Proteomic Approaches and Potential Applications in Autosomal Dominant Polycystic Kidney Disease and Fabry Disease

Although rare, hereditary diseases, such as autosomal dominant polycystic kidney disease (ADPKD) and Fabry disease (FD) may significantly progress towards severe nephropathy. It is crucial to characterize it accurately, predict the course of the illness and estimate treatment effectiveness. A huge effort has been undertaken to find reliable biomarkers that might be useful for an early prevention of the disease progression and/or any invasive diagnostic procedures. The study of proteomics, or the small peptide composition of a sample, is a field of study under continuous development. Over the past years, several strategies have been created to study and define the proteome of samples from widely varying origins. However, urinary proteomics has become essential for discovering novel biomarkers in kidney disease. Here, the extracellular vesicles in human urine that contain cell-specific marker proteins from every segment of the nephron, offer a source of potentially valuable urinary biomarkers, and may play an essential role in kidney development and kidney disease. This review summarizes the relevant literature investigating the proteomic approaches and potential applications in the regular studies of ADPKD and FD

Phosphate in the Context of Cognitive Impairment and Other Neurological Disorders Occurrence in Chronic Kidney Disease

The nervous system and the kidneys are linked under physiological states to maintain normal body homeostasis. In chronic kidney disease (CKD), damaged kidneys can impair the central nervous system, including cerebrovascular disease and cognitive impairment (CI). Recently, kidney disease has been proposed as a new modifiable risk factor for dementia. It is reported that uremic toxins may have direct neurotoxic (astrocyte activation and neuronal death) and/or indirect action through vascular effects (cerebral endothelial dysfunction, calcification, and inflammation). This review summarizes the evidence from research investigating the pathophysiological effects of phosphate toxicity in the nervous system, raising the question of whether the control of hyperphosphatemia in CKD would lower patients' risk of developing cognitive impairment and dementia

Identification of novel molecular signatures of IgA nephropathy through an integrative -omics analysis

IgA nephropathy (IgAN) is the most prevalent among primary glomerular diseases worldwide. Although our understanding of IgAN has advanced significantly, its underlying biology and potential drug targets are still unexplored. We investigated a combinatorial approach for the analysis of IgAN-relevant -omics data, aiming at identification of novel molecular signatures of the disease. Nine published urinary proteomics datasets were collected and the reported differentially expressed proteins in IgAN vs. healthy controls were integrated into known biological pathways. Proteins participating in these pathways were subjected to multi-step assessment, including investigation of IgAN transcriptomics datasets (Nephroseq database), their reported protein-protein interactions (STRING database), kidney tissue expression (Human Protein Atlas) and literature mining. Through this process, from an initial dataset of 232 proteins significantly associated with IgAN, 20 pathways were predicted, yielding 657 proteins for further analysis. Step-wise evaluation highlighted 20 proteins of possibly high relevance to IgAN and/or kidney disease. Experimental validation of 3 predicted relevant proteins, adenylyl cyclase-associated protein 1 (CAP1), SHC-transforming protein 1 (SHC1) and prolylcarboxypeptidase (PRCP) was performed by immunostaining of human kidney sections. Collectively, this study presents an integrative procedure for -omics data exploitation, giving rise to biologically relevant results

The Effect of Treatment on Short-Term Outcomes in Elderly Patients with Acute Kidney Injury

BACKGROUND: Elderly population (≥ 65) are more prone to develop acute kidney injury (AKI) compared to younger, also elderly with AKI have an increased requirement for dialysis treatment and an elevated risk of short-term and long-term mortality.AIM: The objectives of this study were to examine the effect of treatment of short-term outcomes and mortality in elderly patients with AKI.MATERIAL AND METHODS: Seventy elderly AKI patients, that filled one of the criteria of AKI definition and had hospitalization over 24 hours, were enrolled in the study.RESULTS: The median age of patients was 74.28 ± 6.64, with mean CCI (Charlson Comorbidity Index) score of 6.94 ± 1.94. The majority of patients (70%) were classified at stage 3 of AKIN, 20% of patients were classified at stage 2 and 10% at stage 1. In the groups of patients with death outcome, the chronic cardiomyopathy was more frequently present (p = 0.034). Regarding treatment, 58.6% of the AKI patients underwent hemodialysis while 41.4% received conservative treatment. Mortality rate was 52.8%, out of which 28.6% was in-hospital mortality, while in 24.3% of patients death occurred in the follow-up period of 90 days.CONCLUSION: In our study, short- term survival is not related to different treatment options. Applied treatment in elderly patients with AKI should be assessed by measuring the long term outcome

First Experience in Management of Coronavirus Disease 2019 (COVID-19) in Kidney Transplant Patient – Case Report

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has recently emerged in the world. There are limited data describing the clinical progression of COVID-19 in transplanted patients. In the general population, clinical presentation ranges from asymptomatic infection to severe pneumonia and may also develop renal failure. In kidney transplant (KT) patients, management of these patients was mainly based on anecdotal experience. CASE REPORT: We report our first experience of KT patients with COVID-19. A 49-year-old male with KT in 2017 presented on March 20, 2020, with fever, weakness, smell loss, chest pain, and caught. On chest X-ray, he presented ground-glass opacities and bilateral pneumonia. There was a slight progression to acute hypoxic respiratory failure. We reduced immunosuppression therapy and since we suspected seasonal flu, we applied available antiviral oseltamivir till confirmation of RNA sequence of the SARS-CoV-2 virus. Moreover, we applied azithromycin and broad spectrum of antibiotics as well as an anticoagulant therapy. Graft function remained stable during 14 days of hospitalization. The patient clinically improved with decreasing oxygen requirements and manifested clinical recovery. After two negative PCR test, he was discharged and immunosuppression therapy was returned to previous. CONCLUSION: This case highlights the importance of earlier outpatient hospitalization and testing which may improve COVID-19 outcomes among transplanted patients

Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy in TYpe 2 diabetic patients with normoalbuminuria (PRIORITY): essential study design and rationale of a randomised clinical multicentre trial

Introduction: Diabetes mellitus affects 9% of the European population and accounts for 15% of healthcare expenditure, in particular, due to excess costs related to complications. Clinical trials aiming for earlier prevention of diabetic nephropathy by renin angiotensin system blocking treatment in normoalbumuric patients have given mixed results. This might reflect that the large fraction of normoalbuminuric patients are not at risk of progression, thereby reducing power in previous studies. A specific risk classifier based on urinary proteomics (chronic kidney disease (CKD)273) has been shown to identify normoalbuminuric diabetic patients who later progressed to overt kidney disease, and may hold the potential for selection of high-risk patients for early intervention. Combining the ability of CKD273 to identify patients at highest risk of progression with prescription of preventive aldosterone blockade only to this high-risk population will increase power. We aim to confirm performance of CKD273 in a prospective multicentre clinical trial and test the ability of spironolactone to delay progression of early diabetic nephropathy. Methods and analysis: Investigator-initiated, prospective multicentre clinical trial, with randomised double-masked placebo-controlled intervention and a prospective observational study. We aim to include 3280 type 2 diabetic participants with normoalbuminuria. The CKD273 classifier will be assessed in all participants. Participants with high-risk pattern are randomised to treatment with spironolactone 25 mg once daily, or placebo, whereas, those with low-risk pattern will be observed without intervention other than standard of care. Treatment or observational period is 3 years. The primary endpoint is development of confirmed microalbuminuria in 2 of 3 first morning voids urine samples. Ethics and dissemination: The study will be conducted under International Conference on Harmonisation – Good clinical practice (ICH-GCP) requirements, ethical principles of Declaration of Helsinki and national laws. This first new biomarker-directed intervention trial aiming at primary prevention of diabetic nephropathy may pave the way for personalised medicine approaches in treatment of diabetes complications

The future of European Nephrology 'Guidelines' - a declaration of intent by European Renal Best Practice (ERBP)

The disparities of medical practice, together with a growing number of possible interventions, have increased the demand for well-conceived guidance for practitioners [1]. However, this development is hampered by the number and quality of scientific studies that test medical hypotheses, which are often unsatisfactory. This is especially true in nephrology, where well-conducted controlled trials are rare [2]. Because patients with renal failure are generally excluded from controlled studies in the general population [3], the development of sufficiently well-founded guidance in nephrology has always been difficult. With the development of European Best Practice Guidelines (EBPG), the European Renal Association–European Dialysis and Transplantation Association (ERA–EDTA) has created its own guidance-generating process. Similar initiatives have also arisen in the USA (Kidney Disease Outcome Initiative—K/DOQI), Australia (Caring for Australasians with Renal Impairment—CARI), Canada (Canadian Society of Nephrology—CSN), the UK (United Kingdom Renal Association—UKRA), as well as at several other locations around the world. These institutions have generated a plethora of often parallel recommendations on similar topics but sometimes with different messages [4]. The question can be asked: ‘Is there still a place for an institution generating European nephrology guidance?’ If there is, how should such an initiative be managed to conform with current demands? To answer these questions, the Council of ERA–EDTA set up a commission that convened three times in the course of 2008–09. The present text is a distillation of the discussions, reflections and final conclusions of this commission. It is an ad hoc document, reflecting the current status. In the future, concepts and attitudes might change, as medical thinking is influenced by changes in practice, needs, general philosophy, ethics and political/financial conditions

Excess Mortality in a Nephrology Clinic during First Months of Coronavirus Disease-19 Pandemic: A Pragmatic Approach

BACKGROUND: Excess mortality is defined as mortality above what would be expected based on the non-crisis mortality rate in the population of interest. AIM: In this study, we aimed to access weather the coronavirus disease (COVID)-19 pandemic had impact on the in-hospital mortality during the first 6 months of the year and compare it with the data from the previous years. METHODS: A retroprospective study was conducted at the University Clinic of Nephrology Skopje, Republic of Macedonia. In-hospital mortality rates were calculated for the first half of the year (01.01–30.06) from 2015 until 2020, as monthly number of dead patients divided by the number of non-elective hospitalized patents in the same period. The excess mortality rate (p-score) was calculated as ratio or percentage of excess deaths relative to expected average deaths: (Observed mortality rate–expected average death rate)/expected average death rate *100%. RESULTS: The expected (average) overall death mortality rate for the period 2015–2019 was 8.9% and for 2020 was 15.3%. The calculated overall excess mortality in 2020 was 72% (pscore 0.72). CONCLUSION: In this pragmatic study, we have provided clear evidence of high excess mortality at our nephrology clinic during the 1st months of the COVID-19 pandemic. The delayed referral of patients due to the patient and health care system-related factors might partially explain the excess mortality during pandemic crises. Further analysis is needed to estimate unrecognized probable COVID-19 deaths

Current status of transplantation and organ donation in the Balkans-could it be improved through the South-eastern European health Network (SEEHN) initiative?

Organ donation and transplantation activity in the majority of Balkan countries (Albania, Bosnia and Herzegovina, Croatia, Macedonia, Moldova, Montenegro, Serbia, Romania and Bulgaria) are lagging far behind international averages. Inadequate financial resources, unclear regional data and lack of governmental infrastructure are some of the issues which should be recognized to draw attention and problem-solving decisions. The Regional Health Development Centre (RHDC) Croatia, being a technical body of the South-eastern European Health Network (SEEHN), was created in 2011 after Croatia's great success in the field over the last 10 years. The aim of the RHDC is to network the region and provide individualized country support to increase donation and transplantation activity in collaboration with professional societies (European Society of Organ Transplantation, European Transplant Coordinators Organization, The Transplantation Society and International Society of Organ Donation and Procurement). Such an improvement would in turn likely prevent transplant tourism. The regional data from 2010 show large discrepancies in donation and transplantation activities within geographically neighbouring countries. Thus, proposed actions to improve regional donation and transplantation rates include advancing living and deceased donation through regular public education, creating current and accurate waiting lists and increasing number of educated transplant nephrologists and hospital coordinators. In addition to the effort from the professionals, the governmental support with allocated funds per deceased donation, updated legislation and established national coordinating body is ultimately recognized as essential for the successful donation and transplantation programmes. By continuous RHDC communication and support asked from the health authorities and motivated professionals from the SEEHN initiative, an increased number of deceased as well as living donor kidney transplantations in the future should be more realistic

Complications and Risks of Percutaneous Renal Biopsy

BACKGROUND: Renal biopsy performed in native and transplant kidneys is generally considered a safe procedure. AIM: In this study, we evaluated renal biopsy complications and risk factors in one nephrology facility. MATERIAL AND METHODS: We conducted a three-year retrospective study on patients who underwent renal biopsy between January 2014 and December 2016. Strict written biopsy protocol was followed. Clinical and laboratory data were obtained from medical charts. Complications were categorised as minor and major, according to the need for intervention. Minor complications included macrohematuria and/or hematoma that did not require intervention. Major complications included hematuria or hematoma with fall of hematocrit that required a blood transfusion, surgery or caused death. A binary logistic regression model was used to analyse the possible factors associated with complications after the biopsy. RESULTS: We analysed 345 biopsies; samples were taken from patients aged from 15-81 years, of whom 61% were men. A total of 21 (6%) patients developed a complication, 4.4% minor and 1.7% major complications. There were no nephrectomy or death due to biopsy intervention. Overweight patients, as well as those with higher creatinine, lower hemoglobin, higher blood pressure and biopsy due to AKI had higher chances to develop complications (p = 0.037, p = 0.023, p = 0.032, p = 0.002, p = 0.002, respectively). The patients’ age, gender, kidney dimension, number of passes and uninterrupted aspirin therapy were not found as significant predictors of complications. In the multivariate logistic model, body weight (OR = 1.031, 95%CI = 1.002-1.062), lower hemoglobin (OR = 0.973, 95%CI = 0.951–0.996) and hypertension (OR = 1.025, 95%CI = 1.007-1.044) increased the risk of complications in biopsied patients. CONCLUSION: Renal biopsy is a safe procedure with a low risk of complications when strict biopsy protocol is observed. Correction of anaemia and blood pressure is to be considered before the biopsy