Heterogeneity in cardiorenal protection by Sodium glucose cotransporter 2 inhibitors in heart failure across the ejection fraction strata:Systematic review and meta-analysis

BACKGROUND Gliflozins or Sodium glucose cotransporter 2 inhibitors(SGLT2i)are relatively novel antidiabetic medications that have recently been shown to represent favorable effects on patients’cardiorenal outcomes.However,there is shortage of data on potential disparities in this therapeutic effect across different patient subpopulations.AIM To investigate differential effects of SGLT2i on the cardiorenal outcomes of heart failure patients across left ventricular ejection fraction(LVEF)levels.METHODS Literature was searched systematically for the large randomized double-blind controlled trials with long enough follow up periods reporting cardiovascular and renal outcomes in their patients regarding heart failure status and LVEF levels.Data were then meta-analyzed after stratification of the pooled data across the LVEF strata and New York Heart Associations(NYHA)classifications for heart failure using Stata software version 17.0.RESULTS The literature search returned 13 Large clinical trials and 13 post hoc analysis reports.Meta-analysis of the effects of gliflozins on the primary composite outcome showed no significant difference in efficacy across the heart failure subtypes,but higher efficacy were detected in patient groups at lower NYHA classifications(I2=46%,P=0.02).Meta-analyses across the LVEF stratums revealed that a baseline LVEF lower than 30%was associated with enhanced improvement in the primary composite outcome compared to patients with higher LVEF levels at the borderline statistical significance(HR:0.70,95%CI:0.60 to 0.79 vs 0.81,95%CI:0.75 to 0.87;respectively,P=0.06).Composite renal outcome was improved significantly higher in patients with no heart failure than in heart failure patients with preserved ejection fraction(HFpEF)(HR:0.60,95%CI:0.49 to 0.72 vs 0.94,95%CI:0.74 to 1.13;P=0.04).Acute renal injury occurred significantly less frequently in heart failure patients with reduced ejection fraction who received gliflozins than in HFpEF(HR:0.67,95%CI:51 to 0.82 vs 0.94,95%CI:0.82 to 1.06;P=0.01).Volume depletion was consistently increased in response to SGLT2i in all the subgroups.CONCLUSION Heart failure patients with lower LVEF and lower NYHA sub-classifications were found to be generally more likely to benefit from therapy with gliflozins.Further research are required to identify patient subgroups representing the highest benefits or adverse events in response to SGLT2i.

Primary and secondary hyperoxaluria: Understanding the enigma

Hyperoxaluria is characterized by an increased urinary excretion of oxalate. Primary and secondary hyperoxaluria are two distinct clinical expressions of hyperoxaluria. Primary hyperoxaluria is an inherited error of metabolismdue to defective enzyme activity. In contrast, secondary hyperoxaluria is caused by increased dietary ingestion of oxalate, precursors of oxalate or alteration in intestinal microfora. The disease spectrum extends from recurrent kidney stones, nephrocalcinosis and urinary tract infections to chronic kidney disease and end stage renal disease. When calcium oxalate burden exceeds the renal excretory ability, calcium oxalate starts to deposit in various organ systems in a process called systemic oxalosis. Increased urinary oxalate levels help to make the diagnosis while plasma oxalate levels are likely to be more accurate when patients develop chronic kidney disease. Defnitivediagnosis of primary hyperoxaluria is achieved by genetic studies and if genetic studies prove inconclusive, liver biopsy is undertaken to establish diagnosis. Diagnostic clues pointing towards secondary hyperoxaluria are a supportive dietary history and tests to detect increased intestinal absorption of oxalate. Conservative treatment for both types of hyperoxaluria includes vigorous hydration and crystallization inhibitors to decrease calcium oxalate precipitation. Pyridoxine is also found to be helpful in approximately 30% patients with primary hyperoxaluriatype 1. Liver-kidney and isolated kidney transplantation are the treatment of choice in primary hyperoxaluria type 1 and type 2 respectively. Data is scarce on role of transplantation in primary hyperoxaluria type 3 where there are no reports of end stage renal disease so far. There are ongoing investigations into newer modalities of diagnosis and treatment of hyperoxaluria. Clinical differentiation between primary and secondary hyperoxaluria and further between the types of primary hyperoxaluria is very important because of implications in treatment and diagnosis. Hyperoxaluriacontinues to be a challenging disease and a high index of clinical suspicion is often the first step on the path to accurate diagnosis and management.

Therapeutic target for nephrotic syndrome: Identification of novel slit diaphragm associated molecules

The slit diaphragm bridging the neighboring foot pro-cesses functions as a fnal barrier of glomerular capil-lary wall for preventing the leak of plasma proteins into primary urine. It is now accepted that the dysfunction of the sit diaphragm contributes to the development of proteinuria in several glomerular diseases. Neph-rin, a gene product of NPHS1, a gene for a congenital nephrotic syndrome of Finnish type, constitutes an ex-tracellular domain of the slit diaphragm. Podocin was identified as a gene product of NPHS2 , a gene for a familial steroid-resistant nephrotic syndrome of French. Podocin binds the cytoplasmic domain of nephrin. After then, CD2 associated protein, NEPH1 and transient re-ceptor potential-6 were also found as crucial molecules of the slit diaphragm. In order to explore other novel molecules contributing to the development of protein-uria, we performed a subtraction hybridization assay with a normal rat glomerular RNA and a glomerular RNA of rats with a puromycin aminonucleoside ne-phropathy, a mimic of a human minimal change type nephrotic syndrome. Then we have found that synaptic vesicle protein 2B, ephrin-B1 and neurexin were already downregulated at the early stage of puromycin aminonucleoside nephropathy, and that these molecules were localized close to nephrin. It is conceivable that these molecules are the slit diaphragm associated molecules, which participate in the regulation of the barrier func-tion. These molecules could be targets to establish a novel therapy for nephrotic syndrome.

Asymptomatic hyperuricemia following renal transplantation

in the genesis and progression of kidney disease, and a few studies are beginning to show a possible benefcial effect of urate-lowering therapy. Whether this holds true for renal allograft recipients is not clear. In this short review evidence from epidemiological as well as intervention studies is summarized and discussed, with some practical considerations presented at the end.

Role of insulin resistance in uric acid nephrolithiasis

Metabolic syndrome has been implicated in the pathogenesis of uric acid stones.Although not completely understood,its role is supported by many studies demonstrating increased prevalence of uric acid stones in patients with metabolic syndrome and in particular insulin resistance,a major component of metabolic syndrome.This review presents epidemiologic studies demonstrating the association between metabolic syndrome and nephrolithiasis in general as well as the relationship between insulin resistance and uric acid stone formation,in particular.We also review studies that explore the pathophysiologic relationship between insulin resistance and uric acid nephrolithiasis.

Immunoglobulin A vasculitis nephritis:Current understanding of pathogenesis and treatment

The clinical spectrum of immunoglobulin A vasculitis nephritis(IgAVN)ranges from the relatively common transitory microscopic hematuria and/or low-grade proteinuria to nephritic or nephrotic syndrome,rapidly progressive glomerulonephritis,or even renal failure.Clinical and experimental studies have shown a multifactor pathogenesis:Infection triggers,impaired glycosylation of IgA1,complement activation,Toll-like-receptor activation and B cell proliferation.This knowledge can identify IgAVN patients at a greater risk for adverse outcome and increase the evidence for treatment recommendations.

Advanced wasting in peritoneal dialysis patients

AIM To identify patients with end-stage renal disease treated by peritoneal dialysis(PD) who had zero body fat(BF) as determined by analysis of body composition using anthropometric formulas estimating body water(V) and to compare nutritional parameters between these patients and PD patients whose BF was above zero.METHODS Body weight(W) consists of fat-free mass(FFM) andBF.Anthropometric formulas for calculating V allow the calculation of FFM as V/0.73,where 0.73 is the water fraction of FFM at normal hydration.Wasting from loss of BF has adverse survival outcomes in PD.Advanced wasting was defined as zero BF when V/0.73 is equal to or exceeds W.This study,which analyzed 439 PD patients at their first clearance study,used the Watson formulas estimating V to identify patients with V_(Watson)/0.73 ≥ W and compared their nutritional indices with those of PD patients with V_(Watson)/0.73 < W.RESULTS The study identified at the first clearance study two male patients with V_(Watson)/0.73 ≥ W among 439 patients on PD.Compared to 260 other male patients on PD,the two subjects with advanced wasting had exceptionally low body mass index and serum albumin concentration.The first of the two subjects also had very low values for serum creatinine concentration and total(in urine and spent peritoneal dialysate) creatinine excretion rate while the second subject had an elevated serum creatinine concentration and high creatinine excretion rate due,most probably,to non-compliance with the PD prescription.CONCLUSION Advanced wasting(zero BF) in PD patients,identified by the anthropometric formulas that estimate V,while rare,is associated with indices of poor somatic and visceral nutrition.

Proton pump inhibitor-induced hypomagnesemia: A new challenge

Proton pump inhibitors （PPIs） are commonly used in clinical practice for the prevention and treatment of peptic ulcer, gastritis, esophagitis and gastroesophageal refux. Hypomagnesemia has recently been recognized as a side effect of PPIs. Low magnesium levels may cause symptoms from several systems, some of which being potentially serious, such as tetany, seizures and arrhythmias. It seems that PPIs affect the gastrointesti-nal absorption of magnesium. Clinicians should be vigi-lant in order to timely consider and prevent or reverse hypomagnesemia in patients who take PPIs, especially if they are prone to this electrolyte disorder.

Oxidative stress as a potential causal factor for autoimmune hemolytic anemia and systemiclupuserythematosus

The kidneys and the blood system mutually exert infuence in maintaining homeostasis in the body. Because the kidneys control erythropoiesis by producing erythropoietinand by supporting hematopoiesis, anemia is associated with kidney diseases. Anemia is the most prevalent genetic disorder, and it is caused by a deficiency of glucose 6-phosphate dehydrogenase （G6PD）, for which sulfhydryl oxidation due to an insufficient supply of NADPH is a likely direct cause. Elevated reactive oxygen species （ROS） result in the sulfhydryl oxidation and hence are another potential cause for anemia. ROS are elevated in red blood cells （RBCs） under superoxide dismutase （SOD1） defciency in C57BL/6 mice. SOD1 defcient miceexhibit characteristics similar to autoimmune hemolytic anemia （AIHA） and systemic lupus erythematosus （SLE） at the gerontic stage. An examination of AIHA-prone New Zealand Black （NZB） mice, which have normal SOD1 and G6PD genes, indicated that ROS levels in RBCs are originally high and further elevated during aging. Transgenic overexpression of human SOD1 in erythroid cells effectively suppresses ROS elevation and ameliorates AIHA symptoms such as elevated anti-RBC antibodies and premature death in NZB mice. These results support the hypothesis that names oxidative stress as a risk factor for AIHA and other autoimmune diseases such as SLE. Herein we discuss the association between oxidative stress and SLE pathogenesis based mainly on the genetic and phenotypic characteristics of NZB and New Zealand white mice and provide insight into the mechanism of SLE pathogenesis.

ACE and ACE2 in kidney disease

Renin angiotensin system （RAS） activation has a significant influence on renal disease progression. The classical angiotensin-converting enzyme （ACE）-angio-tensin Ⅱ （Ang Ⅱ）-Ang Ⅱ type 1 （AT1） axis is considered to control the effects of RAS activation on renal disease. However, since its discovery in 2000 ACE2 has also been demonstrated to have a significant impact on the RAS. The synthesis and catabolism of Ang Ⅱ are regulated via a complex series of interactions, which involve ACE and ACE2. In the kidneys, ACE2 is expressed in the proximal tubules and less strongly in the glomeruli. The synthesis of inactive Ang 1-9 from Ang Ⅰ and the catabolism of Ang Ⅱ to produce Ang 1-7 are the main functions of ACE2. Ang 1-7 reduces vasoconstriction, water retention, salt intake, cell proliferation, and reactive oxygen stress, and also has a renoprotective effect. Thus, in the non-classical RAS the ACE2-Ang 1-7-Mas axis counteracts the ACE-Ang Ⅱ-AT1 axis. This review examines recent human and animal studies about renal ACE and ACE2.

Cardiovascular co-morbidity in chronic kidney disease:Current knowledge and future research needs

Chronic kidney disease(CKD) is recognised as a health concern globally and leads to high rates of morbidity,mortality and healthcare expenditure.CKD is itself an independent risk factor for unfavorable health outcomes that include cardiovascular disease(CVD).Coronary artery disease is the primary type of CVD in CKD patients and a significant cause of death among renal transplant patients.Traditional and non-traditional risk factors for CVD exist in patients with CKD.Traditional factors include smoking,hypertension,dyslipidemia and diabetes which are highly prevalent in CKD patients.Non-traditional risk factors of CKD are mainly uraemiaspecific and increase in prevalence as kidney function declines.Some examples of uraemia-specific risk factors that have been well documented include low levels of haemoglobin,albuminuria,and abnormal bone and mineral metabolism.Therapeutic interventions targeted at more traditional risk factors which contribute to CVD,have not had the desired effect on lowering CVD events and mortality in those suffering with CKD.Future research is warranted to delineate clear evidence to the benefit of modifying non-traditional risk factors.

Uric acid and chronic kidney disease: A time to act?

A role for uric acid in the pathogenesis and progression of renal disease had been proposed almost a century ago, but, too hastily dismissed in the early eighties. A body of evidence, mostly accumulated during the last decade, has led to a reappraisal of the infuence of uric acid on hypertension, cardiovascular, and renal disease. The focus of this review will be solely on the relationship between serum uric acid and renal function and disease. We will review experimental evidence derived from ani-mal and human studies, evidence gathered from a num-ber of epidemiological studies, and from the few （up to now） studies of uric-acid-lowering therapy. Some space will be also devoted to the effects of uric acid in special populations, such as diabetics and recipients of kidney allografts. Finally we will briefy discuss the challenges of a trial of uric-acid-lowering treatment, and the recent suggestions on how to conduct such a trial.

Should pediatric idiopathic hypercalciuria be treated with hypocalciuric agents?

BACKGROUND Hypercalciuria is the most common metabolic risk factor for calcium urolithiasis and is associated with bone loss in adult patients.Reduced bone mineral density(BMD)was already described in idiopathic hypercalciuria(IH)children,but the precise mechanisms of bone loss or inadequate bone mass gain remain unknown.Life-long hypercalciuria might be considered a risk to change bone structure and determine low bone mass throughout life.The peak of bone mass should occur without interferences.A beneficial effect of citrate formulations and thiazides on bone mass in adult and pediatric patients with IH have been shown.AIM To evaluate whether pharmacological therapy has a beneficial effect on bone mass in children and adolescents with IH.METHODS This retrospective cohort study evaluated 40 hypercalciuric children nonresponsive to lifestyle and diet changes.After a 2-mo run-in period of citrate formulation(Kcitrate)usage,the first bone densitometry(DXA)was ordered.In patients with sustained hypercalciuria,a thiazide diuretic was prescribed.The second DXA was performed after 12 mo.Bone densitometry was performed by DXA at lumbar spine(L2-L4).A 24-h urine(calcium,citrate,creatinine)and blood samples(urea,creatinine,uric acid,calcium,phosphorus,magnesium,chloride,hemoglobin)were obtained.Clinical data included age,gender,weight,height and body mass index.RESULTS Forty IH children;median age 10.5 year and median time follow-up 6.0 year were evaluated.Nine patients were treated with Kcitrate(G1)and 31 with Kcitrate+thiazide(G2).There were no differences in age,gender,body mass index z-score and biochemical parameters between G1 and G2.There were no increases in total cholesterol,kalemia and magnesemia.Calciuria decreased in both groups after treatment.Lumbar spine BMD z-score increased after thiazide treatment in G2.There was no improvement in G1.CONCLUSION Results point to a beneficial effect of thiazide on lumbar spine BMD z-score in children with IH.Further studies are necessary to confirm the results of the present study.

Monoclonal gammopathy of renal significance:Diagnostic workup

The clinical spectrum of diseases associated withmonoclonal gammopathies is wide and they are most commonly the consequence of renal deposition of monoclonal immunoglobulin or its components. The differential diagnosis is difficult and renal biopsy is essential. To distinguish many of these pathologies is necessary to use techniques that are not always avai-lable, even in tertiary central hospitals. This review will discuss the clinical presentation, pathologic features, treatment, prognosis and common diagnostic diffculties of these entities.

How botulinum toxin in neurogenic detrusor overactivity can reduce upper urinary tract damage?

Intradetrusor injections of botulinum toxin are the cornerstone of medical treatment of neurogenic detrusor overactivity. The primary aim of this treatment is to ensure a low pressure regimen in the urinary bladder, but the mechanisms leading to long-term protection of the urinary tract remain poorly understood. In this paper, we highlight the potential benefts of intradetrusor injections of botulinum toxin regarding local effects on the bladder structures, urinary tract infections, stone disease, vesico ureteral refux, hydronephrosis, renal function based on a comprehensive literature review.

Prolonged hypernatremia triggered by hyperglycemic hyperosmolar state with coma: A case report

A man with past lithium use for more than 15 years, but off lithium for two years and not carrying the diagnosis of diabetes mellitus or nephrogenic diabetes insipidus(NDI), presented with coma and hyperglycemic hyperosmolar state(HHS). Following correction of HHS, he developed persistent hypernatremia accompanied by large volumes of urine with low osmolality and no response to desmopressin injections. Urine osmolality remained < 300 m Osm/kg after injection of vasopressin. Improvement in serum sodium concentration followed the intake of large volumes of water plus administration of amiloride and hydrochlorothiazide. Severe hyperglycemia may trigger symptomatic lithium-induced NDI years after cessation of lithium therapy. Patients with newonset diabetes mellitus who had been on prolonged lithium therapy in the past require monitoring of their serum sodium concentration after hyperglycemic episodes regardless of whether they do or do not carry the diagnosis of NDI.

Complement activation and long-term graft function in ABO-incompatible kidney transplantation

BACKGROUND ABO-incompatible and ABO-compatible kidney transplantation are equivalent in terms of short-term graft and patient survival. This is thought to be the result of ABO-incompatible graft accommodation, which occurs when anti-blood group antibodies re-occur after transplantation but somehow do not yield their detrimental effect. The underlying mechanism is unclear, but one of the hypotheses is that this is the result of complement inhibition. Since virtually all ABO-incompatible graft biopsies are C4d positive, this complement inhibition must occur somewhere in the complement cascade after the formation of C4d has already taken place, but where exactly is unclear. It is also unclear whether complement inhibition is complete. Incomplete accommodation could explain why recent studies have shown that long-term graft function in ABOincompatible transplantation is somewhat inferior to ABO-compatible kidney transplantation.AIM To unravel the relationship between pre-transplant anti-ABO antibodies,complement activation, and long-term graft function.METHODS We included all 27 ABO-incompatible transplantations that were performed between 2008 and 2013 at the Academic Medical Center Amsterdam and the University Medical Center Groningen. For each ABO-incompatible transplantation, we included four ABO-compatible controls matched by age, sex,and transplantation date.RESULTS Graft and patient survival were not significantly different. The slope of kidney function during five-year follow-up was also not significantly different, but ABOincompatible recipients did have a lower kidney function at three months(creatinine clearance 58 vs 69 mL/min, P = 0.02, Modification of Diet in Renal Disease 46 vs 52 mL/min/1.73 m^2, P = 0.08), due to a high rate of early rejection(33% vs 15%, P = 0.03), mostly T-cell mediated. Pre-transplant anti-ABO Ig G titers were positively correlated with C5b-9 staining, which itself was positively correlated with the occurrence of T-cell mediated rejection. This may be the result of concurrent C5a formation, which could function as a costimulatory signal for T-cell activation.CONCLUSION Co-stimulation of T-cell activation by ongoing complement activation by antiABO antibodies may be responsible for an impaired long-term graft function in ABO-incompatible kidney transplantation.

Receptor activator of nuclear factorκB ligand/osteoprotegerin axis and vascular calcifications in patients with chronic kidney disease

Vascular calcifications are commonly observed in patients with chronic kidney disease （CKD） and contri-bute to the excessive cardiovascular morbidity and mortality rates observed in these patients populations. Although the pathogenetic mechanisms are not yet fully elucidated, recent evidence suggests a link between bone metabolism and the development and progression of vascular calcifications. Moreover, accumulating data indicate that receptor activator of nuclear factor κB ligand/osteoprotegerin axis which plays essential roles in the regulation of bone metabolism is also involved in extra-osseous bone formation. Further studies are required to establish the prognostic significance of the above biomarkers as predictors of the presence and severity of vascular calcifications in CKD patients and of cardiovascular morbidity and mortality. Moreover, randomized clinical trials are needed to clarify whether inhibition of osteoclast activity will protect from vascular calcifcations.

Experimental models of renal calcium stones in rodents

In human nephrolithiasis, most stones are containing calcium and are located within urinary cavities; they may contain monohydrate calcium oxalate, dihydrate calcium oxalate and/or calcium phosphates in various proportion. Nephrolithiasis may also be associated with nephrocalcinosis, i.e., crystal depositions in tubular lumen and/or interstitium, an entity which suggests specific pathological processes. Several rodents models have been developed in order to study the pathophysiology of intrarenal crystal formation. We review here calcium rodent models classified upon the presence of nephrolithiasis and/or nephrocalcinosis. As rodents are not prone to nephrolithiasis, models require the induction of a long standing hypercalciuria or hyperoxaluria(thus explaining the very few studies reported), conversely to nephrocalcinosis which may occur within hours or days. Whereas a nephrotoxicity leading to tubular injury and regeneration appears as a critical event for crystal retention in nephrocalcinosis models, surprisingly very little is known about the physiopathology of crystal attachment to urothelium in nephrolithiasis. Creating new models of nephrolithiasis especially in different genetic mice strains appears an important challenge in order to unravel the early mechanisms of urinary stone formation in papilla and fornices.

Cooling dialysate during in-center hemodialysis:Beneficial and deleterious effects

The use of cooled dialysate temperatures first came about in the early 1980s as a way to curb the incidence of intradialytic hypotension （IDH）. IDH was then, and it remains today, the most common complication affecting chronic hemodialysis patients. It decreases quality of life on dialysis and is an independent risk factor for mortality. Cooling dialysate was first employed as a technique to incite peripheral vasoconstriction on dialysis and in turn reduce the incidence of intradialytic hypotension. Although it has become a common practice amongst in-center hemodialysis units, cooled dialysate results in up to 70% of patients feeling cold while on dialysis and some even experience shivering. Over the years, various studies have been performed to evaluate the safety and effcacy of cooled dialysate in comparison to a standard, more thermoneutral dialysate temperature of 37℃. Although these studies are limited by small sample size, they are promising in many aspects. They demonstrated that cooled dialysis is safe and equally efficacious as thermoneutral dialysis. Although patients report feeling cold on dialysis, they also report increased energy and an improvement in their overall health following cooled dialysis. They established that cooling dialysate temperatures improves hemodynamic tolerability during and after hemodialysis, even in patients prone to IDH, and does so without adversely affecting dialysis adequacy. Cooled dialysis also reduces the incidence of IDH and has a protective effect over major organs including the heart and brain. Finally, it is an inexpensive measure that decreases economic burden by reducing necessary nursing intervention for issues that arise on hemodialysis such as IDH. Before cooled dialysate becomes standard of care for patients on chronic hemodialysis, larger studies with longer follow-up periods will need to take place to confrm the encouraging outcomes mentioned here.