This is a descriptive survey-based study, in which we systematically collected data on the recommendations contained in the GLOSEN Consensus Document (Appendix 1) by means of a structured, self-administered, online questionnaire following a quantitative analysis methodology. The survey was designed to assess both the degree of understanding of the recommendations and their impact on clinical practice. We used closed questions with single or multiple answers, which allowed us to obtain quantitative results on the level of knowledge and the frequency of application of each of the recommendations included in the questionnaire. Likewise, we carefully considered the order of the questions to avoid a response to previous questions conditioning subsequent answers; thus, we listed questions about the reality of clinical practice before those evaluating GLOSEN knowledge.

Between November-December 2023, a scientific committee composed of 3 GLOSEN consensus authors supervised the conceptualization of the survey. After review and validation, we opened the questionnaire for participation from March 20 to May 21, 2024, and completed the final statistical analysis of the results in June 2024.

We invited specialist participants in the GLOSEN Group, the Spanish Society of Nephrology (SENEFRO), which endorses this study, and other regional nephrology societies.

We chose to conduct a survey because it makes it possible to easily access a broad group of nephrologists, to collect data systematically, and efficiently to evaluate the aggregated data. In addition, it allows professionals to express their perspectives anonymously without bias, facilitating a better understanding of the real impact of recommendations on the diagnosis and treatment of LN.

The survey was aimed at nephrologists in Spain with direct and relevant experience in the management of LN. Selection questions ruled out the participation of other medical specialties or resident interns, nephrologists with less than 3 years of experience, those who referred patients after the first visit, those who were not involved in the management of LN and/or those who managed a number of patients with LN equal to or less than one per month.

The nephrologists were invited by GLOSEN to participate in the questionnaire through a link sent by e-mail, guaranteeing the confidentiality of the responses. Although the sample was not systematic or randomized, we invited specialists all over the country, to achieve homogeneous geographical representation and include hospitals of various levels, thus giving greater validity to the results. Instructions were given for completing the survey and assistance was provided to resolve doubts.

All the participants selected (n = 51) met the inclusion criteria and there was no inconsistency in any of their responses. Of 119 experts who initiated the survey 68 were excluded (Fig. S1 of the Supplementary material), mainly due to an incomplete survey (n = 41).

Descriptive statistical analysis was performed for quantitative questions. For ordinal/nominal variables, absolute frequency (number) and relative frequency (percentage of responses for each category relative to total responses [%]) were calculated.

We collected the data in a database and analyzed it using the IBM SPSS Statistics Base 27 software program.

The demographic characteristics and profile of the participants are represented in Table 1. Some 43% (n = 51) of the invited nephrologists fully completed the questionnaire. The expert panel consisted mostly of women (65%), older than 35 years and with more than 10 years of experience in LN. Fifty-three percent of the nephrologists considered themselves the main decision-makers in the treatment of LN, attending a minimum of 2–10 patients per month and, for the most part, in public hospitals (92%), where 37% of the experts attended their patients in a glomerular disease monographic consultation. In addition, 49% had a monographic unit for the management of LN and 45% had a multidisciplinary management of the disease with Rheumatology and/or Internal Medicine units.

All participants were aware of the contents of the GLOSEN document (82% belonged to GLOSEN). It is considered a standard clinical practice guideline for 92% of respondents and highly valued (considered necessary, easy to understand and practical); it is used more frequently than other guidelines such as European Alliance of Associations for Rheumatology (EULAR)8,9 or Kidney Disease Improving Global Outcomes (KDIGO).10

The panel's opinion on treatment goals for LN shows different levels of stringency, probably due to the variety of parameters included in the different guidelines. Proteinuria is currently the most widely used marker to assess treatment efficacy in LN.11,12 However, different techniques can be used for its determination, which would lead to a certain disparity between the possible methods of evaluation for this and other parameters. GLOSEN warns that the use of urine test strips, or quantifications by urine volume, should be avoided because they will provide inaccurate measurements.6 Regarding urinary sediment, automated techniques, for use in the quantification of red blood cells and leukocytes per field, have replaced traditional manual techniques, which are superior for the detection of casts and morphological abnormalities.13,14

The efficacy of treatment depends on whether the patient response is complete or partial. In all cases, the aim is to achieve complete response as quickly as possible to extend renal survival.6 It is very important to have a clear definition of treatment response and adherence by all healthcare professionals to homogenize decision-making on the therapeutic approach to LN. The definition of CR was clearer than that of PR. Although improvement or normalization of urinary sediment is not included in the EULAR8 or KDIGO10 guidelines, most respondents described hematuria as a sensitive marker of clinical activity, especially in cases of previous relapse and residual proteinuria.6

Between 10 and 50% of patients with LN present relapses.15–17 The differences between the parameters included in the different guidelines to define a relapse of LN are even greater than in the definitions of CR or PR.8,10 The disparity demonstrated by the participants on relapse indicators highlights the need to strengthen the criteria and values of proteinuria, hematuria and eGFR defining relapse for a more uniform implementation in clinical practice, as well as to ensure appropriate patient management. Although the risk of relapse is higher in the first years after the onset of LN, it can occur at any time, even after several years of inactivity. Therefore, ongoing periodic monitoring is recommended.6 Although GLOSEN does not specify the frequency of follow-up, a clear need for patient monitoring was shown during all phases, opting to schedule a regimen of visits every month or every 3 months, in the induction or maintenance therapeutic phases, respectively.

The usual clinical and analytical parameters are not sufficient to identify renal histological alterations in many cases of LN,6 so we used renal biopsy. This technique is key to determine the histological class of LN, establish a prognosis and plan treatment. According to the survey, there was a high level of agreement regarding the GLOSEN-recommended criteria6 for biopsy in patients with SLE: proteinuria > 0.5 g/24 h, active urine sediment, and/or rapid deterioration of renal function.

On the other hand, re-biopsy is still under debate because of its possible complications and its influence on patient management,18 with clinicians considering it unnecessary in cases with good progress and response.19 Although its implementation is progressing and has good adherence to guidelines/consensus, its use depends on the resources available in each hospital. Some experts prefer serological biomarkers (cytokines, growth factors and/or urine autoantibodies)20–23 as an alternative to rebiopsy.24

The survey results show that 45% of experts prefer re-biopsy before deciding to withdraw immunosuppressive treatment. One of the risks of withdrawal of immunosuppression is that LN may flare up and require reintroduction of treatment.25 A renal biopsy performed prior to withdrawal of immunosuppression may help this decision by assessing for the existence of activity lesions that may predict relapse.26 However, this is a controversial issue, as other authors advocate a gradual withdrawal of immunosuppression with careful assessment of analytical and serological data without the need for biopsy.27

The identification, assessment and follow-up of extrarenal clinical manifestations is fundamental in LN. However, most of the respondents do so without scale. This is a problem that may perhaps be due to the required consultation time and the lack of training of nephrologists and patients. Better training in this regard would help in the systematization of this assessment, in line with the GLOSEN consensus.

The therapeutic algorithm of the GLOSEN document recommends selecting the therapeutic scheme according to the patient's clinical and analytical profile, from double (GC + MMF or CYC in Eurolupus guideline) or triple (GC + MMF + BEL or GC + MMF + CNI) initial immunosuppressive therapies. During the last few years the BLISS-LN,28 BEL and AURORA29 (voclosporin) clinical trials have illuminated multitarget or triple therapy of LN,30 changing the usual management of this disease. However, and as reflected in the results of this survey, the use of dual therapy is still the general preference in all patient profiles.

Regarding the patient profile candidate for BEL or CNI, in general there was a good overall agreement between the recommendations of the GLOSEN document and the opinion of the respondents: BEL was preferable for patients with extrarenal manifestations, persistent serological activity, need to reduce the dose of GC or relapse prevention; and CNI for patients with proteinuria >3 g/day or complete nephrotic syndrome.

Regarding maintenance therapy, respondents agree with GLOSEN about the use of MMF with low-dose GC as the mainstay of immunosuppressive treatment. Forty-three percent consider the use of BEL in this maintenance phase, which coincides with the demonstrated ability of this drug to reduce the risk of relapse and progressive loss of renal function.31

Despite the lack of international consensus on the definition and treatment of refractory LN,32 the experts followed the GLOSEN recommendations, mainly using rituximab. Importantly, despite reported evidence of rituximab efficacy in refractory disease,33,34 triple therapy with GC + MMF + rituximab failed to demonstrate superiority over dual therapy with GC + MMF.35 However, a sub-analysis of this study suggested that this was due to incomplete depletion of CD19+ lymphocytes.36 Other studies show that the response to rituximab remains subject to complete CD20 lymphocyte depletion.37

Another striking result of the survey is the use of rituximab as first-line treatment for relapsed LN, which is not in line with GLOSEN recommendations. One possible explanation is that respondents may have confused the terms relapse and refractoriness when answering the survey, since the drug is indicated in GLOSEN as first-line treatment for refractory LN. Another possibility is the unavailability of BEL as an officially accepted therapy for patients with LN and frequent relapse before 2021.

The GLOSEN document recommends withdrawal of maintenance immunosuppressive treatment (both GC and MMF) after at least 3–5 years of therapy, always with due flexibility and considering the possibility of relapse. However, the survey results reflect a significant tendency to maintain long-term use of immunosuppressive and steroids for fear of relapse, even respondents recognized the benefits for side effects of reducing their use. There are several clinical challenges in investigating the reasons for this low discontinuation of immunosuppression. This is a controversial and complex issue because national and international guidelines show discrepancies, resulting in a lack of clear guidance. This highlights the need for prospective studies on immunosuppressive withdrawal in LN and, no less important, the prospective validation of emerging serum and/or urinary biomarkers that reliably reveal the presence or absence of histological activity and that justify, in a non-invasive and safer way, the therapeutic decisions to maintain or withdraw IS treatment.

Many specialists are empirically in favor of maintaining lifelong immunosuppression, since abandoning immunosuppression could mean a flare-up of the disease and an increased risk of relapses. Studies such as MAINTAIN show that more than 50% of patients maintained some type of immunosuppression after 10 years.38 Other authors, on the other hand, advise maintaining or gradually reducing immunosuppression until discontinuation in patients with LN in complete or partial clinical remission, after the results of a renal biopsy.24 This new perspective of recent use of sparing therapies, not only of GC, but also of IS, could allow better long-term treatment management, contributing to decrease organ damage derived from prolonged IG use.30

This study has certain limitations. The participants included do not represent all geographical areas of Spain, and more than half of the nephrologists who initially responded to the survey were eventually excluded from the analyses, all of which could generate opinion and selection bias. Nevertheless, inclusion criteria were established to ensure that the respondents had direct and relevant experience in the management of LN, with the aim of obtaining well-founded and useful responses for the purpose of the study and seeking to maintain a balance between the breadth of participation and the quality of the information collected. Likewise, the voluntary and unpaid nature of participation meant that the final sample size depended on the availability and motivation of the professionals to complete the questionnaire. While it is true that the sample size did not allow for robust statistical sub-analyses, we did explore trends according to classificatory variables, such as years of professional experience or number of patients seen, without observing significant differences between groups.

There was no direct interaction among the participants, which limits the possibility of discussing and debating different points of view, and valuable information could be lost, so that, to mitigate this limitation, a scientific committee was responsible for designing and evaluating the whole process and interpreting the results obtained. However, the systematic and anonymous collection of data on professionals who frequently treat patients with LN gives strength to the results found.

Finally, the GLOSEN 2023 consensus is highly valued for its utility and clarity, although its impact is not expected to increase in the future. Its potential can still be maximized; its practicality in the clinic and ease of implementation of key messages aimed at specialists and managers, should be reinforced. Thus, according to those surveyed, the main barrier to implementation is resistance to change on the part of managers due to the cost of some treatments or techniques, so it would be advisable to discuss with them the benefits of applying these recommendations using objective cost-effectiveness and cost-utility data.

In this regard, practitioners should ensure that guidelines are easily applicable in clinical practice and that the consensus is updated according to expert feedback and therapeutic advances in LN. We propose that medical societies create summaries or infographics with key points and visual formats, and that seminars, workshops and clinical sessions be organized to facilitate their implementation.

In conclusion, the degree of variability and discrepancy in some survey results has highlighted aspects of LN pending a more consensual definition, such as the case of the criteria for partial remission and relapse, and the performance of re-biopsies throughout follow-up. Another aspect to highlight is the low percentage of nephrologists using specific scales to evaluate extrarenal manifestations. The experts surveyed agreed with the initial immunosuppressive treatment schemes (double or triple therapy) proposed by the GLOSEN document based on patient profile, although with a greater use of double therapy, mainly with GC + MMF, versus initial triple therapy (adding BEL or CNI depending on the clinical profile). Finally, another relevant finding is the low number of respondents who discontinue immunosuppressive medication after the 3−5 year maintenance period recommended by GLOSEN. This important discrepancy highlights the need for further studies on this poorly studied aspect of LN.