure in Patients with Chronic Kidney Disease.

BACKGROUND: Hemodialysis is a prevalent treatment for the end-stage chronic kidney disease (CKD) worldwide. The primary arteriovenous fistula (AVF), widely considered the optimal hemodialysis access method, fails to mature in up to two-thirds of the cases. The etiology of the early AVF failure, defined as thrombosis or inability to use within three months post-creation remains less understood, and is influenced by various factors including patient demographics, surgical techniques, and genetic predispositions. Neointimal hyperplasia is a primary histological finding in stenotic lesions leading to the AVF failure. However, there are insufficient data on the cellular phenotypes and the impact of the preexisting CKD-related factors. This study aims to investigate the histological, morphometric, and immunohistochemical alterations in the fistula vein, pre-, peri-, and post-early failure. MATERIALS AND METHODS: Eighty-nine stage 4-5 CKD patients underwent standard preoperative assessment, including the Doppler ultrasound, before a typical radio-cephalic AVF creation. Post-failure, a new AVF was created proximally. The vein specimens were collected during the surgery, processed, and analyzed for morphometric analyses and various cellular markers, including Vimentin, TGF, and Ki 67. RESULTS: The study enrolled 89 CKD patients, analyzing various aspects of their condition and AVF failures. The histomorphometric analysis revealed substantial venous luminal stenosis and varied endothelial changes. The immunohistologic analysis showed differential marker expressions pre- and post-AVF creation. CONCLUSION: This study highlights the complexity of the early AVF failures in CKD patients. The medial hypertrophy emerged as a significant preexisting lesion, while the postoperative analyses indicated a shift towards neointimal hyperplasia. The research underscores the nuanced interplay of vascular remodeling, endothelial damage, and cellular proliferation in the AVF outcomes.

Using a Catheter for Hemodialysis Placed in the Inferior Vena Cava for the First Time in N. Macedonia - Translumbar Approach.

Maintenance of vascular access for hemodialysis remains a challenge for every doctor. Exhausted conventional vascular access is the cause for the placement of the central venous catheter in unconventional sites such as enlarged collateral vessels, hepatic veins, hemiazygos, azygos, renal veins, and the inferior vena cava. The percutaneous translumbar catheter for hemodialysis in the inferior vena cava was described over 20 years ago. In this article, we report on the procedure and complications arising from the percutaneous translumbar approach of a hemodialysis catheter. This was done for the first time in N. Macedonia. This approach is a potential option in adults and children when conventional approaches are limited.

The blood flow rate on the first day after arteriovenous fistula creation is a predictor of successful fistula maturation.

BACKGROUND: The determination of blood flow rate (BFR) is a useful tool for assessing the function of arteriovenous fistula (AVF). METHODS: Eighty patients with a newly created radio cephalic AVF were analyzed. Hemodynamics and morphological characteristics of the blood vessels were assessed by Doppler ultrasound. RESULTS: The mean age of patients was 59.9 ± 13.5 years. A successful rate of AVF maturation was 62.5% at 8 weeks. Six adjusted models of multivariate analysis showed that BFR at Day 1 was a predictor for AVF maturation both at 4 weeks (p < 0.001) and 8 weeks (p < 0.001). Receiver operating characteristic analysis showed an optimal cut-off point for BFR at Day 1 of 395 ml/min for successful maturation at 4 weeks (sensitivity 0.714, specificity 0.889) and 344 ml/min for successful maturation at 8 weeks (sensitivity 0.860, specificity 0.867). CONCLUSION: BFR at Day 1 is a powerful predictor for successful AVF maturation at 4 and 8 weeks.

Impact of preoperative arterial and venous diameter on achievement of the adequate blood flow in arteriovenous fistula for hemodialysis.

An arteriovenous fistula (AVF) remains the best choice of vascular access (VA) for hemodialysis (HD). The aim of the study was to determine the factors associated with the achievement of adequate blood flow (BF) of AVFs at the 4th week after creation. Created AVFs in 63 patients with chronic kidney disease (CKD) stage 4/5 and CKD stage 5 on hemodialysis (CKD5D) were analyzed in a prospective study. Doppler ultrasound (DUS) was used for measuring the diameter of the radial artery, the brachial artery and the cephalic vein before AVF creation. The BF of AVF was calculated by DUS at the 4th week after creation and adequate BF was defined as ≥ 600 mL/min. The average age of patients was 61.31 ± 12.9 years. An adequate BF of AVF at the 4th week after creation was achieved in 43.54% of patients. The BF of AVF measured in male patients was significantly higher compared to the BF of AVF obtained in females (576.03 mL/min vs 375.12 mL/min, P = 0.004). The diameter of the blood vessels with achieved adequate BF was significantly larger compared to the diameter of the blood vessels without adequate BF (radial artery: 2.45 mm vs 2.03 mm, P = 0.000; brachial artery: 4.78 mm vs 4.06 mm, P = 0.001 and cephalic vein: 3.12 mm vs 2.83 mm P = 0.018). The gender and the diameter of the blood vessels before AVF creation were significantly associated with achievement of adequate BF of AVF at the 4th week of creation.

Efficacy of Medium Cut-Off Dialyzer and Comparison with Standard High-Flux Hemodialysis.

BACKGROUND: A new medium cut-off (MCO) membranes has been designed to achieve better removal capacities for middle and large middle molecules in hemodialysis (HD) treatment. AIM: The aim of this study was to evaluate the removal efficacy of Theranova® in standard HD in comparison with standard high-flux HD. METHODS: Four HD patients (M/F 1/4) were included in 12-week observational pilot study in HD with Theranova® 400 and Theranova® 500 dialyzers. Each patient was assessed 4 times, T0 with high-flux dialyzers, T1 at 1 month, T2 at second month, and T3 at third month, by measuring pre- and post-HD samples of urea, Cr, ß2-microglobilin (ß2M), myoglobin, albumin, free light chains kappa (FLC-k), and free light chains lambda (FLC-λ). RESULTS: The data showed a higher average removal rate for all the uremic toxins with Theranova® dialyzers for ß2M, myoglobin, FLC-k, and FLC-λ (62.7, 56.9, 63.5, and 54.6%, respectively) during the 3 months. Albumin retention was observed and did not change between T0 and T3 (p = 0.379). CONCLUSION: Compared to high-flux membranes, MCO membranes show greater permeability for middle molecules in midterm report.

Primary Failure of the Arteriovenous Fistula in Patients with Chronic Kidney Disease Stage 4/5.

BACKGROUND: An Arteriovenous fistula (AVF) is a creation of the natural blood vessels. It is a "gate of life" for the patients on hemodialysis. AIM: The study aimed to analyze the predictors for primary failure of AVF such as gender, age, number and location of AVF, and primary renal disease in patients with chronic kidney disease (CKD) stage 4/5. MATERIAL AND METHODS: The medical records of 178 created arteriovenous fistulae in patients with CKD stage 4/5, were retrospectively studied. Primary failure of AVF was defined as thrombosis or inability for cannulation of AVF within 3 months. Adequate maturation of AVF was defined as successful cannulation of AVF treatment and blood flow of > 600 ml/min. RESULTS: The mean age of the patients was 59.75 ± 14.65 years, and 65.16% (116/178) were men. Adequate maturation of AVF was achieved in 83.71% (149/178). Primary failure of AVF occurred in 16.29% (29/178) of the created fistulae, while 10.11% (18/178) had early thrombosis. The distal arteriovenous fistulae were significantly more frequently created in male patients (51 vs 18; p = 0.015). The female patients were significantly older than the male patients (63.27 vs 57.86 years; p = 0.018). CONCLUSION: Male gender was associated with better maturation of AVF. The age, number and location of AVF, and primary renal disease in patients with CKD stage 4/5 were not associated with primary failure of AVF.

Carnitine Palmitoyltransferase II Deficiency (CPT II) Followed By Rhabdomyolysis and Acute Kidney Injury.

BACKGROUND: Carnitine palmitoyltransferase II deficiency (CPT II) is an autosomal recessive disorder and the most common inherited disorder of mitochondrial long-chain fatty acid oxidation, characterised by attacks of myalgia and myoglobinuria. The most common "classic" myopathic form occurs in young adults and is characterised by recurrent episodes of rhabdomyolysis triggered by prolonged exercise, fasting or febrile illness. CASE PRESENTATION: We present a case of a 22-year-old Caucasian male admitted to our hospital with fever, dyspnea, fatigue, myalgia and dark urine (brown-coloured). The symptoms appeared after viral infection followed by fever. Acute kidney injury (AKI) developed as a complication, and there was a need for treatment with hemodialysis. At the clinical presentation, the patient had plasma creatine kinase (pCK) level of 130.383 U/L and plasma myoglobin level over 5000 µg/L. Genetic testing (molecular analysis) confirmed the diagnosis of inherited rhabdomyolysis, a metabolic disorder of carnitine palmitoyltransferase II deficiency. A previous episode with the same symptoms, the patient had four years ago but did not ask for medical treatment. The patient was discontinued from hemodialysis because of the resolution of acute kidney injury. The patient was discharged from the hospital in good condition, with a recommendation about his future lifestyle in order to prevent similar episodes. CONCLUSION: Every patient presenting with myalgia, dark urine (brown-coloured), high level of pCK and development of AKI requiring hemodialysis, should be explored for inherited rhabdomyolysis induced by CPT II deficiency.

Severe Endothelial Damage in Chronic Kidney Disease Patients Prior to Haemodialysis Vascular Access Surgery.

BACKGROUND: Hemodialysis as an efficient therapy for advanced CKD is the most used treatment modality all over the world. Even though primary AVF is widely accepted as a best permanent vascular access in hemodialysis patients, up to 60% of all fistulas fail to mature. The pathogenesis of early fistula failure is not very well understood. Many general and local factors are involved: patient's age, sex, primary renal disease, small vessel's diameter, presence of accessory veins, prior venipunctures, surgical skill, genetics, etc. Histological investigations have confirmed the neointimal venous hyperplasia as a major pathological finding in stenotic lesions of AVF failure, due to local inflammation, oxidative stress and migration and proliferation of myofibroblasts, fibroblasts and endothelial cells. MATERIALS AND METHODS: A total of 89 patients with stadium 4-5 of CKD are involved in the study. A typical radio-cephalic AVF is created in all patients. Part of the fistula vein was taken for histological, immunohistochemical (Vimentin, TGF ß and KI67) and morphometric analysis. Appriopriate statistical method was applied. RESULTS: Up to 80% of the patients showed some degree of endothelial changes at the time of creation of AVF, among them 19 pts with substantial intimal hyperplasia, 51 with medial hypertrophy and 19 pts with normal histology. Almost two thirds of the patients did not have expression of TGFß. More than 95% had some expression of Vimentin. None of the patients had expression of the marker KI 67. CONCLUSION: Medial hypertrophy is predominant preexisting pathohistological lesion prior the AVF creation, despite the presence of neointimal hyperplasia. The absence of TGFß expression in majority of our patients could suggest that inflammation and oxidative stress are developing later, after vascular access surgery. The dominant cells within the stenosis in the veins are myofibroblasts. Their increased presence maybe a reason why some patients are prone to developing venous endothelial changes as a results of exaggerated vascular endothelial response to the effect of uremia, hypertension and other insults.

Protocol for performing nephrological activity in the Republic of Macedonia.

The fast development of nephrology in the world, especially in the second half of the 20 th century demanded protocol (guidelines) for nephrological activity for all levels of medical care, of doctors and specialists. The International Society of Nephrology, the European Renal Association and other national associations created their own protocol (guidelines) for nephrological activity. The Macedonian Society of Nephrology, Dialysis, Transplantation and Artificial Organs (MSNDTAO) proclaimed the First Protocol for Performing Nephrological Activity in the Republic of Macedonia at the First Congress of the MSNDTAO, held in Ohrid 1993, and it was published in the Macedonian Medical Review, 1994; Supplement 14: 397-406 [1]. The update of the Protocol for Performing Nephrological Activity in the Republic of Macedonia was proclaimed at the Fourth Congress of MSNDTAO, held in Ohrid 2012 and it presented in this text.

Can an increased nitric oxide level be accepted as non-invasive marker for sub/acute rejection of the kidney allograft?

BACKGROUND: Subclinical and acute rejections (SAR/AR) continue to have a negative impact on graft survival. The aim of our study was to analyze allograft rejection and nitric oxide (NO) levels in patients with protocol- and clinically-indicated biopsies in relationship with other causes of allograft dysfunction, and to evaluate the clinical impact of NO measurement as non-invasive marker for early diagnosis of SAR/AR. METHODS: In 45 living-related kidney transplants, serum NO levels were measured at: 20 min after reperfusion (NO1); on days 1 (NO2), 5 (NO3), and 14 (NO4); and at the first (NO5) and sixth (NO6) months after transplantation (Tx). Protocol biopsies (Bx) were performed at the first and sixth months after Tx. RESULTS: 38 (42.2%) Bx showed histological features of (SAR), 4 (4.5%) Bx showed mild tubulointerstitial rejection, while 48 (53.3%) Bx had no histological signs of SAR/AR. Significantly higher (NO3) levels were found in patients with AR and (NO5)/(NO6) in SAR as compared to other causes of allograft dysfunction occurred within the first posttransplant month (delayed graft function, urinary tract infection, and cyclosporine toxicity). Sensitivity/specificity for cut-off NO level of 70 µmol/l were 69.2% and 88.4% in AR, and 78.9% and 75.4% for the level of 50 µmol/l in SAR patients, respectively. CONCLUSIONS: Our study reports significantly higher serum NO levels at day 5 and a gradual decrease at day 14 (prior to and at the time of clinically manifested AR), and at 1- and 6-month protocol biopsies in SAR patients as compared to all other causes of renal dysfunction. NO measurement may have a satisfactorily diagnostic performance as a useful non-invasive marker not only for AR, but also for SAR patients.