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REVIEW ARTICLE


Nutritional Challenges in Post Renal Transplant Patients

Anita Saxena

Associate Professor, Department of Nephrology SGPGIMS, Lucknow



T

T

he recipients of renal transplants experience an improvement in general sense of well being along with a marked improvement in appetite and increase inbodyweight. It is expected that a successfully transplanted kidney would restore near-normal renal function and correct nutritional abnormalities arising from pre-transplant renal insufficiency. However, some patients do not attain optimal renal function, while others experience decline in renal function with the passage of time. Hence, many recipients of transplant may require nutritional management as appropriate for patients with chronic renal failure even though these patients do not require dialysis. Furthermore, transplant patients face many nutritional challenges because of metabolic complications of pre-existing medical conditions and as a consequence of transplant related immunosuppression. Hence, evaluation of nutritional status, body composition and resting energy expenditure (REE) is a must in post transplant patients with functioning renal graft and longer survival of the

transplanted kidney.

Changes in body composition after renal transplantation are due to increased appetite and reversal of the uremic state, as well as immunosuppressive therapy, in particular immediately after surgery. Therefore there are two clearly distinct phases regarding nutritional changes: the early and late post transplant phase. The major nutritional and metabolic problems of the early phase are malnutrition (associated or not associated with systemic inflammation), obesity, lipid abnormalities, glucose intolerance, hypertension, as well as calcium, phosphorus, and vitamin D imbalance.

Malnutrition: Malnutrition during the pre-transplant phase is associated with higher post-transplant morbidity and mortality rates, which is due in part to impaired surgical wound healing and higher risk of infection. Chrusciel et al have shown that despite increase in weight which is partially attributed to immunosuppression, malnutrition is present in >20% of the post transplant patients. Malnutrition can best be defined by a body mass index (BMI) <21. 15% of the


452 kidney transplant patients had BMI less than 21 kgm2 which the investigators attributed to malnutrition. There is depletion of protein stores at the cellular level after 45 days of transplantation, which normalizes in long term

Effect of Immuno-suppression on body weight: Within two to three weeks a significant increase in body weight is due to high doses of cyclosporine and steroids which cause an increase in total body water (TBW). On an average body weight increases by 14% in men and 10% in women when compared with their respective dialytic dry weight. Evaluation of body composition by bioelectrical impedance shows that patients with a renal transplant show a tendency towards higher fat-free mass compared to healthy control. Some authors have found no correlation between cumulative steroid dose and post transplant weight gain. On the contrary, a slight tendency toward weight loss has even been observed.

Nearly up to the first post transplantation year, serum albumin levels may be below normal suggesting that protein malnutrition may persist after renal transplantation. Thus although weight gain is common, malnutrition is not negligible. The presence of malnutrition may affect graft and patient survival. Conversely factors such as co-morbidity and graft failure may result in malnutrition.

Obesity: Obesity is associated with decreased patient and graft survival particularly due to a greater incidence of surgical, metabolic, and cardiovascular complications. Potential mechanisms for the negative effect of obesity include greater chance for mismatches in recipients and donor size and hence for nephron underdosing and hyperfiltration; underdosing or perhaps impaired bioavailability of immunosuppresiive agents; or the effect of effect of hyperlipidemia to promote chronic graft dysfunction. Dislipidemia is yet another challenge in obese patients. Introduction of proper nutritional counseling at an early stage in renal transplant patients with a low BMI might allow the functional life of the kidney graft to be prolonged long-term without any significant side effects,

such as occur with almost all of the medicinal products used in transplantation medicine. There is impaired long-term kidney graft survival among patients with reduced nutritional status which reflects improved immune function due to reduced nutrient availability, thus leading to reinforcement of chronic rejection processes.

ProteinMetabolismandProteinlntakeRecommendation: The early phase of renal transplantation namely 4-6 weeks after surgery is characterized by increased nutritional demands due to a combination of the surgical stress and the high doses of immunosuppressive medications. Acute rejection and infection are also major concern. Both the surgical stress and high corticosteroid doses may lead to severe protein catabolism. One possible metabolic effect of corticosteroids is an increase in hepatic gluconeogenesis leading to hyperglycemia and hyperinsulinemia associated with elevated protein and aminoacid catabolism and decreased anabolism All these effects may be exacerbated in the previously malnourished patient, adding substantial problems in the immediate post-transplant phase such as wound healing and increased infection susceptibility. Negative nitrogen balance can be prevented in immediate post transplant period by increasing protein intake.

In randomized studies, the use of steroid withdrawal and steroid avoidance protocols suggest that steroid withdrawal does not have much effect on post transplant weight gain and that weight gain is not significantly related to steroid dose. Instead, some of these studies suggest that limited physical activity may be the most important factor in post transplant obesity. These observations also suggest that greater emphasis on activity and exercise would be a more effective approach to preventing post transplant obesity. Recent randomized studies in obese subjects demonstrate that following a low carbohydrate diet modest loss in weight along improvement in lipid profile can be observed over a period of 6 to 12 months. Since these studies are not based on transplant patients therefore these patients should not be counseled to pursue such diets.

The daily protein intake recommendation in the immediate post transplant phase is 1.3 to 1.5 g/kg/day. Protein intake should be controlled in the presence of acute tubular necrosis with associated uremic symptoms. Similar to protein metabolism, surgical stress and high doses of immunosuppressive medication may increase energy expenditures of these patients. It has been observed that these patients have a significantly higher REE (27.6 ±2.5 kcal/kg) compared to controls (23.7± 2.7 kcal/kg: P<0.001). This suggests that transplant patients present increased energy expenditure (30-35 kcal/kg/ d) during immediate post transplant phase. After 4 weeks if the patients has recovered well, then protein intake should be brought down to 1g/kg/d and should continue till three months post transplant. At three months protein intake should be brought down to 0.8 g/kg/d for proper functioning of graft.

Once the patient has stabilized after transplant (3rd month post transplant onwards) and the immunosuppressive

medication trough levels have stabilized, the patient should gradually start reducing his water intake from 6-7 liters to approximately no more than 3 liters. Blood pressure is a good guide for water intake. Ifpatient is requiring too many antihypertensive medications, it is possible that his total body water may be more than required. Bioimpedance technique can measure water compartments and also estimate dry weight. Ifthere is difference between actual weight and dry weight, this would imply expanded water compartments and so water intake will have to be reduced. Patients should be advised not to indulge in excessive water drinking. Water intake should be thirst driven. High dose of corticosteroids also cause retention of salt and water.

The late post transplant period is frequently marked by a variety of nutritional problems, which may impact patient and graft survival. Despite adjusted doses, long­ term immunosuppression is associated with protein hypercatabolism, obesity, dyslipidemia, glucose intolerance, hypertension, hypercalcemia, and alteration of vitamin D metabolism and action. Serum albumin levels may still continue to be below normal up to 1 year post transplant suggesting that protein malnutrition may persist after transplant. This situation seems to normalize subsequently in patients with functioning renal grafts. Additionally there are abnormalities in amino acid metabolism, causing long term elevations of plasma and muscle concentrations Although the true mechanism of these abnormalities is still unknown, corticosteroids may be involved by increasing gluconeogenesis and protein catabolism. But a diet containing large amounts of protein may lead to renal hyperfiltration. It has been shown that 0.8g/kg/d protein intake as well as sodium restriction stabilized long term renal function as well as maintained an adequate nutritional status of recipient Also regular exercise is usually recommended to avoid muscle mass loss.

The post transplant nutritional care of diabetic patients is considerably complicated by insulin resistance induced by steroid therapy. Some patients develop clinical diabetes (new onset diabetes after transplantation: NODAT) as a result of immunosuppressive therapy with glucocorticoids and calcineurin inhibitors (cyclosporine and tacrolimus). Even recipients of renal transplants with overtly normal glucose tolerance have evidence of insulin resistance when studied by the insulin clamp technique. The diabetogenic effect of tacrolimus is dose dependent so that with downward dose adjustment, the long term prevalence of diabetes decreases and may eventually be similar to the rate observed in cyclosporine treated patients. Insulin therapy is recommended to keep blood sugar under control.

Nutritional recommendations to prevent atherosclerotic cardiovascular disease: The major cause of long term morbidity and mortality in these patients is atherosclerotic cardiovascular disease. In dialysis population development of this disease is due to traditional risk factors such as dyslipidemia,hypertension,glucose intolerance andsedentary lifestyle. Nontraditional risk factors such as altered calcium

and phosphate homeostasis, homocystein, inflammation and oxidative stress have also been associated with cardiovascular disease Among these, dyslipidemia is an important and potentially modifiable risk factor in transplant patients. Approximately 60% of renal recipients develop dyslipidemia after 1 month, and 50%-70% after 10 years postransplant Low LDL and high triglycerides are the main predictors of cardiovascular disease in this population. Alterations in lipid metabolism may be associated with medications, such as corticosteroids, cyclosporine, sirolimus, thiazide diuretics, or beta-blockers as well as with renal dysfunction, nephrotic syndrome, glucose intolerance, insulin resistance or obesity Initial intervention involves diet modification (weight reduction along with low fat diet American Heart Association (AHA) "step one" diet ), which frequently results in improvement of the lipid profile. It appears reasonable to advocate 3 months of a low fat diet before recommending drug therapy. In addition, other strategies include regular exercise and a high fiber (25to 30 g/d) diet and the lowest possible corticosteroid and cyclosporine doses. Omega-3 fatty acid supplementation has been proposed to reduce serum triglycerides and consequently the vascular burden. It has been observed that in recipients who do not gain weight their lipid levels do not worsen indicating that control of body weight by a combination of diet and exercise is critical in this patient population.

Dietary salt restriction is another recommendation with important impacts on cardiovascular burden since salt intake may play a role in cyclosporine induced hypertension caused by sodium retention. Long-term 2.4g/d sodium restriction along with control of protein intake stabilized renal function. A lower range (1-3 g/d) may be indicated in cases of hypertension related to fluid retension.

Nutritional Recommendations Regarding Potassium Calcium and Phosphorus and Vitamin D: During immediate post transplant phase, high doses of cyclosporine have been implicated with substantial incidence of hypercalcemia. Additionally, antihypertensive treatment with beta blocker agents or with ACE inhibitors may exacerbate hypercalcemia. In case of hypercalcemia or oliguria, dietary restrictions of potassium to 1-3 g/d may be indicated. Calcium, phosphorus and vitamin D metabolism are influenced by several interlinked factors (necrosis, fractures, bone mass loss, prolonged therapy with steroids leading to osteopenia and osteonecrosis as well as incomplete restoration of renal function after transplant resulting in the earlier period of the chronic renal failure. The daily recommendation for dietary calcium is about 800-1500 mg/d. The diet should contain adequate amount of calcium and phosphorus content and be relatively free of phosphate binders including magnesium-containing antacids. Administration of calcitiol can significantly ameliorate the renal phosphate leak and hyperparathyroidism and the depressed intestinal absorption of calcium and perhaps increase rate of bone formation. One large randomized double blind study showed that use of calcitriol (0.5 to 1 µg/d) could significantly reduce bone loss from lumbar spine in patients during 1 year

of corticosteroid therapy given for a variety of reasons including organ transplantation. However, calcitriol must be used judiciously because it can cause hypercalcemia and hypercalciuria and lead to stone formation in transplanted kidney. Hypercalcemia can also lead to vascular calcification which occurs at much higher frequency in the population of patients with end stage renal disease. Dietary intake of phosphorus should be individualized according to patients serum levels. The daily intake should be 1200-1500 mg/d as hypophosphatemia may persist indefinitely for majority of renal recipients. Some patients may require phosphorus supplementation and some may require supplementation of active vitamin D in doses 1-2µg/d.

Nutritional Recommendations Regarding Magnesium, Uric Acid And Vitamins: Hypomagnesemia (serum magnesium< 1.5mg/dl) may occur secondaryto cyclosporine (25 % of patients) and hyperlipediemia. Hypomagnesemia requires supplementation. Hyperuricemia is common in recipients with reduced renal function or those treated with diuretics. Cyclosporin and tacrolimus induce renal magnesium wasting.

Nutritional recommendations in chronic rejection: Chronic rejection (GFR <40-50 mL/min) is one of the commonest cause of graft loss. Although immunological mechanisms play a central role in the renal graft failure, a component of progressive loss of renal function may be related to initially adaptive and but eventually maladaptive functional and structural alterations which are common to many progressive diseases. Low protein diets can reduce proteinuria and may slow the rate of progression of graft dysfunction. Protein restriction suppresses the rennin­ angiotensin system and blunts the deleterious adaptive responses to nephron loss including effect on glomerular capillary hemodynamics, renal growth, ammoniagenesis and metabolic rate

The pathogenesis of chronic rejection is poorly understood and there is no specific therapy. Nutritional intervention may have a role to play in such a situation. Dietary restriction of 0.6 -0.8 g/kg/d should be considered for patients with adequate calorie intake, if prednisone dosage does not exceed 0.2 mg/kg/d balance.

On restricted protein diet nutritional status and body muscle mass should be regularly monitored. Patients on low protein diets may require regular multivitamin supplements. Dietary phosphorus restriction (800 mg/d) would be necessary. Hyperlipidemia is yet another important aspect of chronic rejection as abnormal lipoprotein levels may lead to glomerulosclerosis and renal disease progression and even graft failure Hence hyperlipidemia control may have a crucial role to play in progression of chronic vascular rejection.

Hence frequent nutritional evaluation and repeated nutritional intervention to facilitate improvement in dietary habits are important in all renal transplant phases, including pretransplant phase. During the first year the goal is to treat preexisting malnutrition and prevent excessive weight gain.

Water intake should be thirst driven. Saxena et al have 2.

shown that excessive intake of water can cause expansion of water compartements which can adverslty affect blood

pressure. This study has shown that in non edematous 3.

patients, the dry weight is different from actual weight which implies accumulation of water in th body. Patients who are 4. on more than one antihypertensive drug have expanded water compartemnst compared to those on one drug.

Quereshi AR, Levine SE, Alvestrand A et al 1994 Nutritional status muscle composition, and plasma and muscle free amino acids in renal transplant patients Clin Nephrol 42: 237

Co morbidity and graft failure-two main causes of malnutrition in kidney transplant patients. Nephrol Dial Transplant 18 suppl 5: V 68,

Van Den Ham EC, Koornan JP, Christiaans MH etal 2003 Weight changes after renal transplantation: a comparison between patients on 5 mg maintenance steroid therapy and those on steroid-free irnrnunosuppressive therapy. Transplant Int. 16: 300.


Body composition:

Factors influencing body composition in renal transplant recipients are manifold, including steroid administration, acute or chronic infection, rejection, nutritional behaviour, and higher grade uremia-the later evidently involving only a small proportion of patients. The pathogenetic background to an impaired nutritional status is "malnutrition­ inflammation complex syndrome" which probably palys a central role not just in renal transplant patients, resulting in breakdown of energy stores, reduced energy uptake, and thus ultimately reduced energy availability.The body composition is prone to rapid change after transplantation. Thus the BMI at 1 year after transplantation seems to be a suitable parameter to assess long-term effects as it is recorded at a point where it is expected that stabilization of graft function, drug dosage and overall well-being has been achieved.

Conclusion: Frequent evaluation of nutritional status may be of great importance in all renal transplant patients as well as in the prerenal transplantation period and should be complemented by intervention in the nutritional intake.


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References:

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