Tag: acute kidney injury

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Intraoperative Drug Combo Reduces Acute Kidney Injury in Septic Shock

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Photo by Natanael Melchor on Unsplash

In adults with septic shock undergoing surgical source control, a new study found that adding intraoperative dobutamine to norepinephrine reduces the risk of acute kidney injury (AKI) over norepinephrine alone.

International guidelines recommend dobutamine for management of septic shock and cardiac dysfunction with persistent hypoperfusion in adults, but this is based on very low–certainty evidence, and there is even less for dobutamine plus norepinephrine.

Norepinephrine is a potent vasoconstrictor and can decrease regional renal blood flow, potentially increasing AKI risk. Conversely, the role of dobutamine in septic AKI prevention “has remained controversial,” the researchers noted in their study published in JAMA. While dobutamine can increase renal blood flow and glomerular filtration rate, some prior observational studies suggested an association with greater AKI progression or need for kidney replacement therapy (KRT).

Open-label randomised clinical trial

The researchers therefore conducted a multicentre, open-label, randomised clinical trial conducted across 39 tertiary hospitals in China, from June 2024 to August 2025). Adults with septic shock requiring surgical source control of anticipated duration > 1 hour were eligible. Key exclusions included recent use of dobutamine, levosimendan, epinephrine, or recombinant human B-type natriuretic peptide.

Of 714 patients screened, 584 were randomised 1:1 (stratified by site): 290 to dobutamine plus norepinephrine and 294 to norepinephrine alone. Median age was 67.5 years (IQR 55–76); 32.9% were female. Most patients had preoperative septic shock; common procedures involved gastrointestinal perforation (41.8%) or obstruction (29.6%).

Norepinephrine was titrated in both arms to a target mean arterial pressure of 65 mm Hg. In the intervention arm, dobutamine was initiated at 5 µg/kg/min intraoperatively (with dose reduction or discontinuation for tachycardia or arrhythmia). Treatment began after induction for preoperative shock or after recognition of intraoperative shock.

The primary outcome was New-onset AKI or worsening of preoperative AKI (by ≥1 Kidney Disease: Improving Global Outcomes [KDIGO] stage) within 7 postoperative days. This occurred in 66/290 (22.8%) patients receiving dobutamine plus norepinephrine versus 102/294 (34.7%) receiving norepinephrine alone (adjusted risk ratio 0.64; 95% CI 0.49–0.83; P = .001). Absolute risk reduction was approximately 11.9 percentage points.

The benefit was driven mainly by reductions in stage 2 (4.8% vs 9.9%; ARR 0.48) and stage 3 (7.9% vs 13.6%; ARR 0.56) AKI. Stage 1 rates were similar. Secondary outcomes: SOFA score on postoperative day 1 was lower (adjusted difference −0.53; 95% CI −0.98 to −0.07) and urine output 1 hour after intervention start was higher (adjusted difference +0.55 mL/kg/h; 95% CI 0.03–1.07) with combination therapy. No significant differences were seen in most other secondary outcomes, including mortality, kidney replacement therapy, or length of stay.

Adverse events included tachycardia being more common (≈41% with dobutamine plus norepinephrine vs 30%). Other reported cardiovascular events were similar between groups.

The researchers concluded that “While hypothesis generating, these data suggest an opportunity to explore dobutamine treatment response heterogeneity across different clinical subtypes.”

Limitations of the study include being an open-label trial and largely restricted to Chinese patients and settings.

Categories : UrologyTags :

Why Some Injured kidneys Fail to Heal

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Photo by Robina Weermeijer on Unsplash

Cedars-Sinai investigators have discovered why some injured kidneys heal while others develop scarring that can lead to kidney failure. Their findings, detailed in a paper published in the peer-reviewed journal Science, could lead to the development of noninvasive tests to detect kidney scarring and, eventually, new therapies to reverse the condition.

“The key to this discovery was our ability to directly compare injured kidney cells that successfully regenerated with those that did not,” said Sanjeev Kumar, MD, PhD, a nephrologist-scientist in the Board of Governors Regenerative Medicine Institute and the Department of Medicine at Cedars-Sinai and senior author of the study.

“Injured cells activate a protein called SOX9 to regenerate themselves. When they have healed, the cells silence this protein. Cells that aren’t able to regenerate leave SOX9 active, and this leads to a type of scarring called fibrosis. But when we deactivate SOX9 in a timely fashion, the scarring literally goes away.”

The kidneys can be injured by diabetes and high blood pressure, serious infections such as COVID-19, and overuse of antibiotics and non-steroidal anti-inflammatory pain medications, said Kumar, who is also part of the Department of Biomedical Sciences at Cedars-Sinai.

The SOX9 protein plays a major role in organ development but is not active in healthy adult kidneys.

In previous work at another institution, Kumar and team found that when kidneys are injured, the surviving cells reactivate SOX9 as part of the healing process.

In this study, Kumar and fellow investigators studied kidney damage in laboratory mice.

They labeled individual cells at the point of injury, then followed how the cells’ progeny evolved over time.

“At Day 10, some cells’ descendants were fully healed while others were not,” Kumar said.

“The cell lineage that healed had switched off SOX9 expression, while the unhealed lineage, in a continuing attempt to fully regenerate, maintained SOX9 activity. It’s like a sensor that switches on when cells want to regenerate, and off when they are restored, and we are the first to identify this.”

Further, investigators discovered that cells that were unable to regenerate began recruiting proteins called Wnts, another key player in organ development. Over time, this accumulation of Wnts triggered scarring. And they found that deactivating SOX9 a week after injury promoted kidney recovery.

Investigators observed the same process in patient databases from collaborating institutions in Switzerland and Belgium.

“We could see that by Day 7, human patients with transplanted kidneys that were slow to begin working also activated SOX9,” Kumar said.

“And in our collaborators’ database, we were able to distinguish that patients who had sustained SOX9 activation had lower kidney function and more scarring than those who did not. Human kidneys with cells that maintained SOX9 were also enriched with Wnts and showed increased fibrosis.”

These discoveries provide targets for drug development, as well as for noninvasive biomarker discovery permitting diagnosis of kidney fibrosis through the urine, Kumar said.

Currently, the only available test for kidney fibrosis is a biopsy, which carries many risks.

“Elucidating the mechanisms of scarless healing versus fibrosis has eluded investigators for decades and has implications beyond the kidney, including for certain cancers,” said Paul Noble, MD, chair of the Department of Medicine and director of the Women’s Guild Lung Institute at Cedars-Sinai and a co-author of the study.

Source: Cedars-Sinai Medical Center

Categories : Diet and Nutrition Injury & TraumaTags :

Specialised Omega-3 Lipid Could be a New Treatment for Acute Kidney Injury

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Photo by Robina Weermeijer on Unsplash

Researchers from Singapore have identified a potential dietary supplement of omega-3 that may improve recovery following acute kidney injury (AKI). The finding, published in the Journal of Lipid Research, may offer a new way to treat this serious condition, which currently has few therapies.

The study was part of a long-running research programme at Duke-NUS Medical School investigating how cells take up a specialised omega-3 lipid called LPC-DHA.

AKI affects some 13.3 million people globally each year, with a mortality rate of 20 to 50% depending on the economic status of the country and stage of the disease. One of the main causes of AKI is ischaemic reperfusion injury, which occurs when the kidney’s blood supply is restored after a period of restricted blood flow and poor oxygen delivery due to illness, injury or surgical intervention. In particular, it damages a crucial part of the kidney called the S3 proximal tubules that regulate the levels of absorption of water and soluble substances, including salts.

“AKI is a serious health problem with limited treatment options,” said Dr Randy Loke, first author of the study. “We sought to understand how these tubules repair themselves and found that the activity of the protein Mfsd2a, which transports LPC-DHA into cells, is a key factor influencing the rate of recovery of kidney function after ischaemic reperfusion injury.”

In their study, the researchers discovered that preclinical models with reduced levels of Mfsd2a showed delayed recovery, increased damage and inflammation after kidney injury. However, when these models were treated with LPC-DHA, their kidney function improved and the damage was reduced. LPC-DHA also restored the structure of the S3 proximal tubules, helping them function properly again.

“While more research is needed, the potential of LPC-DHA as a dietary supplement is exciting for future recipients who have suffered from AKI,” said senior study author Professor David Silver. “As our results suggest that LPC-DHA could become a safe and effective treatment that offers lifelong protection, its potential can help protect the kidneys and aid in recovery for these individuals.”

In the next phase, the research team plans to continue investigating the beneficial functions of LPC in the kidney and are aiming to initiate clinical testing of LPC supplements to determine their effectiveness in improving renal function and recovery following AKI in patients.

They also plan to continue their investigations of the protein Mfsd2a to learn more about its role in LPC transport and its involvement in diseases affecting other tissues and organs. Previous research by Prof Silver’s group, with collaborators from other institutions, have already highlighted the significance of the protein’s LPC-transporting activities in diseases of other organs, including the liver, lungs and brain.

Source: Duke–NUS Medical School