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Glomerular filtration rate (GFR) assesses kidney function. GFR is measured by renal clearance techniques; inulin clearance is the gold standard but is not easily measured. Thus, other methods to determine GFR have been utilized. Endogenous creatinine clearance (CrCl) is the most widely used, but creatinine secretion falsely elevates GFR. Cimetidine inhibits creatinine secretion, such that CrCl equals GFR, provided there are no difficulties with bladder emptying. Estimation of GFR from serum creatinine (e.g. Schwartz formula) is useful clinically; however, such formulae have not been updated for enzymatic creatinine autoanalyzers. Cystatin C, a small protein, is produced at a relatively constant rate and is reabsorbed in the proximal tubule. Cystatin C may be more sensitive than creatinine in detecting a reduction in GFR, but further studies are needed to prove this. Single injection (plasma) clearance techniques are the most precise measures of GFR. Iohexol is an exogenous marker that is comparable to inulin and (51)Cr-EDTA and can be measured by high-performance liquid chromatography (HPLC). Our pilot and the Chronic Kidney Disease in Children (CKiD) North American studies show that iohexol can accurately measure GFR using a four-point plasma disappearance curve national studies show that iohexol can accurately measure GFR using a four-point plasma disappearance curve (10, 30, 120, and 300 min) or, in most cases, a two-point disappearance time (120 and 300 min).

Due to advances in medical and surgical care, there are more adults than children living with congenital heart disease (CHD). Acute kidney injury (AKI) is a common complication following cardiac surgery in patients with CHD, with creatinine lacking sensitivity for early detection. Renal functional reserve (RFR), the kidney’s capacity to increase filtration under stress, has emerged as a potential predictor of AKI. Our primary study objective was to evaluate whether preoperative RFR, using both creatinine clearance (CrCl) and cystatin C estimated glomerular filtration rate (eGFR) methods, predicts AKI following cardiopulmonary bypass in young adults with CHD. As a secondary objective, we compared RFR in CHD patients to that of healthy controls. This prospective cohort study included 30 young adults (ages 18–40) with acyanotic CHD and 8 healthy controls with normal baseline kidney function by serum creatinine. Preoperative RFR was measured using CrCl and cystatin C eGFR before and after a protein load. Postoperative AKI was diagnosed using the Kidney Disease Improving Global Outcomes criteria. Twelve (40%) CHD patients developed AKI, exhibiting significantly lower RFR when compared to those without AKI (median CrCl RFR: 9.6 vs. 35.0 mL/min/1.73m 2 ; cystatin C eGFR RFR: 5.5 vs. 11.5 mL/min/1.73m 2 ; P  < 0.01). The ROC curve area for AKI prediction was 1.0 (CrCl RFR) and 0.88 (95% CI: 0.72–1.00, cystatin C eGFR RFR). CHD patients had lower RFR than controls (median CrCl: 25.5 vs. 56.4 mL/min/1.73m 2 , P  < 0.01; median cystatin C eGFR: 9.0 vs. 13.5 mL/min/1.73m 2 , P  = 0.03). In conclusion, preoperative RFR accurately predicts AKI in young adults with acyanotic CHD, providing a tool for the identification of high-risk patients and potentially improving perioperative care.

The International Study of Kidney Disease in Children (ISKDC), begun in 1966, conducted the first international collaborative randomized blinded controlled trial in pediatric nephrology and one of the first in either pediatrics or nephrology. For this trial, the ISKDC developed the criteria, such as those for response and relapse, used today to describe the clinical course of the nephrotic syndrome, and the trial generated the nephropathologic terminology and criteria which largely remain the current standards. Over an approximately 20-year span, the ISKDC followed the natural history and evaluated the therapeutic effectiveness of therapies in over 500 children with the nephrotic syndrome from three continents. It published 14 peer-reviewed studies and several reports and commentaries, many of which helped create current standards of practice for therapy of childhood nephrotic syndrome and consequently remain highly cited today. The ISKDC continues to be an important model for subsequent collaborative studies and was the impetus for the development of regional and national pediatric nephrology societies leading to the recognition and growth of pediatric nephrology as a separate subspecialty.

Acidosis is associated with E. coli  induced pyelonephritis but whether bacterial cell wall constituents inhibit HCO 3 transport in the outer medullary collecting duct from the inner stripe (OMCDi) is not known. We examined the effect of lipopolysaccharide (LPS), on HCO 3 absorption in isolated perfused rabbit OMCDi. LPS caused a ~ 40% decrease in HCO 3  absorption, providing a mechanism for E. coli pyelonephritis-induced acidosis. Monophosphoryl lipid A (MPLA), a detoxified TLR4 agonist, and Wortmannin, a phosphoinositide 3-kinase inhibitor, prevented the LPS-mediated decrease, demonstrating the role of TLR4-PI3-kinase signaling and providing proof-of-concept for therapeutic interventions aimed at ameliorating OMCDi dysfunction and pyelonephritis-induced acidosis.

The Na ⁺ concentration of the intracellular milieu is very low compared with the extracellular medium. Transport of Na ⁺ along this gradient is used to fuel secondary transport of many solutes, and thus plays a major role for most cell functions including the control of cell volume and resting membrane potential. Because of a continuous leak, Na ⁺ has to be permanently removed from the intracellular milieu, a process that is thought to be exclusively mediated by the Na ⁺/K ⁺-ATPase in animal cells. Here, we show that intercalated cells of the mouse kidney are an exception to this general rule. By an approach combining two-photon imaging of isolated renal tubules, physiological studies, and genetically engineered animals, we demonstrate that inhibition of the H ⁺ vacuolar-type ATPase (V-ATPase) caused drastic cell swelling and depolarization, and also inhibited the NaCl absorption pathway that we recently discovered in intercalated cells. In contrast, pharmacological blockade of the Na ⁺/K ⁺-ATPase had no effects. Basolateral NaCl exit from β-intercalated cells was independent of the Na ⁺/K ⁺-ATPase but critically relied on the presence of the basolateral ion transporter anion exchanger 4. We conclude that not all animal cells critically rely on the sodium pump as the unique bioenergizer, but can be replaced by the H ⁺ V-ATPase in renal intercalated cells. This concept is likely to apply to other animal cell types characterized by plasma membrane expression of the H ⁺ V-ATPase.

More than two-thirds of the world's HIV-positive individuals live in sub-Saharan Africa, where genetic susceptibility to kidney disease is high and resources for kidney disease screening and antiretroviral therapy (ART) toxicity monitoring are limited. Equations to estimate glomerular filtration rate (GFR) from serum creatinine were derived in Western populations and may be less accurate in this population. We compared results from published GFR estimating equations with a direct measure of GFR by iohexol clearance in 99 HIV-infected, ART-naïve Kenyan adults. Iohexol concentration was measured from dried blood spots on filter paper. The bias ratio (mean of the ratio of estimated to measured GFR) and accuracy (percentage of estimates within 30% of the measured GFR) were calculated. The median age was 35 years, and 60% were women. The majority had asymptomatic HIV, with median CD4+ cell count of 355 cells/mm(3). Median measured GFR was 115 mL/min/1.73 m(2). Overall accuracy was highest for the Chronic Kidney Disease Epidemiology Consortium (CKD-EPI) equation. Consistent with a prior report, bias and accuracy were improved by eliminating the coefficient for black race (85% of estimates within 30% of measured GFR). Accuracy of all equations was poor in participants with GFR 60-90 mL/min/1.73 m(2) (<65% of estimates within 30% of measured GFR), although this subgroup was too small to reach definitive conclusions. Overall accuracy was highest for the CKD-EPI equation. Eliminating the coefficient for race further improved performance. Future studies are needed to determine the most accurate GFR estimate for use in individuals with GFR <90 mL/min/1.73 m(2), in whom accurate estimation of kidney function is important to guide drug dosing. Direct measurement of GFR by iohexol clearance using a filter paper based assay is feasible for research purposes in resource-limited settings, and could be used to develop more accurate GFR estimates in African populations.

Acute pyelonephritis caused by uropathogenic E. coli (UPEC) can cause renal scarring and lead to development of chronic kidney disease. Prevention of kidney injury requires an understanding of host factors and/or UPEC adaptive responses that are permissive for UPEC colonization of the urinary tract. Although some studies have suggested urine acidification limits UPEC growth in culture, other studies have described acid‐resistance mechanisms (AR) in E. coli such as the CadC/CadBA module that promotes adaptation to acid and nitrosative stress. Herein we confirm and extend our previous study by demonstrating that despite urine acidification, metabolic acidosis induced by dietary ammonium chloride (NH4Cl‐A) exacerbates cystitis and pyelonephritis in innate immune competent (C3H‐HeN) mice characterized by: (1) markedly elevated UPEC burden and increased chemokine/cytokine and NOS2 mRNA expression, (2) accumulation of intravesicular debris noninvasively detected by Power Doppler Ultrasound (PDUS), and (3) collecting duct (CD) dysfunction that manifests as a urine concentration defect. Bladder debris and CD dysfunction were due to the inflammatory response, as neither was observed in Tlr4‐deficient (C3H‐HeJ) mice. The effect of NH4Cl‐A was unrelated to acidosis as dietary administration of hydrochloric acid (HCl‐A) yielded a comparable acid–base status yet did not increase UPEC burden. NH4Cl‐A increased polyamines and decreased nitric oxide (NO) metabolites in urine indicating that excess dietary ammonium shifts arginine metabolism toward polyamines at the expense of NO synthesis. Furthermore, despite increased expression of NOS2, NO production post UPEC infection was attenuated in NH4Cl‐A mice compared to controls. Thus, in addition to induction of metabolic acidosis and urine acidification, excess dietary ammonium alters the polyamine:NO balance and thereby compromises NOS2‐mediated innate immune defense. Acute pyelonephritis caused by uropathogenic E. coli (UPEC) can cause renal scarring and lead to development of chronic kidney disease. Excess dietary ammonium alters the polyamine:NO balance and thereby compromises NOS2‐mediated innate immune defense.

The two-fold purpose of this paper [1] was to 1) compare accuracy and bias of widely used glomerular filtration rate (GFR) estimating equations to a gold-standard GFR measure (iohexol disappearance from plasma) in HIV-positive and HIV-negative volunteers, and 2) to assess factors associated with bias and accuracy of the creatinine-based and cystatin C-based equations. Recently, our co-investigators, who performed the laboratory analyses and calculations for the iohexol GFR, identified a drift that occurred in their measurement of iohexol (prior to this study) that led to an across-the-board underestimation of iohexol concentrations from blood samples, which produced a systematic overestimation of GFR by approximately 10%. Correlation of estimated glomerular filtration rate (eGFR) bias, defined as the difference between eGFR and measured GFR, with percentage of activated CD8 T cells (CD38+ and HLA-DR+) using the creatine-based CKD-EPI equation in HIV-negative (A) and HIV-positive (B) subjects, and the cystatin C-based CKD-EPI equation in HIV negative (C) and HIV-positive (D) subjects.

Serum creatinine and cystatin C are used as markers of glomerular filtration rate (GFR). The performance of these GFR markers relative to exogenously measured GFR (mGFR) in HIV-positive individuals is not well established. We assessed the performance of the chronic kidney disease epidemiology collaboration equations based on serum concentrations of creatinine (eGFRcr), cystatin C (eGFRcys) and both biomarkers combined (eGFRcr-cys) in 187 HIV-positive and 98 HIV-negative participants. Measured GFR was calculated by plasma iohexol clearance. Bias and accuracy were defined as the difference between eGFR and mGFR and the percentage of eGFR observations within 30% of mGFR, respectively. Activated CD4 and CD8 T-cells (CD38+ HLA-DR+) were measured by flow cytometry. The median mGFR was >100 ml/min/1.73 m(2) in both groups. All equations tended to be less accurate in HIV-positive than in HIV-negative subjects, with eGFRcr-cys being the most accurate overall. In the HIV-positive group, eGFRcys was significantly less accurate and more biased than eGFRcr and eGFRcr_cys. Additionally eGFRcys bias and accuracy were strongly associated with use of antiretroviral therapy, HIV RNA suppression, and percentages of activated CD4 or CD8 T-cells. Hepatitis C seropositivity was associated with larger eGFRcys bias in both HIV-positive and HIV-negative groups. In contrast, eGFRcr accuracy and bias were not associated with HIV-related factors, T-cell activation, or hepatitis C. The performance of eGFRcys relative to mGFR was strongly correlated with HIV treatment factors and markers of T-cell activation, which may limit its usefulness as a GFR marker in this population.

Acute pyelonephritis is a common, serious bacterial infection in children. The prevalence of acute pyelonephritis is due at least in part to vesicoureteral reflux (VUR). Although an association between abnormalities in electrolyte and acid–base balance and pyelonephritis is common in young children, the impact of metabolic acidosis (MA) on progression of acute pyelonephritis is not fully understood. In this study, the effect of MA on pyelonephritis was studied in C3H mouse strains prone to VUR. MA induced by ammonium chloride supplementation in food specifically impaired clearance of urinary tract infection with uropathogenic Escherichia. coli (UPEC‐UTI) in innate immune competent C3H strains (HeOuJ, HeN), whereas kidney UPEC burden in Tlr‐4‐deficient HeJ mice was unaffected. Antibody‐mediated depletion of myeloid cells (monocytes, neutrophil) markedly increased UPEC burden in the bladder and kidney confirming the pivotal role of neutrophils and tissue‐resident macrophages in clearance of UPEC‐UTI. MA concurrent with UPEC‐UTI markedly increased expression of cytokine (TNFα, IL‐1β, IL‐6) and chemokine (CXCL 1, 2, and 5) mRNA in isolated kidney CD cells and kidney neutrophil infiltrates were increased four‐ to fivefold compared to normal, UPEC‐infected mice. Thus, MA intensified pyelonephritis and increased the risk of kidney injury by impairing clearance of UPEC‐UTI and potentiating renal inflammation characterized by an elevated kidney neutrophil infiltrate. The burden of E coli was increased 3–4 order of magnitude higher in bladder and kidney in TL4‐sufficient mice made acidotic before infection.