Patients with lupus nephritis characterized by nephrotic syndrome at baseline were less likely to achieve renal responses at 1 year, a post-hoc analysis of two clinical trials found.
In placebo-controlled studies known as BELONG and LUNAR that evaluated ocrelizumab (Ocrevus) and rituximab (Rituxan), respectively, for lupus nephritis, only 26% of those with baseline nephrotic syndrome had a renal response at week 48 compared with 52.5% of those without nephrotic syndrome (P<0.001), according to Liliana Michelle Gomez Mendez, MD, of the University of California, San Francisco, and colleagues.
After adjustment for the treatment received and use of ACE inhibitors/angiotensin receptor blockers, the odds ratio for achieving a renal response was 0.32 (95% CI 0.19-0.54, P<0.001) among patients with nephrotic syndrome at baseline, the researchers reported online in Lupus Science & Medicine.
Nephrotic syndrome is defined as a high level of proteinuria, low serum albumin, and hyperlipidemia. It can lead to complications such as hypertension and infections, and has "important prognostic implications" in patients with lupus nephritis, the researchers explained. For example, in an earlier longitudinal cohort, patients with nephrotic syndrome at the time of enrollment had significantly lower renal survival 25 years later.
Biopsy specimens of patients with nephrotic syndrome have revealed effacement, or thinning, of podocytes, which may occur following deposition of immune complexes surrounding the glomerulus.
While patients with nephrotic syndrome have a lower likelihood of renal responses within a year, many do respond over a longer period of time. In addition, a decline of 50% in proteinuria during the first 6 months predicts a good outcome "and may be a better long-term prognostic indicator than 1-year proteinuria levels in those with baseline nephrotic syndrome," the researchers wrote.
Because there have been no major studies in lupus nephritis that specifically analyzed treatment effects for patients with nephrotic syndrome, Gomez Mendez and colleagues analyzed data in this subgroup from the two large earlier clinical trials.
LUNAR enrolled 144 patients from 2006 to 2008, randomizing them to placebo or rituximab, 1 g on days 1, 15, 168, and 182, plus background mycophenolate mofetil (CellCept) and tapered oral steroids.
BELONG included 381 patients who were randomized to receive placebo or 400 mg or 1,000 mg ocrelizumab on days 1 and 15, and then every 16 weeks, plus mycophenolate or cyclophosphamide followed by azathioprine, along with tapered oral steroids.
Nephrotic syndrome was defined as a urine protein/creatinine ratio of 3.5 g/g or higher plus serum albumin below 3 g/dL.
Renal response criteria in BELONG required a urine protein/creatinine ratio of 0.5 g/g or less plus at least a 25% increase in creatinine at week 48, while in LUNAR, renal response required a urine protein/creatinine ratio of 0.5 g/g or less, an increase in creatinine of at least 15%, and inactive urinary sediment at week 52. To combine the data from the two trials, the current analysis used the definition of renal response from BELONG at week 48.
At baseline, 157 (30%) of the combined cohort had nephrotic syndrome, and had higher urine protein/creatinine ratios, total cholesterol, low density lipoprotein, and triglyceride levels. These patients also had lower levels of serum albumin, IgG, and C3, as well as lower estimated glomerular filtration rates.
More patients with nephrotic syndrome had a 50% decline in proteinuria by week 24 (71% vs 61%, P=0.04) and by week 48 (80% vs 70%, P=0.05). In patients from LUNAR, who were followed up to week 78, the lowest urine protein/creatinine ratios among patients with nephrotic syndrome were seen at week 64 compared with week 52 in those without nephrotic syndrome.
The likelihood of normalization of C3 levels was not significantly different between nephrotic and non-nephrotic patients (HR 1.08, 95% CI 0.8-1.3, P=0.4), but the likelihood of becoming antibody negative for anti-ds-DNA was 1.5 (95% CI 1.18-1.96, P=0.001) for the nephrotic patients. Daily steroid and mycophenolate doses did not differ between the two groups.
Among those with nephrotic syndrome at baseline, resolution of the nephrotic syndrome itself was seen in 80%, at a median time of 4 months.
Despite the lower rates of renal response in the nephrotic patients, this analysis found that these patients did experience "clinically important improvements," including declines in proteinuria, normalization of serologic markers, and resolution of the nephrotic syndrome.
The observation that fewer patients with nephrotic syndrome achieved renal responses in LUNAR and BELONG does not mean that these patients should be excluded from future clinical trials, Gomez Mendez and co-authors cautioned. "This would greatly limit our understanding of how these participants differ from those who are non-nephrotic as well as what therapies would work best for them."
A limitation of the analysis, the researchers said, was its post-hoc design.
No funding agency was involved in the study, but several of the authors are employees of Roche/Genentech.
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