Proton pump inhibitors and adverse effects in kidney transplant recipients: A meta-analysis

Table 1 Characteristics of included studies

Ref.	Country	Type	Total N	Race	Immuno-suppre-ssive regimen	CNI use (% Cyclos-porine)	PPI			No PPI			Quality Scale3
							N	Age	M/F	N	Age	M/F
Patel et al[32] 2012	United States	Retrospec-tive	561	NR	Tacroli-mus, MMF, Predni-sone	0%	155	52±131	NR	406	48±14	NR	3-2-2
Knorr et al[20] 2014	United States	Retrospec-tive	597	52% Black	rATG, MMF, Tacroli-mus, Predni-sone	<3%	213	55±12	122/91	384	55±13	210/174	4-2-3
van Boekel et al[22] 2014	The Netherlands	Retrospec-tive	202	98.5% Caucasi-an	Tacroli-mus, MMF. Predni-sone	0%	125	47.7±12.8	61.6%/38.4%	77	46.7±13.3	66.2%/43.8%	4-2-3
Van Ende et al[33] 2014	Belgium	Cross-sectional	512	98% Caucasi-an	Varies	47% (tacroli-mus 35 %)	101	53 ± 13	59%/41%	411	53 ± 13	59%/41%	4-2-3
Alhosaini et al[34] 2015	United States	Retrospec-tive	83	59% Caucasi-an, 19% Black	CNI (Tacroli-mus, Cyclospo-rine), MPA, Predni-sone	5/83 (6%)	43	54 ± 15.1	25/18	40	49.7 ± 16.4	24/16	4-2-3
Sezer et al[35] 2015	Turkey	Retrospec-tive	354	NR	NR	NR	164	38.6 ±1 0.7	NR	96	NR	38.6 ±1 0.7	3-2-2
Courson et al[21] 2016	United States	Retrospec-tive	286	51% Caucasi-an, 17% Black, 10% Asian	Tacroli-mus, MMF or MPS, early steroid withdra-wal	0%	171	56±13	118/53	115	54±13	88/27	4-2-3
Patel et al[23] 2017	United States	Retrospec-tive	522	24% Black	Tacroli-mus, reduced-dose MMF, predni-sone	11/522 (2%) convert-ed to cyclospo-rine	183	54 (44-63)2	102/81	339	53 (43-60)	219/120	4-2-3
Shabaka et al[36] 2017	Spain	Cross-sectional	938	NR	CNI-based regimen	NR	NR	NR	NR	NR	NR	NR	3-2-2
Rouse et al[24] 2017	United States	Retrospec-tive	211	55% Caucasi-an, 30% Black	Tacroli-mus, MMF or MPS, Predni-sone	0%	35	55±10.7	25/10	176	63±14	124/52	4-2-3
Uludag et al[37] 2017	Turkey	Retrospec-tive	292	NR	NR	NR	223	36±10	129/104	69	33±11	42/27	3-2-2
Kipp et al[39] 2018	United States	Retrospec-tive	819	NR	NR	NR	404	NR	NR	415	NR	NR	3-1-2
Douwes et al[40] 2018	The Nether-lands	Cross-sectional	706	NR	NR	NR	NR	53 ± 13	57%/43%	NR	53 ± 13	57%/43%	3-1-2
Gomes-Neto et al[38] 2018	The Nether-lands	Cross-sectional	703	NR	NR	NR	NR	53 ± 13	57%/43%	NR	53 ± 13	57%/43%	3-1-2

¹Data expressed as mean ± SD;

²Data expressed as Median (Range);

³According to the NOS (Newcastle-Ottawa Scale) classification. NR: Not reported; CNI: Calcineurin inhibitor; MMF: Mycophenolate mofetil; MPS: Mycophenolate sodium; MPA: Mycophenolate; rATG: Rabbit antithymocyte globulin; PPI: Proton pump inhibitors.

Table 2 Acute rejection and graft loss

Ref.	Biopsy-proven acute rejection at ⩾ 1 yr (%)	Biopsy-proven or presumed rejection at 3 mo (%)	Median time to rejection	Antibody mediated rejection (%)	Graft loss (%)
Patel et al[32] 2012
PPI	25 (16%)	NR	4.1 mo	3.3%	NR
No PPI	60 (15%)	NR	3.3 mo	3.1%	NR
P	0.69	-	NS	NS	-
Knorr et al[20] 2014
PPI	32/213 (15%)	NR	110 ± 91 d	1/32 (3.1%)	9/213 (4.2%)
H2A	46/384 (12%)	NR	110 ± 112 d	2/46 (4.3%)	19/384 (4.9%)
P	0.15	-	1.0	NR	0.84
van Boekel et al[22] 2014
PPI	NR	25/125 (20%) BPAR: 13/125 (10.4%)	NR	NR	NR
H2RA	NR	15/77 (19.5%) BPAR: 7/77 (9.1%)	NR	NR	NR
P	-	NS	-	-	-
Courson et al[21] 2014
PPI	16/171 (9.4%)	NR	116±92 d1	5/16 (31%)	4/171 (2.3%)
H2RA	3/115 (2.6%)	NR	both	0	2/115 (1.7%)
P	0.029	-	NS	0.53	1
Patel et al[23] 2017
PPI	11/183 (19%)	12/183 (4.9%)	106 (57-286) days2	1/11 (9.1%)	9/183 (4.9%)
H2RA	28/339 (14%)	9/339 (3.5%)	139 (96-339) days	2/28 (7.1%)	8/339 (2.4%)
P	0.35	0.44	0.28	NR	0.12
Rouse et al[24] 2017
PPI	5/35 NR		NR	2/5 (40%)	NR
H2RA	26/176	NR	NR	3/26 (12%)	NR
P	1.0	-	-	0.03	-
Uludag et al[37] 2017
PPI	36/233 (15.5%)	NR	NR	NR	11/233 (4.7%)
No PPI	5/69 (7.2%)	NR	NR	NR	2/69 (2.9%)
P	0.08	-	-	-	0.51

¹Data expressed as mean ± SD;

²Data expressed as Median (Range). NR: Not reported; NS: Not significant; H2RA: H2-receptor antagonists; PPI: Proton pump inhibitors.

Table 3 Renal function

Ref.	eGFR			Cr
	PPI	No PPI	P	PPI	No PPI	P
Knorr et al[20]	53.1 ± 20.21	55.1 ± 20.6	0.29	NR	NR	-
van Boekel et al[22]	49.5 ± 12.3	50.7 ± 12.5	NS	1.5 ± 0.4 at 3 mo	1.5 ± 0.4	NS
Patel et al[23]	49.0 (39.4–63.2)2	49.9 (39.3–60.8)	0.78	NR	NR	-
Uludag et al[37]	-	-	-	1.49 ± 0.99 mg/dL	1.24 ± 0.46 mg/dL	0.017
Alhosaini et al[34]	49.4 ± 14.9	52.8 ± 14.3	0.29	-	-	-
Kipp et al[39]	NR	NR	-	1.896 ± 1.53	1.812 ± 1.25	P = 0.4098

¹Data expressed as mean ± SD;

²Data expressed as Median (Range). NR: Not reported; NS: Not significant; eGFR: Estimated glomerular filtration rate; PPI: Proton pump inhibitors.

Table 4 Hypomagnesemia

Ref.	Serum / Plasma magnesium level			Hypomagnesemia					Magnesium supplemen-tation
	PPI	No PPI	P	Definition of hypomagne-semia	PPI	No PPI	P	Correlation between PPI and hypomagne-semia
Sezer et al[35]	1.5 ± 0.04 mg/dl	1.7 ± 0.02 mg/dl	P < 0.05	NR	NR	NR		NR	NR
Shabaka et al[36]	NR	NR		NR	OR 1.55, (95%CI 1.09-2.20)	1		NR	NR
Kipp et al[39]	NR	NR		NR	215 (53.1%)	185 (44.6%)	P < 0.013	NR	NR
Alhosaini et al[34]	1.70 ± 0.12	1.79 ± 0.17	0.006	Serum Mg < 1.8 mg/dL	33/43	24/40	P > 0.05	NR	Use of Mg supplement: PPI 47% vs Non-PPI 21% (P = 0.02)
				Serum Mg < 1.3 mg/dL	9/43 (21%)	2/40 (5%)	P = 0.03
Uludag et al[37]	0.728 mmol/L	vs 0.755 mmol/L,	P = 0.061	NR	NR	NR		NR	NR
Van Ende et al[33]	NR	NR		Serum Mg < 1.7 mg/dL	β: −0.84 (0.26; 2.71), P = 0.78			β: −0.84 (0.26; 2.71), P = 0.78	NR
Douwes et al[40]	NR	NR		Serum Mg < 1.8 mg/dL (0.75 mmol/L)	HR 3.25 (1.26-8.39)	1		β: -0.08, P = 0.046	Mean Mg intake: 330 ± 85 mg/d, (P = 0.204)
Gomes-Neto et al[38]	NR	NR		NR	β: -0.05, P = 0.04	NR		β: -0.05, P = 0.04	NR

¹Data expressed as mean ± SD; ²Data expressed as Median (Range); NR: Not reported; NS: Not significant; PPI: Proton pump inhibitors; Mg: Magnesium.

Table 5 Mortality

Ref.	1-yr mortality			Mortality beyond 1 yr (PPI vs no PPI)
	PPI	No PPI	P
Knorr et al[20]	9/213 (4.2%)	17/384 (4.4%)	1
Courson et al[21]	3/171 (1.8%)	3/115 (2.6%)	0.687
Patel et al[23]	6/183 (3.3%)	3/339 (0.9%)	0.007
Douwes et al[40]	NR	NR		HR 1.94 (95%CI: 1.32-2.88)
Gomes-Neto et al[38]	NR	NR		HR 2.01 (95%CI: 1.43-2.83)

NR: Not reported; NS: Not significant; eGFR: Estimated glomerular filtration rate; PPI: Proton pump inhibitors.