Renal arteriosclerosis is common in patients with lupus nephritis and occurs two decades earlier than it does in people without the condition, say investigators in a study that examined the prevalence of renal arteriosclerosis in patients with lupus nephritis compared with healthy controls.1
The finding suggests that renal arteriosclerosis could be used as a biomarker for early prediction of cardiovascular disease (CVD) risk in patients with lupus nephritis and subsequently lead to timely CVD prevention.
Improving prevention of CVD in patients with lupus nephritis is needed given the high risk of CVD in these patients. Compared with their healthy controls, patients with lupus nephritis have a ninefold higher risk of CVD, according to the researchers. (Note: Another study by Garg et al. presented at the 2019 ACR/ARP Annual Meeting showed that severe renal arteriosclerosis at diagnosis of lupus nephritis increased the risk of CVD tenfold compared with patients without severe renal arteriosclerosis. The study also found a correlation between advanced chronic kidney disease and increased cardiovascular risk in patients with lupus nephritis, with patients with stage 3 or greater chronic kidney disease at a fivefold increased risk of CVD.2 To date, however, biomarkers or tests to predict future CVD are lacking, limiting the ability to identify early who may develop CVD.
Using renal arteriosclerosis as a biomarker or predictor of CVD risk in patients with lupus nephritis is supported by previous studies showing renal arteriosclerosis predicts CVD in other glomerulonephritis diseases, such as IgA nephropathy as well as in renal transplant patients.3-5 Until now, however, no studies have shown a positive association between the presence of renal arteriosclerosis and CVD occurrence in patients with lupus nephritis.
One reason may be the lack of emphasis in the current International Society of Nephrology/Renal Pathology Society (ISN/RPS) guidelines on universal reporting using standard criteria for renal arterial changes, according to Shivani Garg, MD, MS, assistant professor of medicine, Division of Rheumatology, University of Wisconsin, Madison.
The study bore this out. Garg et al. also looked at whether renal arteriosclerosis and its severity were under-reported in pathology reports of patients with lupus nephritis and found they were overlooked or missed in >50% of the pathology reports reviewed.
“Clinicians urgently need early predictors of CVD in patients with lupus nephritis to prevent related morbidity and mortality,” state the authors in the study. “Renal arteriosclerosis on pathology reports could be an early predictor of CVD in patients [with lupus nephritis].”
Prevalence of Blood Vessel Disease
To test their hypothesis that renal arteriosclerosis would occur at a younger age in patients with lupus nephritis compared with healthy controls, Garg et al. reviewed data on 189 patients with lupus nephritis who underwent native renal biopsy between 1994 and 2017 at the University of Wisconsin Hospital and Clinics. Patients ranged in age from 2–79 years (median age of 25 years), and the majority were female (78%) and white (73%).
Biopsy reports showed that 41% had renal arterial changes (31% had renal arteriosclerosis and 12% had hyaline arteriolosclerosis), and that renal arteriosclerosis increased with age. Overall, one in three patients 60–69 years old had moderate-to-severe sclerosis.
When compared with healthy controls, the onset of any arteriosclerosis in patients with lupus nephritis occurred two decades earlier. Patients with lupus nephritis aged 30–39 years had comparable renal arteriosclerosis to healthy kidney donors aged 50–59 years (41% vs. 44%), and patients with lupus nephritis aged 40–49 years had comparable renal arteriosclerosis to controls 60–69 years (52% vs. 51%). Patients with lupus nephritis aged 60–69 years had a fivefold higher prevalence of moderately severe arteriosclerosis compared with age-matched healthy donors (33% vs. 6%).
The study found age and lupus nephritis chronicity were independent predictors of renal arteriosclerosis. Patients with lupus nephritis who were older than 30 years had threefold higher odds of developing renal arteriosclerosis than patients younger than 30 (odds ratio [OR] 3.3; confidence interval [CI], 1.3, 9.1; P=0.02), and patients with chronic lupus nephritis had a fourfold greater odds (OR 4.0; CI, 1.5, 11.6; P=0.01)
Commenting on these findings, Ram Raj Singh, MD, professor of medicine, rheumatology, and pathology at the David Geffen School of Medicine, University of California, Los Angeles, emphasizes the need for more research to better understand why some patients with lupus nephritis develop renal arteriosclerosis. He also notes the need for additional research given the small numbers in the study and the predominance of white patients.
“Because non-white patients generally have more severe lupus nephritis and poorer outcomes from lupus, future studies involving diverse patient populations would be needed to further realize the importance of this research,” he says.
The authors note the lack of diversity as a study limitation, and according to Dr. Garg, future research will focus on diverse cohorts and the correlation between renal arteriosclerosis and CVD occurrence.
Universal Reporting
By over-reading renal biopsies in a subset of 42 patients using the Banff criteria for grading, the researchers also examined whether the burden of renal arteriosclerosis is under-reported in lupus nephritis biopsies. The Banff grading system categorizes renal arteriosclerosis as none, mild (<25%), moderate (26–50%) and severe (>50%) luminal narrowing. Patients included in this analysis had a mean age of 31 years at the time of their diagnosis of lupus nephritis, most were women (75%), a minority were Black (25%), and nearly half (49%) had chronic lupus nephritis.
When comparing these readings to the original pathology reports, the investigators found that >50% of the original reports missed renal arteriosclerosis and nearly 40% lacked details on arteriosclerosis or arterial changes.
Although the positive predictive value of the routine pathology reporting was 80% in the study, the over-read analysis using the Banff criteria showed that the assessment of arteriosclerosis in lupus nephritis biopsies is under-reported.
“Our study underscores a need for universal use of systemic Banff renal arteriosclerosis grading criteria in all lupus nephritis biopsies, similar to transplant pathology reporting standards,” says Dr. Garg.
Dr. Singh believes more emphasis will now be placed on looking for renal arteriosclerosis in patients with lupus nephritis, given the findings of the study. He urges clinicians to ask pathologists to comment on the presence or absence of renal arteriosclerosis when examining kidney biopsies from patients with lupus nephritis.
“The increased awareness that the presence of arteriosclerosis in kidney biopsies from patients with lupus nephritis predicts future development of cardiovascular disease will lead to increased reporting of arteriosclerosis on kidney biopsies,” predicts Dr. Singh.
Mary Beth Nierengarten is a freelance medical journalist based in Minneapolis.
References
- Garg S, Bartels CM, Hansen KE, et al. High burden of premature arteriosclerosis on renal biopsies in incidence lupus nephritis. Arthritis Care Res (Hoboken). 2020 Jan 7. doi: 10.1002/ acr.24138. [Epub ahead of print]
- Garg S, Panzer S, Hansen K, et al. Renal arteriosclerosis predicts cardiovascular disease in lupus nephritis [abstract 1564]. Arthritis Rheumatol. 2019;71(suppl 10).
- Myllymäki J, Syrjänen J, Helin H, et al. Vascular diseases and their risk factors in IgA nephropathy. Nephrol Dial Transplant. 2006;21(7):1876–1882.
- Myllymäki J, Honkanen T, Syrjänen J, et al. Uric acid correlates with the severity of histopathological parameters in IgA nephropathy. Nephrol Dial Transplant. 2005;20(1):89–95.
- Loupy A, Vernerey D, Viglietti D, et al. Determinants and outcomes of accelerated arteriosclerosis: Major impact of circulating antibodies. Circ Res. 2015;117(5):470–482.
Previously published in The Rheumatologist in February 2021.
