Critical Stepwise Decline of Antibodies against SARS-CoV-2 among Chronic Hemodialysis Patients 180 Days Post Comirnaty Vaccine.

BACKGROUND: The reduced immune response of maintenance hemodialysis patients to coronavirus disease 2019 (COVID-19) vaccines is a major concern. OBJECTIVES: To analyze the late (6 months after full vaccination) antibody response and compare it to early post-vaccination titer. METHODS: We conducted a multicenter prospective study of 13 hemodialysis units in Israel. RESULTS: We demonstrated that the low titers observed among ESRD patients 2-3 months after vaccination with the Comirnaty vaccine (median 63.8 AU/ml) declined to critically lower values 6 months after full vaccination. (Mediananti S antibodies, 31 AU/ml). Seropositivity significantly declined among hemodialysis patients from 89% to 74% (P < 0.0001), although it did not significantly change among controls. CONCLUSIONS: We recommend all patients on hemodialysis receive a booster COVID-19 vaccine 6 months after the second dose.

Minimal Change Disease Following the Pfizer-BioNTech COVID-19 Vaccine.

We report on the development of minimal change disease (MCD) with nephrotic syndrome and acute kidney injury (AKI), shortly after first injection of the BNT162b2 COVID-19 vaccine (Pfizer-BioNTech). A 50-year-old previously healthy man was admitted to our hospital following the appearance of peripheral edema. Ten days earlier, he had received the first injection of the vaccine. Four days after injection, he developed lower leg edema, which rapidly progressed to anasarca. On admission, serum creatinine was 2.31 mg/dL and 24-hour urinary protein excretion was 6.9 grams. As kidney function continued to decline over the next days, empirical treatment was initiated with prednisone 80 mg/d. A kidney biopsy was performed and the findings were consistent with MCD. Ten days later, kidney function began to improve, gradually returning to normal. The clinical triad of MCD, nephrotic syndrome, and AKI has been previously described under a variety of circumstances, but not following the Pfizer-BioNTech COVID-19 vaccine. The association between the vaccination and MCD is at this time temporal and by exclusion, and by no means firmly established. We await further reports of similar cases to evaluate the true incidence of this possible vaccine side effect.

Long-term effectiveness of the Diabetes Conversation Map™ Program on health outcomes: A case-control retrospective cohort study.

AIM: To evaluate the clinical and health behavioural outcomes of a large sample of participants from the Diabetes Conversation Map™ Program. DESIGN: A matched-case-control study that was performed on a retrospective cohort study. METHODS: Participants were 11,053 Clalit Health Services members with type 2 diabetes who enrolled in the Diabetes Conversation Map™ Program between January 2010 - April 2016. The matched-control group was formulated using sequential matching, by matching cases to controls at a ratio of 1:3, based on age, sex, and HbA1c level. The associations between the programme group and annual clinical and health behaviours were assessed between cases and controls at five time points using linear and Poisson regression analyses. RESULTS: The intervention group had significantly lower HbA1c, glucose, and low-density lipoprotein levels and more frequent glucose blood testing each year up to 36 month post-enrolment compared with the matched controls. Other outcomes were significantly different for shorter time periods, including higher high-density lipoprotein and lower triglyceride levels at 6- and 12-month follow-up and lower diastolic blood pressure and greater medication adherence at 6-month follow-up. CONCLUSIONS: Enrolment in the programme was associated with improved clinical and health behaviour outcomes for at least 6 months and most outcomes persisted for up to 36 months. IMPACT: This is the first study to evaluate the Diabetes Conversation Map™ Program with a large sample over long period of time. This nurse-led group intervention evaluation adds to the literature on health outcomes on the lives of patients with type 2 diabetes. STUDY REGISTRATION: This study was registered retrospectively to the Open Science Framework, the registration form can be found at: https://osf.io/63cse.

Effectiveness of Managing Diabetes During Ramadan Conversation Map intervention: A difference-in-differences (self-comparison) design.

BACKGROUND: Some individuals with diabetes fast during Ramadan despite medical concerns for risk of adverse outcomes. The Managing Diabetes During Ramadan Conversation Map is a self-management education group-based intervention for Muslim individuals with type 2 diabetes, specifically addressing diabetes management during Ramadan. OBJECTIVE: The aim of this study was to evaluate the effectiveness of the Managing Diabetes During Ramadan Conversation Map intervention in improving short-term clinical outcomes and reducing healthcare utilization following Ramadan. DESIGN: This was a retrospective rolling cohort study. SETTINGS: Participants were Clalit Health Services members with type 2 diabetes who participated in the intervention between 2014 and 2017 across Israel. PARTICIPANTS: This study included 1732 participants who enrolled in the intervention over the five-year study period. The cohort was mainly between the ages of 45 and 74 years (83.3%), female (71.9%), of lower socioeconomic status (92.1%), with a diabetes duration of 10 years or more (51.7%), obese (64.0%), and had never smoked (73.8%). METHODS: The data used in this study came from Clalit Health Services' electronic health records, which are integrated in a central data warehouse. We used a difference-in-differences (self-comparison) design to examine the effect of the intervention on changes in laboratory results and healthcare utilization over a six month baseline and follow-up. Mixed model linear regressions and Poisson regressions were used to estimate continuous and count outcomes, respectively. RESULTS: Post intervention, participants experienced a reduction of 8.61 mg/dL in their glucose levels (p = 0.005) and 0.34% in their HbA1c levels (p < 0.001). In a sub-group analysis of participants with HbA1c > 7%, larger reductions in glucose (17.02 mg/dL [p < 0.001]) and HbA1c (0.63% [p < 0.001]) levels were recorded. This sub-group also experienced a reduction of 4.83 mg/dL in LDL level (p = 0.007) and had 0.2 fewer primary care visits (p < 0.001). CONCLUSIONS: Participation in the Managing Diabetes During Ramadan Conversation Map improved patient glucose and HbA1c levels. A greater benefit was reported in those individuals with HbA1c > 7%. These findings hold important global health implications for the millions of individuals with type 2 diabetes for whom Ramadan can pose a challenge in disease control.

Inflammatory Biomarkers in Refractory Congestive Heart Failure Patients Treated with Peritoneal Dialysis.

Proinflammatory cytokines play a pathogenic role in congestive heart failure. In this study, the effect of peritoneal dialysis treatment on inflammatory cytokines levels in refractory congestive heart failure patients was investigated. During the treatment, the patients reached a well-tolerated edema-free state and demonstrated significant improvement in NYHA functional class. Brain natriuretic peptide decreased significantly after 3 months of treatment and remained stable at 6 months. C-reactive protein, a plasma marker of inflammation, decreased significantly following the treatment. Circulating inflammatory cytokines TNF-α and IL-6 decreased significantly after 3 months of peritoneal dialysis treatment and remained low at 6 months. The reduction in circulating inflammatory cytokines levels may be partly responsible for the efficacy of peritoneal dialysis for refractory congestive heart failure.

Iron metabolism in hemodialyzed patients - a story half told?

INTRODUCTION: All living organisms have evolved sophisticated mechanisms to maintain appropriate iron levels in their cells and within their body. Recently our understanding of iron metabolism has dramatically increased. Overt labile plasma iron (LPI) represents a component of non-transferrin bound iron (NTBI) that is both redox active and chelatable, capable of permeating into organs and inducing tissue iron overload. The LPI measures the iron-specific capacity of a given sample to produce reactive oxygen species. We studied for the first time NTBI correlations with markers of iron status and inflammation in prevalent hemodialyzed patients. MATERIAL AND METHODS: Complete blood count, urea, serum lipids, fasting glucose, creatinine, ferritin, serum iron, total iron binding capacity (TIBC) were studied by standard laboratory method. The NTBI was assessed commercially available kits from Aferrix Ltd in Tel Aviv, Israel. A test result of 0.6 units of LPI or more indicates a potential for iron-mediated production of reactive oxygen species in the sample. RESULTS: Patients with LPI units ≥ 0.6 had higher serum iron, erythropoiesis stimulating agents (ESA) dose, ferritin, high-sensitivity C-reactive protein (hsCRP), hepcidin and lower hemojuvelin. In hemodialyzed patients NTBI correlated with hsCRP (r = 0.37, p < 0.01), ferritin (r = 0.41, p < 0.001), IL-6 (r = 0.43, p < 0.001). In multivariate analysis predictors of NTBI were hemoglobin and alkaline phosphatase, explaining 58% of the variability. CONCLUSIONS: Elevated NTBI in HD may be due to disturbed iron metabolism. Anemia and liver function might also contribute to the presence of NTBI in this population.

Renalase, hypertension, and kidney - the discussion continues.

Hypertension and cardiovascular complications are very common in chronic kidney disease (CKD). Overactivation of sympathetic nervous system is also widely recognized in CKD. Renalase may play an important role in the control of blood pressure (BP) by its regulatory function of catecholamine metabolism. Renalase could be synthesized not only by the kidney but also by cardiomyocytes, liver, and adipose tissue. It probably exerts a hypotensive action, at least in animal models. Whether it metabolizes catecholamines remains to be proved. Another issue that remains to be resolved is the relationship between renalase and renal natriuresis and phosphaturia. In this review, the updated experimental and clinical data on renalase are presented and possible interactions with the endothelium are discussed. Renalase is "a new postulated therapeutic target." Proof of concept studies are needed to define the pathophysiological link between the kidney, sympathetic tone, BP, and cardiovascular complications.

New parameters in iron metabolism and functional iron deficiency in patients on maintenance hemodialysis.

INTRODUCTION: Iron metabolism has been studied for many years. New substances involved in iron metabolism continue to be described. Functional iron deficiency (FID) is characterized by the presence of adequate iron stores (as defined by standard criteria) but insufficient iron mobilization required for erythropoiesis during administration of erythropoiesis-stimulating agents. OBJECTIVES: The aim of the study was to evaluate new parameters of iron metabolism and the prevalence of FID as well as to assess potential correlations in patients on hemodialysis (HD). PATIENTS AND METHODS: The study included 98 patients on maintenance HD. Standard laboratory methods were used to measure the iron status, complete blood count, creatinine, calcium, phosphorus, albumin, intact parathyroid hormone, and lipids. Commercially available kits were used to measure high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), tumor necrosis factor-α, N-terminal pro-B-type natriuretic peptide (NT-proBNP), growth differentiation factor (GDF15), bone morphogeneticprotein (BMP6), hemojuvelin, and hepcidin. RESULTS: FID was present in 23% of the patients on HD and was associated with significantly higher serum ferritin, IL-6, hsCRP, hepcidin, and NT-proBNP levels. There were no significant differences in BMP6 and GDF15 levels between patients with and without FID. Patients on HD had increased prevalence of hypertension, diabetes, and left ventricular hypertrophy and required slightly, but insignificantly, higher erythropoietin doses. Predictors of FID included serum iron levels and residual renal function. CONCLUSIONS: FID is present in a substantial proportion of patients on HD, who thus should be screened for reversible causes of inflammation. New parameters in iron metabolism do not seem to be related to FID in patients on HD.

Iron metabolism in solid­organ transplantation: how far are we from solving the mystery?

Iron is the most abundant transition metal in the human body and an essential element required for growth and survival. Our understanding of the molecular control of iron metabolism has increased dramatically over the past 10 years due to the discovery of hepcidin, which regulates the uptake of dietary iron and its mobilization from macrophages and hepatic stores. Although general practitioners and internists encounter iron deficiency and anemia in their everyday practice, little is known about iron metabolism in patients after solid-organ transplantation. The aim of this review was to summarize the current knowledge on iron metabolism in kidney, heart, and liver transplant recipients. Iron deficiency and/or anemia, as well as iron overload, are frequently observed but the precise mechanism of these disturbances have not been fully elucidated. Iron deficiency is more prevalent in kidney and heart transplant patients, while iron overload in liver transplant recipients. Secondary and potentially reversible causes of these disturbances should be considered such as inflammation, graft failure, and type of immunosuppression. Iron status check­up should be a part of long term follow-up because disturbances in iron metabolism are a possible risk factor of infections and mortality in solid transplant recipients. Internists and general practitioners are often the first doctors to take care of organ transplant recipients (before they will present at outpatient transplant clinics or hospital transplant units); therefore, knowledge about the disturbances in iron metabolism in this specific population would be useful for better diagnosis and treatment both before and after transplantation.

Copeptin and its relation to arteriovenous fistula (AVF) type and NYHA class in hemodialysis patients.

Copeptin is cosynthesized with vasopressin, also known as anti-diuretic hormone, with similar plasma levels. In the past 2 years, copeptin has been studied as a diagnostic and prognostic marker in infections and other diseases. In patients with decompensated heart failure, copeptin was an accurate prognostic marker for mortality. Cardiovascular disease is a major contributor to the mortality and morbidity in chronic kidney disease. Creation of an arteriovenous fistula (AVF) might contribute to the development or worsening of congestive heart failure (CHF). The aim of the study was to assess associations between copeptin, New York Heart Association (NYHA) class, and the location of the AVF in hemodialysis (HD) patients. The cross-sectional study was performed on a cohort of 93 clinically stable HD patients. Patients with proximal AVF tend to be older, with decreased renal residual function and increased NYHA functional class. These patients were also highly anemic, had more acidosis, and had increased high-sensitivity C-reactive protein along with increased copeptin and NT-proBNP levels. These changes were also associated with significant changes in all intra-cardiac dimensions, including right ventricle, both atria, and intraventricular septum and increase in end-systolic and end-diastolic left ventricular intra-cardiac dimensions. In multiple logistic regression analysis, the only associate of copeptin was NYHA functional class. Copeptin level in HD patients depends on cardiac function and it might be involved in the pathophysiology of cardiovascular disease in these patients. Proximal AVF creation might contribute to the development or worsening of CHF in HD patients.

The emerging role of NO and IGF-1 in early renal hypertrophy in STZ-induced diabetic rats.

BACKGROUND: Diabetic nephropathy (DN) is a major complication of diabetes mellitus, and the most common cause of end-stage renal disease. DN is characterized by early hyperfiltration and renal hypertrophy, which are associated with increased renal insulin-like growth factor-1 (IGF-1) levels. The relationship between IGF-1 and nitric oxide (NO) in DN is not established. The aim of this study was to investigate the effects of NO system modulation on the IGF-1-mediated hypertrophy and hyperfiltration during the first week after diabetes induction. METHODS: Diabetes was induced in rats by streptozotocin (STZ) injection. Diabetic rats were treated with NO synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME). Various serum IGF-binding proteins (IGFBPs) and renal IGFBP1 expression was evaluated. Urine and plasma NO(2) + NO(3) level analysis was also performed. RESULTS: STZ induced hyperglycaemia decreased plasma insulin levels and brought about a decrease in body weight. L-NAME administration to diabetic rats significantly prevented renal hypertrophy and hyperfiltration. Serum IGFBP3, IGFBP4 and 30-kDa IGFBP fraction were all significantly reduced in diabetic rats, compared with those in non-diabetic control rats. However, the renal IGFBP1 mRNA expression in diabetic rats was significantly higher. These changes were accompanied by an increased in NO production. L-NAME administration prevented the serum IGFBP decline, without significantly affecting the renal IGFBP1 mRNA expression. CONCLUSIONS: We have shown that increased renal IGF-1 and increased NO production during the very early stages of STZ-induced DN are associated with renal hypertrophy and hyperfiltration in diabetic rats. Modulating the IGF-1 availability to the kidney by nitric oxide synthase inhibition significantly reduced renal hypertrophy and hyperfiltration during the first week of STZ-induced diabetes mellitus.

Molecular study of proteinuria in patients treated with B12 supplements: do not forget megaloblastic anemia type 1.

BACKGROUND/AIMS: Current consensus supports the notion that proteinuria is a marker of renal disease with prognostic implications. Whereas most chronic kidney disease patients with proteinuria would often require antiproteinuric agents, there are some exceptions. Megaloblastic anemia type 1 (MGA1) is characterized by megaloblastic anemia due to congenital selective vitamin B(12) malabsorption and proteinuria. In the present study, we describe 2 Israeli Jewish patients with MGA1 and isolated proteinuria. METHODS: Because of their origin, the patients were screened for the presence of the already studied Tunisian AMN mutation, by direct sequencing the corresponding region from genomic DNA. PCR products were purified and sequenced. RESULTS: Genomic DNA sequencing of the AMN gene of both patients confirmed that the acceptor splice site in intron 3 was changed from CAG to CGG (208-2A→G). CONCLUSION: We determined the molecular basis of MGA1 in both patients and discuss the involvement of the cubilin/AMN complex in this pathology and its role in the development of the proteinuria. We also discuss the questionable significance of antiproteinuric treatment for these patients.

Prevalence of chronic kidney disease and anemia in patients with coronary artery disease with normal serum creatinine undergoing percutaneous coronary interventions: relation to New York Heart Association class.

BACKGROUND: Kidney disease and cardiovascular disease seem to be lethally synergistic and both are approaching the epidemic level. A reduced glomerular filtration rate is associated with increased mortality risk in patients with heart failure. Many patients with congestive heart failure are anemic. Anemia is very often associated with chronic kidney disease. OBJECTIVES: To assess--in relation to New York Heart Association class--the prevalence of anemia and chronic kidney disease in patients with normal serum creatinine in a cohort of 526 consecutive patients with coronary artery disease undergoing percutaneous coronary interventions. METHODS: GFR was estimated using the simplified MDRD formula, the Cockcroft-Gault formula, the Jeliffe and the novel CKD-EPI formula. RESULTS: According to the WHO definition the prevalence of anemia in our study was 21%. We observed a progressive decline in GFR and hemoglobin concentration together with a rise in NYHA class. Significant correlations were observed between eGFR and systolic blood pressure, diastolic blood pressure, age, NYHA class, complications of PCI, including bleeding, and major adverse cardiac events. CONCLUSIONS: The prevalence of anemia and chronic kidney disease is high in patients undergoing PCI despite normal serum creatinine, particularly in higher NYHA class. Lower eGFR and hemoglobin are associated with more complications, including bleeding after PCI and higher prevalence of major adverse cardiac events. In patients with risk factors for cardiovascular disease, GFR should be estimated since renal dysfunction and subsequent anemia are important risk factors for cardiovascular morbidity and mortality.

Truncating mutations in the chloride/proton ClC-5 antiporter gene in Seven Jewish Israeli families with Dent's 1 disease.

Dent's disease is an X-linked hereditary renal tubular disorder characterized by low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis, nephrolithiasis, rickets and progressive renal failure. About 60% of patients have mutations in the CLCN5 gene (Dent 1), which encodes a kidney-specific chloride/proton antiporter, and 15% of patients have mutations in the OCRL1 gene (Dent 2). The aim of the study was to identify CLCN5 mutations in Jewish Israeli families with Dent's disease and to characterize the associated clinical syndromes. We studied 17 patients from 14 unrelated Israeli families with a clinical diagnosis of Dent's disease. LMWP was detected in all patients. Most of the affected individuals had hypercalciuria and nephrocalcinosis. Renal stones were found in 1 patient, and renal insufficiency developed in 2 patients. We identified six different truncating CLCN5 mutations that were segregated with the disease in 7 families: three nonsense mutations (Arg28stop, Arg467stop and Arg637stop), one deletion mutation (505delA) and two novel mutations, consisted of one deletion mutation (1493delG) and one insertion mutation (409insC). All the mutations cause premature termination of protein translation and result in a non-functional truncated protein. The clinical characteristics of patients with different mutations were, in general, similar.

Late diagnosis of primary hyperoxaluria type 2 in the adult: effect of a novel mutation in GRHPR gene on enzymatic activity and molecular modeling.

PURPOSE: Genetic causes of nephrolithiasis are underestimated. Primary hyperoxaluria type 2 is a rare autosomal recessive disease caused by mutations in the GRHPR gene, leading to an accumulation of oxalate and L-glycerate with recurrent kidney stone formation and nephrocalcinosis, and the later development of renal failure and systemic oxalate depositions. We studied the effects of a novel GRHPR mutation on GRHPR enzymatic activity and molecular modeling. MATERIALS AND METHODS: Genomic DNA from a 50-year-old male with a late diagnosis of primary hyperoxaluria type 2 was extracted, analyzed and compared with the established human GRHPR gene sequence. Restriction enzyme analysis of the patient, 30 healthy controls and 30 patients with nephrolithiasis of various causes was done to confirm the presence of the mutation. GRHPR activity was analyzed by site directed mutagenesis of WT and mutant clones. We studied the effects of the mutation on enzymatic molecular modeling. RESULTS: We found the novel homozygous single missense mutation A975G in exon 9, creating an amino acid change from asparagine to aspartic acid in position 312. No mutations were detected in restriction enzyme analysis in all 30 healthy controls and 30 patients with nephrolithiasis of various causes. Transfected cells with the mutant clone showed abolished GRHPR activity. Molecular modeling studies revealed that the mutation was likely to disrupt the correct folding of the GRHPR substrate binding domain, hence affecting the enzyme active site. CONCLUSIONS: Primary hyperoxaluria type 2 should be considered in patients at adult stone clinics who have had a history of nephrolithiasis since childhood, especially in those with consanguineous parents. Biochemical analysis followed by mutation identification should be the approach for making the definitive diagnosis of primary hyperoxaluria type 2.

Tubular and glomerular L-arginine transport (uptake and transporters) and the nitric oxide synthases in ischemic acute renal failure (iARF) in streptozotocin-induced diabetic rats (STZ-DM).

BACKGROUND: L-arginine or its metabolites may be important pathogenetic factors in ischemic acute renal failure (iARF) in rats. It was found that the L-arginine-nitric oxide synthase-nitric oxide system plays an important role in the renal hemodynamic alterations in the early stages of diabetes. The iARF in diabetic rats is much more severe than the normal rats exposed to a same ischemia time. The purpose of the present study was to evaluated L-arginine uptake and its transporters and nitric oxide synthase isoform expression in tubuli and glomeruli of STZ-induced diabetic rats with iARF. METHODS: iARF was induced by right nephrectomy and left renal artery clamping for 60 min followed by a 60 min reflow period. iARF was induced in STZ diabetes rats two weeks after intraperitoneal streptozotocin (60 mg/kg body weight) and in normal control rats. L-arginine uptake, L-arginine transporters (CAT1 and CAT2) and nitric oxide synthases (iNOS, eNOS, and bNOS) were determined by RT-PCR) in both glomeruli and tubuli preparations. RESULTS: The STZ diabetic rats compared with the non diabetic normal rats have a higher glomerular L-arginine uptake, higher iNOS mRNA, lower eNOS mRNA, and lower tubular CAT1 mRNA, eNOS mRNA, and bNOS mRNA. The diabetic iARF after one hour of reperfusion had lower glomerular L-arginine uptake, lower CAT1 mRNA, lower eNOS mRNA, lower bNOS, and higher tubular iNOS mRNA compared with iARF in normal rats. CONCLUSIONS: Our findings suggest a prolonged and more severe post-glomerular vasoconstriction very early after the reflow in the iARF of STZ diabetic rats compared with the iARF in the normal control rats. That may be a plausible explanation to the very significant decline in GFR and tubular necrosis that characterize the iARF in diabetic rats.