[Classification of glomerulopathies]. / Klasifikacija glomerulopatija.

Glomerular diseases may be classified as acute or chronic, primary or secondary, hereditary or acquired, proliferative or non-proliferative etc. The most commonly used is the classification according to the histopathological finding. For certain types of glomerulonephritides histopathological image, as well as clinical presentation, may vary widely. A while ago there was no classification based on the pathogenesis of certain types of glomerular diseases. However, as scientists ellucidate the underlying pathogenetic mechanism, current classifications change. The latter is best shown at the example of membranoproliferative glomerulonephritis.

[Treatment of resistant primary glomerulopathies]. / Lijecenje rezistentnih primarnih glomerulopatija.

Considerable progress in understanding of the pathogenesis of a number of primary glomerular diseases is evident. Scientific achievements in this field led to reclassification of certain types of glomerulonephritides, development of new diagnostic tests, as well as new therapeutic approaches. These new findings will enable us to treat primary glomerulopathies more efficiently thus reducing incidence of resistant disease. Novelties in diagnostics, treatment algorithm, characteristics of the resistant disease and the possibilities of specific treatment are shown in this review.

[Blood pressure measurement--do not sweat the small stuff and it is all small stuff?! Position paper of the Croatian national referral center for hypertension, center of excellence of the European Society of Hypertension]. / Mjerenje arterijskoga tlaka--ne mari za male stvari i ostat ce male stvari?! Preporuke Hrvatskoga referalnog centra za hipertenziju centra izvrsnosti Europskog drustva za hipertenziju.

Office blood pressure measurement using mercury sphygmomanometer is the gold standard for making diagnoses of hypertension, evaluation of cardiovascular risk and estimation of obtained control of treated hypertensives. The vast majority of epidemiologic data are based on this method. However, the importance of blood pressure variability, white coat effect as well as availability of simple devices, home and ambulatory blood pressure measurements became routine parts in routine clinical work. As mercury will be soon forbidden in clinical work such devices and methodology will be even more important. In everyday clinical practice all three techniques should be implemented and in this paper advantages and drawbacks of all techniques are discussed. In the end, based on recent data and recommendations of international societies, diagnostic algorithm was proposed. Additionally, we described the technique of non-invasive central blood pressure measurement, determination of pulse wave velocity and calculation of augmentation index, new proposed risk factors.

Obesity and systolic blood pressure in young adult men born small for gestational age.

Individuals born small for gestational age (SGA) are supposed to be at higher risk to develop cardiovascular disorders, and recent report showed that concurrent obesity influences blood pressure (BP) in SGA children. Our aim was to investigate the impact of obesity and birth weight on blood pressure values in young adult men born SGA and controls born after normal pregnancy, Normotensive, non-treated adult men were enrolled (N = 185; mean age 21.29 +/- 0.9 years). Birth parameters were obtained from medical records and SGA was defined as birth weight (BW) under 10th percentile for gestational age and obesity as BMI > 25 kg/m2. According to the presence or absence of obesity and BW the subjects were divided into four groups: (1) non-obese with normal BW (N = 50), (2) non-obese SGA (N = 67), (3) obese with normal BW (N = 40), (4) obese SGA (N = 28). BP was measured using Omron M6 and Spacelab 90207 device following the ESH/ESC guidelines. Systolic BP, 24-hour BP variability and pulse pressure were significantly higher in SGA subjects than in those with normal BW (p < 0.05). The highest 24-hour and daytime systolic BP values as well as 24-hour pulse pressure were found in the subgroup of obese SGA subjects (p < 0.001). Significant differences for the above parameters were observed between obese SGA group and non-obese SGA group (p < 0.05). Obese SGA subjects had higher 24-hour and daytime systolic BP values compared to obese normal BW group. No difference was found in BP between non-obese SGA and non-obese group with normal BW (p > 0.05). In addition to BW and shorter pregnancy duration, obesity concurrently and significantly determines systolic BP in young normotensive men and point to a need for more aggressive implementation of healthy lifestyle as early as possible.

Hypertension, overweight and obesity in adolescents: the CRO-KOP study.

The objective of this study was to determine the prevalence of hypertension, overweight and obesity in Croatian adolescents. In this cross-sectional survey (the sub-study of the EH-UH study) 375 boys and 381 girls (mean age 15.9 +/- 0.5 years) from four high schools in the city of Koprivnica were enrolled. Blood pressure, body height and body weight were measured according to the current ESH/ESC guidelines. Data on life style were obtained from questionnaire. Average blood pressure values were higher in boys than in girls (117/74 mmHg vs. 111/69 mmHg; p < 0.001). Significantly higher blood pressure values were obtained in overweight children compared to those with normal weight (119/76 mmHg us. 115/72 mmHg; p < 0.01). Prevalence of hypertension was 8.5% in the whole group being significantly higher in boys than in girls (11.2% vs. 5.8%; p = 0.0007). As expected, prevalence of hypertension was significantly higher in obese children than in those with normal weight (20.0% vs. 6.8%; p = 0.015). A significant correlation was found between body mass index and blood pressure (p = 0.0001). The overall prevalence of obesity was 3.54% (boys 2.2%; girls 4.9%). Our results confirmed positive relationship between overweight, obesity and hypertension starting from childhood pointing again the utmost importance of preventive measures beginning from early life.

Prevalence, treatment and control of hypertension in a Croatian endemic nephropathy area.

BACKGROUND: Hypertension is not considered to be a characteristic of endemic nephropathy (EN). Recent observations suggested that it might be more prevalent than it was reported before. AIM: The aim of our study was to analyze prevalence, treatment and control of hypertension in a Croatian endemic area. METHODS: In the present cross-sectional study, 1,602 farmers were enrolled, 1,246 from EN and 356 from control villages. Epidemiological and medical histories were taken and clinical and laboratory examinations performed for kidney function. Blood pressure was measured following the ESH/ESC guidelines. RESULTS: The prevalence of hypertension in EN villages was higher than in control (50.8 vs. 46.5%, p = 0.005). There was no difference in overall treatment, control of all and treated hypertensives between the villages. In all villages, women were treated more than men (EN 41.6 vs. 28.4%, p < 0.001; control 46.4 vs. 27.3%, p < 0.001), but better control of treated was achieved in men (EN 24.7 vs. 17.4%, p = 0.002; control 29.6 vs. 15.5%, p = 0.002). Women had lower income and level of education than men (p < 0.01). CONCLUSION: Hypertension is highly prevalent in endemic villages. In all villages, men had better blood pressure control despite being treated less. This finding could be explained by poorer education and income in women.

Stage II of Chronic Kidney Disease-A Tipping Point in Disease Progression?

Chronic kidney disease (CKD) is the progressive loss of renal function. Although advances have been made in understanding the progression of CKD, key molecular events in complex pathophysiological mechanisms that mark each stage of renal failure remain largely unknown. Changes in plasma protein profiles in different disease stages are important for identification of early diagnostic markers and potential therapeutic targets. The goal of this study was to determine the molecular profile of each CKD stage (from 1 to 5), aiming to specifically point out markedly expressed or downregulated proteins. We performed a cross-sectional shotgun-proteomic study of pooled plasma across CKD stages and compared them to healthy controls. After sample pooling and heparin-column purification we analysed proteomes from healthy to CKD stage 1 through 5 participants' plasma by liquid-chromatography/mass-spectrometry. We identified 453 proteins across all study groups. Our results indicate that key events, which may later affect the course of disease progression and the overall pathophysiological background, are most pronounced in CKD stage 2, with an emphasis on inflammation, lipoprotein metabolism, angiogenesis and tissue regeneration. We hypothesize that CKD stage 2 is the tipping point in disease progression and a suitable point in disease course for the development of therapeutic solutions.

First Characterization of ADAMTS-4 in Kidney Tissue and Plasma of Patients with Chronic Kidney Disease-A Potential Novel Diagnostic Indicator.

Background: We have previously shown that metzincin protease ADAMTS-4 accompanies renal fibrogenesis, as it appears in the blood of hemodialysis patients. Methods: Native kidney (NKB) and kidney transplant (TXCI) biopsy samples as well as plasma from patients with various stages of CKD were compared to controls. In paired analysis, 15 TXCI samples were compared with their zero-time biopsies (TX0). Tissues were evaluated and scored (interstitial fibrosis and tubular atrophy (IFTA) for NKB and Banff ci for TXCI). Immunohistochemical (IHC) staining for ADAMTS-4 and BMP-1 was performed. Plasma ADAMTS-4 was detected using ELISA. Results: ADAMTS-4 IHC expression was significantly higher in interstitial compartment (INT) of NKB and TXCI group in peritubular capillaries (PTC) and interstitial stroma (INT). Patients with higher stages of interstitial fibrosis (ci > 1 and IFTA > 1) expressed ADAMTS-4 in INT more frequently in both groups (p = 0.005; p = 0.013; respectively). In paired comparison, TXCI samples expressed ADAMTS-4 in INT and PTC more often than TX0. ADAMTS-4 plasma concentration varied significantly across CKD stages, being highest in CKD 2 and 3 compared to other groups (p = 0.0064). Hemodialysis patients had higher concentrations of ADAMTS-4 compared to peritoneal dialysis (p < 0.00001). Conclusion: ADAMTS-4 might have a significant role in CKD as a potential novel diagnostic indicator.

Two novel variants in the lecithin:cholesterol acyltransferase gene resulted in classic LCAT deficiency.

Background and aims: We report the first two cases of familial lecithin:cholesterol acyltransferase (LCAT) deficiency in Croatia with classical clinical and biochemical features. Patients and methods: A 30-year-old man with nephrotic syndrome, corneal opacities, hepatosplenomegaly, anemia, low high-density lipoprotein (HDL)-cholesterol levels and arterial hypertension (blood pressure >200/100 mmHg) was admitted to our department. At admission, he had an elevated creatinine serum level (233 µmol/L), proteinuria of 12 g in 24-h urine (g/24 h), 3-7 erythrocytes in urine sediment and notable anemia (hemoglobin level 90 g/l). His HDL-cholesterol was significantly low (0.42 mmol/L). Besides chronic kidney disease (CKD), other secondary causes of hypertension were ruled out. The patient was previously diagnosed with membranous nephropathy and treated unsuccessfully with immunosuppressive agents (steroids, cyclosporine, cyclophosphamide). Re-evaluation of histopathological findings of kidney biopsy revealed massive deposition of lipid material in the glomerular basal membrane and in the mesangial region. His 4-year younger brother was also evaluated due to corneal opacities and new-onset arterial hypertension. Nephrotic range proteinuria with preserved global renal function was determined. He also had very low HDL-cholesterol levels. Results: Kidney biopsies from both patients were consistent with LCAT deficiency. The disease was confirmed by measurement of LCAT enzyme activity, plasma cholesterol esterification rate, and genetic testing. Two novel missense variants in the LCAT gene (c.496G > A and c.1138T  >  C) were found. Conclusions: To our knowledge, the presented cases are the first reported cases of genetic LCAT deficiency in Croatia. Given the clinical presentation, the complete lack of LCAT activity and cholesterol esterification rate, diagnosis of familial LCAT deficiency was made.

Chronic Kidney Disease in Balkan Countries-A Call to Action for Timely Diagnosis and Monitoring.

Chronic kidney disease (CKD) is a serious illness with important consequences for patients and health systems. Estimation of prevalence and incidence, especially in early stages, is difficult due to a lack of epidemiological studies and consolidated registries. In general, the disease awareness is low, and thus CKD is not timely diagnosed in most cases. Robust screening programs are not implemented in Eastern European countries. A panel consisting of Primary Care Physicians and Nephrologists from Bulgaria, Croatia, Serbia, and Slovenia virtually met in December 2021 to discuss current CKD awareness and diagnostic approaches in the Balkan area The meeting resulted in specific calls to action in the region to improve the number and quality of epidemiology studies and the level of awareness among patients and medical communities, as well as implementation of screening programs in high-risk populations. Collaboration between specialists was acknowledged as a crucial driver for optimal management of patients with CKD. Joint efforts are required to persuade healthcare authorities to establish specific policies for better care of kidney patients.

Drug-drug-gene interactions as mediators of adverse drug reactions to diclofenac and statins: a case report and literature review.

Concomitant treatment with drugs that inhibit drug metabolising enzymes and/or transporters, such as commonly prescribed statins and nonsteroidal anti-inflammatory drugs (NSAIDs), has been associated with prolonged drug exposure and increased risk of adverse drug reactions (ADRs) due to drug-drug interactions. The risk is further increased in patients with chronic diseases/comorbidities who are more susceptible because of their genetic setup or external factors. In that light, we present a case of a 46-year-old woman who had been experiencing acute renal and hepatic injury and myalgia over two years of concomitant treatment with diclofenac, atorvastatin, simvastatin/fenofibrate, and several other drugs, including pantoprazole and furosemide. Our pharmacogenomic findings supported the suspicion that ADRs, most notably the multi-organ toxicity experienced by our patient, may be owed to drug-drug-gene interactions and increased bioavailability of the prescribed drugs due to slower detoxification capacity and decreased hepatic and renal elimination. We also discuss the importance of CYP polymorphisms in the biotransformation of endogenous substrates such as arachidonic acid and their modulating role in pathophysiological processes. Yet even though the risks of ADRs related to the above mentioned drugs are substantially evidenced in literature, pre-emptive pharmacogenetic analysis has not yet found its way into common clinical practice.

FHR-5 Serum Levels and CFHR5 Genetic Variations in Patients With Immune Complex-Mediated Membranoproliferative Glomerulonephritis and C3-Glomerulopathy.

Background: Factor H-related protein 5 (FHR-5) is a member of the complement Factor H protein family. Due to the homology to Factor H, the main complement regulator of the alternative pathway, it may also be implicated in the pathomechanism of kidney diseases where Factor H and alternative pathway dysregulation play a role. Here, we report the first observational study on CFHR5 variations along with serum FHR-5 levels in immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) patients together with the clinical, genetic, complement, and follow-up data. Methods: A total of 120 patients with a histologically proven diagnosis of IC-MPGN/C3G were enrolled in the study. FHR-5 serum levels were measured in ELISA, the CFHR5 gene was analyzed by Sanger sequencing, and selected variants were studied as recombinant proteins in ELISA and surface plasmon resonance (SPR). Results: Eight exonic CFHR5 variations in 14 patients (12.6%) were observed. Serum FHR-5 levels were lower in patients compared to controls. Low serum FHR-5 concentration at presentation associated with better renal survival during the follow-up period; furthermore, it showed clear association with signs of complement overactivation and clinically meaningful clusters. Conclusions: Our observations raise the possibility that the FHR-5 protein plays a fine-tuning role in the pathogenesis of IC-MPGN/C3G.

[Fixed combinations of antihypertensive medications--new opportunity in treatment of hypertension]. / Fiksne kombinacije antihipertenzivnih lijekova--nove mogucnosti lijecenja arterijske hipertenzije.

Arterial hypertension is one of the major public health problems. Early recognition and treatment, based on total cardiovascular risk assessment, is crucial for cardiovascular and renal protection. The choice of initial drug is often futile because most of hypertensive patients will need more than one medication for achieving blood pressure control. Initiation of treatment wih combination of antihypertensive drugs is reasonable choice especially in high or very high risk patients where it is important to achieve prompt and intensive blood pressure control in order to reduce cardiovascular complications. Fixed combination of two antihypertensive drugs can simplify treatment and favour compliance. The last, 2007 ESH/ESC guidelines, and several studies published in the meantime, favour use of ACE inhibitors or angiotensin receptor blockers with calcium channel blockers or diuretics as the combination of choice. Fixed combination of ramipril and felodipine is in agreement with guidelines recomendations with proven benefit on cardiovascular protection and non-diabetic kidney disease in patients with essential hypertension.

Corrigendum to "The Association of TNF-Alpha Inhibitors and Development of IgA Nephropathy in Patients with Rheumatoid Arthritis and Diabetes".

[This corrects the article DOI: 10.1155/2020/9480860.].

The Association of TNF-Alpha Inhibitors and Development of IgA Nephropathy in Patients with Rheumatoid Arthritis and Diabetes.

IgA nephropathy (IgAN) is a rather uncommon complication of TNF-alpha inhibition with a range of findings such as asymptomatic microscopic/macroscopic hematuria or different degrees of proteinuria and could progress to end-stage renal disease. We are reporting three patients with longstanding rheumatoid arthritis (RA), which developed IgAN while receiving TNF-alpha inhibitors. All off our three patients had RA, which lasted 2-4 years, and none of them had a prior history of chronic kidney disease. Two patients were treated with adalimumab while one patient was treated with golimumab. Discontinuation of anti-TNF-alpha therapy and initiation of immunosuppressive therapy led to improvement in serologic abnormalities and renal function in two patients, while the third patient's 24-hour proteinuria was only partially reduced, which supports previous reports on TNF-alpha inhibitor induced autoimmunity. Two of our patients had previously been diagnosed with type 2 diabetes mellitus while the third patient developed diabetes years after the onset of IgAN. This is in line with the previously described association of IgAN and diabetes mellitus. To our best knowledge, this is the first report to analyze the development of IgAN as a potential consequence of anti-TNF-alpha therapy and its possible association with pretreatment or posttreatment diabetes.

Validation of distinct pathogenic patterns in a cohort of membranoproliferative glomerulonephritis patients by cluster analysis.

BACKGROUND: A novel data-driven cluster analysis identified distinct pathogenic patterns in C3-glomerulopathies and immune complex-mediated membranoproliferative glomerulonephritis. Our aim was to replicate these observations in an independent cohort and elucidate disease pathophysiology with detailed analysis of functional complement markers. METHODS: A total of 92 patients with clinical, histological, complement and genetic data were involved in the study, and hierarchical cluster analysis was done by Ward method, where four clusters were generated. RESULTS: High levels of sC5b-9 (soluble membrane attack complex), low serum C3 levels and young age at onset (13 years) were characteristic for Cluster 1 with a high prevalence of likely pathogenic variations (LPVs) and C3 nephritic factor, whereas for Cluster 2-which is not reliable because of the small number of cases-strong immunoglobulin G staining, low C3 levels and high prevalence of nephritic syndrome at disease onset were observed. Low plasma sC5b-9 levels, decreased C3 levels and high prevalence of LPV and sclerotic glomeruli were present in Cluster 3, and patients with late onset of the disease (median: 39.5 years) and near-normal C3 levels in Cluster 4. A significant difference was observed in the incidence of end-stage renal disease during follow-up between the different clusters. Patients in Clusters 3-4 had worse renal survival than patients in Clusters 1-2. CONCLUSIONS: Our results confirm the main findings of the original cluster analysis and indicate that the observed, distinct pathogenic patterns are replicated in our cohort. Further investigations are necessary to analyse the distinct biological and pathogenic processes in these patient groups.

Kidney volume and albuminuria as markers of birth weight-blood pressure relationship in essential hypertension.

Our aim was to analyze whether birth weight contributes to future hypertension through reduced kidney volume, and whether albuminuria could be a marker of this pathway. We included 103 patients with newly diagnosed essential hypertension and 92 normotensive controls. Blood pressure (BP) was measured using a mercury sphygmomanometer and a ABP monitor. Kidney volume was determined by ultrasound. Data on birth weight were obtained from mothers. Albuminuria was determined in 24-hour urine samples. Hypertensive patients had lower birth weight and higher albuminuria than normotensives. There was no difference in kidney volume between the two groups. We found a negative correlation between birth weight and systolic BP in the hypertensive group. BP was significantly correlated with BMI and albuminuria in the hypertensive group. Multiple regression analysis had shown the greatest impact of BMI on BP and had also demonstrated that 24-hour systolic BP showed the greatest risk for developing albuminuria in hypertensive patients. In conclusion, birth weight influences BP values in adult age, but it is not mediated by a reduced kidney volume. A strong correlation, independent of birth weight, was observed between albuminuria and BP values. Increased BMI is the most important independent risk factor responsible for BP increase, even in an early phase of essential hypertension.

C4 nephritic factor in patients with immune-complex-mediated membranoproliferative glomerulonephritis and C3-glomerulopathy.

BACKGROUND: Acquired or genetic abnormalities of the complement alternative pathway are the primary cause of C3glomerulopathy(C3G) but may occur in immune-complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) as well. Less is known about the presence and role of C4nephritic factor(C4NeF) which may stabilize the classical pathway C3-convertase. Our aim was to examine the presence of C4NeF and its connection with clinical features and with other pathogenic factors. RESULTS: One hunfe IC-MPGN/C3G patients were enrolled in the study. C4NeF activity was determined by hemolytic assay utilizing sensitized sheep erythrocytes. Seventeen patients were positive for C4NeF with lower prevalence of renal impairment and lower C4d level, and higher C3 nephritic factor (C3NeF) prevalence at time of diagnosis compared to C4NeF negative patients. Patients positive for both C3NeF and C4NeF had the lowest C3 levels and highest terminal pathway activation. End-stage renal disease did not develop in any of the C4NeF positive patients during follow-up period. Positivity to other complement autoantibodies (anti-C1q, anti-C3) was also linked to the presence of nephritic factors. Unsupervised, data-driven cluster analysis identified a group of patients with high prevalence of multiple complement autoantibodies, including C4NeF. CONCLUSIONS: In conclusion, C4NeF may be a possible cause of complement dysregulation in approximately 10-15% of IC-MPGN/C3G patients.

[Guidelines for diagnostics and treatment of arterial hypertension. Practical recommendations of the Croatian Working Group for Hypertension. Consideration on the ESH-ESC 2007 guidelines]. / Smjernice za dijagnosticiranje i lijecenje arterijske hipertenzije. Prakticne preporuke hrvatske radne skupine i osvrt na smjernice ESH/ESC 2007.

ESH/ECS guidelines for diagnostics and treatment of arterial hypertension 2007 is a basic paper for all physicians who treat hypertensive patients. Since publishing, this article has been the most cited medical paper. According to ESH/ECS guidelines some local peculiarities in each country should be considered when diagnosing and treating hypertensive patients. Practical recommendations of the Croatian working group for the diagnostics and treatment of hypertension are in agreement with ESH/ECS guidelines. However, few additional issues are added and further discussed in this paper (hypertensive crisis, treatment of hypertension in patients undergoing dialysis and in renal transplanted patients, role of family physicians, role of nurse). We believe that this paper will contribute better control of hypertension in Croatia. All medical societies and institutions that took part in writing this document, have to consider this paper as an official statement.