Zinc supplementation as an adjunct to standard therapy in childhood nephrotic syndrome - a systematic review

Table 1 Characteristics of included studies

Ref.	Setting, country	Participants	Intervention	Outcomes measured	Comments
Arun et al[5]	Hospital (out-patient), India	Number: 81 [Frequent relapse = 52 (zinc = 26; placebo = 26); Infrequent relapse = 29 (zinc = 14; placebo = 15)] Age: 1-16 yr Inclusion: SSNS with infrequent relapses or FRNS with prednisolone requirement ≤ 0.75 mg/kg on alternate days	Dose: Zinc sulfate 10 mg/d (1 h before or 2 h after meal) Duration: 12 mo	Frequency of relapses, number of relapses (mean), time to first relapse, adverse drug affects, proportion of infection associated relapses, and change in serum zinc level	Double blind placebo-controlled trial. ITT analysis not done. Small sample size (underpowered to show significant differences in the groups). Inclusion of infrequent relapsers may have diluted the significance of the findings. Authors proposed testing of a higher zinc dose along with immunological correlation
Sherali et al[12]	Hospital (out-patient), Pakistan	Number: 60 (zinc = 30; placebo = 30) Age: 2-15 yr Inclusion: FRNS	Dose: Zinc sulfate 10 mg/d Duration: 6 mo	Frequency of relapses, number of relapses (mean), episodes of infections, adverse drug affects, and change in serum zinc level	Double blind placebo-controlled trial. ITT analysis not done. Small sample size. Allocation concealment not clear. Post-supplementation zinc level was not measured in all subjects. Authors proposed testing of a higher zinc dose in a larger cohort
Afzal et al[18]	Hospital (out-patient), India	Number: 30 (zinc = 16; placebo = 14) Age (mean ± SD): 6.45 ± 2.92 yr Inclusion: FRNS (n = 24) and SDNS	Dose: Zinc 20 mg/d Duration: 2 wk starting at the onset of an episode of infection (for 12 mo)	Frequency of relapses, number of relapses (mean), episodes of infections, adverse drug affects, and change in serum and hair zinc level	Open label trial. ITT analysis not clear. Small sample size. Post-supplementation. Authors proposed testing of a higher zinc dose in a larger population
Pardillo et al[19]	Hospital (out-patient), Philippines	Number: 34 Age: Not clear (only children included) Inclusion: SSNS (majority) and SDNS	Dose: RDA Duration: 6 mo	Frequency of relapses, number of relapses (mean), episodes of infections, and adverse drug affects	Double blind placebo-controlled trial. ITT analysis not clear. Small sample size. Authors proposed testing of a higher zinc dose in a larger population

SSNS: Steroid sensitive nephrotic syndrome; FRNS: Frequently relapsing nephrotic syndrome; SDNS: Steroid dependent nephrotic syndrome; ITT: Intention-to-treat analysis; SD: Standard deviation; RDA: Recommended daily allowance.

Table 2 Zinc for nephrotic syndrome (steroid sensitive nephrotic syndrome)

	Patient or population: Patients with nephrotic syndrome
	Settings: Hospital setting
	Intervention: Zinc
Outcomes	Illustrative comparative risks3 (95%CI)		Relative effect (95%CI)	No. of participants (studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Control	Zinc
Frequency of relapses in 12 mo Follow-up: 12 mo	The mean frequency of relapses in 12 mo in the control groups was 2%	The mean frequency of relapses in 12 mo in the intervention groups was 0.2 lower (0.71 lower to 0.31 higher)		81 (1 study)	Very low1,2
Frequency of relapses in 6 mo Follow-up: 12 mo	The mean frequency of relapses in 6 mo in the control groups was 19%	The mean frequency of relapses in 6 mo in the intervention groups was 0.19 lower (0.57 lower to 0.19 higher)		81 (2 studies)	Very low1,2
Risk of relapse per year Follow-up: 12 mo	725 per 1000	500 per 1000 (326 to 776)	RR = 0.69 (0.45 to 1.07)	78 (1 study)	Very low1,2
Mean length of time to next relapse Follow-up: 12 mo	The mean length of time to next relapse in the control groups was 1.5 mo	The mean length of time to next relapse in the intervention groups was 1.5 higher (0 to 0 higher)		78 (1 study)	Very low1,2

¹Single trial;

²Small sample size;

³The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95%CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95%CI). CI: Confidence interval; RR: Risk ratio; GRADE: Working Group grades of evidence; high quality: Further research is very unlikely to change our confidence in the estimate of effect; moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; very low quality: We are very uncertain about the estimate.

Table 3 Zinc for nephrotic syndrome (frequent relapses/steroid dependent)

	Patient or population: Patients with nephrotic syndrome
	Settings: Hospital setting
	Intervention: Zinc
Outcomes	Illustrative comparative risks4 (95%CI)		Relative effect (95%CI)	No. of participants (studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Control	Zinc
Frequency of relapses in 12 mo Follow-up: 12 mo	The mean frequency of relapses in 12 mo in the control groups was 17%	The mean frequency of relapses in 12 mo in the intervention groups was 0.17 lower (0.39 lower to 0.04 higher)		103 (2 studies)	Very low1,2,3
Frequency of relapses in 6 mo	The mean frequency of relapses in 6 mo in the control groups was 16%	The mean frequency of relapses in 6 mo in the intervention groups was 0.16 lower (0.6 lower to 0.3 higher)		50 (2 studies)	Very low1,2
Sustained remission/no relapse Follow-up: 12 mo	426 per 1000	605 per 1000 (422 to 873)	RR = 1.42 (0.99 to 2.05)	103 (2 studies)	Very low1,2,3
Proportion of infection episodes associated with relapse Follow-up: 12 mo	The mean proportion of infection episodes associated with relapse in the control groups was 17%	The mean proportion of infection episodes associated with relapse in the intervention groups was 0.17 lower (0 to 0 higher)		30 (1 study)	Very low1,2

¹Single trial;

²Small sample size;

³Allocation concealment not clear in one study;

⁴The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95%CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95%CI). CI: Confidence interval; RR: Risk ratio; GRADE: Working Group grades of evidence; high quality: Further research is very unlikely to change our confidence in the estimate of effect; moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; very low quality: We are very uncertain about the estimate.