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L-Arginine Supplementation Improves Function and Reduces Inflammation in Renal Allografts

INGRID H. C. VOS^*, TON J. RABELINK, BERT DORLAND, REMKO LOOS, BEN VAN MIDDELAAR^*, HERMANN-JOSEF GRÖNE^§ and JAAP A. JOLES^*

^* Department of Nephrology and Hypertension, University Medical Center, Utrecht, the Netherlands
Department of Vascular Medicine, University Medical Center, Utrecht, the Netherlands
Department of Laboratory of Metabolic Diseases, Wilhelmina Children's Hospital, Utrecht, the Netherlands
^§ Department of Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.

Correspondence to Dr. Ton J. Rabelink, Department of Vascular Medicine, University Medical Center, Utrecht, F02-126, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. Phone: 31-30-2537399; Fax: 31-30-2523741; E-mail: T.Rabelink{at}digd.azu.nl

	Abstract

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Abstract. Recovery from ischemia/reperfusion and immune-mediated injury in the renal transplant is associated with reduced renal hemodynamics and increased leukocyte infiltration. In diverse models of renal failure, L-arginine supplementation improved hemodynamics and reduced inflammation. However in a proinflammatory environment, L-arginine can worsen renal injury. This study investigated the therapeutic potential of L-arginine supplementation in allogeneic renal transplantation: Brown Norway rat kidneys were transplanted into Lewis rat recipients, with one native kidney remaining. Recipients received low-dose cyclosporin A (2.5 mg/kg per d subcutaneously) to obtain moderate vascular and interstitial rejection, with or without 1% L-arginine in drinking water for 7 d posttransplantation. Transplantation increased renal vasoconstriction (from 16.9 ± 1.33 to 35.1 ± 8.6 units; P < 0.01), thereby reducing GFR (from 0.96 ± 0.09 to 0.48 ± 0.10 ml/min; P < 0.05). Treatment with L-arginine restored renal graft function to levels found in normal donors (renal vascular resistance, 15.7 ± 1.69 units; GFR, 0.80 ± 0.06 ml/min). L-arginine significantly reduced vascular occlusion because of less inflammation, endothelial disruption, and thrombosis. L-arginine also decreased tubulitis, interstitial injury, and macrophage infiltration. These protective effects suggest that L-arginine might be useful as additive therapy to conventional immune suppression.

	Introduction

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Nephroprotective effects of L-arginine have been observed in diverse models of renal failure, including uranyl nitrate-induced acute renal failure (1), puromycin-induced nephrotic syndrome (2), and chronic renal insufficiency caused by ablation (3,4) or obstructive nephropathy (5,6). L-arginine supplementation was consistently associated with improvement of GFR and reduction in macrophage infiltration (7). In the current study, we investigated the effects of L-arginine on renal function and rejection in renal allografts. This is of particular interest as L-arginine may have nephroprotective as well as proinflammatory effects, considering that renal allograft rejection is characterized by a proinflammatory milieu.

There are multiple pathways by which L-arginine could influence function and morphology of the transplanted kidney. L-arginine can be converted by arginine decarboxylase into agmatine, which could increase GFR (8,9). L-arginine can also stimulate secretion of glucagon (10), which is known to increase GFR (11). When metabolized by nitric oxide synthase (NOS) to nitric oxide and L-citrulline, L-arginine supplementation could be expected to cause vasodilation as well as to reduce inflammation (12).

Conversely, L-arginine may be harmful if it enhances activity of inducible NOS. We previously demonstrated that tubulointerstitial rejection in renal allografts is mediated by activation of the inducible isoform of NOS (13). Moreover, when L-arginine is metabolized by arginase to urea and L-ornithine (14), polyamine and proline can be generated, which could promote proliferation and collagen formation respectively (15). Hence, the dual ability of L-arginine to mediate renal protection as well as renal injury emphasizes the need to investigate the net effects of supplementary L-arginine on functional and inflammatory aspects of rejection in allogeneic kidney transplantation.

	Materials and Methods

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Animals
Left kidneys of male Brown Norway (BN = RT1ⁿ) rats were transplanted heterotopically into male Lewis (LEW = RT1¹) recipients, with one native kidney in situ. The donors (180 to 210 g) and the recipients (300 to 350 g) were obtained from Harlan (Bicester, UK) and housed under standard conditions (day/night, 12/12; humidity, 55%; temperature, 22°C) with water and chow (RMH-TM rat chow: protein, 22.2%; fat, 4.8%; potassium, 0.85%; sodium, 0.40%; arginine 1.26%; Hope Farms, Woerden, The Netherlands) ad libitum. The Utrecht University Committee for study in experimental animals approved the protocol.

Experimental Design
Two groups of kidney recipients were examined. All recipients received a low dose of cyclosporin (CyA; 2.5 mg/kg per d; Sandimune, Novartis Pharma AG, Basel, Switzerland) to allow moderate vascular and interstitial rejection. CyA was injected twice daily subcutaneously in half daily doses. Experimental groups consisted of recipients that were treated with CyA alone (n = 7), recipients that received CyA plus 1% L-arginine in the drinking water (n = 6), and recipients that were untreated (n = 6). Administration of CyA and supplementation with L-arginine started approximately 5 h after transplantation; the first administration of L-arginine was by gavage (1 g L-arginine/kg dissolved in a maximum volume of 1 ml of distilled water) and was continued by supplementation in the drinking water (10 g/L). Body weight and water intake were monitored daily. In addition, we included sham controls: Brown Norway rats that received L-arginine (10 g/L) in the drinking water (n = 8) or that were left untreated (n = 10), as well as untreated Lewis rats (n = 6).

Surgical Procedures
Donor nephrectomy, preservation, and heterotopic kidney transplantation procedures were performed as described previously by Fisher and Lee (16) with some modification (12). The right donor kidney was perfused with and preserved in Custodiol (HTK-Tramedico, Alsbach, Germany) at 4°C. Cold ischemia was limited to 15 min. The vascular anastomoses were performed in an end-to-side manner using 8-0 nylon suture (Ethicon, Norderstedt, Germany). Blood flow was restored to the graft within 30 min. After vascular anastomoses were checked for leakage, the ureter anastomosis was performed using 11-0 nylon suture in an end-to-end manner.

Clearance experiments occurred 7 d posttransplantation under Inactin anesthesia to determine clearances of inulin (C_in) and paraaminohippuric acid (C_PAH), using conventional techniques (17). Therefore, the left jugular vein was catheterized for infusions. The right femoral artery was catheterized for continuous measurement of mean arterial pressure and to draw arterial blood samples for determination of hematocrit and plasma concentrations of inulin and PAH. An arterial blood sample was drawn at the start, midpoint, and end of the whole clearance period. We catheterized the ureter of the contralateral kidney while the transplanted kidney continued to drain into the bladder, in which a catheter was placed through a midline incision. Equivalent collections were performed in the sham controls. After a 1-h equilibration period, C_PAH and C_in were measured during four 30-min urine collections to assess GFR and renal blood flow (RBF) in both kidneys separately. Inulin and PAH concentrations were measured photometrically with indoleacetic acid after hydrolyzation to fructose and by a chromogenic aldehyde reaction respectively.

Amino Acid Analysis
Terminal blood samples were used for assessment of plasma L-arginine levels. Quantitative analysis of plasma L-arginine was performed on a Biochrom 20 amino acid analyzer with an ion-exchange column (Amersham Pharmacia Biotech, Cambridge, UK).

Graft Sampling and Immunohistochemical Staining
At day 7 posttransplantation, after the clearance experiment, the rats were exsanguinated and kidneys were harvested and processed for immunohistochemistry. The middle slices of the harvested graft were fixed in formalin or methacarn, embedded in paraffin, and stained with periodic acid-Schiff and trichrome.

Immunohistochemistry was carried out on 5-µm sections of paraffin-embedded tissue. The monoclonal antibody ED1 (Serotec, Camon, Wiesbaden, Germany) was used on methacarn-fixed tissue at a dilution of 1:100 to demonstrate monocytes/macrophages. An alkaline phosphatase anti-alkaline phosphatase detection system was applied (Dako, Hamburg, Germany).

Histologic Evaluation
Periodic acid-Schiff stained sections of grafts were evaluated (coded, blinded) for evidence of rejection and tubulointerstitial injury using light microscopy. The various types of injury were semiquantitatively scored from 0 to 3, with 0 indicating no pathologic changes, 1 slight, 2 moderate, and 3 severe alterations (13). Vascular changes caused by adhesion of inflammatory mononuclear cells to intima, thrombosis, or necrosis were evaluated for all preglomerular vessels per whole kidney section. Total vascular injury index was calculated as the sum of the severity scores (1, slight; 2, moderate; 3, severe lesions), which were multiplied by the percentage of vessels displaying the concerning score. Fifty glomeruli per kidney section were evaluated for ischemic collapse, capillary obliteration by thrombosis, and mesangial matrix increase. Tubulitis was evaluated in 10 high-power fields (40x objective) with interstitial inflammation, by the number of infiltrated mononuclear cells in the tubular epithelium; a score of 1, indicated 4 cells per tubular cross section; 2, 4-9 cells; 3, more than 10 cells per cross section. The interstitial injury index was semiquantitatively scored in 10 high-power fields (40x objective); a score of 0 indicated interstitial integrity; 1, occasional infiltration; 2, focal infiltration and minor edema; 3, infiltration of mononuclear inflammatory cells, with more than 60% of the interstitial field covered, combined with edema and/or collapse of tubular cross sections. The number of ED1⁺ cells (monocytes/macrophages) was counted per glomerular cross section in 100 glomeruli and also in 15 high-power fields (40x objective) of tubulointerstitium.

Statistical Analyses
T test was used to compare the morphologic data between CyA-treated controls and CyA+ L-arginine-treated kidney recipients. One way ANOVA was used to analyze the clearance data of the transplanted and contralateral kidneys. P < 0.05 was considered significant. Data are presented as mean ± SEM.

	Results

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Arginine Intake
L-arginine intake increased to 101 ± 5 mg/100 g body wt per d in the supplemented LEW recipients as compared with recipients that were treated with CyA alone (57 ± 10 mg/100 g body wt per d), where intake was via the diet only. L-arginine did not increase water intake. L-arginine intake in the sham BN donors with and without L-arginine in the drinking water was 190 ± 9 mg/100 g body wt per d and 51 ± 10 mg/100 g body wt per d, respectively. L-arginine intake in the sham donors was higher than in the transplanted LEW rats (P < 0.01). This was not due to differences in food intake. However, sham BN rats drank more than did LEW rats that underwent transplantation (12 ± 0.4 ml/100 g body wt per d versus 6 ± 0.4 ml/100 g body wt per d, respectively; P < 0.01). Plasma L-arginine levels were slightly increased in terminal blood samples after clearance experiments in the L-arginine supplemented rats (105 ± 6 versus 83 ± 10 µmol/L; P = 0.08).

Renal Function
To assess the effect of L-arginine supplementation on renal function in the early phase posttransplantation, we examined renal function of the renal allograft after 7 d of treatment with CyA alone versus CyA plus L-arginine as well as in sham controls with and without L-arginine. Untreated recipients were also studied. Means of functional parameters are presented in Tables 1 and 2.

There were no differences in mean arterial pressure. Hematocrit was decreased in the untreated recipients. Transplantation with low-dose CyA resulted in a twofold reduction of GFR in the graft, a substantial decrease of RBF, and a higher renal vascular resistance (RVR) compared with control donor kidneys (Table 1). L-arginine increased GFR and RBF in the renal graft; hence, RVR was decreased. L-arginine had no effects in sham controls, even though L-arginine intake was higher (see above). Untreated grafts were anuric. The hemodynamic parameters of the recipient's contralateral kidney are presented in Table 2. Absolute values of GFR, RBF, and RVR did not differ between the sham and immune-suppressed groups. However, renal function in the contralateral kidney of untreated recipients showed a compensatory increase.

Renal Pathology
To examine the effect of L-arginine supplementation on the pathologic features of renal allografts, we evaluated kidney weight and the extent of vascular, glomerular, interstitial, and tubular lesions in CyA alone compared with L-arginine-supplemented renal transplants. At 7 d after transplantation, the relative weight of renal graft and the spleen were comparable in the CyA alone and L-arginine-supplemented groups (Table 3). The contralateral native kidneys did not show pathologic lesions. However, in renal allografts treated with only a low-dose CyA, there were indications of acute cellular rejection with vascular, glomerular, and tubulointerstitial lesions as a result of the residual allogeneic response (Figure 1A).

View larger version (144K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. (A) Allograft treated with cyclosporine A (CyA, 2.5 mg/kg per d) showing a slight ischemic glomerulus with three granulocytes and an injured artery with activated endothelium. (B) Allograft treated with CyA+L-arginine with a normal glomerulus and a regular vessel with nonactivated flat endothelium. (C) Allograft treated with CyA showing an injured arteriole with subendothelial hyalinosis and perivascular mononuclear cell infiltrate. (D) Allograft treated with CyA+L-arginine with a normal blood vessel and only minor infiltration of mononuclear cells. Magnifications: x 100 (periodic acid-Schiff [PAS]) in A and B; x 150 (PAS) in C and D.

L-arginine supplementation significantly reduced intrarenal vascular occlusion (Figure 1, B and D). There was less endothelial swelling, inflammation, and thrombosis than in the CyA-treated grafts (Figure 1, A and C). Tubulointerstitial injury was also reduced by L-arginine. Renal cortex and outer medulla demonstrated less tubulitis. Interstitial injury, including amount and expansion of interstitial cell infiltrates and interstitial edema, was clearly reduced after L-arginine supplementation (Figures 1B and 2B).

View larger version (77K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 2. (A) Allograft treated with CyA with perivascular infiltration of monocytes and macrophages in the cortex. (B) Allograft treated with CyA+L-arginine with only slight and focal perivascular infiltration of monocytes and macrophages. Magnification, x50 (ED1).

Native kidneys had practically no adherent and infiltrating cells in glomeruli or around blood vessels. In the grafts, treated with low doses of CyA, ED1⁺ cells were the dominant infiltrating cells that accumulated in perivascular and periglomerular clusters (Figure 2A). Although L-arginine did not significantly affect the number of ED⁺ cells in glomeruli or in interstitium, CyA+L-arginine-treated grafts demonstrated smaller perivascular cell infiltrates with minor extension to the interstitium (Figure 2B).

Untreated allografts characteristically showed a fibrotic capsule enclosing necrotic tissue (12). Graft weight was increased (0.69 ± 0.05 g/100 g body wt; P < 0.05). Spleen weight was also increased (0.37 ± 0.03 g/100 g body wt; P < 0.05), indicating an unsuppressed immune response. Histologic examination revealed practically no viable tissue.

	Discussion

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Daily supplementation of L-arginine to low-dose CyA-treated recipients of a renal allograft improved renal function, i.e., increased GFR and RBF. L-arginine supplementation also reduced inflammation, endothelial disruption, and thrombosis and decreased interstitial injury by reducing macrophage infiltration and edema formation. This is the first study that supports the use of L-arginine as an additive therapy to conventional immune suppression in renal allograft rejection.

Whole organ and micropuncture measurements in rejecting allogeneic kidney transplants showed that decreases in GFR and RBF were due to increased afferent arteriolar resistance, decrease of glomerular capillary pressure, plasma flow, and single-nephron GFR. Because only minor glomerular lesions accompanied these alterations in renal hemodynamics, it was postulated that these changes were due to preglomerular vasoactive constriction (18,19). It has also been demonstrated that such hemodynamic changes contribute to the development of chronic graft failure (20,21). Chronic administration of high doses of CyA to normal rats increased afferent resistance and reduced the ultrafiltration coefficient, leading to a fall in single-nephron and whole-kidney GFR (22). Thus, both transplantation and CyA can induce a decline in GFR and RBF. In the current study, however, we presumed no functional vasoactive effects of the low dose of CyA that we used, because L-arginine did not increase GFR or RBF in the contralateral native kidneys of the recipients. Furthermore, these kidneys were free of vascular and glomerular injury and the beneficial effects of L-arginine on renal hemodynamics were restricted to the grafts. This suggests that the hemodynamic effects in the renal allograft were through direct interference of L-arginine with ischemia/reperfusion (23,24) and with the subsequent inflammation.

Timing of L-arginine supplementation also seems to be critical for its effects. Saunder et al. (24) showed that L-arginine in the perfusate improved renal function and survival after 5-d perfusion preservation of the isogenic donor kidney. Also, Shoskes et al. (25) observed improved recovery from ischemic damage when L-arginine was started on the day before surgery. In nonischemic models of renal failure, when treatment was started immediately after surgery, L-arginine markedly increased GFR in rats after release of ureteral obstruction (2) as well as in 5/6 nephrectomized rats (3,26). However, when L-arginine supplementation was started after the onset of chronic renal failure, no nephroprotective effects of L-arginine in chronic renal failure were detected (27). In the present study, 1% L-arginine, started on the day of transplantation, in fact could prevent the fall of GFR in the graft. We administered a 1% supplementation in the drinking water, because this dose is in the optimal range as described by Tanaka et al. (28), who found that larger doses of L-arginine failed to increase NO and aggravated glomerulosclerosis in a remnant kidney model. This concentration of L-arginine in drinking water still caused a 20-µM increase in plasma L-arginine concentration 4 to 5 h after last access to supplemented L-arginine water. Arnal et al. (29) demonstrated that adding L-arginine at 10 µM or more to endothelial cells dose-dependently increased NO release.

Proinflammatory effects of L-arginine administration have been reported in models of renal injury characterized by leukocyte influx (30). However, in the present study, L-arginine numerically reduced perivascular and tubulointerstitial macrophage infiltration. Others and we previously established that this macrophage influx facilitates immune-mediated rejection (31,32,33). This indicates that L-arginine supplementation would support anti-inflammatory mechanisms rather that stimulate proinflammatory or proliferative pathways such as inducible NOS activity or arginase-proline metabolism, despite that renal allograft rejection is characterized by leukocyte infiltration. Our data do not allow conclusions to the mechanisms involved, but we recently demonstrated that activation of the transcription factor NF-B is a key mechanism that controls macrophage influx in the renal allograft (34). It is therefore of interest that the same dose of L-arginine blunted the activation of NF-B (35) in kidneys with unilateral ureter obstruction and reduced expression of RANTES (36). Notably, NF-B-mediated inflammation is inhibited by NO (37,38,39), and it is therefore attractive to postulate that the beneficial effects of L-arginine were at least partly due to increased formation of NO. Moreover, in a similar renal transplantation model, the L-arginine analogues L-NAME and L-NNA demonstrated exacerbation of rejection, namely macrophage infiltration and vascular injury (12). Our study indicates that L-arginine administration as additive treatment to immune suppression in renal transplantation deserves further exploration because of its anti-inflammatory potential as well as its beneficial effects on recovery of renal graft function.

	Acknowledgments

 
This study was supported by a grant from the Deutsche Forschungsgemeinschaft, Gr7286/1 to 3 to H.-J.G., and by the Dutch Kidney Foundation.

The study was presented in part at the 32nd Annual Meeting of the American Society of Nephrology, Miami Beach, 1999, and published in abstract form (J Am Soc Nephrol 10: A3624, 1999).

The excellent technical assistance of M. Schurink and C. Schmidt is gratefully acknowledged.

	References

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