Plasma cadmium is associated with increased risk of long-term kidney graft failure

The kidney is one of the most sensitive organs to cadmium-induced toxicity, particularly in conditions long-term oxidative stress. We hypothesized that, transplant recipients, nephrotoxic exposure cadmium represents an overlooked hazard for optimal graft function. To test this, we performed a prospective cohort study and included 672 outpatient recipients with functioning beyond year. median plasma was 58 ng/L. During 4.9 years follow-up, 78 developed failure significantly different distribution across tertiles (13, 26, 39 events, respectively). Plasma associated increased risk (hazard ratio 1.96, 95% confidence interval 1.56?2.47 per log2 ng/L). Similarly, dose-response relationship observed over increasing cadmium, after adjustments potential confounders (donor, recipient, lifestyle characteristics), robust both competing sensitivity analyses. These findings were also consistent function decline (graft or doubling serum creatinine). 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Using cutoff points 500 1500 concentrations, respectively, single subject each categories.32Prozialeck Early nephrotoxicity.Biometals. 793-809Crossref A detailed description baseline characteristics (tertile 1: ?48 ng/l; tertile 2: 48?68 3: ?69 ng/l) given Table 1.Table 1Baseline recipientsCharacteristicTertiles concentrationsPtrendTertile 1 (?48 ng/l)Tertile 2 (48–68 3 (?69 ng/l)(n = 224)(n 222)(n 226)Demographics anthropometrics Age, yr48 1454 1256 11<0.001 Sex, male142 (63)132 (60)113 (50)0.01 Body mass index, kg/m226.5 4.627.0 4.926.6 4.70.78 Waist circumference, cm98 1499 1599 150.71 Smoking status0.005Never101 (45)94 (42)72 (32)Former90 (40)88 (40)107 (47)Current21 (9)27 (12)32 (14)Alcohol use0.320 g/d18 (8)27 (12)30 (13)0?10 g/d123 (55)127 (57)119 (53)10?30 g/d43 (19)44 (20)44 (20)>30 g/d15 (7)5 (2)10 (4) Systolic pressure, mm Hg134 17136 16137 190.18 Diastolic Hg83 1183 1182 110.60 Use antihypertensive medication187 (84)197 (89)208 (92)0.02 intakeTotal energy intake, kcal/d2259 6332088 6342152 5870.45Cereals, g/d187 (147–231)176 (146–211)178 (138–212)0.21Potatoes, g/d111 (70–146)118 (73–166)122 (76–173)0.29Vegetables, g/d80 (56–116)80 (48–124)75 (53–107)0.54Fruits, g/d100 (48–189)110 (53–197)104 (39–186)0.22Legumes, g/d29 (14–48)30 (18–45)31 (17–43)0.88Nuts, g/d5.6 (1.1–10.6)5.1 (1.9–10.4)4.5 (1.4–8.9)0.41Meat, g/d94 (73–112)95 (77–118)98 (75–117)0.03Dairy products, g/d389 (239–482)374 (245–510)361 (264–514)0.54Fish seafood, g/d13 (7–21)16 (6–23)13 (6–24)0.85Kidney history eGFR, m260 1952 1845 19<0.001 Proteinuria43 (19)50 (23)57 (25)0.31 Urinary protein excretion, g/24 h0.15 (0.02?0.28)0.19 (0.02?0.35)0.21 (0.02?0.45)0.01 Dialysis vintage, mo20 (5?43)25 (10?48)30 (11?55)0.001 Transplant yr7 (3?13)5 (1?12)5 (1?10)0.003 Acute rejection53 (24)64 (29)60 (27)0.46 Cold ischemia time, h13 (2?21)16 (3?21)15 (3?21)0.09 Warm min42 1544 1644 150.36 HLA mismatches2.1 1.52.1 1.62.4 1.60.69 Donor type, deceased133 (59)150 (68)158 (70)0.05Primary disease0.40 Glomerulosclerosis70 (31)61 (28)60 (27) Glomerulonephritis19 (9)19 (9)13 (6) Tubulointerstitial nephritis32 (14)20 (9)24 (11) Polycystic disease40 (18)47 (21)54 (24) hypo/dysplasia10 (5)12 (5)7 (3) Renovascular disease8 (4)15 (7)16 (7) Diabetes7 (3)10 (5)15 Other/miscellaneous38 (17)38 (17)37 (16)Immunosuppressive therapy calcineurin inhibitor110 (49)136 (61)139 (62)0.01 proliferation inhibitor196 (88)180 (81)184 (81)0.12 Corticosteroid dose <10 mg/24 h95 (42)97 (44)84 (37)0.35 Liver parametersASAT, U/l21 (18?26)22 (19?27)22 (18?27)0.09ALAT, U/l19 (14?26)19 (14?26)18 (14?26)0.93Alkaline phosphatase, U/l66 (51?81)67 (55?85)68 (54?91)0.06GGT, U/l25 (19?34)28 (19?46)28 (18?45)0.02 Fasting lipidsTotal cholesterol, mmol/l4.9 1.05.1 1.15.3 1.20.01HDL mmol/l1.4 0.41.4 0.51.4 0.50.39LDL mmol/l2.8 (2.3?3.4)2.8 (2.3?3.6)3.0 (2.4?3.6)0.05Triglycerides, mmol/l1.7 (1.2?2.2)1.6 (1.2?2.1)1.8 (1.3?2.7)0.08 Diabetes glucose homeostasisDiabetes41 (18)58 (26)64 (28)0.03Glucose, mmol/l5.2 (4.7?5.8)5.2 (4.8?6.1)5.3 (4.8?6.2)0.09HbA1C, %5.9 0.76.0 1.06.1 0.80.04 Markers toxicityuEGF, ng/ml5.45 (2.99?8.13)3.99 (2.16?7.21)3.57 (1.47?7.26)<0.001uLFABP, ng/ml0.65 (0.27?2.11)0.91 (0.43?3.13)1.21 (0.50?5.90)<0.001ALAT, alanine aminotransferase; ASAT, aspartate rate; GGT, gamma-glutamyl transferase; HbA1C, glycated hemoglobin; HDL, high-density lipoprotein; HLA, human leukocyte antigen; LDL, low-density uEGF, epidermal growth factor; uLFABP, liver-type fatty acid binding protein.Values presented SD, range), n (%). Differences among studied variance linear regression continuous variables chi-square categorical variables. Open table tab ALAT, protein. Values follow-up (IQR, 3.4?5.5 years), (12%), respectively; P < 0.001) (Figure 1a). crude [HR], 1.89; [CI], 1.47?2.43 0.001). consistently found either middle highest (HR, 2.19; CI, 1.13?4.27 HR, 3.38; 1.80?6.33; respectively) lowest (reference group). multivariable-adjusted these remained materially unchanged (Table Figure 2).33Fine Gray R.J. proportional subdistribution risk.J Stat Assoc. 94: 496-509Crossref (8717) ScholarTable 2Association failureModelCadmium (ng/l)Tertiles cadmiumTertile 1Tertile 2Tertile 3Tertile 3bTertile 3ce values calculated estimate (HR) limit CI closest null third exclusion extreme outliers. Multivariable adjusted age sex. Subsequently, additive adjustment rate, dialysis acute rejection, antigens mismatches, type (model 2); systolic glucose, diabetes 3); smoking alcohol use 4); induction (anti–thymocyte globulin, interleukin-2 receptor antibody, muromonab-CD3, rituximab; 5); dietary intake groups (e.g., cereals, potatoes, vegetables, fruits, legumes, nuts, meat, milk dairy fish seafood; 6).e valuesce 6).(n 672)e 226)(n 194)(n 215)HR (95% CI)PReferenceHR CI)HR CI)Death-censored analysesCrude1.89 (1.47?2.43)<0.0012.48, 1.941.002.19 (1.13?4.27)3.38 (1.80?6.33)3.17 (1.66?6.05)3.29 (1.74?6.20)3.93, 2.29Model 11.96 (1.56?2.47)<0.0012.56, 2.061.002.67 (1.36?5.26)4.31 (2.25?8.22)4.23 (2.16?8.27)4.26 (2.21?8.21)4.78, 2.85Model 21.88 (1.31?2.69)0.0012.46, 1.701.002.49 (1.14?5.43)3.11 (1.41?6.86)2.50 (1.14?5.48)3.09 (1.37?6.93)3.72, 1.79Model 31.87 (1.30?2.69)0.0012.45, 1.691.002.48 (1.14?5.41)3.08 (1.40?6.82)2.47 (1.12?5.42)3.07 (1.36?6.90)3.73, 1.78Model 41.93 (1.36?2.75)<0.0012.52, 1.781.002.57 (1.16?5.70)3.36 (1.50?7.54)3.45 (1.48?5.05)3.34 (1.46?7.64)3.98, 1.92Model 51.87 (1.33–2.62)<0.0012.45, 1.731.002.50 (1.14–5.47)3.03 (1.37–6.69)3.22 (1.40–7.39)2.96 (1.31–6.66)3.62, 1.70Model 61.81 (1.28?2.56)0.0012.38, 1.661.002.31 (1.02?5.22)2.82 (1.25?6.40)2.89 (1.24?5.00)2.76 (1.20?6.35)3.42, 1.53Competing analysesCrude1.90 (1.49?2.42)<0.0012.49, 1.961.002.04 (1.05?3.96)3.09 (1.65?5.78)2.83 (1.48?5.41)2.99 (1.59?5.63)3.65, 2.10Model 11.97 (1.66?2.35)<0.0012.57, 2.191.002.57 (1.33?4.97)4.13 (2.22?7.69)4.01 (2.11?7.63)4.07 (2.17?7.64)4.62, 2.80Model 21.81 (1.43?2.30)<0.0012.38, 1.881.002.17 (1.02?4.62)2.80 (1.32?5.94)2.69 (1.22?5.93)2.69 (1.24?5.80)3.35, 1.59Model 31.81 (1.41?2.30)<0.0012.38, 1.851.002.28 (0.99?5.26)3.00 (1.35?6.67)2.98 (1.30?6.83)2.95 (1.30?6.67)3.61, 1.69Model 41.76 (1.41?2.20)<0.0012.32, 1.851.002.12 (0.99?4.55)2.74 (1.26?5.55)2.70 (1.21?6.04)2.68 (1.22?5.86)3.34, 1.56Model 51.79 (1.42–2.26)<0.0012.35, 1.871.002.15 (0.98–4.71)2.65 (1.22–5.77)2.54 (1.16–5.57)2.54 (1.18–5.45)3.20, 1.49Model 61.99 (1.38?2.85)<0.0012.59, 1.811.001.96 (0.90?4.26)2.66 (1.24?5.68)2.89 (1.24?6.75)2.59 (1.17?5.71)3.25, 1.47CI, interval; ratio.Cox analyses assess (nevents 78), accounting death (with graft) censoring time performing Fine Gray.33Fine Associations variable overall without aall (n 32) bextreme 11) outliers.c e 6). death-censored (a) population, (b) all outliers, (c) Data fitted Cox (58 reference value. black line ratio, gray area interval.View Large Image ViewerDownload Hi-res image Download (PPT) ratio. Effect modification between plasm