Chronic Kidney Disease: Research Highlights

A genome-based risk score for everyone

Current estimates suggest that between a quarter and half of the risk of developing chronic kidney disease (CKD) can be attributed to one’s genes. However, the genetic data on which these estimates are based is dominated by individuals of European ancestry, confusing efforts to develop predictive tests that are broadly applicable to all populations. This is particularly problematic because there are known differences in risk factors between racial and ethnic groups. Specifically, people of African descent are more likely to carry variants in the APOL1 gene that increases the likelihood of developing CKD. A team led by scientists from Columbia University in New York has now developed a multi-gene risk score that can identify those most at risk of developing CKD. It is based on the combined effects of multiple disease-linked genomic sequence variants, regardless of a person’s race or ethnicity.

Part of Nature Outlook: Chronic Kidney Disease

The authors began by identifying genetic variants that have a strong statistical association with impaired kidney function, based on a 2019 meta-analysis of genetic data from one million participants. Because this study was biased towards people of European and East Asian ancestry, the present study authors also included risk data from a cohort of 7,158 British Biobank donors of African ancestry. . In particular, they focused on the specific risk contributions associated with the contributions of the variants in the APOL1 embarrassed.

The researchers then tested the performance of the risk score against 15 cohorts from diverse backgrounds. These included six groups of participants of African descent, as well as four cohorts of East and South Asian descent and two Latinx cohorts. The authors’ score was consistent across all populations assessed, and people ranked in the top 2% risk based on this score were three times more likely to have been diagnosed with CKD. Future iterations of this score could guide preventive care to avoid the onset of CKD in high-risk individuals, and potentially guide screening and organ selection for kidney donation.

NatureMed. 281412-1420 (2022).

Humanizing kidney disease research

A challenge in developing effective interventions for CKD is that animal models do not fully reflect human biology and may not predict efficacy and safety in humans. A study by researchers at Massachusetts General Hospital in Boston and their colleagues shows how stem cell-based models of human organoids that mimic key structural and functional features of the kidney can provide insight into the mechanisms underlying the IRC that could be clinically relevant.

Starting with induced pluripotent stem cells—adult cells that have been experimentally brought to an embryonic-like state—the authors applied a culture system that promoted maturation and self-organization into kidney organoids. These had the distinctive tubular structures expected of kidney tissue surrounded by supporting cells, including fibroblasts and pericytes. This model allowed the authors to study the early stages of CRF, when recurrent damage leads to a state in which kidney tubule damage is not fully repaired, setting the stage for further tissue damage and fibrosis.

After recreating these conditions in organoids, the authors analyzed changes in gene expression of injured tubular cells. Their data highlighted several DNA repair genes that were activated upon successful tissue repair, but whose expression dropped sharply when tubules were incompletely repaired. The authors then confirmed this change in expression for a repair enzyme called FANCD2 in biopsy samples.

Based on this evidence, they treated their organoid model with a drug that stimulates FANCD2 activity, demonstrating that this treatment could prevent atrophy and fibrosis in damaged tubules. The experiments highlight the promise of human organoid models as a research tool in CKD.

Science. Transl. Medium. 14eabj4772 (2022).

Immune agents in renal fibrosis

The formation and accumulation of fibrous scar tissue is central to the progression of CRF, and a well-established inflammatory component underlies this process. However, which immune cell subsets are involved and how these cells interact with kidney tissue are poorly understood.

A team of researchers from the University of Pennsylvania in Philadelphia and their colleagues addressed this question with extensive comparative transcriptomic analysis experience. Messenger RNA from tens of thousands of cells from healthy mouse kidney tissue was compared to cellular mRNA obtained from the kidneys of an animal model of CRF to identify differences in which genes are turned on or off . Using gene expression to classify these different cell types, the authors found that fibrotic kidney tissue tends to be highly enriched in basophils. This is a rare subtype of inflammatory cells that has been previously linked to kidney immune diseases, but not specifically to CKD.

Subsequent analysis revealed that in fibrotic kidneys, proximal tubule cells – a crucial part of the renal filtration machinery – express a protein called CXCL1 that can actively recruit basophils. These then release a set of signaling molecules causing inflammation. Human tissue samples provided further confirmation of this mechanism, with 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 eliminate basophils or block the effect of their inflammatory signals can reduce or even prevent fibrosis. Identification of a specific subpopulation of immune cells underlying disease progression should allow the development of treatments that preserve kidney health and function.

Nature Immunol. 23947–959 (2022).

A chance to intercept inflammation

Sphingosine 1-phosphate (S1P) is a pro-inflammatory biomolecule that contributes to the formation of fibrotic tissue in the kidney during the progression of CKD. Drugs can be used to block S1P activity by inhibiting its receptor, but have been shown to work poorly in people with kidney disease and can cause serious side effects.

Researchers at the University of Virginia at Charlottesville and their colleagues have now dissected how S1P contributes to kidney fibrosis and identified a mechanism by which they can effectively disrupt 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. Previous work has also strongly indicated that the production of S1P in these cells is directly involved in the onset of fibrosis.

First, the authors confirmed that inhibiting S1P production in these kidney cells suppressed the pro-inflammatory response that would normally be triggered in response to kidney injury. Next, they determined that this response was dependent on a protein called Spns2. Perivascular cells use Spns2 to release newly synthesized S1P into the extracellular space, where it can associate with its receptor and thereby trigger inflammation.

This suggests that there is an opportunity to break the immunological chain of 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 perivascular cells. They also observed protective effects of this drug in a rodent model of renal fibrosis, whereas an existing drug that blocks the S1P receptor conferred no such benefit. Whether these therapeutic effects translate to people with CKD remains to be seen, but early results suggest that targeting Spns2 may offer a promising avenue to prevent or slow fibrosis.

Science. Transl. Medium. 14eabj2681 (2022).

Protect heart health

Many people with CKD also have hypertension, a condition that can further aggravate kidney disease while worsening cardiovascular health. A clinical trial by researchers at Indiana University in Indianapolis now demonstrates that a drug already used to treat high blood pressure can also provide safe and significant protection for people with advanced CKD.

Chlorthalidone is a diuretic drug known to reduce the risk of stroke and heart failure, but there have been some concerns about giving it or related compounds to people with advanced CKD. To test whether people at this stage of the disease might benefit, the authors randomized 160 people with severe CKD and high blood pressure to receive 12 weeks of chlorthalidone or a placebo, alongside standardized treatment of other drugs. antihypertensives.

More from Nature Outlooks

The treatment arm experienced a noticeable decrease in blood pressure within four weeks of starting treatment, compared to the placebo arm. The difference in blood pressure between the two groups persisted throughout the study and remained statistically significant at 12 weeks, when treatment was stopped. Beyond this point, the blood pressure in the treatment arm began to rise again. Those taking chlorthalidone also showed other signs of clinical improvement, including weight loss and reduced levels of various blood biomarkers of heart failure risk. Importantly, people in the treatment group experienced only a marginal increase in adverse events overall, with fewer serious events requiring hospitalization than in the placebo group.

Although this is a small study with an underrepresentation of women and people of Asian or Hispanic ancestry, it offers evidence that this drug may protect heart and kidney function in people with CKD . The authors say a phase III trial to demonstrate the drug’s effectiveness in a larger cohort is needed.

N.Engl. J.Med. 3852507-2519 (2021).