Hydroxychloroquine in IgA nephropathy: a systematic review

Figures & data

Figure 1. Study selection process of the systematic review (PRISMA diagram, Preferred Reporting Items for Systematic Reviews and Meta-Analyses).

Table 1. Characteristics of the studies included in the systematic review.

Reference	Study design, follow-up time, N	Jadad score	RASI	Intervention	Control	Baseline proteinuria (g/d)		End of study proteinuria (g/d)		Baseline eGFR (mL/min)		End of study eGFR (mL/min)
						HCQ	Control	HCQ	Control	HCQ	Control	HCQ	Control
Gao, 2017 [10]	prospective, paired case-control study. 24 weeks. 14 HCQ/14 control.	1	Both groups	HCQ + Losartan	RASI (Losartan)	0.9 ± 0.4	0.7 ± 0.2	0.5 ± 0.2*	0.7 ± 0.3*	83 ± 18	84 ± 19	81 ± 21	81 ± 19
Liu, 2019 [11]	RCT, double-blind, placebo controlled. 6 months. 30 HCQ/30 control	3	Both groups	HCQ + RASI	RASI	1.6 [1.1, 2.2]	1.9 [1.3, 2.6] g/d	0.9* [0.6, 1.0] g/d	1.9* [0.9, 2.6] g/d	52.1 ± 19.7	55.5 ± 18.7	53.1 ± 20.2	55.2 ± 19.7
Yang, 2019 [13]	retrospective, case-control PPS. 6 months. 92 HCQ/92 control	0	Both groups	HCQ	CS therapy	1.7 [1.2, 2.3]	1.8 [1.3, 2.5]	0.8 * [0.6, 1.1]	0.7 * [0.3, 1.1]	56.8 ± 20.4	55.2 ± 22.9	57.1 ± 20.2	56.1 ± 21.9
Tang, 2020 [12]	retrospective, case-control PPS. 6 months. 26 HCQ/26 control	0	Both groups	HCQ + IS therapy	IS therapy	2.3 [1.4, 2.9]	2.3 [1.5, 2.9]	1.1 [0.8, 1.6]	1.2 [0.8, 2.5]	47.6 [34.6, 67.4]	51.5 [26.4, 82.3]	50.9 [30.9, 71.1]	56.3 [19.3, 79.2]
Tang, 2021 [19]	retrospective, cohort. 2 years. 180 patients	0		HCQ	–	1.6 [1.2, 2.3]	–	1.0 [0.5, 1.7]	–	65.8 ± 25.2	–	63.9 ± 25.9	–

Bd: two times a day; CS: corticosteroids; HCQ: hydroxychloroquine; IS: immunosuppressive; od: one time a day; PPS: propensity matched score; RASI: renin angiotensin system inhibitors; RCT: randomized controlled trial; td: three times a day.

*Statistically significant.

Table 2. Adverse events of HCQ in the studies included in the systematic review.

Adverse events	Gao 2017	Liu 2019	Yang 2019	Tang 2020	Total
	n = 14	n = 30	n = 92	n = 26	N = 162
Cardiovascular
Palpitations	0	1	1	0	2
Gastrointestinal
Liver dysfunction Nausea Diarrhea	0	0	1	0	1
	0	1	1	1	3
	0	0	0	1	1
Ophtalmologic
Intraocular pressure elevation	0	0	1	0	1
Renal
eGFR decline	0	2	2	0	4
Neuropsyhiatric
Dizziness	0	1	0	0	1
Mucocutaneous
Pruritus Skin pigmentation Desquamation Alopecia	0	1	2	0	3
	0	1	1	1	3
	0	0	1	0	1
	0	0	1	0	1
Anaphylactic
Dyspnea Rashes	0	0	1	0	1
	1	1	2	0	4
Total n (%)	1 (7)	8 (27)	14 (15)	3 (12)	26 (16)

Figure 2. Potential mechanisms for hydroxychloroquine (HCQ) action in IgA nephropathy (IgAN). HCQ can interfere with immune activation at various cellular levels by inhibiting the innate and adaptive immune systems. In IgAN, mucosal Toll like receptor-9 (TLR-9) activation induces B-cell activating factor (BAFF) overexpression in dendritic cells, stimulates the generation of proliferation-inducing ligand (APRIL) and interleukin-6 (IL-6), which act concurrently to stimulate the production of galactose deficient IgA1. HCQ interferes with TLR9 ligand binding and TLR signaling (through lysosomal inhibition), which inhibits TLR-mediated cell activation and cytokine production. Moreover, in antigen presenting cells, such as dendritic cells and B cells, HCQ inhibits antigen processing and subsequent MHC class II presentation to T cells, preventing T cell activation, differentiation and expression of co-stimulatory molecules.

Gao R, Wu W, Wen Y, et al. Hydroxychloroquine alleviates persistent proteinuria in IgA nephropathy. Int Urol Nephrol. 2017;49(7):1233–1241.

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Liu LJ, Yang YZ, Shi SF, et al. Effects of hydroxychloroquine on proteinuria in IgA nephropathy: a randomized controlled trial. Am J Kidney Dis. 2019;74(1):15–22.

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Yang YZ, Chen P, Liu LJ, et al. Comparison of the effects of hydroxychloroquine and corticosteroid treatment on proteinuria in IgA nephropathy: a case-control study. BMC Nephrol. 2019;20(1):297.

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Tang C, Lv JC, Shi SF, et al. Effect of hydroxychloroquine in patients with IgA nephropathy with insufficient responses to immunosuppressive therapy: a retrospective case-control study. BMC Nephrol. 2020;21(1):469.

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Tang C, Lv JC, Shi SF, et al. Long-term safety and efficacy of hydroxychloroquine in patients with IgA nephropathy: a single-center experience. J Nephrol. 2021.DOI:10.1007/s40620-021-00988-1.

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Data availability statement

Data extracted from the included studies in this review are available on request from the corresponding author.