No Effect of Dietary Fish Oil on Renal Hemodynamics, Tubular Function, and Renal Functional Reserve in Long-Term Renal Transplant Recipients1
Jesper Meichior Hansen,2 Hans L#{248}kkegaard, Carl-Erik H#{248}y,Niels Fogh-Andersen, Niels Vidlendal Olsen, and Svend Sfrandgaard
supplementation with fish oil in these patients did not J.M. Hansen, N.y. Olsen, Department of Clinical improve renal function. Physiology, Herlev Hospital, University of Copenhagen, Key Words: Amino acids, cyclosporin A, GFR, lithium clear- Herlev, Denmark once, renal circulation H. L#{248}kkegaard, S. Strandgaard, Department of Nephrology, Herlev HospItal, University of Copenha- T he use of cyclosporin A (CsA) in clinical immuno- gen, Herlev, Denmark suppression is associated with nephrotoxlcity, characterized by a dose-dependent, initially reversible N. Fogh-Andersen, Department of Clinical Chemistry, decline in the GFR and RBF (1 ,2). The renal hemody- Herlev Hospital, University of Copenhagen, Herlev, namic changes are most likely due to a direct CsA- Denmark induced constriction of the afferent arteriole (3). The C.-E. H#{248}y,Department of Biochemistry and Nutrition, precise mechanism of this vasoconstriction is still Technical UniversIty of Denmark, Lyngby, Denmark unclear, but some evidence does suggest a CsA-in- (J. Am. Soc. Nephroi. 1995; 5:1434-1440) duced alteration in the synthesis of the eicosanoids (4-6). In addition to the renal functional changes, prolonged treatment with CsA may cause structural ABSTRACT lesions in the kidney with arteriolopathy and intersti- Dietary supplementation with fish oil rich In n-3 poly- tial fibrosis (7). unsaturated fatty acids has been suggested to pro- Previous studies in CsA-treated animals (4,8) and humans (9-1 1) have demonstrated that a dietary tect the kIdney agaInst cyclosporin A (CsA) toxicity. supplement of fish oil rich in n-3 polyunsaturated This study Investigated the effects of a 10-wk dietary fatty acids (n-3 PUFA) improves renal function, possi- supplementation with fish oIl on renal function and bly by reducing the synthesis of the vasoconstricting renal functional reserve in healthy volunteers (N = 9) elcosanoid thromboxane (4). DUssing and coworkers and two groups of stable long-term kldney-frans- demonstrated that fish oil also may decrease renal planted patients freated with maintenance low-dose vascular resistance and increase GFR in healthy
CsA (3.0 ± 0.6 mg/kg; N = 9) or without CsA (N = 9). young volunteers (12), suggestIng that the effect of After an overnight fast, the subjects were water fish oil on renal hemodynamics is nonspecific and not loaded, and clearance studies were performed, post- restricted to CsA-induced nephrotoxicity. poning morning medication. GFR and effective RPF In normal kidneys, GFR increases in response to an were measured as the renal clearances of ( Tc)DTPA oral protein load or iv infusion ofamino acids (13,14). This renal functional reserve has been shown to be and (1311)hippuran, respectively. Renal tubular function absent or blunted in CsA-treated kidney-transplanted was evaluated by use of the renal clearance of lithium patients (15, 16). It has not previously been studied and the urinary excretion of 3 -microgIobulin. Fish oil whether treatment with fish oil has any effect on the did not change baseline values of effective RPF, GFR, renal functional reserve in stable CsA-treated kidney- lithium clearance, and urinary excretion of f32-mlcro- transplanted patients. globulin in any of the groups. The infusion of amino In this study, we have therefore investigated the acids induced a comparable Increase in GFR, lithium effect ofa 10-wk daily dietary supplement with 3.5 g of clearance, and the urinary excretion rate of 13 -micro- n-3 PUFA on renal function and renal functional globulin in all three groups with no additional effect of reserve in healthy volunteers and in two groups of fish oil. Thus, long-term renal franspiant recipients stable, long-term, renal transplant recipients treated with and without low-dose CsA. freated with a low maintenance dose of CsA had a well-preserved renal functional reserve, and dietary METHODS
1 Psc.ivd March 22, 1994. Accepted Juno 29, 1994. Subjects 2 coi sspondonc. to Dr. J.M. Hanson, Depa,tment 01 Nephrology, Honey Hospl- The study was approved by the scientific ethical committee sal. Hodov Rlngvej, DK-2730 Honey, Denmark. of Copenhagen County. and all subjects gave Informed con- 1046’6673/0507-1434$03.OO/O Journal ol Wi. American Society of Nephrology sent in accordance with the Helsinki Declaration. The study Copyright 0 1995 by the American society of Nephroiogy included 9 normal volunteers, aged 31 to 55 yr. and 18
1434 Volume 5’ Number 7 ‘ 1995 Hansen et al
nondlabetic renal transplant recipients, aged 32 to 65 yr with investigated before and on the last day with fish oil supple- a well-functioning graft (serum creatinine below 160 pxnol/D mentation. The protocols for the two study days were iden- for more than 22 months before the study. None had expe- tical, and each study was done in the morning after an rienced any episodes ofacute rejection since the Initial period overnight fast. A 24-h urine sample was collected from 8:00 after transplantation, and none had signs of chronic rejec- a.m. on the day before each study. Lithium clearance (Ca) tion. Nine of the transplanted patients had received immu- was used to estimate the proximal tubular outflow of sodium nosuppressive therapy with prednisone, azathioprine Wa), and water (17). A test dose oflithium carbonate (300 mg. 8.1 and CsA for more than 22 months; at the time of inclusion, mmol) was given orally at 8:00 p.m. the evening before each the dose of CsA was at a low maintenance level (3.0 ± 0.6 study day. On the study days, morning medication was mg/kg; CsA group). Nine had never received CsA. but only withheld and the subjects abstained from smoking and from prednisone and azathioprine Wa group). Four patients in caffeine-containing beverages. Renal function was measured both groups received no antihypertensive medications. The during eight 30-mM clearance periods. Except for briefly last dose of immunosuppressive and antihypertensive med- standing when voiding every 30 mm. the subjects were ication was taken by the patients around 6 p.m. the day investigated in a supine resting position. A urine flow of before the study. Patients receiving dthydropyridlne calcium approximately 500 mL/h was maintained by the oral intake antagonists were not included in the study. The demographic of water starting 2 to 2.5 h before the first clearance period and clinical characteristics ofthe normal subjects and of the with an initial load of 750 mL, followed by 250 mL eveiy 30 two groups ofrenal transplant recipients are shown in Table ruin. After two consecutive 30-mm control periods, the infu-
1 . Two additional subjects were excluded from the study- sion of amino acids (2.5 ml/h per kilogram) was started and one normal subject because of incomplete bladder emptying maintained during six consecutive 30-mm periods. during the renal clearance studies, and one transplant re- Effective RPF (ERPF) and GFR were measured by a con- cipient because of noncompliance (changing to a vegetarian stunt infusion technique with I’31llhippuran and ( #{176}‘ ‘TcJ- diet). D’fl’A in a total dose of 0. 10 mCi (3.6 MBq) and 0.73 mCI (27.0 M8i), respectively. After an equilibration period of at Experimental Protocol least 1 h, renal clearances of L’31llhlppuran. t ’ TcJDTPA, lithium, and sodium (CNa) were calculated by the urinary For 10 wk, each subject daily received six capsules of excretion rates and plasma samples drawn in the middle of marine, long-chain n-3 PUFA (each containing 1 g of 35% each period. The urinary excretion rate of -micmglobuim eicosapentaenoic acids 1C20:5 n-31, 23% docosahexaenoic was measured in the last control period, in the third last, and acids (C22:6 n-31, and 3 IU ofvitamln E as an antioxidant; in the last period during amino acid infusion. Arterial blood Plkasol, Lube A/S. Hadsund, Denmark). Patient compliance pressure and heart rate were measured once in each clear- was verified by pifi counting and measurements of the ance period by a semiautomatic blood pressure monitor plasma composition offatty acids. Changes in medication or (‘Fakeda Medical, A & D Company, Tokyo, Japan). intake of nonsteroidal anti-inflammatory drugs were not allowed during a period of 1 month before and until the Analytical Methods termination of the study. Subjects were Instructed not to change their diet and level of physical activity during the Activities of I’31llhlppuran and [#{176} FcIDTPA were deter- study period. mined in a well scintillation counter. Uthium in plasma and Renal function and the renal response to the i.v. infusion of urine was measured by atomic absorption spectrophotome- amino acids (Vamin#{176};Pharmacla, Linioges, France; electro- try (Model 403; Perkln Elmer, Norwalk, fl. Plasma sodium lyte free; 18 g of nitrogen/L; 114 g of amino acids/U were was measured with a Technicon RA 1000, and urinary sodium was measured with a Technicon RA-XT (Tarrytown, NY). -MIcmglobu11n in plasma and urine was measured by TABLE 1. Demographic and clinical characterlstlcsa an enzyme-linked immunosorbent assay (DAKO, Copenha- gen. Denmark). Urine samples for p -micmglobuha were Normal CsA Aza stored at pH >6. 6-Keto-prostaglandln F1,, and thromboxane Characteristic Subjects Groupb Groupb B2 in urine were measured by radloimmunoassay, with (N=9) (N=9) (N=9) specific antisera (Amersham, Little Challont, United King- dom), and iodlnated 6-keto-prostagJandln F1,, and throm- Sex (F/M) 5/4 2/7 5/4 boxane B2 were used as tracers. Plasma lipids were extracted
Age (yr) 39 ±9 49± 9 50 ± 11 with chloroform:methanol, 2: 1 , vol/vol. Fatty acid methylest- Serumcreallnlne 69±8 112±17c 106±26c em were prepared with bortrlfluorlde (18). The fatty acid ( moWL) proffle was determined by gas liquid chromatography with a Monthsafter 42±17 149 44d Hewlett-Packard 5880 instrument with a 50m SP-2330 cap- transplantation illary column (Supelco Inc., Bellefonte, PA). Whole-blood Medication trough levels of CsA, including its metabolites, were mea- Diuretics 4 2 sured by a fluorescence polarization Immunoassay with an Diltlazem 3 2 Abbott TDxFLx (AbbOft Laboratories, Chicago, IL). p-Receptor blockers 0 4 Angiotensin-convertlng 2 0 Calculations enzyme inhibitors ERPF, GFR, C , and CNa calculated by standard formulae. All clearance values were corrected to 1 .73-rn2 a Data ore means ± SD or number of subjects. b Kidney-transplanted patients treated with (CsA group) and wfthout body surface area. Fractional excretion rates of lithium (FE J (Aza group) cs . and of sodium ( ‘r ia) were calculated as CU/GFR and CNa/ C p < o.os compared with normal subjects. GFR, respectively. The urinary excretion rate of -micm- d P < 0.05 compared with CsA group. globulin was calculated as the urine concentration of -
Journal of the American SOciety of Nephrology 1435 Fish Oil in Kidney-Transplanted Patients
microglobulin multiplied by the urine flow rate, and the TABLE 2. Effects of fish oil on fatty acids content in fractional urinary excretion rate of -microglobulln was plasma#{176} calculated as the renal clearance of -micmglobuha divided by GFR Mean arterial blood pressure was calculated as Before Fish Oil During Fish Oil Grou diastolic blood pressure plus one-third ofthe pulse pressure. p (mol %) (mol %)
C18:2 i’i-#{243} Statistical Analysis Normai subjects 30.5 ± 3.4 26.2 ± 39b The baseline values were calculated as the mean of the two CsA group 28.5 ± 4.7 26.6 ± 4.6c 30-mm control periods. and the results during the infusion Aza group 27.2 ± 5.4 25.4 ± 4,3C of amino acids were calculated as the mean of the four last C20:3 n-6 30-mm infusion periods. Data were analyzed by analysis of Normal subjects 1.5 ± 0.2 1.0 ± Q,2b variance for repeated measures. If the analysis of variance CsA group 1.2 ± 0.2 0.8 ± 0#{149}2b
demonstrated a significant difference, paired t tests were Aza group 1.4 ± 0.2 0.9 ± 0,1b used to analyze differences within the groups, and unpaired C20:4 n-6 t tests were used to analyze differences between the groups. Normal subjects 6.8 ± 1.6 6.3 ± 1.2
When multiple comparisons were performed, the Bonferroni CsA group 5.6 ± 1. 1 5.9 ± 1.0 correction was used. The null hypothesis was rejected when Aza group 5.6 ± 1.2 5.9 ± 0.6 P<0.05. Because the urinary excretion rates ofalbumin and C20:5 n-3 -mlcrog1obulin had skewed distributions, logarithmic Normal subjects 1.0 ± 0.3 6.1 ± 08b transformations were performed before statistical testing. CsA group 1.2 ± 0.4 5.4 ± 0,8b Unless otherwise indicated, data are presented as means ± Aza group 1.2 ± 0.6 6.5 ± 1,3b SE. C22:5 n-3
Normal subjects 0.6 ± 0.1 1.1 ± 02b RESULTS CsAgroup 0.6±0.1 1#{149}0 0,2b Azagroup 0.6±0.1 1.1 0,2b The two groups of transplanted patients were com- C22:6 n-3 parable in age, sex, and serum creatinine level (Table Normal subjects 2.6 ± 0.6 5.0 ± 0,7b 1). All patients had been transplanted for more than CSA group 2.7 ± 0.8 5.1 ± 0#{149}6b
22 months before the study, but in the CsA-treated Aza group 2.7 ± 0.8 5.2 ± 0#{149}6b patients, time since transplantation was significanfly 0 Data are means ± SD. Normal subjects (N = 9) and kidney- shorter (Table 1). The medication remained un- transplanted patients treated with (C5A group; N = 9) and without changed in all patients during the study period. There (Aza group; N = 9) CsA. was no difference In the renal response between the b p < 0.001 when compared with before fish oil. C p < 0.05 when compared with before fish oil. patients who received antihypertensive treatment and those who did not. The normal volunteers had a lower serum creatinine level when compared with the trans- planted patients (Table 1). Compliance with the fish oil ues of ERPF, GFR, C , and FE in any of the groups supplementation was excellent in all 27 particIpants, (Figure 1 ; Table 5). asJudged by pifi counting and the increase in plasma During the infusion of amino acids, GFR increased n-3 PUFA C20:5, C22:5, and C22:6 (Table 2). The fish significantly to the same extent before and during fish oil capsules were well tolerated except for a fishy oil supplementation in all three groups (Figure 1). aftertaste. Furthermore, there was no significant difference in There were no significant differences In the 24-h the relative rise in GFR between the groups: in the urinary excretion rates of sodium, potassium, creati- CsA-treated patients, GFR increased 12 ± 4% before nine, albumin, 6-keto-prostaglandin Fia, or throm- and 16 ± 7% durIng fish oil supplementation; GFR in boxane B2 before and during fish oil supplementation the Aza group increased 12 ± 2 and 15 ± 4% and either within or between the groups (Table 3). Fish oil increased 8 ± 2 and 9 ± 2% in the normal subjects supplementation did not affect body weight, heart before and during fish oil supplementation, respec- rate, or the bioavallabfflty of CsA, as reflected by an tively. Amino acids only increased ERPF in the Aza unchanged 12-h CsA whole-blood trough level (Table group during fish oil treatment (Figure 1). 4). Mean arterial blood pressure was lower in the Cu increased in all groups during the Infusion of normal subjects when compared with both groups of amino acids, with no additional effect offish oil (Table transplanted patients. Fish oil tended to decrease 5). Both before and during fish oil supplementation, blood pressure in all groups, but the decrease only FE increased significantly in the normal subjects reached statistical significance in the Aza group (Table and in the transplanted patients treated without CsA, 4). but the increase in the CsA-treated transplanted pa- Baseline ERPF, GFR, and C were significanfly tients did not become significant (Table 5). There were higher and FE was significantly lower in the normal no differences in the baseline values of CNa and FFqq subjects than in both groups of kidney transplanted between the groups, and neither fish oil nor amino patients (Figure 1; Table 5). Dietary n-3 PUFA supple- acid infusion changed CNa and FEpj (Table 5). mentation had no significant effects on baseline val- Baseline values of the urinary excretion rate and
1436 Volume 5 ‘ Number 7 ‘ 1995 Hansen et al
TABLE 3. Twenty-four-hour urinary excretion rates#{176} TABLE 4. Systemic effects of fish oila
P t Before During Before During arame er P tarameer Fish Oil Fish Oil Fish Oil Fish Oil
Urine (1) Body WI (kg) Normal subjects 2.1 ± 1.0 1.8 ± 0.7 Normal subjects 71 ± 15 71 ± 14 CsA group 2.4 ± 0.5 2.3 ± 0.4 CsAgroup 77±9 78±8 Aza group 2.3 ± 0.7 2.3 ± 1.1 Aza group 71 ± 16 72 ± 16 Sodium (mmol) Mean blood pressure (mm Hg) 88 ± 6b.C Normal subjects 176 ± 71 134 ± 49 Normal subjects 89 ± 5b.C CsAgroup 191±43 184±61 CsA group 121 ± 9 119 ± 9 Azagroup 145±50 132±46 Aza group 110 ± 14 103 ± 12d Potassium (mmol) Heart rate (beats/mm) Normal subjects 57 ± 20 62 ± 22 Normal subjects 61 ± 6 59 ± 7 CsAgroup 71±19 71±17 CsAgroup 57±6 57±6 Azagroup 66±22 61±19 Azagroup 59±9 58±7 Creatinine (mmol) CsA (nglmL) Normal subjects 12 ± 3 11 ± 2 CsA group 285 ± 46 302 ±32 CsAgroup 13±3 13±3 0 Data are means ± SD. Normal subjects (N = 9) and kidney- Azagroup 10±2 10±3 transplanted patients treated wiTh (CsA group; N = 9) and without Albumin ( imol) (Aza group; N = 9) CsA. Normal subjects 0.2 (0.1-0.3) 0.2 (0.1-0.3) b p < 0.05 compared with CsA group. CsA group 0.5 (0.3-1 .0) 0.4 (0.3-0.4) C p < 0.05 compared with Aza group. d p < 0.05 compared with before fish oil supplementation. Aza group 0.9 (0.1-6.9) 0.7 (0.1-8.3) 6-Keto-prostaglandin F1,, (ng) Normal subjects 622 ± 267 610 ± 303 n-3 PUFA improved renal function. A dietary supple- CSA group 639 ± 195 629 ± 260 Aza group 444 ± 178 426 ± 140 ment of 6 g ofn-3 PUFA also increased GFR and ERPF Thromboxane B2 (ng) in normal volunteers (12), indicating that the possible Normal subjects 1 277 ± 967 1,159±694 effect offish oil on renal function Is not only associated CsA group 1,239 ± 377 1,433 ± 642 with CsA-induced renal dysfunction. Aza group 985 ± 591 907 ± 423 The discrepancy between this and other studies could be due to several factors. When compared with 0 ,AJbumin excretion rates are geometric mean with quartiles in pa- the previous study in normal volunteers (12), the lack rentheses. and the remaining data are means ± SD. Normal subjects of increase in GFR and ERPF in our study may be (N = 9) and kidney-transplanted patients treated with (CSA group; N = 9) and without (Aza group; N = 9) CsA. explained by a lower dosage ofn-3 PUFA. We used the same dose of n-3 PUFA as in the studies In CsA- treated patients reporting an effect of fish oil fractional clearance of p2-nilcroglobulln were signifi- (10, 1 1 , 19). However, the patients in this study re- cantly higher in the kidney-transplanted patients celved a lower maintenance dose of CsA (2. 1 to 3.7 compared with the normal subjects, with no further mg/k J, which may have caused a smaller effect on effects of fish oil (Table 5). In all three groups, the renal hemodynamics. Furthermore, the renal clear- infusion of amino acids increased the urinary excre- ance investigation in this study was performed with tion rate and fractional clearance of 2-mIcroglobulln the patients blood CsA level at its nadir. Because each (Table 5). administration of CsA is followed by transient renal hypoperfusion (20), renal clearance studies in CsA- DISCUSSION treated patients may show different results, depend- In this study, we found no effect of a daily dietary ing on the time since the most recent CsA dose. fish oil supplement on renal function in kidney-trans- Furthermore, the patients in this study had received planted patients treated with or without CsA or in CsA for more than 22 months, which might have normal humans. This result differs from a number of induced chronic renal changes, eliminating the effects previous observations in rats and humans. Substitut- offish oil on renal hemodynamics. On the other hand, ing fish oil for the conventional olive oil as the drug the well-maintained GFR and the well-preserved renal vehicle for CsA improved renal function in rats (4) and functional reserve do not support this explanation. also caused less CsA-induced renal structural dam- Treatment with calcium antagonists may interfere age, as evaluated by the presence of proximal tubular with the renal response to CsA (20,21). FIve of our vacuolation, basophilla and mlcrocalcffications (4,8). patients were treated with diltiazem. However, in con- In CsA-treated psoriasis patients (9), in heart-trans- trast to dihydropyridine calcium antagonists, dilti- planted patients (1 1), and in both stable and recent azem seems not to influence the renal function in kidney-transplanted patients (9, 19), a daily dietary CsA-treated renal transplant recipients (22). The last supplement of fish oil for 12 wk containing 3 to 6 g of dose of diltiazem was given around 16 h before the
Journal of the American Society of Nephrology 1437 Fish Oil In Kidney-Transplanted Patients
600 treated transplant recipients (15, 16) and unlnephrec- tomized patients (27,28) seemed to respond ade- quately to protein loads. In this study, however, amino E500 acids increased GFR to the same extent in both kid- ney-transplanted patients treated with and without E CsA and in normal subjects. This was also found by Rondeau et aL (29). Again, differences in the CsA dose * 0. 300 and variation in time since the most recent CsA dose w may partly explain the divergence. In support of this, 200 a study by Magailni et aL (30), suggested that an inverse correlation exists between blood levels of CsA o Normal subjects and the renal functional reserve. Further, arterial O CyA-group hypertension (3 1), antihypertensive treatment, and sodium depletion secondary to long-term furosemide therapy (32) may also impair the renal hemodynamic effects of amino acids. One previous study has dem-
120 - onstrated that fish oil supplementation augmented the amino acid-induced rise in GFR 1 month after 110 - transplantation in CsA-treated patients (33). In our .E 100- patients, fish oil had no such effect on the amino acid-induced changes in renal hemodynamics, irre- spective of whether treatment included CsA or not. Some studies have provIded evidence that CsA causes renal tubular injuries, as reflected by vacuol- ization and dystrophic calcification ofthe tubular cell, interstitial fibrosis, and increased urinary levels of tubular brush border enzymes (7). By use of the C method, a decrease in the fractional proximal tubular outflow of sodium and water has been demonstrated I I 1 in CsA-treated rats and humans (34,35). In this study, baseline amino acids baseline amino acids CsA did not affect the proximal tubular function as estimated by the similar values of C and FE when BEFORE FISH OIL DURING FISH OIL compared with the non-CsA-treated patients. Com-
Figure 1. The effects of fish oil and amino acid infusion on pared with the normal subjects, both groups of trans- ERPF and GFR In renal transplant recipients treated with CM planted patients had an elevated fractional proximal (CM group; N = 9) and without CM (Aza group; N = 9) and tubular outflow as evaluated by the higher FED. This
in normal subjects (N = 9). Data are means ± SE. Statistical finding of a higher FE in subjects with a decreased signifIcance: < 0.05 and ** < o,o compared with GFR is in agreement with previous observations in baselIne. renal transplant recipients (36), renal transplant do- nors (37), and patients with chronic nephropathy (38) renal clearance studies, and furthermore, the patients and may reflect a functional tubular adaptation. As receiving diltiazem had the same lack of response in demonstrated in normal humans (14), the infusion of GFR to fish oil as the other patients. Thus, it seems amino acids increased C and FE in all three groups, unlikely that differences in antihypertensive medica- with no additional effects of fish oil. This effect of tion interfered with these results. amino acids on C is most probably secondary to the Mean arterial blood pressure decreased signifi- increase in GFR, even though a primary effect on cantly in the kidney-transplanted subjects treated tubuloglomerular feedback mechanisms cannot be without CsA and tended to decrease in the other two excluded (14). groups. This is in accordance with a recent meta- Although no precise measure of changes in the analysis concluding that fish oil has a dose-depen- tubular protein reabsorption exists, the urinary excre- dent, blood pressure-lowering effect (23). tion rate of -microglobulln can be used as a marker In healthy human volunteers both an oral protein of proximal tubular dysfunction (39). The urinary load (13,24) and a short-term infusion of amino acids excretion rate of -niicroglobulln was higher in the (14) increase GFR, indicating the presence of a renal renal transplant recipients. This has also been dem- functional reserve (25). The majority of studies in onstrated in healthy renal transplant donors (37). The
CsA-treated kidney-transplanted patients have dem- comparable increase in the urinary excretion of - onstrated either a lack of response or a blunted re- mlcroglobulln by amino acid infusion, with no addi- sponse to both an oral protein load (16,26) and an tional effects of fish oil, suggests a similar amino infusion of amino acids (15), whereas non-CsA- acid-induced inhibition of the tubular reabsorption of
1438 Volume 5’ Number 7 1995 Hansen et al
TABLE 5. The effects of dietary fish oil supplementation and amino acid infusion on the renal clearances of lithium and sodium and the urinary excretion rate of p -microgIobulin#{176}
Before FIsh Oil During Fish Oil
Parameter Amino Amino Baseline Baseline acids acids
C (mi/mm) Normal subjects 31 ± 2 41 ± 2C 31 ± 2 41 ± 2C CsAgroup 19±2 22 2d 18±2 23±3#{176} Azagroup 21±2 27±2’ 19±1 26±2c FE (%) Normal subjects 28 ± 1 35 ± 2C 9 ± 1 35 ± 1 CsAgroup 37±3 39±4 33±3 36±4 Azagroup 37±2 43±2#{176} 34±2 C (mi/mm) Normal subjects 1.2 ± 0.1 1.4 ± 0.1 1.2 ± 0.1 1.3 ± 0.1 CM group 0.9 ± 0.2 0.8 ± 0.2 0.9 ± 0.2 0.9 ± 0.2 Aza group 1.2 ± 0.2 1.3 ± 0.2 0.9 ± 0. 1 1.2 ± 0.3 FE (%) Normal subjects 1.2 ± 0.1 1.2 ± 0.2 1.2 ± 0.1 1.1 ± 0.2 CM group 1.7 ± 0.3 1.5 ± 0.3 1.7 ± 0.4 1.6 ± 0.4 Azagroup 2.2±0.4 2.3±0.4 1.6±0.3 1.9±0.5 Urinary Excretion Rate of 13 -Microglobulin ( g/mmn) Normal subjects 0.08 0.30#{176} 0. 1 1 0.44#{176} (0.04-0. 13) (0. 13-0.46) (0.05.0.27) (0.18-1.09) CM group 0.22 0.82#{176} 0. 14 0.68c (0.09-0.64) (0.20-3.40) (0.04-0.28) (0.28-0.78) Aza group 0.22 1,Q7C 0.1 7 1.04c (0. 10-0.53) (0.43-3.97) (0.06-0.45) (0.25-3.92) Fractional Excretion of j3 -MIcrogIobulln (%) Normal subjects 0.05 0.23#{176} 0.05 0.32#{176} (0.02-0.06) (0.09-0.35) (0.03-0.07) (0.23-0.80) CM group 0.25 078d 0.14 0.67c (0. 12-0.49) (0. 18-2.90) (0.03-0.40) (0.22-0.96) Aza group 0.19 0.80c 0.14 1.05c (0.10-0.46) (0.22-3. 18) (0.08-0.36) (0.32-3.31)
0 Excretion rates of -microgIobulin are geometric means with quartiles in parenthesis. and the remaining data are means ± SE. Kidney- transplanted patients treated with (CSA group; N = 9) and without (Aza group; N = 9) C5A and normal subjects (N = 9). C p < 0.001 when compared with baseline. d p < 0.05 when compared with baseline. e p < 0.01 when compared with baseline.
small peptides in normal subjects and renal trans- ACKNOWLEDGMENTS plant recipients. Mogensen and Selling have likewise This study was supported by grants from the Novo Nordlc Founda- demonstrated that the i.v. infusion of certain amino Uon, Copenhagen; Foundation ofKlng Christian X. Copenhagen; and acids inhibits tubular peptide reabsorption in normal the Danish Hospital Foundation for Medical Research; region of humans (40). Copenhagen, The Fame Islands, and Greenland. Lube AS, Denmark, kindly donated the fish oil capsules, and Pharmacia AS, Denmark, results demonstrated that sta- In conclusion, these kindly donated the Vamln#{176}, amino acid solutions. ble, long-term renal transplant recipients treated with or without a low maintenance dose of CsA have a REFERENCES well-preserved renal functional reserve and an ade- 1 . Curtis JJ, Luke RG, Jones P, Dubovsky EV, Whelchel quate renal tubular response to the infusion of amino JD, Diethel AG: Cyclosporine in therapeutic doses in- acids. Furthermore, in these patients, dietary supple- creases renal allograft vascular resistance. Lancet 1986; mentation with fish oil did not seem to have any 2:477-479. beneficial effects on renal function. Additional studies 2. Chapman JR, Harding NGL, Grifflths D, Morris PJ: Reversibifity of cyclosporine nephrotoxicity after three are needed to more clearly define the indications for months treatment. Lancet 1985;1:128-130. fish oil in human kidney transplantation. 3. Myers BD, Newton L: Cyclosporine-induced chronic ne-
Journal of the American Society of Nephrology 1439 Fish Oil in Kidney-Transplanted Patients
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Cassldy MJD, Beck RM: Renal functional reserve in live nopharmacology l990;20:2 1-29. related kidney donors. Am J Kidney Dis 1988;6:468- 9. Stoof TJ, Korstanje MJ, Bib HJG, Starink TM, Huls- 472. mans RFHJ, Donker AJM: Does fish oil protect renal 29. Rondeau E, Paillard F, Peraldi MN, et at: Role of the function in cyclosporin-treated psoriasis patients? J In- renin-angiotensin system on the renal functional reserve tern Med 19a9;226:437-44 1. in renal transplant recipients. Kidney mt 1993;44: 165- 10. Homan van der Heide JJ, Bib LUG, Tegzess AM, 172. Donker MM: The effects of dietary supplementation 30. MagalInI SC, Nanni G, Agnes S, Avolio AW, Tacchino R, with fish oil on renal function In cyclosporin-freated Castagneto M: Paradoxical effect of short-term protein renal transplant recipients. Transplantation 1990;49: loading on CsA-treated kidney transplant recipients. 523-527. TransplantProc 1989;21:1500-1501. 1 1 . Brouwer RML, Wenting GJ, Poe B, Meeter K, Schale- 31. Bochlcchio T, Sandoval G, Ron 0, Perez-Grovaz H, kamp MADH, Welmar W: Fish oil ameliorates estab- Bordes J, Herrera-Acosta J: Fosinopril prevents hyper- lished cyclosporin A nephrotoxicity after heart trans- ifitration and decreases proteinuria in post-transplant plantation (Abstractl. Kidney mt 1991;41:347. hypertensives. Kidney mt 1990;38:873-879. 12. Dussing R, Struck A, G#{246}belBO, Weisser B, Vetter H: 32. Ruilope LM, Rodiclo J, Garcia Robles J, et at: Influence Effects of n-3 fatty acids on renal function and renal of a low sodium diet on the renal response to amino acid prostaglandin E metabolism. Kidney hit 1990;38:315- infusions in humans. Kidney hit 1987;31:992-999. 319. Donker AJM, 13. Hostetter TI!: Human renal response to a meat meal. Am 33. Homan van der Helde JJ, Bio HJG, Wilmink JM, Sluiter WJ, Tegzess AM: Dietary supple- J Physiol 1986;250:F613-F618. 14. Olsen NV, Hansen JM, Ladefoged SD, et aL: Overall mentation with fish oil modifles renal reserve filtration capacity in postoperative. cyclosporine A-treated renal renal and tabular function during infusion of amino transplant recipients. Transplant Int 1990;3: 17 1-175. acids in normal man. Clin Sci 1990;78:497-501. 15. Cairns HS, Raval U, Neild GH: Failure of cyclosporine- 34. Dleperink HI!, LCysSaC PP, Starklint H, Kemp E: Neph- treated renal allograft recipients to increase glornerular rotoxicity of cyclosporin A. A lithium clearance and ifitration rate following an amino acid Infusion. Trans- micropuncture study in rats. Eur J Clin Invest 1986; 16: plantation 1988;46:79-82. 69-71. 16. Nunley JR, King A, Comstock T, Posner M, Marshall C, 35. Dleperink RH, Leyssac PP, Kemp E, et at: The nephro- Sica DA Cyclosporine’s effect on functional reserve in toxicity of cyclosporin A in humans. Effects on glomer- renal ailograft. Transplantation 1991;51: 190-193. ular ifitration and tubular reabsorption rates. Eur J Clin 17. Thomsen K, Holsteln-Rathlou NH, LCySSaC PP: Corn- Invest 1987; 17:493-496. parison ofthree measures ofproxlmal tubular reabsorp- 36. Hansen JM, Abidgaard U, Fogh-Andersen N, Kanstrup tion: Uthium clearance, occlusion time, and micropunc- IL, Brathoim P, Strandgaard S: The transplanted human ture. Am J Physiol 1981 ;241 :F348-F355. kidney does not achieve functional reinnervation. Clin 18. Meted AL, H#{248}yCE: Fatty acid profiles ofbraln phospho- Sd 1994;87:13-20. lipid subclasses of rats fed n-3 polyunsaturated fatty 37. Strandgaard 5, Kamper AL, Skaarup P, Holstein- acids of marine or vegetable origin. Biochim Biophys Rathlou NH, Leyssac PP, Munck 0: Changes in glomer- Acta 1992;! 125:237-244. ular ifitration rate, lithium clearance and plasma protein 19. Homan van der Helde JJ, Bib HJG, Donker AJM, clearance in the early phase after unilateral nephrec- Wilmink JM, Tegzess AM: Effect of dietary fish oil on tomy in living healthy renal transplant donors. Clin Sci renal function and rejection in cyclosporine-treated re- 1988;75:655-659. cipients of renal transplants. N Engl J Med 1993;329: 38. Kamper AL, Holstein-Rathlou NH, Leyssac PP, 769-773. Strandgaard 5: Lithium clearance in chronic nephropa- 20. Ruggenenti P, Perico N, Mosconi L, et at: Calcium thy. Clin Sci 1989;77:31 1-3 18. channel blockers protect transplant patients from cy- 39. SchardlJn GHC, Statius van Eps LW: -Microglobulln: closporine-induced daily renal hypoperfusion. Kidney Its significance in the evaluation of renal function. Kid- Int 1993;43:706-71 1. ney Int 1987;32:635-641. 21. McNally P0, Walls J, Feehally J: The effect of nifedipine 40. Mogensen CE, S#{216}lllngK Studies on renal tubular pro- on renal function in normotensive cyclosporin A-treated tein reabsorption: Partial and near complete inhibition renal allograft recipients. Nephrol Dial Transplant 1990; by certain amino acids. Scand J Clin Lab Invest 1977; 5:962-968. 37:477-486.
1440 Volume 5’ Number 7 ‘1995