Background In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov ( NCT04381936 ). Findings Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding UK Research and Innovation (Medical Research Council) and National Institute of Health Research.

Combination therapy with angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain. Methods We provided losartan (at a dose of 100 mg per day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 ml per minute per 1.73 m(2) of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10 to 40 mg per day) or placebo. The primary end point was the first occurrence of a change in the estimated GFR (a decline of ≥ 30 ml per minute per 1.73 m(2) if the initial estimated GFR was ≥ 60 ml per minute per 1.73 m(2) or a decline of ≥ 50% if the initial estimated GFR was <60 ml per minute per 1.73 m(2)), end-stage renal disease (ESRD), or death. The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia, and acute kidney injury. Results The study was stopped early owing to safety concerns. Among 1448 randomly assigned patients with a median follow-up of 2.2 years, there were 152 primary end-point events in the monotherapy group and 132 in the combination-therapy group (hazard ratio with combination therapy, 0.88; 95% confidence interval [CI], 0.70 to 1.12; P=0.30). A trend toward a benefit from combination therapy with respect to the secondary end point (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P=0.10) decreased with time (P=0.02 for nonproportionality). There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95% CI, 0.73 to 1.49; P=0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P<0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P<0.001). Conclusions Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; VA NEPHRON-D ClinicalTrials.gov number, NCT00555217.).

The distal tubule of the mammalian kidney, defined as the region between the macula densa and the collecting duct, is morphologically and functionally heterogeneous. This heterogeneity has stymied attempts to define functional properties of individual cell types and has led to controversy concerning mechanisms and regulation of ion transport. Recently, molecular techniques have been used to identify and localize ion transport pathways along the distal tubule and to identify human diseases that result from abnormal distal tubule function. Results of these studies have clarified the roles of individual distal cell types. They suggest that the basic molecular architecture of the distal nephron is surprisingly similar in mammalian species investigated to date. The results have also reemphasized the role played by the distal tubule in regulating urinary potassium excretion. They have clarified how both peptide and steroid hormones, including aldosterone and estrogen, regulate ion transport by distal convoluted tubule cells. Furthermore, they highlight the central role that the distal tubule plays in systemic calcium homeostasis. Disorders of distal nephron function, such as Gitelman's syndrome, nephrolithiasis, and adaptation to diuretic drug administration, emphasize the importance of this relatively short nephron segment to human physiology. This review integrates molecular and functional results to provide a contemporary picture of distal tubule function in mammals.

Optimal cellular function is dependent on maintenance of a normal serum phosphorus concentration. Serum phosphorus concentration is affected by several determinants, the most important of which is regulation of phosphorus reabsorption by the kidney. The majority of this reabsorption (80%) occurs in the proximal tubule and is mediated by an isoform of the sodium-phosphate cotransporter (NaPi-II). Parathyroid hormone, via a variety of intracellular signaling cascades leading to NaPi-IIa internalization and downregulation, is the main regulator of renal phosphate reabsorption. Shift of phosphorus from extracellular to intracellular compartments, decreased gastrointestinal absorption, and increased urinary losses, are the primary mechanisms of hypophosphatemia, which affects approximately 2% of hospitalized patients. Hypophosphatemia has been implicated as a cause of rhabdomyolysis, respiratory failure, hemolysis and left ventricular dysfunction. With the exception of ventilated patients, there is little evidence that moderate hypophosphatemia has significant clinical consequences in humans, and aggressive intravenous phosphate replacement is unnecessary. By contrast, patients with severe hypophosphatemia should be treated. Intravenous repletion may be considered, especially for patients who have clinical sequelae of hypophosphatemia.

We have analyzed the regulatory properties of the wild-type cardiac Na+-Ca2+ exchanger expressed in Xenopus laevis oocytes using the giant excised patch technique. The exchanger is activated by cytoplasmic application of chymotrypsin and exhibits a number of properties that can be changed or abolished by chymotrypsin treatment, including cytoplasmic Na+-dependent inactivation, secondary regulation by free cytoplasmic Ca2+, and inhibition by exchanger inhibitory peptide. Thus, the cloned exchanger expressed in oocytes exhibits regulatory properties similar to those of the native sarcolemmal exchanger. The exchanger protein contains a large (520 amino acids) hydrophilic domain modeled to be intracellular. The role of this region in exchanger function and regulation was examined by deletion mutagenesis. Mutants with residues 240-679 and 562-685 deleted exhibited exchange activity, indicating that this extensive region is not essential for transport function. Both mutants were stimulated by chymotrypsin treatment. Neither mutant demonstrated regulation by free cytoplasmic Ca2+ (Ca;+) or inhibition by exchanger inhibitory peptide (XIP). However, mutant A562-685 but not A240-679 displayed Na+-dependent inactivation. The data suggest that the binding sites for XIP and regulatory Ca2+ may reside in the region encompassed by residues 562-685. A chimera made from renal and cardiac exchangers has normal regulatory characteristics and helps to further derme these sites.The Na+-Ca2+ exchanger of the cardiac sarcolemmal membrane is a highly active transporter that mediates the countermovement of three Na+ ions for one Ca2+ ion. The

Na+/H+ exchangers in the brush-border (luminal, apical) membrane of renal proximal tubules are responsible for active, transcellular reabsorption of NaHCO3 and NaCl. Although well characterized kinetically, the protein that mediates Na+/H+ exchange in the renal brush border has not been identified. Several Na+/H+ exchanger genes, including NHE1, NHE2, NHE3, and NHE4, are expressed in the kidney. To identify the NHE3 gene product and to determine its cellular and subcellular localization in the rabbit kidney, an NHE3-isoform-specific antibody was prepared. Guinea pigs were immunized with purified fusion protein containing the carboxy-terminal 40 amino acids of NHE3 (fpNHE3-C40). After affinity purification, immune sera demonstrated specific reactivity to the NHE3 sequence within the fusion protein as well as to an 80-kDa polypeptide expressed in NHE3-transfected LAP1 cells. Western blot analysis showed that anti-fpNHE3-C40 specifically reacted with an 80-kDa protein that is relatively enriched in renal brush-border membrane compared with basolateral membrane. Immunocytochemical studies confirmed that the Na+/H+ exchanger isoform NHE3 is expressed along the microvillar membrane of the brush border of proximal tubule cells in the rabbit kidney.

Gadolinium chelates are commonly used to improve tissue contrast in MRI. Until recently the use of gadolinium was thought to be risk-free compared with alternative contrast agents. Recent studies, however, have raised serious concerns regarding the safety of gadolinium chelates. Although safe in patients with normal kidney function, administration of these agents in people with renal dysfunction can result in up to three clinical problems that the nephrologist should be familiar with. The first is nephrogenic systemic fibrosis (NSF), which was initially observed in 1997. Although manifesting primarily in skin, NSF can also cause systemic fibrosis, leading to disabling contractures and even death. Gadodiamide is the agent that has been most frequently associated with NSF, but other chelates might also pose a risk. The second clinical problem is that gadolinium chelates cause acute kidney injury, especially at high doses required for angiography. The third problem is that several laboratory artifacts are associated with gadolinium administration, with pseudohypocalcemia being the most important. The risk of a patient experiencing all three of these complications increases as renal function declines. In light of these problems, nephrologists need to re-evaluate the risks and benefits of gadolinium administration in patients with chronic kidney disease stage 3 or greater, as well as in those with acute kidney injury.

An electroneutral thiazide-sensitive Na-Cl cotransport pathway (TSC) has been localized functionally to the distal convoluted tubule (DCT), although the TSC has also been detected in the connecting tubule (CNT), the cortical collecting duct, and the medullary collecting tubule as well. The present experiments were designed to localize expression of message for the TSC in rat and human kidney. A riboprobe, generated from the mouse TSC, was used for in situ hybridization. Simultaneous immunocytochemistry, using antibodies to Tamm-Horsfall protein, band 3, and the Na+/Ca2+ exchanger, permitted delineation of specific nephron segments. In rat, message for the TSC was highly expressed in DCT cells but not elsewhere. The transition from thick ascending limb to DCT was abrupt, whereas the transition to CNT was gradual. In the more distal region of rat DCT (DCT-2), which contained few intercalated cells, both TSC message and Na+/Ca2+ exchanger immunoreactivity were present. Treatment of rats with furosemide for 5 days increased expression of TSC message within the DCT but did not induce its expression elsewhere. In humans, expression of TSC message was also highest in cells of the DCT. In humans, however, expression extended well into the CNT. These experiments indicate that the TSC is expressed predominantly by DCT cells in both rat and humans, although expression extends into the CNT cells in humans. They also show that the TSC and Na+/Ca2+ exchanger are coexpressed by a subpopulation of DCT cells near the junction with the CNT.