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Nephrology 20, Suppl. 2 (2015) 36–39

Original Article

Clinical and pathological features of donor/recipient body weight mismatch after kidney transplantation TAKAFUMI YAMAKAWA,1 AKIMITSU KOBAYASHI,1,2 IZUMI YAMAMOTO,1 YASUYUKI NAKADA,1 AKI MAFUNE,1 HARUKI KATSUMATA,1 MAIKO FURUYA,1 KENTARO KOIKE,1 JUN MIKI,3 HIROKI YAMADA,3 YUDO TANNO,1 ICHIRO OHKIDO,1 NOBUO TSUBOI,1 KEITARO YOKOYAMA,1 HIROYASU YAMAMOTO2 and TAKASHI YOKOO1 1 2

Division of Nephrology and Hypertension, Department of Internal Medicine, 3Department of Urology, The Jikei University School of Medicine, Tokyo, and Department of Internal Medicine, Atsugi City Hospital, Kanagawa, Japan

KEY WORDS: body weight mismatch, glomerular enlargement, kidney transplantation. Correspondence: Dr Takafumi Yamakawa, Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shimbashi, Minato-ku, Tokyo 105-8471, Japan. Email: y.takafumi @jikei.ac.jp Accepted for publication 14 March 2015. doi:10.1111/nep.12470 Conflict of Interest: The authors have no conflict of interest to declare.

ABSTRACT: Background: Previous studies have shown that a donor/recipient body weight mismatch affects long-term graft survival and graft function after kidney transplantation. However, the mechanisms are not fully understood. Aim: To address the mechanisms, we compared the pathological and physiological features between patients with a donor/recipient body weight mismatch and those without a mismatch 1 yr after kidney transplantation. Furthermore, we investigated the correlation with the donor/recipient body weight ratio. Methods: We examined allograft biopsy specimens from 10 recipients with stable kidney function, with body weight mismatch (donor/recipient body weight ratio [D/R BWR] < 0.9), and compared them with samples from 13 patients without mismatch. We measured glomerular volume (GV) using the Weibel–Gomez method and glomerular density (GD) defined by nonsclerotic glomerular number/renal cortical area as pathological findings. The physiological parameters included estimated glomerular filtration rate and proteinuria (mg/day). These data were evaluated to identify a correlation with D/R BWR. Results: The pathological features showed that GV and GD were identical in the two groups. However, when glomerular enlargement was defined by ΔGV (GV at the 1-yr biopsy minus GV at baseline biopsy), ΔGV was higher in mismatch cases compared with that in cases without a mismatch (10.6 ± 4.6 vs. 5.5 ± 7.1 × 105 μm3; P = 0.049). Furthermore, D/R BWR was significantly correlated with ΔGV (P = 0.03, r = –0.436). eGFR values were physiologically identical between the two groups, but the mismatch cases had significantly higher proteinuria levels than that of the cases without a mismatch at 1 yr after kidney transplantation. Conclusion: A donor/recipient body weight mismatch could affect glomerular enlargement and increased proteinuria 1 yr after kidney transplantation. How these two features affect long-term graft survival and function must be addressed in the future.

Increasing attention has been paid to non-immunological factors, such as donor age, graft weight, recipient body mass index, and the donor/recipient body weight ratio (D/R BWR).1–7 Among these, donor/recipient body weight mismatch affects long-term graft survival and graft function after kidney transplantation.3,5,7 A previous report showed that donor/recipient body weight mismatch influences long-term 36

graft survival (5-yr graft survival: D/R BWR ≤ 0.9 (71%) vs. D/R BWR ≥ 1.2 (88%); P = 0.01, 10-yr graft survival D/R BWR ≤ 0.9 (28%) vs. D/R BWR ≥ 1.2 (51%); P = 0.05),5 and these tendencies were observed even in the early period after kidney transplantation.7 The postulated mechanism is glomerular enlargement and/or glomerular sclerosis due to glomerular hyperfiltration related to increased metabolic © 2015 Asian Pacific Society of Nephrology

Body weight mismatch after KTx

demand. However, observations of these pathological and physiological features are limited, even during the early posttransplantation period. To address the mechanisms, we compared the pathological and physiological features between patients with a donor/recipient body weight mismatch and those without a mismatch 1 yr after kidney transplantation. Furthermore, we investigated the correlation in donor/ recipient body weight ratio.

METHODS Patients We enrolled 23 patients with stable kidney function who did not have an episode of rejection or any complication that resulted in a functional decrease in the graft from 2005 to 2012. The basic immunosuppressant regimen included tacrolimus, mycophenolate mofetil, prednisolone, and basiliximab. All patients provided informed consent for performance of biopsy and collection of blood samples.

Physiological values Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease equation for Japanese patients.8 A 24-h urinalysis was used to quantify proteinuria at allograft biopsy.

Pathological values All biopsy samples were obtained by percutaneous needle biopsy. We measured the glomerular volume (GV) using the Weibel–Gomez method and glomerular density (GD) using 0- and 1-h biopsy specimens (baseline controls) and 1-yr biopsy specimens. Glomerular area (GA) was defined by the outer area of the tuft capillary loops using a computer-assisted image analyzer (Scion Image: http:// scion-image.updatestar.com/). Mean GV was calculated from the measured GA as follows: GV = (GA)3/2 × β/d, where β is a dimensionless shape coefficient (β = 1.38 for spheres), and d is a size distribution coefficient used to adjust for variations in glomerular size.9 We used d = 1.01, as reported previously.10,11 Glomerular enlargement was defined as ΔGV, which was calculated by: GV at the 1-yr biopsy – GV at baseline. The GD was calculated by the total number of glomeruli that were not globally sclerotic/total renal cortical area. GD was measured using the computer-assisted image analyzer.

RESULTS Donor and recipient characteristics The clinical characteristics of the mismatch patients and those without a mismatch at kidney transplantation are summarized in Table 1. Twenty-three recipients included 15 males and 8 females, and the donors included 10 males and 13 females. Mean age of the recipients was 36.0 ± 9.54 yr at kidney transplantation. The mismatch cases were all male and had higher BSA compared with that in the cases without a mismatch (1.78 ± 0.13 vs. 1.56 ± 0.16; P = 0.002). No significant differences in mean blood pressure or usage of an angiotensin II receptor blocker were observed between the groups. Graft function and proteinuria were assessed 1 month after kidney transplantation as a baseline.

Changes in graft function and proteinuria Graft function as assessed by eGFR did not change remarkably from baseline to 1 yr after kidney transplantation. Mismatch cases were likely to have a lower eGFR at baseline (42 vs. 49 ml/min/1.73 m2; P = NS) and 1 yr after kidney transplantation (43 vs. 50 ml/min/1.73 m2; P = NS) (Table 2, Fig. 1). Mismatch cases showed a higher proteinuria level than that in cases without a mismatch at baseline (215.1 ± 79.8 vs. 83.6 ± 64.5 mg/day; P = 0.0003) and 1 yr after kidney transplantation (102.9 ± 72.0 vs. 47.4 ± 51.8 mg/day; P = 0.04) (Table 2, Fig. 1). A reduction in proteinuria level was observed from baseline to 1-yr after kidney transplantation in both groups.

Table 1 Donor and recipient characteristics at kidney transplantation Variable

Donor age (yr) Donor male (n, %) Recipient age (yr) Recipient male (n, %) BMI (kg/m2) BSA (m2) Graft weight (g)

Mismatch (n = 10)

Non-mismatch (n = 13)

p

61 (54–62) 3 (30.0) 36 (32–46) 10 (100.0) 21.8 (20.0–22.1) 1.78 ± 0.13 140 (132–160)

57 (51–64) 7 (53.9) 33 (29–36) 5 (38.5) 18.6 (18.1–22.7) 1.56 ± 0.16 180 (140–218)

NS NS NS 0.002 NS 0.002 NS

BMI, body mass index; BSA, body surface area.

Statistical analysis Values are expressed as medians or means ± standard deviations. Patients with and without mismatch were defined as having a D/R BWR of ≤0.9 and >0.9, respectively, as in previous studies.3–5 We compared changes in the clinical and pathological data using the paired t-test. Comparisons between unpaired data were performed with the Mann–Whitney U-test. We analyzed the association between pathological features using Spearman’s rank correlation analysis. All p-values were two-tailed, and a p-value < 0.05 was considered to indicate significance. © 2015 Asian Pacific Society of Nephrology

Table 2 Clinical variables 1 yr after kidney transplantation Variables

eGFR (ml/min/1.73 m2) Proteinuria (mg/day) eGFR-1yr (ml/min/1.73 m2) Proteinuria-1 yr (mg/day)

Mismatch (n = 10)

Non-mismatch (n = 13)

p

42 (33–55) 215.1 ± 79.8 43 (40–53) 102.9 ± 72.0

49 (43–58) 83.6 ± 64.5 50 (41–60) 47.4 ± 51.8

NS 0.0003 NS 0.04

eGFR, estimated glomerular filtration rate.8

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T Yamakawa et al.

Fig. 1 Comparison of mismatch patients and patients without a mismatch 1 yr after kidney transplantation. Mismatch patients were likely to have a lower estimated glomerular filtration rate (eGFR) (43 vs. 50 ml/min/1.73 m2; NS) and significantly higher proteinuria levels (102.9 ± 72.0 vs. 47.4 ± 51.8 mg/day; P = 0.04) than those of patients without a mismatch 1 yr after kidney transplantation. Mismatch: D/R BWR ≤ 0.9, non-mismatch: D/R BWR > 0.9

Table 4 Pathological variables associated with D/R BWR

Table 3 Comparison of pathological parameters Variable

GS-baseline (%) GV-baseline (×106 μm3) GD-baseline (/mm2) IFTA-baseline (%) GS-1yr (%) GV-1yr (×106 μm3) GD-1yr (/mm2) IFTA-1yr (%) ΔGV (×105 μm3)

Mismatch (n = 10)

Non-mismatch (n = 13)

p

0 (0–14) 2.4 ± 1.0 2.5 ± 0.8 5.0 ± 4.7 9.4 (0–13) 3.4 ± 1.0 2.0 ± 1.1 10.0 ± 5.3 10.6 ± 4.6

0 (0–9) 2.5 ± 0.7 2.1 ± 0.6 4.6 ± 2.5 6.3 (0–11) 3.0 ± 1.2 2.0 ± 0.7 13.5 ± 7.2 5.5 ± 7.1

NS NS NS NS NS NS NS NS 0.049

GS, glomerular sclerosis; GV, glomerular volume; GD, glomerular density; IFTA, interstitial fibrosis/tubular atrophy; ΔGV = GV – 1 yr – GV – baseline.

Comparison of pathological parameters Pathological parameters at baseline were not significantly different between the groups. The GD did not change, but ΔGV increased significantly in the mismatch cases (10.6 ± 4.6 vs. 5.5 ± 7.1 × 105 μm3; P = 0.049) 1 yr after kidney transplantation (Table 3). The mismatch patients tended to have higher levels of glomerular sclerosis (9.4 vs. 6.3%; P = NS).

Pathological and physiological variables associated with D/R BWR D/R BWR was significantly correlated with ΔGV (P = 0.03, r = –0.436) but no correlation was found in the other parameters (Table 4).

DISCUSSION The main results of our study were: 1) mismatch cases showed higher ΔGV and a higher proteinuria level than those of cases without a mismatch 1 yr after kidney transplantation; 2) the mismatch level estimated by D/R BWR was significantly correlated with ΔGV. 38

Variable GS-1 yr (%) GD-1 yr (/mm2) IFTA-1 yr (%) GV-1yr (×106 μm3) ΔGV (×105 μm3)