Asymmetric (ADMA) and Symmetric (SDMA) Dimethylarginines in Chronic Kidney Disease: A Clinical Approach.

Asymmetric dimethylarginine (ADMA) and its enantiomer, Symmetric dimethylarginine (SDMA), are naturally occurring amino acids that were first isolated and characterized in human urine in 1970. ADMA is the most potent endogenous inhibitor of nitric oxide synthase (NOS), with higher levels in patients with end-stage renal disease (ESRD). ADMA has shown to be a significant predictor of cardiovascular outcome and mortality among dialysis patients. On the other hand, although initially SDMA was thought to be an innocuous molecule, we now know that it is an outstanding marker of renal function both in human and in animal models, with ESRD patients on dialysis showing the highest SDMA levels. Today, we know that ADMA and SDMA are not only uremic toxins but also independent risk markers for mortality and cardiovascular disease (CVD). In this review, we summarize the role of both ADMA and SDMA in chronic kidney disease along with other cardiovascular risk factors.

Fabry Nephropathy: An Evidence-Based Narrative Review.

Fabry disease (FD) is a rare, X-linked disorder caused by mutations in the GLA gene encoding the enzyme α-galactosidase A. Complete or partial deficiency in this enzyme leads to intracellular accumulation of globotriaosylceramide (Gb3) and other glycosphingolipids in many cell types throughout the body, including the kidney. Progressive accumulation of Gb3 in podocytes, endothelial cells, epithelial cells, and tubular cells contribute to the renal symptoms of FD, which manifest as proteinuria and reduced glomerular filtration rate leading to renal insufficiency. A correct diagnosis of FD, although challenging, has considerable implications regarding treatment, management, and counseling. The diagnosis may be confirmed by demonstrating the enzyme deficiency in males and by identifying the specific GLA gene mutation in male and female patients. Treatment with enzyme replacement therapy, as part of the therapeutic strategy to prevent complications of the disease, may be beneficial in stabilizing renal function or slowing its decline, particularly in the early stages of the disease. Emergent treatments for FD include the recently approved chaperone molecule migalastat for patients with amenable mutations. The objective of this report is to provide an updated overview on Fabry nephropathy, with a focus on the most relevant aspects of its epidemiology, diagnosis, pathophysiology, and treatment options.

Fluctuation of pre-hemodialysis serum sodium
.

INTRODUCTION: Low pre-hemodialysis (pre-HD) serum sodium or hyponatremia is associated with higher mortality. Pre-HD serum sodium can be more stable over time with low fluctuation compared to other serum parameters. MATERIALS AND METHODS: We examined variation of pre-HD serum sodium in 24 months and after this point examined all-cause mortality in a cohort of 261 patients followed-up for 48.8 (standard deviation (SD) = 19.1) months. 6,221 determinations of pre-HD serum sodium were made and corrected for glucose concentrations. Serum sodium was measured pre-HD monthly, and the variability was calculated using the coefficient of variation (CV). RESULTS: The mean age was of 60 ± 14.1 years, 60.9% were men, 48% had diabetes mellitus, and diabetic nephropathy was the most frequent cause of end-stage renal disease. Median CV of sodium in 24 months was 1.7% with a mean of 1.78% (95% CI 1.73 - 1.83). Patients with CV > 1.7% had a higher mortality (53 patients a 36.8%) compared to CV < 1.7% (22 patients a 18.8%) (p = 0.002). In Kaplan-Meier analysis, patients with CV > 1.7% had significantly worse overall survival (log rank = 6.395, p = 0.011). We also stratified the sample in serum sodium tertiles (< 138 mEq/L; 138 - 140 mEq/L; > 140 mEq/L) and made a Kaplan-Meier analysis which showed persistent worse survival outcomes in patients with CV > 1.7% (log rank Mantel-Cox 7.64; p = 0.006). Cox regression multivariate model showed that CV of sodium was significantly associated with overall mortality after adjusting for confounder variables (hazard ratio 2.16, 95% CI 1.37 - 3.41; p = 0.001). CONCLUSION: Variation of pre-HD serum sodium in 2 years is less than a 2%. With the limitations of our study, a higher variability of pre-HD serum sodium in 2 years of treatment (CV > 1.7%) is associated with increased mortality.
.

Paraoxonase 1 and 2 gene variants and the ischemic stroke risk in Gran Canaria population: an association study and meta-analysis.

PURPOSE OF THE STUDY: The present study aims to evaluate the relationship between rs662 (Gln(Q)192Arg(R)) and rs854560 (L55M) and the rs7493 (S311C) in the paraoxonase genes and ischemic stroke (IS) in the population of Gran Canaria (Canary Islands). The association with stroke was also evaluated using systematic review and meta-analysis. METHODS: A total of 129 IS patients and 176 age and gender matched controls were enrolled. For meta-analysis, eligible studies were identified through search in public databases. RESULTS: In multivariate regression analysis only the PON2 S311C variant showed to be an independent predictor of IS (OR = 0.093, 95% CI: 0.014-0.627). Overall, no significant association was found between L55M and IS when all studies were pooled nor by subgroup analysis by ethnicity. Gln192Arg showed a modest risk for IS in the global and in Asian population but with high heterogeneity among studies. A modest risk under a dominant inheritance model was found for the S311C variant with an overall random effect OR of 1.004 (95% CI: 1.00-1.35). There was strong evidence of heterogeneity among studies ( p = 0.0097, I2 = 25.35%) which did not disappear after stratification by ethnicity. CONCLUSIONS: The overall analysis shows a significant contribution of the rs662 variant to IS risk. We found that the CC genotype of the PON2 S311C polymorphism is a risk factor for IS. Results of the meta-analysis partially support this conclusion.

Spanish guidelines for the management of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent cause of genetic renal disease and accounts for 6-10% of patients on renal replacement therapy (RRT). Very few prospective, randomized trials or clinical studies address the diagnosis and management of this relatively frequent disorder. No clinical guidelines are available to date. This is a consensus statement presenting the recommendations of the Spanish Working Group on Inherited Kidney Diseases, which were agreed to following a literature search and discussions. Levels of evidence found were C and D according to the Centre for Evidence-Based Medicine (University of Oxford). The recommendations relate to, among other topics, the use of imaging and genetic diagnosis, management of hypertension, pain, cyst infections and bleeding, extra-renal involvement including polycystic liver disease and cranial aneurysms, management of chronic kidney disease (CKD) and RRT and management of children with ADPKD. Recommendations on specific ADPKD therapies are not provided since no drug has regulatory approval for this indication.

Serum chloride as a marker of cardiovascular and all-cause mortality in chronic hemodialysis patients: 5-Year follow-up study.

BACKGROUND: Hypochloremia has been associated with increased mortality in patients with hypertension, heart failure, sepsis, and chronic kidney disease (CKD). The pathophysiological mechanisms of this finding are not clear. There are no studies describing an association between serum chloride levels (Cl-) and mortality in incident chronic hemodialysis (HD) patients. METHOD: Retrospective cohort study of the incident population in our chronic outpatient hemodialysis program between January 1, 2016, and January 1, 2021 (N=374). Survival time was collected in all patients and analyzed using the Kaplan-Meyer method. A multivariate Cox regression model was performed to predict the probability of survival, applying a stepwise procedure. RESULTS: During the median follow-up period of 20 months, 83 patients died. The 5-year overall survival rate for our patients was 45%. Both natremia and chloremia had no significant differences when compared by sex, vascular access, or etiology. There was an inverse correlation between Cl- and interdialytic weight gain (r=-0.15) (p=0.0038). Patients belonging to the quartile with lower Cl- levels had less probability of survival than patients in the quartile with higher Cl- levels (27% and 68%, respectively, p=0.019). On the other hand, in the multivariate Cox regression model, variables significantly associated with higher mortality were being older, having higher baseline comorbidity by modified Charlson index, not taking diuretics and having lower albumin and chloride levels. Particularly, higher Cl- levels was independently associated with both lower all-cause mortality (adjusted hazard ratio [HR]=0.84; 95% confidence interval [CI], 0.77-0.92; p=0.0001) and cardiovascular mortality (HR 0.9; 95% CI, 0.83-0.97; p<0.0057). CONCLUSIONS: Lower Cl- levels were associated with higher all-cause and cardiovascular mortality in incident patients on chronic hemodialysis in our health area.

Inflammation and hemodialysis adequacy: are C-reactive protein levels influenced by the dose of dialysis?

INTRODUCTION: Chronic inflammation and the underlying cardiovascular comorbidity are still current problems in chronic hemodialysis patients. There are few studies comparing the "dialysis dose" with the degree of inflammation in the patient. Our main objective was to determine whether there is a relationship between serum C-reactive protein (CRP) levels and the "dialysis dose" (Kt / V) using ionic dialysance. METHODS: Multicenter cross-sectional study. 536 prevalent chronic hemodialysis patients were included. CRP levels, neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) were collected. Kt was obtained by ionic dialysance and urea distribution volume was calculated from the Watson's formula. The sample was divided into two groups, taking the median CRP as the cut-off point. Dialysis adequacy obtained in each group was compared. Finally, a logistic regression model was carried out to determine the variables with the greatest influence. RESULTS: Median CRP was 4.10 mg/L (q25-q75: 1.67-10) and mean Kt/V was 1.48 ± 0.308. Kt/V was lower in the patients included in the high inflammation group (p = 0.01). In the multivariate logistic regression, the "high" levels of CRP were directly correlated with the Log INL (p < 0.001) and inversely proportional with serum albumin values (p = 0.014), Kt/V (p = 0.037) and serum iron (p < 0.001). CONCLUSION: The poorer adequacy in terms of dialysis doses, lower Kt / V values, may contribute to a higher degree of inflammation in chronic hemodialysis patients.

Silent challenge: Early kidney transplant failure and cardiomyopathy.

Differentiation of hypertrophic cardiomyopathy phenotypes is challenging but crucial for appropriate management. We report a case of myocardial oxalate deposition as an infrequent cause of infiltrative cardiomyopathy.

Consensus document on autosomal dominant polycystic kindey disease from the Spanish Working Group on Inherited Kindey Diseases. Review 2020.

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent cause of genetic renal disease and accounts for 6-10% of patients on kidney replacement therapy (KRT). Very few prospective, randomized trials or clinical studies address the diagnosis and management of this relatively frequent disorder. No clinical guidelines are available to date. This is a revised consensus statement from the previous 2014 version, presenting the recommendations of the Spanish Working Group on Inherited Kidney Diseases, which were agreed to following a literature search and discussions. Levels of evidence mostly are C and D according to the Centre for Evidence-Based Medicine (University of Oxford). The recommendations relate to, among other topics, the use of imaging and genetic diagnosis, management of hypertension, pain, cyst infections and bleeding, extra-renal involvement including polycystic liver disease and cranial aneurysms, management of chronic kidney disease (CKD) and KRT and management of children with ADPKD. Recommendations on specific ADPKD therapies are provided as well as the recommendation to assess rapid progression.

Estimated GFR in autosomal dominant polycystic kidney disease: errors of an unpredictable method.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) causes about 10% of cases of end stage renal disease. Disease progression rate is heterogeneous. Tolvaptan is presently the only specific therapeutic option to slow kidney function decline in adults at risk of rapidly progressing ADPKD with chronic kidney disease (CKD) stages 1-4. Thus, a reliable evaluation of kidney function in patients with ADPKD is needed. METHODS: We evaluated the agreement between measured (mGFR) and estimated glomerular filtration rate (eGFR) by 61 formulas based on creatinine and/or cystatin-C (eGFR) in 226 ADPKD patients with diverse GFR values, from predialysis to glomerular hyperfiltration. Also, we evaluated whether incorrect categorization of CKD using eGFR may interfere with the indication and/or reimbursement of Tolvaptan treatment. RESULTS: No formula showed acceptable agreement with mGFR. Total Deviation Index averaged about 50% for eGFR based on creatinine and/or cystatin-C, indicating that 90% of the estimations of GFR showed bounds of error of 50% when compared with mGFR. In 1 out of 4 cases with mGFR < 30 ml/min, eGFR provided estimations above this threshold. Also, in half of the cases with mGFR between 30 and 40 ml/min, formulas estimated values < 30 ml/min. CONCLUSIONS: The evaluation of renal function with formulas in ADPKD patients is unreliable. Extreme deviation from real renal function is quite frequent. The consequences of this error deserve attention, especially in rapid progressors who may benefit from starting treatment with tolvaptan and in whom specific GFR thresholds are needed for the indication or reimbursement. Whenever possible, mGFR is recommended.

Inflammation and hemodialysis adequacy: Are C-reactive protein levels influenced by dialysis dose? / Inflamación y adecuación de la hemodiálisis: ¿están los niveles de proteína C reactiva influidos por la dosis de diálisis recibida?

INTRODUCTION: Chronic inflammation and the underlying cardiovascular comorbidity are still current problems in chronic hemodialysis patients. There are few studies comparing the "dialysis dose" (Kt/V) with the degree of inflammation in the patient. Our main objective was to determine whether there is a relationship between serum C-reactive protein (CRP) levels and the Kt/V using ionic dialysance. METHODS: Multicenter cross-sectional study. A total of 536 prevalent chronic hemodialysis patients were included. CRP levels, neutrophil-lymphocyte ratio and platelet-lymphocyte ratio were collected. Kt was obtained by ionic dialysance and urea distribution volume was calculated from the Watson's formula. The sample was divided into 2 groups, taking the median CRP as the cut-off point. Dialysis adequacy obtained in each group was compared. Finally, a logistic regression model was carried out to determine the variables with the greatest influence. RESULTS: Median CRP was 4.10mg/L (q25-q75: 1.67-10) and mean Kt/V was 1.48±0.308. Kt/V was lower in the patients included in the high inflammation group (P=.01). In the multivariate logistic regression, the "high" levels of CRP were directly correlated with the Log neutrophil-lymphocyte ratio (P<.001) and inversely proportional with serum albumin values (P=.014), Kt/V (P=.037) and serum iron (P<.001). CONCLUSION: The poorer adequacy in terms of dialysis doses (lower Kt/V values) may contribute to a higher degree of inflammation in chronic hemodialysis patients.

Teaching nephrology as part of a degree in medicine.

The teaching of nephrology as part of a degree in medicine is potentially one of the most decisive factors when choosing a speciality. Until now, however, we have not had an overview of the teaching of nephrology in Spain. We have integrated information available in public databases with a survey and personal interviews with those responsible for teaching in Spanish medical faculties. In 2019, there were 44 universities offering a medicine degree in Spain, in 16 Autonomous Communities (34 of which were public and 10 private). For learning purposes, students have a number of hospital beds ranging from 0.2 to 4.7, and there are Autonomous Communities that have a higher proportion of students per inhabitant or per physician, such as Madrid or the Community of Navarra. In 16 universities there are tenured teaching staff (professors and lecturers), in eight contracted medical lecturers, and in two assistant lecturers. In 21 medical faculties, theoretical and practical nephrology is taught by associate lecturers. The subject is taught between the third and fifth years of the degree, the median being the fourth year. It is usually integrated with another subject and only in the University of Navarra is it an independent subject, with three credits. The total number of hours devoted to theoretical teaching (both theoretical classes and seminars) is highly variable and ranges from 11 to 35, with a median of 17.5. Variability is observed in both the number of theoretical topics (range 11-31) and seminars (range 0-9). Among the faculties that teach seminars, the ratio of theoretical topics to seminars ranges from 1.6 to 18. Most faculties evaluate clinical practices with various modalities and percentage of assessment. Knowledge is mostly assessed by a multiple choice exam. In conclusion, there is a high level of variability in the curriculum for the teaching of nephrology as part of a degree in medicine in Spain. Teaching staff who are tenured or who have a stable affiliation with universities make up just 23% of the total and, in many faculties, teaching depends exclusively on associate professors.

[Teaching nephrology as part of a degree in medicine]. / La docencia de la nefrología en el grado de medicina.

The teaching of nephrology as part of a degree in medicine is potentially one of the most decisive factors when choosing a speciality. Until now, however, we have not had an overview of the teaching of nephrology in Spain. We have integrated information available in public databases with a survey and personal interviews with those responsible for teaching in Spanish medical faculties. In 2019, there were 44 universities offering a medicine degree in Spain, in 16 Autonomous Communities (34 of which were public and 10 private). For learning purposes, students have a number of hospital beds ranging from 0.2 to 4.7, and there are Autonomous Communities that have a higher proportion of students per inhabitant or per physician, such as Madrid or the Community of Navarra. In 16 universities there are tenured teaching staff (professors and lecturers), in 8 contracted medical lecturers, and in 2 assistant lecturers. In 21 medical faculties, theoretical and practical nephrology is taught by associate lecturers. The subject is taught between the third and fifth years of the degree, the median being the fourth year. It is usually integrated with another subject and only in the University of Navarra is it an independent subject, with 3 credits. The total number of hours devoted to theoretical teaching (both theoretical classes and seminars) is highly variable and ranges from 11 to 35, with a median of 17.5. Variability is observed in both the number of theoretical subjects (range 11 to 31) and seminars (range 0 to 9). Among the faculties that teach seminars, the ratio of theoretical topics to seminars ranges from 1.6 to 18. Most faculties evaluate clinical practices with various modalities and percentage of assessment. Knowledge is mostly assessed by a multiple choice exam. In conclusion, there is a high level of variability in the curriculum for the teaching of nephrology as part of a degree in medicine in Spain. Teaching staff who are tenured or who have a stable affiliation with universities make up just 23% of the total and, in many faculties, teaching depends exclusively on associate professors.

[Contributions of the ambulatory blood pressure monitoring to the values measured at the medical office]. / Aportaciones de la monitorización ambulatoria a la presión arterial casual.

OBJECTIVE: To communicate our experience with this technique centred in the definition of the patterns and the peculiar characteristics of the rising pattern. METHODS: During a four year period, the ambulatory blood pressure monitoring was obtained in 500 hypertensive patients with difficult to control blood pressure or of recent detection, following the guide of the Cardiorisk project. RESULTS: The most frequent pattern observed was non-dipper (46.6%). The pulse pressures obtained by ambulatory and office blood pressure monitoring kept a correlation that serve as guide to the office blood pressure measurements. The level of control by ambulatory monitoring blood pressure is only discretely superior to the office blood pressure if the cases of white coat and masked hypertension are considered. The rising pattern is associated to a major vascular risk. CONCLUSIONS: An increased vascular risk is noticed in the rising pattern with respect to other patterns. The morphology of different atypical patterns was also presented. The help of the ambulatory blood pressure monitoring along with one taken in the office determined a great aid to interpret the huge variability of the arterial pressure.

Impact of a phone app on nephrology referral.

BACKGROUND: Various factors can lead to inadequate nephrology referral decisions being taken by clinicians, but a major cause is unawareness of guidelines, recommendations and indications, or of appropriate timing. Today, tools such as smartphone applications (Apps) can make this knowledge more accessible to non-nephrologist clinicians. Our study aim is to determine the effectiveness of a purpose-built app in this respect. METHODS: In a retrospective study, nephrology referrals were compared before and after the introduction of the app in clinical practice. The initial study population consisted of first visits by patients referred to our department in 2015, before the introduction of the app. In 2016, the smartphone app NefroConsultor began to be implemented in our hospital. We compared the initial study population with the results obtained for patients referred in 2017, when the app was in use, taking into account clinical features considered, such as urinalysis, proteinuria or kidney ultrasound, to determine whether these patients met currently recommended criteria for referral. RESULTS: The total study population consisted of 628 patients, of whom 333 were examined before the introduction of the app (in 2015) and 295 when it was in use (in 2017). Among the first group, 132 (39.6%) met established KDIGO criteria for nephrology referral and were considered to be correctly referred. Among the second group, 200 (67.8%) met the criteria and were considered to be properly referred (P = 0.001). The increase in the rate of intervention success (before-after app) was 28.8% with a binomial effect size display (Cohen's d effect size) of 0.751. Before the introduction of the app, data for albuminuria were included in 62.5% of nephrology referrals; in 2017, the corresponding value was 87.5% (P = 0.001). In the same line, referrals including urinalysis rose from 68.5% to 85.8% (P = 0.001). Multivariate regression analysis, using referrals meeting KDIGO criteria as the dependent variable and adjusting for age, sex and referring department, showed that the 2017 group (after the introduction of NefroConsultor) was associated with an odds ratio of 3.57 (95% confidence interval 2.52-5.05) for correct referrals, compared with the 2015 group (P = 0.001). References to proteinuria as the reason for nephrology referral also increased from 23.7% to 34.2% (P = 0.004). CONCLUSIONS: Use of the app is associated with more frequent studies of albuminuria at the time of referral and a greater likelihood of proteinuria being cited as the reason for referral. The smartphone app considered can improve the accessibility of information concerning nephrology referrals and related studies.

Electrocardiographic changes in rats undergoing thoracic surgery under combined parenteral anesthesia.

To compare two protocols of combined parenteral general anesthesia, the authors analyzed electrocardiographic changes in anesthetized rats undergoing left pneumonectomy. One group of rats was anesthetized with a combination of medetomidine and ketamine (group 1, n = 10), and the other was injected with diazepam and ketamine (group 2, n = 10). Investigators obtained two electrocardiograms from each rat, one before surgery (5 min after anesthesia) and one after surgery (60 min after anesthesia). Anesthetic induction was quick for all rats, though four rats in group 2 died before surgery. Mean cardiac frequency and R-wave amplitude were significantly lower in rats in group 1 than in rats in group 2. Rats in group 1 received injections of atipamezole about 60 min after surgery, which reversed the effects of medetomidine; these rats regained voluntary respiratory movement more quickly than did rats in group 2. Two additional rats in group 2 died during postsurgical recovery. These results suggest that for thoracic surgery in rats, medetomidine-ketamine is an appropriate anesthetic combination, may be safer than diazepam-ketamine and yields a shorter recovery time.

Pathological changes of renal biopsy in Sjögren Syndrome.

We are presenting the case of a 53-year-old woman with a history of Sjögren syndrome and a secondary antiphospholipid syndrome admitted at the Nephrology department for the evaluation of renal failure. The patient was initially diagnosed with tubulointerstitial nephritis and subsequently a membranoproliferative type I glomerulonephritis, secondary to cryoglobulins during the course of the disease. Repeated renal biopsies were required to confirm the diagnosis.