Vascular endothelial growth factor-D plasma levels in fluid overload and cardiac function evaluation of elderly patients with cardiovascular disease.

This study aimed to investigate the clinical significance of vascular endothelial growth factor (VEGF) subtypes and growth differentiation factor-15 (GDF-15) plasma levels in evaluating the fluid overload and cardiac function of elderly patients with cardiovascular disease. The plasma levels of VEGF-C, VEGF-D, and GDF-15 were measured using ELISA. Their correlations with N-terminal pro B-type natriuretic peptide (NT-Pro BNP) and echocardiography data were analyzed. 1. Higher plasma levels of VEGF-D and GDF-15 were observed in elderly patients with cardiovascular disease and heart failure(P < .01). VEGF-D plasma levels were higher in patients with chronic heart failure than those with acute myocardial infarction (P < .01). VEGF-D plasma levels were positively correlated with amino-terminal pro-B type natriuretic peptide (NT-pro BNP) (P < .001). VEGF-D plasma levels were positively correlated with echocardiographic parameters, including left atrial diameter, left ventricular end-diastolic diameter and left ventricular ejection fraction, in patients with cardiovascular disease (P < .01). 2. VEGF-C plasma levels were higher in acute myocardial infarction group (P < .05). The plasma levels of VEGF-C were not correlated with either VEGF-D or NT-pro BNP plasma levels. VEGF-C plasma levels had no correlation with echocardiographic parameters. 3. GDF-15 plasma levels were positively correlated with sera biomarkers of cardiac injury (creatine kinase isoenzyme MB and cardiac troponin I). GDF-15 plasma levels were positively correlated with urinary biomarkers of tubular injury (N-acetyl-ß-galactosidase and α1-microglobulin). Both GDF-15 and NT-pro BNP plasma levels were correlated with age, estimated glomerular filtration rate (eGFR), and nutritional biomarkers (albumin and hemoglobin plasma levels). VEGF-D plasma levels is a potential biomarker of fluid overload and cardiac function in elderly patients with cardiovascular disease. Age, nutrition, and kidney injury are factors influencing both GDF-15 and NT-pro BNP plasma levels in estimating cardiac function and fluid overload.

Selonsertib Enhances Kidney Protection Beyond Standard of Care in a Hypertensive, Secondary Glomerulosclerosis CKD Model.

Background: Despite widespread use of renin-aldosterone-angiotensin system inhibitors and the benefits of lowering glomerular pressure in patients with CKD, there remains a major unmet need for therapies targeting underlying causes of CKD progression. Apoptosis signal-regulating kinase 1 (ASK1) promotes apoptosis and glomerulosclerosis, and is implicated in the progression of diabetic kidney disease (DKD), a major cause of CKD. Selonsertib is a selective ASK1 inhibitor currently in clinical development for the treatment of DKD. We examined the added benefits of selonsertib on existing glomerulosclerosis and related molecular pathways in the nondiabetic 5/6 nephrectomy (5/6 Nx) rat model in combination with the angiotensin-converting enzyme inhibitor (ACEI) enalapril. Methods: Male Sprague Dawley rats underwent 5/6 Nx with kidney biopsy 8 weeks later for assessment of glomerulosclerosis, and were randomized to four treatment groups with equal glomerulosclerosis: selonsertib, enalapril, combination (selonsertib plus enalapril), and untreated controls. Serum creatinine, systolic BP (SBP), and urinary albumin were measured at intervals. Animals were euthanized at week 12 for histologic, biochemical, and molecular analyses. Results: All rats developed hypertension, albuminuria, and glomerulosclerosis by week 8. Kidney function further declined, and glomerulosclerosis and albuminuria progressively increased in controls from week 8 to 12. Enalapril treatment alone from week 8 to 12 reduced SBP versus controls, decreased albuminuria, and resulted in numerically lower glomerulosclerosis. Selonsertib alone had no effect on SBP but preserved kidney function. Combined treatment significantly reduced glomerulosclerosis, with more regression than either monotherapy. Enalapril treatment resulted in fewer interstitial macrophages, whereas selonsertib treatment reduced apoptosis and podocyte loss. RNA-seq revealed that combined treatment influenced pathways related to extracellular matrix and wound healing. Conclusions: Selonsertib targets a novel, nonhemodynamic pathway in CKD. Our data suggest that ASK1 inhibition, when combined with ACEI, has additive effects to reduce progression of glomerulosclerosis, attenuate kidney function decline, and reduce podocyte loss.

Immune-related ureteritis and cystitis induced by immune checkpoint inhibitors: Case report and literature review.

Immune checkpoint inhibitors (ICIs), including anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA4) and anti-programmed death cell protein 1 (anti-PD-1), are increasingly prescribed in metastatic carcinoma therapy. ICI-related kidney injury is gradually recognized by clinicians. However, immune-related ureteritis and cystitis easily go undiagnosed. We report three cases of PD-1 monoclonal antibody (mAb)-related ureteritis and cystitis. We further carried out a review of the literature about ICI-related ureteritis and cystitis. The cases in our reports manifest urinary irritation, sterile pyuria, gross hematuria, hydronephrosis, dilation of the ureters, and acute kidney injury. Urinary irritation improved effectively; urinalysis and renal function returned to normal after glucocorticoid therapy. During ICI therapy, urinalysis and renal function and urinary imaging examination are recommended to be monitored regularly. It contributes to identify immune-related ureteritis/cystitis earlier to efficiently alleviate urinary symptoms and immunologic urinary tract injury through glucocorticoid therapy while avoiding the abuse of antibiotics.

Retrospective analysis of renal prognosis in elderly coronary artery disease patients complicated with renal insufficiency.

OBJECTIVE AND METHODS: The aim of this study was to retrospectively analyze the renal prognosis of elderly coronary artery disease (CAD) patients complicated with renal insufficiency. RESULTS: A total of 307 patients were included. The mean follow-up period was 25±11months. The average age was 79±7 years. In the worsening renal function group, there were higher occurrence rate of heart failure and severe coronary artery stenosis, lower rate of percutaneous coronary intervention, lower medication rate of renin-angiotensin blocker, lower plasma albumin, magnesium and hemoglobulin level. There was no significant difference in the rate of worsening renal function or gastrointestinal bleeding between patients who took anti-platelet agents/statins and those without. Patients with reduced left ventricular ejective fraction had higher rate of worsening renal function, yet lower medication rate of renin-angiotensin blockers, lower plasma albumin and hemoglobulin level. Anemia, malnutrition and worsening cardiac function were risk factors of renal function deterioration and mortality. CONCLUSIONS: In the elderly coronary artery disease patients who had renal insufficiency, antiplatelet agents and statin have non-adverse effects on renal function; lower medication rate of renin-angiotensin blocker were found in patients with either worsening renal function or heart failure. Anemia, malnutrition and worsening cardiac function are risk factors of renal function deterioration and mortality.

Significance of M2 macrophage in tubulointerstitial disease secondary to primary Sjogren's disease.

OBJECTIVE: M2 Macrophages could improve tubulointerstitial disease in animal models. HIF-1αpromotes macrophage polarization and is involved in tubular injury. The study aims to observe the clinicopathologic significance of M2 macrophage and HIF-1α in tubulointerstitial injury secondary to primary Sjogren's disease. METHODS: Renal tissue samples from patients with tubulointerstitial disease secondary to primary Sjogren's disease (SS, n = 10), chronic tubulointerstitial nephritis secondary to drug (CIN, n = 8) were included in this study. The expression of CD163, CD68 and HIF-1α were examined by immunohistochemistry or immunofluorescence. RESULTS: (1) Renal involvement was the first manifestation in seven of ten (7/10) patients with pSS, including proteinuria, renal dysfunction, renal tubular acidosis and multiple renal stone; and two patient had intractable hypokalemia. (2) There were numerous CD163- positive cells and CD68- positive cells infiltration in tubulointerstitial injury of pSS, especially in patients with hypokalemia. CD163 positive cells and HIF-1αwere mainly expressed in acute tubulointerstitial injury of pSS, which positively correlated to N-acetyl-ß-D-glucosaminidase and ß2-microglobulin. (3) Compared with CIN, patients with pSS had higher serum globulin level, erythrocyte sedimentation rate (ESR) and lower urinary osmotic pressure. (4) During follow-up of one year, six patients with pSS and acute tubular injury acquired improved renal function on therapy of steroid and total glucosides of peony. The remaining four patients with pSS had stable renal function. CONCLUSION: M2 macrophages are involved in acute tubular injury in patients with primary Sjogren's disease. Early intervention can improve renal function of tubulointerstitial injury secondary to primary Sjogren's disease.

Significance of M2 macrophages in glomerulonephritis with crescents.

OBJECTIVES: CD163 and CD206, markers of M2 macrophages, possesses anti-inflammatory properties. This study aims to investigate the clinicopathologic significance of M2 macrophages in patients of glomerulonephritis with crescents. METHODS: Renal tissue samples from patients of glomerulonephritis with more than 30% cell or cell-fibrous crescents, including lupus nephritis (LN, n=14), anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV, n=14), IgA nephropathy(IgAN) (n=11), Henoch Schonlein purpura glomerulonephritis(HSPGN)(n=8)were included in this study. The expression of CD163, CD206 and CD68 in renal tissues was detected by immunohistochemistry or immunofluorescence. RESULTS: (1) CD163 was mainly expressed in cell or cell-fibrous crescents, proliferative glomerular lesions and acute tubulointerstitial injury. There were numerous CD163-positive cells in LN and AAV in comparison with IgAN and HSPGN. (2) CD206-positive cells were mainly observed in acute tubulointerstitial injury, and proliferative glomerular lesions, especially in LN. Patients with LN had numerous CD206-positive cells in glomerular than other groups. The number of CD163-positive cells and CD206-positive cells in acute tubulointerstitial lesions of LN and AAV were more than IgAN and HSPGN. (3) Both the number of CD163-positive cells and CD206-positive cells in acute tubulointerstitial lesions negatively correlated to estimated glomerular filtration rate. (4) In LN, activity index (AI) positively correlated with the number of CD206-positive cells and CD163-positive cells. Dual staining showed that CD163-positive cells and CD206-positive cells also expressed CD68. CONCLUSIONS: CD163-positive cells and CD206-positive cells, subpopulation of macrophages, which were involved in the pathogenesis of active crescentic glomerulonephritis, especially in LN and AAV.

[Relationship of genotypes with clinical phenotypes and outcomes in children with cobalamin C type combined methylmalonic aciduria and homocystinuria].

OBJECTIVE: To analyze mutation types, clinical features, and treatment outcomes of cobalamin C (cblC) type combined methylmalonic aciduria and homocystinuria (MMA-HC) and to investigate the relationship of genotypes with clinical phenotypes and outcomes. METHODS: The clinical data of 16 Chinese children diagnosed with cblC type MMA-HC by gene analysis were retrospectively analyzed. According to the onset age, the patients were classified into early onset (≤1 year) and late onset (>1 year). According to the clinical phenotype, the patients were classified into mild, moderate, and severe groups. All the patients were treated with vitamin B12 (cyanocobalamin) or hydroxocobalamin, betaine, folate, vitamin B6, and L-carnitine. RESULTS: Fifteen patients belonged to the early onset type, including 11 in the severe group and 4 in the moderate group. The remaining one belonged to the late onset type. Seven reported mutations and two novel mutations (c.445_446delTG and c.349G>c) were detected. The c.609G>A and c.658_660delAAG were the most common mutations detected in 13 (81%) out of 16 patients. The genotype caused by compound heterozygous mutations of these two alleles (c.609 G>A/c.658_660delAAG) was the most common in the patients, detected in 4 (25%) out of 16 patients. Patients with this genotype had severe microcephaly and eye diseases and these clinical manifestations were not improved after the treatment. The patient with late-onset cblC type MMA-HC had normal clinical phenotypes after treatment. In the 15 early onset patients, the more severe the clinical phenotype, the worse the treatment outcome. CONCLUSIONS: The cblC type MMA-HC mainly manifests as early onset in China and c.609G >A and c.658_660delAAG are the most common mutations causing this disease. The clinical phenotypes are associated with the outcomes in children with cblC type MMA-HC.

[Gene mutation analysis of X-linked hypophosphatemic rickets].

OBJECTIVE: To investigate the frequency and type of PHEX gene mutations in children with X-linked hypophosphatemic rickets (XLH), the possible presence of mutational hot spots, and the relationship between genotype and clinical phenotype. METHODS: Clinical data of 10 children with XLH was retrospectively reviewed. The relationship between gene mutation type and severity of XLH was evaluated. RESULTS: PHEX gene mutations were detected in all 10 children with XLH, including 6 cases of missense mutation, 2 cases of splice site mutation, 1 case of frameshift mutation, and 1 case of nonsense mutation. Two new mutations, c.2048T>C and IVS14+1delAG, were found. The type of PHEX gene mutation was not associated with the degree of short stature and leg deformity (P=0.571 and 0.467), and the mutation site was also not associated with the degree of short stature and leg deformity (P=0.400 and 1.000). CONCLUSIONS: Missense mutation is the most common type of PHEX gene mutation in children with XLH, and c.2048T>C and IVS14+1delAG are two new PHEX gene mutations. The type and site of PHEX gene mutation are not associated with the severity of XLH.

[Clinical analysis and genetic diagnosis of short-limb inherited short stature diseases in children].

OBJECTIVE: To analyze the clinical manifestations, bone X-ray findings and genetic analysis results of three short-limb inherited short stature diseases: achondroplasia (ACH), hypochondroplasia (HCH) and pseudoachondroplasia (PSACH). METHODS: The clinical manifestations, bone X-ray findings, and genetic analysis results of 10 children with genetically confirmed short-limb inherited short stature diseases, including 4 cases of ACH 3 cases of HCH, and 3 cases of PSACH, were analyzed. RESULTS: The 10 patients had a mean body height of -3.69±1.79 SD, a mean sitting height/standing height ratio of 0.65±0.03, and a mean finger spacing/body height ratio of 0.93±0.04. Four ACH cases and 3 PSACH cases showed typical bone X-ray findings; one HCH case showed a smaller sciatic notch, and another HCH case showed no widening of interpedicular distance. G380R mutation in FGFR3 gene was detected in 3 of 4 ACH cases, and Y278C mutation in the other ACH case, N540K mutation in FGFR3 gene was detected in 3 HCH cases, and heterozygous mutations in COMP gene were detected in 3 PSACH cases. CONCLUSIONS: Children with ACH and PSACH have severer short stature and skeletal deformities than children with HCH, who have mild, atypical clinical manifestations. Bone X-ray and genetic analysis are helpful for the diagnosis and differential diagnosis of the three diseases. The mutational hotspots in two genes are involved in the three diseases, which is conducive to clinical genetic diagnosis.

Clinical effects of pulse high-volume hemofiltration on severe acute pancreatitis complicated with multiple organ dysfunction syndrome.

To evaluate the effects of pulse high-volume hemofiltration (PHVHF) on severe acute pancreatitis (SAP) with multiple organ dysfunction syndrome (MODS). Thirty patients were divided into two groups: PHVHF group and continuous venovenous hemofiltration (CVVH) group. They were evaluated in terms of clinical symptoms, acute physiology and chronic health evaluation (APACHE) II score, sequential organ failure assessment (SOFA) score, simplified acute physiology (SAPS) II score and biochemical changes. The levels of IL-6, IL-10 and TNF-α in plasma were assessed by ELISA before and after treatment. The doses of dopamine used in shock patients were also analyzed. In the two groups, symptoms were markedly improved after treatment. Body temperature (BT), breath rate (BR), heart rate (HR), APACHE II score, SOFA score, SAPS II score, serum amylase, white blood cell count and C-reactive protein were decreased after hemofiltration (P < 0.05). The PHVHF group was superior to the CVVH group, especially in APACHE II score, CRP (P < 0.01), HR, temperature, SOFA score and SAPS II score (P < 0.05). The doses of dopamine for shock patients were also decreased in the two groups (P < 0.05), with more reduction in the PHVHF group than the CVVH group (P < 0.05). The levels of IL-6, IL-10 and TNF-α decreased (P < 0.05) in the PHVHF group more significantly than the CVVH group (P < 0.01). PHVHF appears to be superior to CVVH in the treatment of SAP with MODS.