Metabolic Acidosis in Renal Transplant Patients

Chronic kidney disease is developing to become one of the major health problems in the Western world with more than one million patients on renal replacement therapy, and many more expected in the years ahead [1]. Survival of patients with end stage renal disease has become possible with the introduction of dialysis therapy. Renal transplantation has resulted both in further reduction of mortality and improvement in quality of life for patients with end stage renal disease. Nevertheless, successful transplantation with regard to graft and patient survival is still associated with significant morbidity. Apart from infectious complications and cardiovascular disease, limitations in physical capacity from musculoskeletal disorders have become a relevant problem, resulting in reduced quality of life, poor physical functioning and inability to work.

Muscle and bone metabolism in chronic kidney disease are typically disturbed resulting in significant pathology and dysfunction of the affected tissues. They are associated with metabolic disorders related to renal insufficiency, among which metabolic acidosis is a major contributor. Metabolic acidosis is a well recognized problem in renal transplant patients. However, its prevalence, pathogenesis, course and sequelae are not well established. In particular, its relation to post-transplant bone and muscle disorders, and the impact on physical capabilities in renal transplant patients have not been comprehensively investigated so far.

The purpose of the proposed project is to examine the characteristics and pathogenesis of post-transplant metabolic acidosis, and its relation to bone and muscle pathologies and impact on physical capabilities in renal transplant patients. In particular, the following aims are proposed to investigate in de novo and long-term renal transplantation:

Aim # 1: To examine the type, degree and course of metabolic acidosis in renal transplant patients, early and long-term after transplantation

Aim # 2: To examine alterations in mineral and bone metabolism, and bone structure, and their relationship to the acid/base disorder

Aim # 3: To examine overall physical performance, exercise capacity and muscle energy content, and their relationship to the acid/base disorder

In order to analyze secondary effects of subclinical and overt acidosis on bone (Aim # 2) and muscle (Aim # 3), patients will be studied at baseline, and then be supplemented with base equivalents in order to achieve a stable plasma serum bicarbonate concentration of 24-26 mmol/l, and be reexamined thereafter. Completion of the three aims will allow to comprehensively analyze the pathogenesis of and interrelations between acid/base status, mineral metabolism, bone disorders and muscle function in renal transplant patients. This will be the first study to link metabolic alterations to structural and functional measures of the musculoskeletal system, and to the impact of the resulting pathologies on physical disabilities in patients with a kidney graft. We are in dire need to know the magnitude of the problem, whether to treat, and how aggressive to treat these patients. The results of this project will be indispensable regarding justification to rigorously evaluate and treat metabolic acidosis in patients with chronic renal insufficiency and after transplantation.

Inclusion criteria

• Patients with a renal graft having been transplanted within the previous 8 years and being at least 3 months post transplantation, or, patients scheduled to undergo transplantation from a living organ donor within the upcoming 3 months
• Venous serum bicarbonate concentration < 24 mmol/L at time of baseline determination
• Renal transplant function with a calculated glomerular filtration rate (GFR) greater or equal 30 ml/min according to the Cockcroft-Gault formula
• Immunosuppressive therapy including a calcineurin inhibitor (cyclosporine A or tacrolimus)
• Age 20 through 65 years of either sex
• Written informed consent for study participation

Exclusion criteria

• Acute rejection episode requiring specific therapy within 4 weeks before study inclusion
• Severe impairment in general health and/or physical handicaps (malignant neoplasia, catabolic state, acute systemic infection requiring therapy)
• Mental illness, psychiatric disorder
• Tetracycline intolerance
• Planned or "overt" pregnancy