Greater Glomerular Filtration Rate Research Articles

Reduction of BMPR2 mRNA Expression in Peripheral Blood of Pulmonary Arterial Hypertension Patients: A Marker for Disease Severity?

Pulmonary arterial hypertension (PAH) can be caused by pathogenic variants in the gene bone morphogenetic protein receptor 2 (BMPR2). While BMPR2 protein expression levels are known to be reduced in the lung tissue of heritable PAH (HPAH) patients, a systematic study evaluating expression in more easily accessible blood samples and its clinical relevance is lacking. Thus, we analyzed the BMPR2 mRNA expression in idiopathic/HPAH patients and healthy controls in blood by quantitative polymerase chain reaction and protein expression by enzyme-linked immunosorbent assay. Clinical parameters included right heart catherization, echocardiography, six-minute walking test and laboratory tests. BMPR2 variant-carriers (n = 23) showed significantly lower BMPR2 mRNA expression in comparison to non-carriers (n = 56) and healthy controls (n = 30; p < 0.0001). No difference in BMPR2 protein expression was detected. Lower BMPR2 mRNA expression correlated significantly with greater systolic pulmonary artery pressure and pulmonary vascular resistance. Higher BMPR2 mRNA expression correlated with greater glomerular filtration rate, cardiac index and six-minute walking distance. We demonstrated the feasibility to assess BMPR2 expression in blood and, for the first time, that BMPR2 mRNA expression levels are significantly reduced in variant carriers and correlated with clinical parameters. Further studies may evaluate the usefulness of BMPR2 mRNA expression in blood as a new marker for disease severity.

Extensive cell salvage and postoperative outcomes following thoracoabdominal and descending aortic repair

ObjectiveCell salvage (CS) reduces intraoperative blood transfusion. However, it may cause deformity of the red blood cells and loss of coagulation factors, which may lead to unwanted sequelae. Thus, we hypothesized that extensive CS would lead to adverse outcomes after descending/thoracoabdominal aortic aneurysm (D/TAAA) repair. MethodsBetween 1991 and 2017, 2012 patients undergoing D/TAAA repair were retrospectively reviewed. After we excluded patients without reported intraoperative CS amount, patients were enrolled in the study (N = 1474) and divided into 2 groups: low CS (salvaged units <40, N = 983) and high CS (salvaged units ≥40, N = 491). Analyses were performed to verify the extensive CS as the risk factor for adverse outcomes. ResultsPreoperative demographics showed that the high-CS group had a significantly greater incidence of male patients (72% vs 58%), heritable aortic disease (24% vs 17%), redo (27% vs 20%), greater glomerular filtration rate (mL/min/1.73 m2, 75 vs 66) and more extensive aneurysms (TAAA extent II-IV). The high-CS group had significantly more postoperative complications compared with the low-CS group, including respiratory failure, renal failure, cardiac complications, neurologic deficits, bleeding, and 30-day mortality. Multivariable analysis confirmed high CS was an independent risk factor for renal failure along with long bypass time, older age, and extent of repairs. There was an incremental risk of renal failure and 30-day mortality proportional to salvaged cell unit (P < .001 in both). ConclusionsIncreased salvaged cell units were associated with adverse postoperative outcomes after D/TAAA repairs. Risk of renal failure and mortality increased proportionally to the salvaged cell units.

Chronic Peptide Therapy With B-Type Natriuretic Peptide in Patients With Pre-Clinical Diastolic Dysfunction (Stage B Heart Failure)

ObjectivesThis study determined whether there is development of tachyphylaxis to enhancement of cardiorenal response to acute volume loading (AVL) with B-type natriuretic peptide (BNP) after 12-week, twice-daily subcutaneous BNP administration in patients with preclinical diastolic dysfunction (PDD). BackgroundPDD is characterized by normal systolic function and moderate or severe diastolic dysfunction but no symptoms of heart failure (HF). Impairment in cardiorenal endocrine response to stress by AVL exists in PDD and is corrected by acute administration of subcutaneous BNP. MethodsA double-blinded, placebo-controlled proof-of-concept study was conducted to compare 12 weeks of twice daily subcutaneous BNP, 10 μg/kg (n = 24), versus placebo (n = 12) in PDD. Subjects underwent 2 study visits, at baseline and after 12 weeks. At each study visit, echocardiography, renal, and neurohumoral assessments were performed before and after intravascular AVL. ResultsAmong those with PDD, there was a statistically significant improvement in diastolic function after 12 weeks of BNP, as measured by a decrease in the Doppler E/e′ ratio (where E is early mitral inflow velocity and e′ is mitral annulus early diastolic motion) (p = 0.004) and improvement of diastolic dysfunction grade (p = 0.008). After 12 weeks, there was statistically significantly greater sodium excretion, urine flow, and urinary cyclic guanosine monophosphate excretion to AVL (all p < 0.001), as well as a trend toward greater glomerular filtration rate (p = 0.050) in the BNP group as compared to the placebo group. ConclusionsIn subjects with PDD, chronic BNP administration resulted in sustained improvement in diastolic function without development of tachyphylaxis to the enhancement of cardiorenal response to volume expansion with BNP. (Human Brain Natriuretic Peptide [BNP] [or Nesiritide] to Help Heart, Kidney and Humoral Function; NCT00405548)

A comparative study of renal function in the desert-adapted spiny mouse and the laboratory-adapted C57BL/6 mouse: response to dietary salt load

The desert-adapted spiny mouse has a significantly lower glomerular number, increased glomerular size, and a more densely packed renal papillae compared with the similar-sized laboratory-adapted C57BL/6 mouse. In the present study we examined the functional consequences of these structural differences in young adult male spiny and C57BL/6 mice and detailed the impact of 1 wk of a high-salt (10% wt/wt NaCl) diet. Basal food and water intake, urine and feces production, and urinary electrolyte concentrations were not different between species, although urinary urea concentrations were higher in spiny mice (P < 0.05). On normal salt, MAP of the anesthetized spiny mouse was approximately 18 mmHg lower, effective renal plasma flow (ERPF) was 40% lower (P < 0.001), and glomerular filtration rate (GFR) tended to be lower than in the C57BL/6 mouse. On the high-salt diet, both species had similar 24-h NaCl excretions; but C57BL/6 mice required a significantly increased amount of water (lower urine NaCl concentration) than the spiny mice. Filtration fraction was greater in both species on the high-salt diet. Spiny mice had greater GFR and ERPF after the high-salt diet, whereas the C57BL/6 mouse showed little change in GFR. The ability of the spiny mouse to tolerate a significantly higher plasma osmolality after salt, measured by a decreased drinking response, and the ability to increase ERPF at a lower MAP are features that allow this species to conserve water more efficiently than can be done in the C57BL/6 mouse. These features are important, particularly since the desert mouse has a smaller kidney, with fewer nephrons.

An Evaluation of a Shared Primary and Secondary Care Nephrology Service for Managing Patients With Moderate to Advanced CKD

Chronic kidney disease (CKD) is common, and nephrology services may not cope with the comprehensive referral of patients with CKD. We evaluated a shared primary and secondary care nephrology scheme, hypothesizing that some patients with less progressive moderate to advanced CKD can be identified and safely managed without attending the renal unit. A retrospective review of 949 new referrals with stages 3 to 5 CKD managed in either the hospital nephrology clinic (HC) or the shared care scheme (SCS), in which nephrologists review patients remotely by using regular biochemical tests and clinical data recorded in primary care. Two hundred sixty-six patients (28%) were enrolled in the SCS and 683 patients (72%) were managed solely in the HC. Median time to entering the SCS was 111 days (interquartile range, 0 to 328 days). Baseline factors independently predictive of enrollment in the SCS were increasing age, greater glomerular filtration rate (GFR) and serum albumin levels, and no diabetic nephropathy. Few SCS patients did not attend reviews. Forty-one patients (15%) required recall to the HC, mostly because of a decline in GFR. Beneficial changes were seen in blood pressure levels and prescribing of angiotensin-system inhibitors from first referral to 3 years in all patients. Those enrolled in the SCS had good prognosis, with a lower risk for death or renal replacement therapy than the HC group after adjustment for age, sex, GFR, diabetic nephropathy, and vascular disease (hazard ratio, 0.64; 95% confidence interval, 0.38 to 0.89; P = 0.003). In this setting, it was possible to select nearly 30% of patients with stages 3 to 5 CKD for management in the SCS. More than half enrolled within 4 months of nephrology referral. Systematic surveillance was effective, and most patients remained stable, with few progressing to renal replacement therapy or death.

Effect of Comorbidity on the Increased Mortality Associated With Early Initiation of Dialysis

Current recommendations for initiating dialysis therapy are based on level of kidney function and clinical evidence of uremia. Several studies reported no benefit in patient survival from initiating dialysis therapy with a greater glomerular filtration rate (GFR). Whether this is explained by a greater comorbidity burden or detrimental effect of early initiation remains unclear. We thus undertook an evaluation of the impact of comorbidity on the association between GFR at initiation and death. Data from the Center for Medicare & Medicaid Services were used to derive 3 incident dialysis populations: (1) general population aged 18+ years, (2) older patients aged 67+ years, and (3) a "low-risk" subgroup without diabetes, heart failure, or atherosclerotic heart disease. A Cox proportional hazard regression technique was used. Greater GFR at initiation of dialysis therapy was associated with a greater risk for death in all populations, and sequential adjustment for additional covariates attenuated the effect. Patients in the general dialysis population who initiated dialysis therapy at a GFR greater than 10 mL/min/1.73 m2 (>0.17 mL/s) had a 42% increased risk for death compared with patients with a GFR less than 5 mL/min/1.73 m2 (<0.08 mL/s) at initiation of dialysis therapy after adjusting for all covariates. In the older and healthier populations, adjusted increased risks were 25% and 39%, respectively. Patients initiating dialysis therapy at greater GFRs have an increased risk for death not fully explained by comorbidity. Additional research is required to determine the reasons for poor survival in patients who start dialysis therapy with significant residual renal function.

A Comprehensive Assessment of Renal Function in Patients With Gaucher Disease

Gaucher disease (GD) is caused by deficiency of acid beta-glucocerebrosidase and is the most common lysosomal storage disease. Patients may have massive hepatosplenomegaly, severe bone disease, and, occasionally, pulmonary or neurological involvement. Although other storage diseases, such as Fabry disease, frequently affect the kidneys, reports of renal abnormalities in patients with GD are limited to case reports. Our aim was to perform a comprehensive evaluation of renal function in patients with GD. Evaluation was performed at routine clinic visits and included blood pressure recording and renal ultrasound. Serum chemistries, urinalysis, urine electrolytes, total protein, and tubular proteinuria were assessed, and estimated glomerular filtration rate (GFR) was calculated. One hundred sixty-one patients underwent evaluation, including 26 children. GFR was significantly greater in patients with GD than in age- and sex-matched healthy controls (P = 0.01 in men, P < 0.001 in women, P = 0.003 in children). Subgroups of patients with markers of more severe disease had a greater GFR than other patients. No patient had decreased renal function. Significant proteinuria was found only in patients with such comorbidities as diabetes mellitus or multiple myeloma. No evidence of renal tubular abnormalities was found, and kidney sonographic appearance and size were normal. Despite the multiorgan nature of the disease, a systematic evaluation did not find renal abnormalities in patients with GD. Glomerular hyperfiltration was observed in a proportion of patients, particularly those with markers of more severe disease. This phenomenon does not seem to be associated with a subsequent decline in renal function.

L-arginine as a therapeutic tool in kidney disease

Infusion of L-arginine in experimental animals increases renal plasma flow (RPF) and glomerular filtration rate (GFR). It is likely that a component of these hemodynamic changes are mediated by nitric oxide (NO) as suggested by studies with specific antagonists of L-arginine metabolism. L-arginine administration ameliorates the infiltration of the renal parenchyma by macrophages in rats with obstructive nephropathy or rats with puromycin-induced nephrotic syndrome. L-arginine administration also blunts the increase in interstitial volume, collagen IV, and α-smooth muscle actin. Rats with a remnant kidney given 1% L-arginine in the drinking water had a greater GFR and RPF. L-arginine administration also decreased proteinuria. Diabetic rats given L-arginine had significantly lower excretion of protein and cyclic guanosine monophosphate than diabetic rats not receiving L-arginine. Despite persistent hyperglycemia, the administration of L-arginine prevented the development of hyperfiltration and ameliorated proteinuria in diabetic rats. In the setting of ischemic acute renal failure, the administration of L-arginine had a beneficial effect on GFR and RPF, decreased O 2 − production, diminished up-regulation of soluble guanylate cyclase, and prevented up-regulation of inducible NO synthase (iNOS). The pharmacokinetics of L-arginine indicate that side effects are rare and mostly mild and dose dependent.

L-arginine decreases the infiltration of the kidney by macrophages in obstructive nephropathy and puromycin-induced nephrosis

We examined the effect of 1% L-arginine in the drinking water on the infiltration of the kidney by macrophages in rats with puromycin aminonucleoside-induced nephrosis (PAN) and in rats with bilateral ureteral obstruction (BUO) of 24 hours duration. Rats given L-arginine in the drinking water for three days before BUO or PAN was initiated had a greater glomerular filtration rate after release of BUO or induction of PAN than similar rats not given L-arginine (P < 0.0001). Administration of L-arginine decreased the renal infiltration by macrophages in rats with PAN (P < 0.0001) or BUO (P < 0.0001) compared to rats with PAN or BUO given tap water alone. Chemotaxis studies suggested that macrophages were activated during obstruction as evidenced by the greater random migration of peritoneal macrophages obtained from rats with 24-hour urethral obstruction than from sham-operated rats (SOR; P < 0.0001). In vitro, maximal chemotaxis induced by 7% zymosan-activated serum (ZAS) in peritoneal macrophages from SOR was enhanced by low (10(-6) to 10(-5) M) and decreased by high concentrations (10(-3) to 10(-2) M) of L-arginine in the incubation medium. Migration of macrophages from rats with urethral obstruction was increased by 7% ZAS but the increase diminished with high concentrations of L-arginine (10(-3) to 10(-2) M). Random migration of peritoneal macrophages obtained from rats with urethral obstruction given L-arginine prior to obstruction was significantly lower than that of peritoneal macrophages obtained from similar rats given tap water alone prior to obstruction.(ABSTRACT TRUNCATED AT 250 WORDS)

Dissociation of systemic and renal effects in endotoxemia. Prostaglandin inhibition uncovers an important role of renal nerves.

To elucidate the mechanisms responsible for systemic and renal hemodynamic changes in early endotoxemia, the roles of prostaglandins (PG) and renal nerves were investigated. Endotoxin (E, 3 micrograms/kg i.v.) was given to two groups of anesthetized dogs that had undergone unilateral renal denervation: Group I (n = 9) E only; Group II (n = 11) E + indomethacin (10 mg/kg i.v.) or meclofenamate (5 mg/kg i.v.). A third group of dogs (Group III, n = 5) received indomethacin (10 mg/kg i.v.) only. 1 h after E group I dogs, mean arterial pressure (MAP) decreased from 126 to 94 mm Hg (P less than 0.001), and prostacyclin (6-keto-Fl alpha metabolite, PGI2) increased (from 0.64 to 2.08 ng/ml, P less than 0.005). Glomerular filtration rate (GFR) and renal blood flow (RBF) declined comparably both in innervated and denervated kidneys. In marked contrast, group II dogs had a stable MAP (136-144 mm Hg, NS) and no increase in PGI2 levels. Plasma renin activity (0.7-2.5 ng/ml per h, P less than 0.005) increased, and renin secretion was greater in innervated compared with denervated kidneys (255 vs. 74 U/min, P less than 0.01) in these PG-inhibited dogs. In addition, denervated kidneys in group II dogs had a greater GFR (42 vs. 34 ml/min, P less than 0.01) and RFB (241 vs. 182 ml/min, P less than 0.01) than innervated kidneys after E. Group III animals had no significant changes in systemic or renal hemodynamics, plasma renin activity or PGI2 during the study. These results suggest that PGI2 mediates the systemic hypotension of early endotoxemia in the PG-intact animal. Moreover, PG inhibition uncovers an important effect of E to increase efferent renal nerve activity with a consequent decline in GFR and RBF independent of changes in MAP. Finally, the results demonstrate that renal nerves are important stimuli to renin secretion in early endotoxemia via pathways that are PG-independent.