Better days ahead: Improving renal repair after LN flare

Lupus nephritis (LN), kidney inflammation caused by lupus, is the most common severe complication in lupus, affecting 25-50% of patients. Remission is only reached in 30-40% of cases, up to 30% are diagnosed with chronic kidney disease, and up to 10% of people with LN progress to end-stage kidney disease. A major challenge is identifying individuals likely to progress to end-stage kidney disease, highlighting the need to better understand the mechanisms underlying LN and markers for predicting outcomes.

Dr. Limaye previously found that patients with poor long-term outcomes had higher levels of cell senescence, which is a state where cells stop dividing due to stress or damage. Dr. Limaye will now test whether cell senescence actually contributes to LN disease progression, or whether it is simply a sign of damage. Senescent cells release pro-inflammatory, pro-fibrotic (scar tissue formation) molecules that are critical for tissue repair and wound healing, but the build-up of senescent cells in diseases like lupus can be harmful. Renal progenitor cells (RPCs) are kidney cells that regenerate and repair damaged kidney structures. Dr. Limaye will test whether senescent RPCs can no longer do their job, preventing tissue repair. Importantly, these cells can be obtained and studied, not only from kidney biopsies, but also urine samples from patients. She will first use cutting edge techniques to identify potential causes and consequences of senescence in LN and determine how certain kidney cells are changed by senescence. Dr. Limaye will also explore how RPCs differ between healthy individuals and those with LN and whether RPCs from people with LN can still repair kidney injury. Lastly, she will test drugs that target senescent cells in a mouse model of lupus both before and after the onset of senescence and kidney disease.

What this means for people with lupus:

Pinpointing individuals who are likely to progress to chronic kidney disease remains a challenge in the field. Dr. Limaye’s study could identify a non-invasive marker to guide treatment and shed light on the future use of “senotherapies,” potentially improving outcomes and quality of life for people with LN.

Despite current therapies, one-third of lupus nephritis (LN) patients suffer from a progressive decline in kidney function. We contend that improving renal repair mechanisms in the aftermath of LN flare may be a useful approach to improving patient outcomes, complementary to current immune-targeted therapies. Understanding the determinants of heterogeneity in kidney repair potential amongst patients will be key in developing the tailored, cost-effective tools required to do so. We previously showed that LN patients with poor long-term outcome exhibited higher levels of renal cell senescence (measured using the marker p16INK4A) in baseline biopsy. We hypothesize that renal cell senescence (i) promotes tissue damage via the proinflammatory, pro-fibrotic senescence-associated secretome, and (ii) hampers tissue repair due to dysfunction of renal progenitor cells, culminating in a catastrophic loss of kidney repair potential. Our specific aims are: (1) Identify potential causes and consequences of cellular senescence in LN: (a) We will perform ex vivo (spatial transcriptomic and proteomic) characterization of p16INK4A-positive regions and surrounding tissue in patient kidney biopsies, and (b) Characterize the effects of cellular senescence induced in vitro using well-established as well as LN-mimetic stimuli, on primary human renal cells. (2) Investigate repair-associated properties of (senescent) kidney and urine-derived RPCs: (a) We will compare ex vivo transcriptomic profiles of kidney and urine-derived RPCs (uRPCs) from patients versus healthy controls, and (b) in vitro transcriptomic, (somatic) genetic and functional properties of uRPCs cultured from patients with active disease, patients at follow-up, and healthy controls (with and without senescence-induction). (c) We will compare in vivo repair capacities of uRPCs from healthy controls and patients with LN (with and without in vitro senescence-induction), in a mouse model of adriamycin-induced acute nephropathy. (3) Testing therapeutic targeting of cellular senescence in the B6.Sle1.2.3 lupus mouse model. We will test for the effects of senolytic therapy (dasatinib plus quercetin), before and after onset of overt kidney disease in the B6.Sle1.2.3 mouse model of lupus. The study of cellular senescence and its impact on RPC function in the LN kidney has the potential for immediate as well as longer term clinical translation. Senolytic agents, which eliminate senescent cells, may provide a useful treatment strategy. In the longer term, more targeted approaches (e.g., mono or bi-specific antibodies or CAR-T cells targeting senescence-specific markers on particular kidney cell subsets) may be developed. The project is also designed to identify potential (kidney, urine) biomarkers for improved patient stratification and prediction of outcomes; these would be tested in future large-scale studies at our own as well as collaborating centers.