www.kidney-international.

org KDIGO executive conclusions

Executive summary of the KDIGO 2024 Clinical

Practice Guideline for the Management of OPEN
Lupus Nephritis
Brad H. Rovin1, Isabelle M. Ayoub1, Tak Mao Chan2, Zhi-Hong Liu3, Juan M. Mejı́a-Vilet4, Ethan M. Balk5,
Craig E. Gordon6, Gaelen Adam5, Marcello A. Tonelli7, Michael Cheung8, Amy Earley8 and Jürgen Floege9
1
Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, Ohio, USA; 2Division of Nephrology,
Department of Medicine, University of Hong Kong, Hong Kong, China; 3National Clinical Research Center of Kidney Diseases, Nanjing
University School of Medicine, Nanjing, China; 4Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias
Medicas y Nutricion, Salvador Zubiran, Mexico City, Mexico; 5Center for Evidence Synthesis in Health, Brown University School of Public
Health, Providence, Rhode Island, USA; 6Division of Nephrology, Tufts Medical Center, Boston, Massachusetts, USA; 7Department of
Medicine, University of Calgary, Calgary, Alberta, Canada; 8KDIGO, Brussels, Belgium; and 9Division of Nephrology, University Hospital,
Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany

S
The Kidney Disease: Improving Global Outcomes (KDIGO) ince publication of the Kidney Disease: Improving
Clinical Practice Guideline for the Management of Global Outcomes (KDIGO) 2021 Clinical Practice
Glomerular Diseases was published in 2021. Since then, the Guideline for the Management of Glomerular Diseases,1
pace of drug development for glomerular diseases has belimumab and voclosporin have been approved by the
accelerated, due in large part to rapidly accumulating United States Food and Drug Administration (FDA) and the
insights into disease pathogenesis from genetic and European Medicines Agency (EMA) as add-on immunosup-
molecular studies of afflicted patients. To keep the pressives to standard-of-care (SOC) for the treatment of lupus
Glomerular Diseases Guideline as current as possible, nephritis (LN).2,3 These additions to the therapeutic arma-
KDIGO made a commitment to the nephrology community mentarium for the treatment of LN energized patients and
to provide periodic updates, based on new developments providers in the lupus community with the promise of su-
for each disease. After the 2021 guideline was published, perior response rates compared to SOC alone. At the same
two novel drugs received regulatory approval for the time, however, the availability of new therapies raised
management of lupus nephritis, leading to the first KDIGO important questions of how best to apply them. After all, the
guideline update. Herein, an executive summary of the new therapies are expensive, they do not reduce immuno-
most important guideline changes from the Lupus suppression but increase exposure, and they require patients
Nephritis chapter is provided as a quick reference. historically challenged by medication adherence to take even
Kidney International (2024) 105, 31–34; https://doi.org/10.1016/ more drugs on a regular basis. Perhaps the most divisive issue
j.kint.2023.09.001 has been identifying the profile of an LN patient who needs
KEYWORDS: glomerular diseases; glomerulonephritis; guideline; KDIGO; more than SOC, and whether belimumab or voclosporin
lupus nephritis; systematic review would be best for that individual. Because belimumab and
Copyright ª 2023, Kidney Disease: Improving Global Outcomes (KDIGO). voclosporin are poised to significantly change the approach to
Published by Elsevier Inc. on behalf of the International Society of
management of LN, the Lupus Nephritis chapter of the
Nephrology. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/). KDIGO 2021 Glomerular Diseases Guideline is the first to
be updated (Supplementary Table S1; https://kdigo.org/
guidelines/gd/). This Executive Summary provides a brief
snapshot of the updated guideline, but all readers are
encouraged to view the full chapter for detailed discussion and
useful practice points.
The most significant update in the LN guideline was
the recommendation for the initial treatment of prolifer-
ative LN, which now reads: We recommend that patients
Correspondence: Brad H. Rovin, Division of Nephrology, 4th Floor, 1664 Neil
Avenue, Columbus, OH 43201, USA. E-mail: [email protected]
with active Class III or IV LN, with or without a
membranous component, be treated initially with glu-
The complete KDIGO 2024 Clinical Practice Guideline for the Management
of Lupus Nephritis is published in Kidney International, volume 105, issue
cocorticoids plus any one of the following: i. myco-
1S, January 2024, which is available online at www.kidneyinternational. phenolic acid analogs (MPAA) (1B); or ii. low-dose
org. intravenous cyclophosphamide (1B); or iii. belimumab
Received 2 August 2023; revised 29 August 2023; accepted 7 and either MPAA or low-dose intravenous cyclophos-
September 2023 phamide (1B); or iv. MPAA and a calcineurin inhibitor

Kidney International (2024) 105, 31–34 31

KDIGO executive conclusions BH Rovin et al.: Executive summary of KDIGO 2024 Lupus Nephritis Guideline

Kidney biopsy showing

Class III/IV ± V lupus nephritis

Concomitant thrombotic Assess activity and

microangiopathy chronicity items
(Section 10.3.1)

Active Class III/IV ± V lupus nephritis Chronic Class III/IV ± V lupus nephritis
without activity

Supportive treatment If concomitant Class V

for chronic kidney disease manage as Class V
(Section 10.2.4)

Glucocorticoids
Methylprednisolone i.v. 0.25–0.50 g/d for 1–3 days as appropriate
depending on disease severity and rate of progression, then
prednisone p.o. at approximately 0.35–1.0 mg/kg/d
(not to exceed 80 mg/d) and taper over a few months to
maintenance dose (the lower steroid dosing option referring
to the reduced-dose regimen in the voclosporin trials)†
(Practice Point 10.2.3.1.1)

and one of the

following options

CNI + MPAA Mycophenolic acid Cyclophosphamide Belimumab + MPAA or

Voclosporin 23.7 mg b.i.d. and MPAA in patients analogs (MPAA) for up to 6 months reduced-dose cyclophosphamide
with eGFR >45 ml/min per 1.73 m2 for at least 6 months i.v. 500 mg q2wk × 6 or Belimumab (i.v., 10 mg/kg q2wk for
Tacrolimus (trough level approximately 5.5 ng/ml MMF p.o. 1.0–1.5 g b.i.d. or 0.5–1.0 g/m2 monthly × 6; 3 doses then q4wk) and MPAA or i.v.
[6.8 nmol/l], data mainly from Chinese patients) mycophenolic acid sodium or p.o. 1.0-1.5 mg/kg/d cyclophosphamide 500 mg q2wk × 6
and reduced-dose MPAA in patients with SCr 0.72–1.08 g b.i.d. for 3 months (Practice Point 10.2.3.1.5)
<3.0 mg/dl (265 µmol/l) as initial and (Practice Point 10.2.3.1.3) (Practice Point 10.2.3.1.2)§ Belimumab duration up to 2.5 years
maintenance therapy
Consider cyclosporine when voclosporin
and tacrolimus are not available
(Practice Point 10.2.3.1.4)
CNI duration up to 3 years‡

Figure 1 | Recommended approach for initial therapy of active Class III/IV lupus nephritis. Caution is warranted when a calcineurin
inhibitor (CNI) is used in patients with significantly impaired kidney function, in view of increased susceptibility for severe consequences due to
CNI nephrotoxicity. The estimated glomerular filtration rate (eGFR) and serum creatinine (SCr) levels stated in the figure were patient selection
criteria adopted in the respective clinical trials. †Refer to Figure 7 in the full guideline for examples of glucocorticoid treatment regimens. ‡Refer
to Figure 9 in the full guideline for durations of CNI or belimumab treatment in clinical trials. §Refer to Figure 6 in the full guideline for
comments on cyclophosphamide regimens. b.i.d., twice daily; i.v., intravenous; MMF, mycophenolate mofetil; p.o., oral; q2wk, every 2 weeks;
q4wk, every 4 weeks; s.c., subcutaneous.

(CNI) when kidney function is not severely impaired events) and methodological limitations, including lack of
(i.e., estimated glomerular filtration rate [eGFR] £45 ml/ blinding in several trials and other risks of bias.
min per 1.73 m2) (1B) (Figure 1). Each recommended The choice of initial therapy is often based on factors that
therapeutic regimen has been graded as 1B, meaning a are not related to specific disease manifestations. These
strong recommendation based on moderate certainty of include, but are not limited to, cost, local availability of the
evidence. The recommendations are based on randomized therapeutics, local healthcare resources (e.g., availability of
controlled trials and often more than one randomized infusion suites), likelihood of adherence, prior immunosup-
controlled trial; however, the results have been down- pression, fertility concerns, and the presence and severity of
graded to moderate certainty because of trial limitations chronic kidney disease (CKD). In an idealized healthcare
such as imprecision in estimated effects for many priori- environment where cost and accessibility are not factors, it
tized outcomes (due to small study size or number of would be hard to argue against starting treatment with triple

32 Kidney International (2024) 105, 31–34

BH Rovin et al.: Executive summary of KDIGO 2024 Lupus Nephritis Guideline KDIGO executive conclusions

Table 1 | Factors to consider when using United States Food and Drug Administration (FDA)–approved drugs in lupus nephritis
Clinical attributes Voclosporin Belimumab

Kidney function Use cautiously if GFR is impaired (e.g., <45 ml/min May be used if GFR is at least 30 ml/min
per 1.73 m2) per 1.73 m2; may slow decline of GFRa

Kidney histology Use cautiously if widespread sclerotic and/or fibrotic Not determined
changes are present

Proteinuria Effective at any level of proteinuria; may be especially More effective in patients with proteinuria <3 g/d
effective in patients with severe proteinuria with
significant podocyte damage

High risk of disease flare No effect on flare rate May decrease rate of severe flares

Background Was not tested in combination with cyclophosphamide Effective in combination with MMF; uncertain
immunosuppression effectiveness in combination with
cyclophosphamide

Need for parenteral therapy Oral only Intravenous/subcutaneous

Significant extrarenal lupus Efficacy in extrarenal lupus to be determined Long track record of efficacy in extrarenal lupus

Safety Add-on therapy did not increase the incidence of adverse Add-on therapy did not increase the incidence of
events; monitor acute eGFR variations with voclosporin adverse events

Pregnancy Use not recommended (consider tacrolimus) Use not recommended

GFR, glomerular filtration rate; MMF, mycophenolate mofetil.
a
In patients with advanced chronic kidney disease, the benefit of any immunosuppression should be carefully weighed against the likelihood of harm.

therapy given that it has similar safety as dual therapy but an open-label extension of an additional 28 weeks showed that
better efficacy. Nonetheless, many patients may not need the belimumab-treated patients had a sustained efficacy benefit
triple-therapy level of immunosuppression, but identifying with no increase in adverse events.6 Similarly, the endpoint of
such patients a priori is not yet possible. the phase 3 voclosporin trial was 1 year, but patients doing well
For practitioners who want to use triple therapy, the on voclosporin received it for 2 additional years with no decline
guideline does offer some suggestions, by way of practice in kidney function and maintenance of proteinuria reduction.7
points, to help decide between belimumab and a CNI. For Of note, during this 2-year extension, many patients had a
example, a triple-drug regimen with a CNI may be considered reduction in their voclosporin dose, which could have posi-
in patients with relatively good kidney function (e.g., tively impacted eGFR readings.
eGFR $45 ml/min per 1.73 m2) who have heavy proteinuria The immunosuppressive management of pure Class V
due to podocyte injury, given the known benefits of CNIs on (membranous) LN remains without definitive recommenda-
podocyte structure and function.4 Alternatively, a triple-drug tions, but rather has only suggested practice points, even though
regimen with belimumab may be considered in patients who the belimumab and voclosporin trials did include such patients.
are at high risk of LN flare or who have advanced CKD that is Voclosporin plus SOC was more effective than SOC alone in
likely to progress, based on a post hoc analysis of the Efficacy patients with Class V LN, but this difference did not quite reach
and Safety of Belimumab in Patients with Active Lupus statistical significance, possibly due to a very small number of
Nephritis (BLISS-LN) trial that showed belimumab-treated Class V patients. There were also a small number of Class V
patients had fewer LN flares and a slower decline in kidney patients treated with belimumab plus SOC, and compared to
function than patients treated with SOC alone.5 This same SOC alone, they showed no tendency toward a better rate of
post hoc analysis suggested that triple therapy with belimumab remission. Given this, for Class V patients with nephrotic-range
worked best on a background of SOC with MPAA, and in proteinuria, the guideline continues to suggest management
patients with non-nephrotic range proteinuria.5 Examples of with glucocorticoid plus MPAA, CNI, or cyclophosphamide,
clinical situations where one drug may be preferred to the but highlights the need for trials that focus on Class V LN.
other are given in Table 1. Although glucocorticoids are used for the management of
The randomized controlled trials of triple therapy promp- LN, there has been considerable effort in the lupus com-
ted a reconsideration of maintenance immunosuppression for munity to reduce cumulative glucocorticoid dosing. The
proliferative LN. Although MPAA remain the maintenance updated guideline pointed out that a limited number of
immunosuppressive of choice, the revised LN guideline does intravenous methylprednisolone pulses given at the start of
indicate patients treated with SOC plus belimumab or a CNI treatment may allow reduced dosing and more rapid
may remain on triple therapy for an extended time. The pri- tapering of glucocorticoids in LN, even in the context of
mary endpoint of the phase 3 belimumab trial was 2 years, but conventional therapy.

Kidney International (2024) 105, 31–34 33

KDIGO executive conclusions BH Rovin et al.: Executive summary of KDIGO 2024 Lupus Nephritis Guideline

The updated guideline includes a small but critical new pertaining to this topic from Astellas and GlaxoSmithKline; and con-
section on CKD progression in LN. Loss of nephron mass sultancy fees from AstraZeneca, GlaxoSmithKline, and Novartis.
occurs with every episode of active LN, putting patients JMMV reports receiving funding for educational presentations from
AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Roche; and
on track toward progressive loss of kidney function, and serving on the advisory board for Kezar Life Sciences. CEG reports
even kidney failure. Management of patients with LN receiving consultancy fees from Alexion; serving in the speaker bureau
must include not only immunosuppression for acute for Alexion; and receiving funding for travel and/or accommodation
treatment of active LN, but also measures to slow or stop from Alexion. MAT reports receiving payment for expert testimony
CKD progression. While this section is currently limited from Gilead Sciences (not related to the guideline topic). JF reports
to blood pressure control, renin-angiotensin-aldosterone receiving consultancy fees and/or speaker honoraria from AstraZeneca,
system blockade, flare prevention, and nephrotoxin Bayer, Calliditas, Chinook, GlaxoSmithKline, Novartis, Omeros, Otsuka,
Stadapharm, and Travere; and serving on data safety monitoring
avoidance, it is likely to expand in the future as data on boards for Novo Nordisk and Visterra. All the other authors declared no
LN and sodium-glucose cotransporter-2 inhibitors or competing interests.
other new agents such as endothelin-A receptor blockers *Monies paid to institution.
become available.
Finally, there are several additional therapeutics
SUPPLEMENTARY MATERIAL
currently being evaluated for the treatment of LN. These Supplementary File (PDF)
novel drugs are in phase 2 and 3 trials. When these trials Supplementary Table S1. Comparison of the 2021 and 2024 KDIGO
are completed, hopefully with success, the KDIGO Clinical Practice Guideline for the Management of Lupus Nephritis.
guideline will be updated again to provide the nephrology
community with timely evidence-based recommendations
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34 Kidney International (2024) 105, 31–34