Chronic Kidney Disease: Research Highlights

A genome-based risk score for everyone

Current estimates suggest that one-fourth to one-half of the risk of developing chronic kidney disease (CKD) may be genetic. However, the genetic data underlying these estimates are dominated by individuals of European descent, confounding efforts to develop predictive tests that are broadly applicable across populations. This is particularly problematic as there are known differences in risk factors between races and ethnic groups. Most notably, people of African ancestry are more likely to have atypia. APOL1 Genes that increase the likelihood of developing CKD. A team led by scientists at Columbia University in New York City has devised a multi-gene risk score that can identify people at highest risk of developing CKD. It is based on the combined effects of multiple genomic sequence variants associated with disease, regardless of a person’s race or ethnicity.

Part of Nature Outlook: Chronic Kidney Disease

The authors began by identifying genetic variants with strong statistical associations with renal dysfunction based on a 2019 meta-analysis of genetic data from 1 million participants. Because the study was skewed to individuals of European and East Asian ancestry, the authors of this study also included risk data from a cohort of 7,158 UK Biobank donors of African ancestry. We focused on specific risk contributions related to the contribution of APOL1 gene.

The researchers then tested the risk score’s performance against 15 cohorts with various backgrounds. These included his six groups of participants of African descent, his four cohorts of East and South Asian descent, and two cohorts of Latin descent. The authors’ score performed consistently across all populations assessed, and individuals who ranked in the top 2% of risk based on this score were three times as likely to be diagnosed with CKD as she was . Future iterations of this score may guide preventative care to avoid the development of CKD in high-risk people and guide screening and selection of organs for kidney donation.

nature med. 281412–1420 (2022).

Humanized renal disease research

One of the challenges in developing effective interventions for CKD is that animal models do not fully reflect human biology and may not predict human efficacy and safety. A study by researchers at Massachusetts General Hospital in Boston suggests that a stem cell-based human organoid model that recapitulates key structural and functional features of the kidney may be the mechanism underlying CKD that may be clinically relevant. It shows how we can provide insight into

Starting with induced pluripotent stem cells (adult cells ly induced to an embryo-like state), the authors applied a culture system that facilitates their maturation and self-assembly into kidney organoids. They had the unique tubular structure expected of renal tissue surrounded by supporting cells such as fibroblasts and pericytes. This model allowed the authors to investigate the early stages of CKD, in which recurrent injury leads to incomplete repair of damage to the renal tubules, leading to further tissue damage. and pave the way for fibrosis.

After recapitulating these conditions in organoids, the authors analyzed changes in gene expression in injured tubular cells. Their data highlighted several DNA repair genes that were activated during successful tissue repair but were sharply down-regulated when tubules were incompletely repaired. The authors then confirmed this shift in the expression of a repair enzyme called FANCD2 in biopsy samples.

Based on this evidence, they treated an organoid model with an agent that stimulated FANCD2 activity and showed that this treatment could prevent atrophy and fibrosis of injured tubules. This experiment highlights the promise of human organoid models as tools for CKD research.

Science.Translating. 14eabj4772 (2022).

Immune agent in renal fibrosis

The formation and accumulation of fibrous scar tissue is central to CKD progression, and an established inflammatory component underlies this process. However, which subset of immune cells are involved and how these cells interact with kidney tissue are poorly understood.

A team of researchers at the University of Pennsylvania in Philadelphia and their colleagues are addressing this question in a detailed comparative transcriptome analysis experiment. We compared messenger RNA from tens of thousands of cells from healthy mouse kidney tissue to mRNA from cells from kidneys of animal models of CKD to identify differences in which genes are activated or inhibited. bottom. By using gene expression to classify these different cell types, the authors found that fibrotic kidney tissue tends to be highly enriched in basophils. These are rare subtypes of inflammatory cells previously associated with immune disorders in the kidney, but not particularly he in CKD.

Subsequent analysis revealed that in fibrotic kidneys, cells in the proximal tubules, a key part of the renal filtration system, express a protein called CXCL1 that can actively recruit basophils. became. These then release a series of pro-inflammatory signaling molecules. Human tissue samples provided further confirmation of this mechanism, showing clearly detectable enrichment of CXCL1 expression and basophil aggregation in fibrotic kidneys. The researchers tested their findings in mice and found that treatments that selectively eliminated basophils or blocked the effects of inflammatory signals could reduce or even prevent fibrosis. Identification of specific immune cell subpopulations that underlie progression should enable the development of therapies that preserve renal health and function.

natural immunity. twenty three947–959 (2022).

Opportunity to stop inflammation

Sphingosine 1-phosphate (S1P) is a pro-inflammatory biomolecule that contributes to the formation of fibrous tissue in the kidney during the progression of CKD. Drugs that block S1P activity by blocking S1P’s receptors are available, but these have been shown to be less effective in people with kidney disease and can cause serious side effects.

Researchers at the University of Virginia in Charlottesville and their colleagues analyzed how S1P contributes to renal fibrosis and identified mechanisms that can effectively interfere with this process. They focused specifically on the role of renal perivascular cells, which line the capillaries of the kidney and communicate closely with the immune system. Direct involvement is also strongly indicated.

First, the authors confirmed that inhibition of S1P production in these renal cells suppressed the pro-inflammatory response normally induced in response to renal injury. They then found that this reaction depends on a protein called Spns2. Perivascular cells use Spns2 to release her newly synthesized S1P into the extracellular space where it can bind to receptors and cause inflammation.

This suggests an opportunity to interrupt the chain of immunological events leading to fibrosis. The authors tested a newly identified small-molecule inhibitor of Spns2 and showed that it could attenuate the inflammatory response in cultured human pericytes. They also observed a protective effect from this drug in a rodent model of kidney fibrosis, whereas existing drugs that block S1P receptors conferred no such benefit. Whether it applies to CKD patients remains to be seen, but early results suggest that targeting Spns2 could provide a promising means of preventing or delaying fibrosis.

Science.Translating. 14eabj2681 (2022).

protect heart health

Many people with CKD experience high blood pressure. This is a condition that can further exacerbate kidney disease and worsen cardiovascular health. have shown that it can provide safe and meaningful protection for people with advanced CKD.

Chlorthalidone is a diuretic known to reduce the risk of stroke and heart failure, but there are some concerns about giving chlorthalidone or related compounds to patients with late-stage CKD. To test whether they would receive, the authors randomized 160 individuals with severe CKD and hypertension to receive either chlorthalidone or placebo for 12 weeks plus a standardized course of other antihypertensive drugs. administered in parallel.

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Blood pressure decreased significantly in the treatment group compared to the placebo group within 4 weeks of starting treatment. The difference in blood pressure between the two groups persisted throughout the study and remained statistically significant for 12 weeks when treatment was discontinued. After this point, blood pressure in the treatment arm began to rise again. Those taking chlorthalidone also showed other signs of clinical improvement, including weight loss and lower levels of various blood biomarkers of heart failure risk. They experienced only a modest increase in adverse events overall, with fewer serious events requiring hospitalization than the placebo group.

This was a small study in women and people of Asian or Hispanic descent, but it provides evidence that this drug can protect heart and kidney function in people with CKD. The authors say a phase III trial demonstrating the drug’s efficacy in a larger cohort is needed.

N. Engl. J. Med. 3852507–2519 (2021).