- Email: [email protected]
Long-term protein intake control in kidney transplant recipients: Effect in kidney graft function and in nutritional status
Long-Term Protein Intake Control in Kidney Transplant Recipients: Effect in Kidney Graft Function and in Nutritional Status Annamaria Bernardi, MD, Franco Biasia, MD, Tecla Pati, MD, Michele Piva, MD, Angela D’Angelo, MD, and Giuseppe Bucciante, MD ● Background: Reduction in renal mass is followed by progressive renal failure. The reduction in filtration surface area, caused by the absence of 50% of renal mass, in patients with customary salt intake is followed by expansion of extracellulary volume and systemic and glomerular hypertension. High protein intake may contribute to renal allograft injury arising from insufficient renal mass. Methods: The authors studied outcome of 48 patients with kidney transplant to whom normocaloric diets and moderate intake of protein (0.8 g/kg), of sodium (3 g/d), and lipids (no more than 30% of total energy) were prescribed. Monthly 24-hour urea excretion and 24-hour sodium excretion were measured. Renal function was assessed by creatinine clearances and by renal scintigraphy. The 30 patients who followed prescriptions exactly were the compliant group (group 1). The other 18, who followed the diet prescribed only partially (their intakes were 1.4 g/kg of protein and 5 g/d of sodium) were the control group (group 2). Results: Patients of the compliant group maintained unchanged renal function, whereas patients of the control group lost more than 40% of excretion efficiency as a mean. Conclusions: Dietary restrictions of protein and sodium can stabilize renal function in patients with kidney transplant. Wider use of this treatment is indicated. Am J Kidney Dis 41(S1):S146-S152. © 2003 by the National Kidney Foundation, Inc. INDEX WORDS: Kidney transplantation; chronic rejection; protein intake; nutritional status.
T
HE LITERATURE regarding kidney transplantation shows us that less than 50% of cadaveric allografts survive for more than 10 years after engraftment.1 Graft losses are attributed to “chronic rejection.” We can consider somewhat antigen-independent factors, particularly mechanisms of disease progression caused by reduction of renal mass.1-5 Reduction of filtration surface area in patients with customary salt intake is followed by expansion of extracellular and plasmatic volumes. Systemic and glomerular hypertension might eventually be maladaptive and dangerous for the remnant nephrons.6,7 Also, proteinuria has been attributed to hyperfiltration in remnant nephrons.8 Dietary protein intake may contribute to renal allograft injury arising from insufficient renal mass and may be slowed From the Renal Unit, Rovigo, Italy and the Departments of Clinical Nephrology and Clinical Nutrition, University of Padua, Padua, Italy. We acknowledge the Commemorative Association for the Japan World Exposition (1970), Japanese Association of Dialysis Physicians, Osaka Pharmaceutical Manufacturers Association, and the Pharmaceutical Manufacturers Association of Tokyo for financial support to publish this supplement. Address reprint requests to: Annamaria Bernardi, MD, Via Silvestri n.6 45100 Rovigo, Italy. E-mail: [email protected]; [email protected] © 2003 by the National Kidney Foundation, Inc. 0272-6386/03/4103-0132$30.00/0 doi:10.1053/ajkd.2003.50105
S146
by dietary protein restriction.9,10 Studies regarding a small number of transplant patients undergoing reduction of dietary protein have shown hopeful results. Mild hyperhomocysteinemia is common in patients with a functioning renal transplant, as in uremic and regular dialytic treatment (RDT) patients. METHODS The patients who received renal transplant were observed monthly in our renal unit starting 2 months from surgical intervention. From 1989 to 2002, 48 patients (36 men and 12 women) entered our center for control of renal graft function and chronic rejection progression and nutritional status. The recruitment during the years of observation is shown in Table 1. The primary renal disease is in 35 patients, glomerular disease: membranous and focal segmental glomerulonephritis; in 4 patients, polycystic kidney disease; in 2 patients, obstructive uropathy; and in 7 patients, hypertensive nephropathy. The mean age for women is 41.45 ⫾ 22.69 years, and for men 43.43 ⫾ 12.42 years. The mean duration of renal transplantation was 90.36 ⫾ 49.5 months for women and 81.68 ⫾ 59.2 months for men. The pretransplant dialytic age for all was 132.18 ⫾ 66.5 months. The monthly regular check-ups included routine blood laboratory tests including the measurement of erythrocytes and leucocytes, glucose, urea, creatinine, uric acid, total proteins, albumin and globulins, sodium, kalium, calcium, phosphorus, magnesium, cholesterol, HDL cholesterol, triglycerides, alkaline phosphatase and bone isoenzyme, parathyroid hormone (PTH), iron, and ferritin; the tests also included the collection of 24-hour urine samples for proteins, urea, sodium, potassium, cal-
American Journal of Kidney Diseases, Vol 41, No 3, Suppl 1 (March), 2003: pp S146-S152
LOW-PROTEIN DIET CONTROLS CHRONIC REJECTION Table 1. Year
New patients Deceased patients Surviving patients
1989
1990
11
1
-
-
11
12
1991
1992
1993
1994
S147 Recruitmen
1995
1996
1997
1998
1999
2000
2001
1
7
6
6
3
3
1
2
3
2
-
-
-
-
-
-
-
2
2
1
-
12
13
20
26
32
35
38
37
37
39
41
cium, uric acid excretion and creatinine for clearance (glomerular filtration rate [GFR]) determination. At yearly intervals sequential scintigram of the grafted kidney with technetium (TC) 99 m was performed. A physical examination and anthropometric measurements (height, weight, body mass index, skinfolds) were performed monthly. Every 6 months, bioelectrical impedance (RXc graph)11 with BIA 109 Akern (Fig 1) and resting energy expenditure [REE] by MM Horizon Calorimeter were performed. At least every 2 months the patients had to keep a dietary diary for a period of 2 days (including weekends) with weighing method. At the time of diary control, the dietetic interview was performed. For all patients, a diet with 30 kcal/kg and 0.7 to 0.8 g of protein/kg, sodium intake of 3 g/d, and a lipid intake of no more than 30% of the total energy intake was instituted. Proteins rich in sulfurcontaining amino acids were reduced. The maintenance immune suppressive treatment for our patients was cyclosporine (CsA), 30 mg/kg/d, plus steroids (prednisone, 5 mg), in 28 patients; CsA, 30 mg/d, plus steroids, plus azathioprine, 50 to 75 mg/d, in 12 patients; tacrolimus, 8 to 10 mg/d, plus mycofenolate mofetil (MMF), 1000 to 1500 mg/d, for 5 patients; rapamycin, 2 to 3 mg/d, plus Steroids (5 mg/d), plus CsA, 100 mg/d, for 3 patients. Fourteen patients followed antihypertensive therapy with calcium channel blockers and beta blockers; small doses of ACE inhibitors for reducing proteinuria are used. Fourteen patients followed therapy with statins only
Fig 1. All patients have values of resistance (R) and reactance (Xc) comprised within 95% tolerance ellipses of the healthy population.
2002
2
Total
48 5
43
43
for 3 to 4 months after intervention. Physical exercise was recommended.
RESULTS
During the 12 years of observation, 5 patients died of causes not related to renal transplant and, respectively, 3 patients of cirrhosis and hepatic coma HCV related and 2 patients of brain hemorrhage and ictus. The other patients (n ⫽ 43), had been followed up monthly by a nephrologist and dietitian. The stratification of patients for the group 1 “compliant group” and group 2 “control group” proved to be very important for predicting progression in renal graft failure. In group 1 (30 patients), all patients were compliant to dietetic prescriptions; in particular, the protein intake prescribed was strictly observed: the determination of urea in 24-hour urine samples showed that daily mean protein intake was 51.64 ⫾ 7.7 g/d corresponding to 0.73 ⫾ 0.11 g/kg for 70 kg of body weight. To determine the protein intake from urinary urea excretion the formula
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BERNARDI ET AL
Fig 2. (A) Urinary urea nitrogen (g/24 h) in patients of group 1 (left) and of patients of group 2 (right). Nitrogen intakes are very different in the 2 groups (lower in group 1). (B) Protein intakes calculated from urea excretion for group 2 (control group; upper) and for group 1 (compliant group; lower). Mean protein intake of first group is higher than the other.
Urinary urea g/24 hours 䡠 0.47 䡠 6.25 ⫽ Protein intake g/24 hours was applied. The patients of group 2 (n ⫽ 18) were inadequately compliant to prescribed protein intake; their daily mean protein intake was 89.9 ⫾ 16.5
g/d corresponding to 1.4 ⫾ 0.23 g/kg for 70 kg of body weight (Fig 2A, and B). The outcome of serum creatinine in patients of group 1, who complied with prescribed protein intake, compared with serum creatinine in group 2 shows significant differences (P ⬍ 0.001). The
LOW-PROTEIN DIET CONTROLS CHRONIC REJECTION
S149
Fig 3. Serum creatinine values of compliant group (squares), which are stable between 1 and 1.2 mg% in the years, and of control group (circles) which are increasing progressively from 1.2 to 2 mg%.
creatinine values were stable in the years for group 1, whereas there was significantly increase in group 2 (Fig 3). The GFR, detected by formula Creatinine clearance mL/min ⫽ U creatinine mg% 䡠 U volume ml/min:Screatinine 䡠 1.73 mq and by results of renal scintigrams showed stable values in group 1 and progressive decline in group 2 with a very significant difference (P ⬍ 0.0001; Fig 4). Table 2 shows the mean values of serum creatinine obtained per year from mean values of monthly sample determinations and GFR values obtained with formula and validated by renal angioscintigraphy. The moderate protein diet was associated with a very significant reduction in 24-hour urinary
excretion of protein (P ⬍ 0.002) in group 1, whereas the proteinuria values in group 2 were reduced but not significantly (Fig 5). In all patients, no changes in serum protein were found. Reduction in salt intake was obtained; mean values of natriuria (127.91 ⫾ 35.56 mmol/24 hours in group 1 and 193.5 ⫾ 50.8 mmol/24 hours) showed a moderate daily salt intake (Fig 6). The reduced and controlled lipid intake permit normalization of serum lipids (Fig 7); only for 14 patients, who at start of study had high levels of serum lipid, therapy with sinvastatin was mandatory. All patients have maintained or gained adequate nutritional status. The values in Table 3 (mean values of monthly determination performed by dietitian) show that anthropometric measurements are in normal range (body weight, skinfold thicknesses, body composition detected by biolectrical impedance). DISCUSSION
Fig 4. Stable values of GFR in the years of patients of compliant group, whereas GFR of the other group is progressively lower.
Protein intake is very important in human beings. However, in subjects with renal insufficiency a protein intake that is too high may have negative effects. A protein-rich diet causes a pronounced increase in glomerular filtration rate in dogs, rats, and humans. In men as in rodents, the greater the reduction of renal mass, the greater the severity of hypertension, proteinuria, and eventual glomerulosclerosis.12 The reduction in filtration surface area, caused by absence of 50% of renal mass, might lead to high blood pressure levels. Among mechanisms that can cause these effects we know that endothelin-1 (ET-1) acti-
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Table 2. Mean Values of Serum Creatinine by Year and GFR (mL/min) by Year of Patients of Group 1 (Stable Values) and of Group 2: Increasing Values of Serum Cretonne and Decreasing Values of GFR 1989
Group 1 S.Cr (mg%) 1 DS GFR (mL/m) DS Group 2 S Cr (mg%) DS GFR (mL/m) DS
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
1.17 1.08 1.16 1.14 1.21 1.1 1.07 1.15 1.22 1.12 1.01 1.04 1.02 1.03 0.18 0.2 0.21 0.17 0.19 0.21 0.16 0.16 0.15 0.2 0.3 0.12 0.13 0.11 65.5 68.3 69.5 70.6 67.6 67.51 67.75 68.54 67.8 68.7 68.1 69.2 70 70.21 6.37 8.8 7.75 9.67 14.7 14.0 16.7 16.8 15.6 16.9 16.2 17.5 18.1 18.6 1.29 1.39 1.39 1.45 1.6 1.69 1.76 1.82 1.85 1.91 1.95 1.89 1.96 2.01 0.15 0.26 0.26 0.33 0.23 0.24 0.22 0.14 0.2 0.21 0.18 0.16 0.21 0.15 70.7 69.8 67.8 64.9 67.4 65.0 61.21 58.7 50.19 48.5 49.13 50.5 47.1 41.9 5.62 16.8 20.1 20.5 17.1 18.1 16.3 16.5 15.8 17.9 12.1 10.14 11.0 9.6
vates mesangial cell proliferation.13 Renal mass reduction and increased dietary protein each increase urine excretion and renal parenchymal production of ET-1.14 Savin et al15 showed, in subtotally nephrectomized rats, that a reduction in dietary protein content decreases glomerular hypertrophy. It was reported that protein intake is associated with decline of renal function in women with mild renal insufficiency (whereas this was not observed in association between protein intake and decline in renal function in women with normal renal function).16 Protein restriction has been used by many researchers in the treatment of patients with chronic renal failure. Reports by researchers suggest that protein-restricted diets retard progression of renal insufficiency and can be used safely without adverse effects on the clinical and nutritional status of the patients.
Fig 5. Mean values of protein excretion in transplanted patients. Column 1, proteinuria in all patients at start of study. Column 2, mean protein excretion in patients of group II; we have obtained only little reduction. Column 3, the reduction in group 1 was very significant.
Only few studies have investigated the control of protein intake after renal transplant. Chronic renal allograft failure and chronic renal failure have several similarities. Mackenzie and Brenner17 pointed out that these are characterized clinically by progressive decline in renal function and the histopathologic features of the chronically failing allograft resemble those encountered in end-stage renal disease. High protein intake may contribute to renal allograft injury (arising from insufficient renal mass).18,19 Studies performed in a few patients treated with protein restricted diets after renal transplantation have shown good results.9,17-19 Mild hyperhomocysteinemia is common in patients with a functioning renal transplant, as in uremic and RDT patients.20 The mechanisms of the action of homocysteine toxic effects are oxidation, acylation, and hypomethylation. With regard to the last mechanism, it has been shown that homocysteine, through S-adenosyl homocysteine accumu-
Fig 6. Daily sodium excretion in patients of group 1 and group 2: reduction of salt intake was better in compliant group.
LOW-PROTEIN DIET CONTROLS CHRONIC REJECTION
lation, inhibits S-adenosylmethionine–dependent transmethylation. This toxic mechanism affects the repair of protein damage, especially in arterial and coronary vessels, accelerating the arteriosclerotic processes also in patients with renal graft. Our data show that patients who have undergone renal transplant taking a diet with physiologic energy and protein selected intake and controlled lipid intake can obtain a stabilization of renal function for many years. A diet containing 0.8 g/kg is not hypoproteic one, because 0.8 g/kg is normal intake for adults by RDA. CONCLUSION
The adequate long-term dietetic strategies applied to patients with a functioning renal transplant suggest that moderate and selected protein intake may improve the course of chronic (but not antigen-related) rejection, slowing the progression of graft failure. The selective protein intake (reduction of sulfured protein intake) may reduce high homocysteine serum levels. The control of energy and fat intake induces weight loss in overweight patients and is effective in hyperlipidemia. These data suggest that a dietetic approach in renal transplant recipients can delay the course of chronic rejection through a low protein diet, help patients obtain desirable body weight by lowering caloric intake, reduce the high risk of cardiovascular events by controlling hyperlipidemia, and reducing homocysteine serum levels, if accompanied by adequate physical activity.
Fig 7. Outcome of lipid profile in patients with kidney transplant following controlled diet. (1) Cholesterol; (2) TG; (3) HDL.
S151 Table 3.
Anthropometric Measurements of All Patients Were in Normal Range
Men Age years TX months B W kg Height cm BMI Triceps sk Arm circ. A. M. Circ AMA cmq R(resistance) Xc(reactance) R/Height Xc/Height Women Age years TX months B W kg Height cm BMI Triceps sk Arm circ. A. M. Circ AMA cmq R(resistance) Xc(reactance) R/Height Xc/Height
Mean
⫾ ds
43.43 81.68 73.49 172.4 24.8 12.07 28.93 25.12 50.73 450.7 46.93 261.7 27.18
12.42 59.22 7.61 6.81 2.73 5.04 2.63 1.8 7.12 42.8 42.84 25.32 5.9
41.45 90.36 61.5 160.18 24.12 15 29 24.22 47.8 527.45 52.45 329.37 32.78
22.69 49.5 13.3 5.9 5.6 8.7 5.1 3.06 13.82 70.7 12.4 18.52 4.23
REFERENCES 1. Carpenter CB: Long term failure of renal transplants: adding insult to injury. Kidney Int 48:40-44, 1995 (Suppl 50) 2. Brenner BM: Hemodinamically mediated glomerular injury and the progressive nature of kidney disease. Kidney Int 23:647-655, 1983 3. Feehally J, Harris KP, Bennet SE, Walls J: Is chronic renal transplant rejection a non-immunological phenomenon? Lancet 2:486-488, 1986 4. Hostetter TH: Chronic transplant rejection. Kidney Int 46:266-279, 1994 5. Paul L: Chronic renal transplant loss. Kidney Int 47:1491-1499, 1995 6. Brenner BM, Garcia DL, Anderson S: Glomeruli and blood pressure. Less of one, more the other? Am J Hypertens 1:335-347, 1988 7. Oldrizzi L, Rugiu C, De Biase V, Maschio G: The solitary kidney: A risky situation for progressive renal damage? Am J Kidney Dis 17:57-61, 1991 (Suppl 1) 8. Fotino S: The solitary kidney: A model of chronic hyperfiltration in humans. Am J Kidney Dis 13:88-98, 1989 9. Modena FM, Hostetter TH, Salahudeen AK, Najarian JS, Matas AJ, Rosemberg ME: Progression of kidney disease in chronic renal transplant rejection. Transplantation 52:239-244, 1991
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10. Salahudeen AK, Hostetter TH, Raatz Rosemberg ME: Effect of dietary protein in patients with chronic renal transplant rejection. Kidney Int 41:183-190, 1992 11. Piccoli A, Rossi B, Pillon L, Bucciante G: A new method for monitoring body fluid variation by bioimpedance analysis: The RXc graph. Kidney Int 46:534-539, 1994 12. Novick AC, Gephardt GC, Guz B, Steinmuller D, Tubbs RR: Long-term follow up after partial removal of a solitary kidney: A model of chronic hyperfiltration in humans. N Engl J Med 325:1058-1062, 1991 13. Hong Hua, Snezana Munk, Catharine I: Whiteside: Endothelin-1 activates Mesangial Cell ERK1/2 Via EGFReceptor Transactivation and Caveolin-1 Interaction. J Am Soc Nephrol 13:498A, SU-P0146, 2002 14. Khanna A, Hacker C, Wesson DE: Reduced renal mass and increased dietary protein independently increase renal levels of endothelin-1 messenger RNA. J Am Soc Nephrol 13:498A, SU-P0147, 2002 15. Savin VY, Seaton RD, Richardson VP, et al: Dietary
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protein and glomerular response to subtotal nephrectomy in the rat. J Lab Clin Med 113:41-49, 1989 16. Knight EL, Stampfer MJ, Hankinson SE, Curhan GC: The impact of protein intake on renal function decline in women with normal renal function or mild renal insufficiency. J Am Soc Nephrol 13:629A, SU-P0785, 2002 17. Mackenzie HS, Brenner BM: Antigen-independent determinants of late renal allograft outcome: The role of renal mass. Curr Opin Nephrol Hypertens 5:289-296, 1996 18. Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA, Brenner BM: Hyperfiltration in remnant nephrons: A potentially adverse response to renal ablation. Am J Physiol 241:F85-F93, 1981 19. Hostetter TH, Meyer TW, Rennke HG, Brenner BM: Chyronic effects of dietary protein in the rat with intact and reduced renal mass. Kidney Int 30:509-517, 1986 20. Boston AG, Shemin D, Gohh RG, et al: Treatment of hyperhomocysteinemia in hemodialysis patients and renal transplant recipients. Kidney Int 78:S246-S252, 2001 (Suppl 59)
T
HE LITERATURE regarding kidney transplantation shows us that less than 50% of cadaveric allografts survive for more than 10 years after engraftment.1 Graft losses are attributed to “chronic rejection.” We can consider somewhat antigen-independent factors, particularly mechanisms of disease progression caused by reduction of renal mass.1-5 Reduction of filtration surface area in patients with customary salt intake is followed by expansion of extracellular and plasmatic volumes. Systemic and glomerular hypertension might eventually be maladaptive and dangerous for the remnant nephrons.6,7 Also, proteinuria has been attributed to hyperfiltration in remnant nephrons.8 Dietary protein intake may contribute to renal allograft injury arising from insufficient renal mass and may be slowed From the Renal Unit, Rovigo, Italy and the Departments of Clinical Nephrology and Clinical Nutrition, University of Padua, Padua, Italy. We acknowledge the Commemorative Association for the Japan World Exposition (1970), Japanese Association of Dialysis Physicians, Osaka Pharmaceutical Manufacturers Association, and the Pharmaceutical Manufacturers Association of Tokyo for financial support to publish this supplement. Address reprint requests to: Annamaria Bernardi, MD, Via Silvestri n.6 45100 Rovigo, Italy. E-mail: [email protected]; [email protected] © 2003 by the National Kidney Foundation, Inc. 0272-6386/03/4103-0132$30.00/0 doi:10.1053/ajkd.2003.50105
S146
by dietary protein restriction.9,10 Studies regarding a small number of transplant patients undergoing reduction of dietary protein have shown hopeful results. Mild hyperhomocysteinemia is common in patients with a functioning renal transplant, as in uremic and regular dialytic treatment (RDT) patients. METHODS The patients who received renal transplant were observed monthly in our renal unit starting 2 months from surgical intervention. From 1989 to 2002, 48 patients (36 men and 12 women) entered our center for control of renal graft function and chronic rejection progression and nutritional status. The recruitment during the years of observation is shown in Table 1. The primary renal disease is in 35 patients, glomerular disease: membranous and focal segmental glomerulonephritis; in 4 patients, polycystic kidney disease; in 2 patients, obstructive uropathy; and in 7 patients, hypertensive nephropathy. The mean age for women is 41.45 ⫾ 22.69 years, and for men 43.43 ⫾ 12.42 years. The mean duration of renal transplantation was 90.36 ⫾ 49.5 months for women and 81.68 ⫾ 59.2 months for men. The pretransplant dialytic age for all was 132.18 ⫾ 66.5 months. The monthly regular check-ups included routine blood laboratory tests including the measurement of erythrocytes and leucocytes, glucose, urea, creatinine, uric acid, total proteins, albumin and globulins, sodium, kalium, calcium, phosphorus, magnesium, cholesterol, HDL cholesterol, triglycerides, alkaline phosphatase and bone isoenzyme, parathyroid hormone (PTH), iron, and ferritin; the tests also included the collection of 24-hour urine samples for proteins, urea, sodium, potassium, cal-
American Journal of Kidney Diseases, Vol 41, No 3, Suppl 1 (March), 2003: pp S146-S152
LOW-PROTEIN DIET CONTROLS CHRONIC REJECTION Table 1. Year
New patients Deceased patients Surviving patients
1989
1990
11
1
-
-
11
12
1991
1992
1993
1994
S147 Recruitmen
1995
1996
1997
1998
1999
2000
2001
1
7
6
6
3
3
1
2
3
2
-
-
-
-
-
-
-
2
2
1
-
12
13
20
26
32
35
38
37
37
39
41
cium, uric acid excretion and creatinine for clearance (glomerular filtration rate [GFR]) determination. At yearly intervals sequential scintigram of the grafted kidney with technetium (TC) 99 m was performed. A physical examination and anthropometric measurements (height, weight, body mass index, skinfolds) were performed monthly. Every 6 months, bioelectrical impedance (RXc graph)11 with BIA 109 Akern (Fig 1) and resting energy expenditure [REE] by MM Horizon Calorimeter were performed. At least every 2 months the patients had to keep a dietary diary for a period of 2 days (including weekends) with weighing method. At the time of diary control, the dietetic interview was performed. For all patients, a diet with 30 kcal/kg and 0.7 to 0.8 g of protein/kg, sodium intake of 3 g/d, and a lipid intake of no more than 30% of the total energy intake was instituted. Proteins rich in sulfurcontaining amino acids were reduced. The maintenance immune suppressive treatment for our patients was cyclosporine (CsA), 30 mg/kg/d, plus steroids (prednisone, 5 mg), in 28 patients; CsA, 30 mg/d, plus steroids, plus azathioprine, 50 to 75 mg/d, in 12 patients; tacrolimus, 8 to 10 mg/d, plus mycofenolate mofetil (MMF), 1000 to 1500 mg/d, for 5 patients; rapamycin, 2 to 3 mg/d, plus Steroids (5 mg/d), plus CsA, 100 mg/d, for 3 patients. Fourteen patients followed antihypertensive therapy with calcium channel blockers and beta blockers; small doses of ACE inhibitors for reducing proteinuria are used. Fourteen patients followed therapy with statins only
Fig 1. All patients have values of resistance (R) and reactance (Xc) comprised within 95% tolerance ellipses of the healthy population.
2002
2
Total
48 5
43
43
for 3 to 4 months after intervention. Physical exercise was recommended.
RESULTS
During the 12 years of observation, 5 patients died of causes not related to renal transplant and, respectively, 3 patients of cirrhosis and hepatic coma HCV related and 2 patients of brain hemorrhage and ictus. The other patients (n ⫽ 43), had been followed up monthly by a nephrologist and dietitian. The stratification of patients for the group 1 “compliant group” and group 2 “control group” proved to be very important for predicting progression in renal graft failure. In group 1 (30 patients), all patients were compliant to dietetic prescriptions; in particular, the protein intake prescribed was strictly observed: the determination of urea in 24-hour urine samples showed that daily mean protein intake was 51.64 ⫾ 7.7 g/d corresponding to 0.73 ⫾ 0.11 g/kg for 70 kg of body weight. To determine the protein intake from urinary urea excretion the formula
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BERNARDI ET AL
Fig 2. (A) Urinary urea nitrogen (g/24 h) in patients of group 1 (left) and of patients of group 2 (right). Nitrogen intakes are very different in the 2 groups (lower in group 1). (B) Protein intakes calculated from urea excretion for group 2 (control group; upper) and for group 1 (compliant group; lower). Mean protein intake of first group is higher than the other.
Urinary urea g/24 hours 䡠 0.47 䡠 6.25 ⫽ Protein intake g/24 hours was applied. The patients of group 2 (n ⫽ 18) were inadequately compliant to prescribed protein intake; their daily mean protein intake was 89.9 ⫾ 16.5
g/d corresponding to 1.4 ⫾ 0.23 g/kg for 70 kg of body weight (Fig 2A, and B). The outcome of serum creatinine in patients of group 1, who complied with prescribed protein intake, compared with serum creatinine in group 2 shows significant differences (P ⬍ 0.001). The
LOW-PROTEIN DIET CONTROLS CHRONIC REJECTION
S149
Fig 3. Serum creatinine values of compliant group (squares), which are stable between 1 and 1.2 mg% in the years, and of control group (circles) which are increasing progressively from 1.2 to 2 mg%.
creatinine values were stable in the years for group 1, whereas there was significantly increase in group 2 (Fig 3). The GFR, detected by formula Creatinine clearance mL/min ⫽ U creatinine mg% 䡠 U volume ml/min:Screatinine 䡠 1.73 mq and by results of renal scintigrams showed stable values in group 1 and progressive decline in group 2 with a very significant difference (P ⬍ 0.0001; Fig 4). Table 2 shows the mean values of serum creatinine obtained per year from mean values of monthly sample determinations and GFR values obtained with formula and validated by renal angioscintigraphy. The moderate protein diet was associated with a very significant reduction in 24-hour urinary
excretion of protein (P ⬍ 0.002) in group 1, whereas the proteinuria values in group 2 were reduced but not significantly (Fig 5). In all patients, no changes in serum protein were found. Reduction in salt intake was obtained; mean values of natriuria (127.91 ⫾ 35.56 mmol/24 hours in group 1 and 193.5 ⫾ 50.8 mmol/24 hours) showed a moderate daily salt intake (Fig 6). The reduced and controlled lipid intake permit normalization of serum lipids (Fig 7); only for 14 patients, who at start of study had high levels of serum lipid, therapy with sinvastatin was mandatory. All patients have maintained or gained adequate nutritional status. The values in Table 3 (mean values of monthly determination performed by dietitian) show that anthropometric measurements are in normal range (body weight, skinfold thicknesses, body composition detected by biolectrical impedance). DISCUSSION
Fig 4. Stable values of GFR in the years of patients of compliant group, whereas GFR of the other group is progressively lower.
Protein intake is very important in human beings. However, in subjects with renal insufficiency a protein intake that is too high may have negative effects. A protein-rich diet causes a pronounced increase in glomerular filtration rate in dogs, rats, and humans. In men as in rodents, the greater the reduction of renal mass, the greater the severity of hypertension, proteinuria, and eventual glomerulosclerosis.12 The reduction in filtration surface area, caused by absence of 50% of renal mass, might lead to high blood pressure levels. Among mechanisms that can cause these effects we know that endothelin-1 (ET-1) acti-
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Table 2. Mean Values of Serum Creatinine by Year and GFR (mL/min) by Year of Patients of Group 1 (Stable Values) and of Group 2: Increasing Values of Serum Cretonne and Decreasing Values of GFR 1989
Group 1 S.Cr (mg%) 1 DS GFR (mL/m) DS Group 2 S Cr (mg%) DS GFR (mL/m) DS
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
1.17 1.08 1.16 1.14 1.21 1.1 1.07 1.15 1.22 1.12 1.01 1.04 1.02 1.03 0.18 0.2 0.21 0.17 0.19 0.21 0.16 0.16 0.15 0.2 0.3 0.12 0.13 0.11 65.5 68.3 69.5 70.6 67.6 67.51 67.75 68.54 67.8 68.7 68.1 69.2 70 70.21 6.37 8.8 7.75 9.67 14.7 14.0 16.7 16.8 15.6 16.9 16.2 17.5 18.1 18.6 1.29 1.39 1.39 1.45 1.6 1.69 1.76 1.82 1.85 1.91 1.95 1.89 1.96 2.01 0.15 0.26 0.26 0.33 0.23 0.24 0.22 0.14 0.2 0.21 0.18 0.16 0.21 0.15 70.7 69.8 67.8 64.9 67.4 65.0 61.21 58.7 50.19 48.5 49.13 50.5 47.1 41.9 5.62 16.8 20.1 20.5 17.1 18.1 16.3 16.5 15.8 17.9 12.1 10.14 11.0 9.6
vates mesangial cell proliferation.13 Renal mass reduction and increased dietary protein each increase urine excretion and renal parenchymal production of ET-1.14 Savin et al15 showed, in subtotally nephrectomized rats, that a reduction in dietary protein content decreases glomerular hypertrophy. It was reported that protein intake is associated with decline of renal function in women with mild renal insufficiency (whereas this was not observed in association between protein intake and decline in renal function in women with normal renal function).16 Protein restriction has been used by many researchers in the treatment of patients with chronic renal failure. Reports by researchers suggest that protein-restricted diets retard progression of renal insufficiency and can be used safely without adverse effects on the clinical and nutritional status of the patients.
Fig 5. Mean values of protein excretion in transplanted patients. Column 1, proteinuria in all patients at start of study. Column 2, mean protein excretion in patients of group II; we have obtained only little reduction. Column 3, the reduction in group 1 was very significant.
Only few studies have investigated the control of protein intake after renal transplant. Chronic renal allograft failure and chronic renal failure have several similarities. Mackenzie and Brenner17 pointed out that these are characterized clinically by progressive decline in renal function and the histopathologic features of the chronically failing allograft resemble those encountered in end-stage renal disease. High protein intake may contribute to renal allograft injury (arising from insufficient renal mass).18,19 Studies performed in a few patients treated with protein restricted diets after renal transplantation have shown good results.9,17-19 Mild hyperhomocysteinemia is common in patients with a functioning renal transplant, as in uremic and RDT patients.20 The mechanisms of the action of homocysteine toxic effects are oxidation, acylation, and hypomethylation. With regard to the last mechanism, it has been shown that homocysteine, through S-adenosyl homocysteine accumu-
Fig 6. Daily sodium excretion in patients of group 1 and group 2: reduction of salt intake was better in compliant group.
LOW-PROTEIN DIET CONTROLS CHRONIC REJECTION
lation, inhibits S-adenosylmethionine–dependent transmethylation. This toxic mechanism affects the repair of protein damage, especially in arterial and coronary vessels, accelerating the arteriosclerotic processes also in patients with renal graft. Our data show that patients who have undergone renal transplant taking a diet with physiologic energy and protein selected intake and controlled lipid intake can obtain a stabilization of renal function for many years. A diet containing 0.8 g/kg is not hypoproteic one, because 0.8 g/kg is normal intake for adults by RDA. CONCLUSION
The adequate long-term dietetic strategies applied to patients with a functioning renal transplant suggest that moderate and selected protein intake may improve the course of chronic (but not antigen-related) rejection, slowing the progression of graft failure. The selective protein intake (reduction of sulfured protein intake) may reduce high homocysteine serum levels. The control of energy and fat intake induces weight loss in overweight patients and is effective in hyperlipidemia. These data suggest that a dietetic approach in renal transplant recipients can delay the course of chronic rejection through a low protein diet, help patients obtain desirable body weight by lowering caloric intake, reduce the high risk of cardiovascular events by controlling hyperlipidemia, and reducing homocysteine serum levels, if accompanied by adequate physical activity.
Fig 7. Outcome of lipid profile in patients with kidney transplant following controlled diet. (1) Cholesterol; (2) TG; (3) HDL.
S151 Table 3.
Anthropometric Measurements of All Patients Were in Normal Range
Men Age years TX months B W kg Height cm BMI Triceps sk Arm circ. A. M. Circ AMA cmq R(resistance) Xc(reactance) R/Height Xc/Height Women Age years TX months B W kg Height cm BMI Triceps sk Arm circ. A. M. Circ AMA cmq R(resistance) Xc(reactance) R/Height Xc/Height
Mean
⫾ ds
43.43 81.68 73.49 172.4 24.8 12.07 28.93 25.12 50.73 450.7 46.93 261.7 27.18
12.42 59.22 7.61 6.81 2.73 5.04 2.63 1.8 7.12 42.8 42.84 25.32 5.9
41.45 90.36 61.5 160.18 24.12 15 29 24.22 47.8 527.45 52.45 329.37 32.78
22.69 49.5 13.3 5.9 5.6 8.7 5.1 3.06 13.82 70.7 12.4 18.52 4.23
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BERNARDI ET AL
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