Metabolic and Renal Effects of Rosiglitazone in Kidney Transplant
Condition: Kidney Transplant
Study type: Interventional
Phase: Phase 2

Summary: 
      Abnormalities in glucidic and lipidic metabolism are common features in renal transplant
      patients on chronic immunossupression with steroids and calcineurin inhibitors. In kidney
      transplant patients with chronic rejection these abnormalities cluster with renal and
      cardiovascular risk factors and altogether may sustain premature graft loss and may increase
      the risk of cardiovascular morbidity and mortality. Thiozolidinediones are a new class of
      oral antidiabetic agents that may increase insulin sensitivity improving the glucose
      tolerance and dyslipidemia. Moreover, rosiglitazone -one of these drugs- has been reported to
      decrease blood pressure and albuminuria in subjects with type 2 diabetes and nephropathy.
      Recent finding that glitazones ameliorate the glucidic and lipidic profile induced by steroid
      treatment in healthy subjects, provided a further rationale to evaluate the metabolic and
      renal effects of glitazones in renal transplant patients on chronic steroid therapy. Thus, we
      designed and organized a pilot study to assess the short-term risk/benefit profile of
      rosiglitazone in renal transplant patients with chronic rejection. Ten patients will have a
      basal evaluation of insulin sensitivity, glucose tolerance,lipid profile, renal hemodynamic
      and albuminuria. These evaluations will be repeated at the end of the treatment (4 months of
      therapy with rosiglitazone 8 mg/day) period and 2 months after treatment withdrawal.
    

Detailed description: 
      INTRODUCTION Decreased insulin sensitivity, impaired glucose tolerance and dyslipidemia are
      common features in renal transplant patients on chronic immunosuppression with steroids and
      calcineurine inhibitors. In renal transplant patients with chronic allograft dysfunction
      these metabolic abnormalities typically cluster with well-established renal and
      cardiovascular risk-factors such as hypertension and albuminuria. Altogether these factors
      may sustain and accelerate the progression of chronic allograft dysfunction to end stage
      renal disease (ESRD) and increase the risk of premature cardiovascular morbidity and
      mortality.

      Thiazolidinediones (glitazones) are a new class of oral antidiabetic agents that may increase
      insulin sensitivity through activation of the peroxisome prolipherator-activated receptor
      gamma (PPARgamma). By ameliorating insulin sensitivity, these drugs may also improve glucose
      tolerance and dyslipidemia. These properties have led to their current utility as
      antidiabetic drugs. Moreover, finding that one of these drugs - rosiglitazone - has been
      reported to decrease arterial blood pressure and albuminuria in patients with type 2 diabetes
      and nephropathy, has been taken to suggest that glitazones may also have a specific reno- and
      cardio-protective effect. This effect could specifically apply to renal transplant patients
      with chronic allograft dysfunction in whom glitazones, in addition to ameliorate insulin
      resistance, glucose tolerance and dyslipidemia, might help controlling arterial hypertension
      and reducing albuminuria.

      Recent finding that glitazones ameliorate the insulin resistant status induced by steroid
      treatment in healthy subjects, provides a further rationale to evaluate the metabolic and
      renal effects of glitazones in renal transplant patients on chronic steroid therapy.

      AIM To evaluate the short-term risk/benefit profile of rosiglitazone treatment in renal
      transplant patients with chronic allograft dysfunction.

      DESIGN After a basal evaluation of systolic/diastolic blood pressure,body weight, insulin
      sensitivity (by euglycemic hyperinsulinemic clamp), glucose tolerance (by standard glucose
      tolerance test), lipid profile, renal hemodynamics (GFR and RPF by inulin and PAH renal
      clearances, respectively), albuminuria (mean of three consecutive overnight urine
      collections), albumin, IgG, Na+ and free water fractional clearances and other routine
      laboratory analyses, patients satisfying the selection criteria will enter 4-month therapy
      with rosiglitazone 4 mg/day, up-titrated, if well-tolerated, to 8 mg/day 4 weeks later.
      Baseline evaluations will be repeated at the end of the treatment period and 2 months after
      treatment withdrawal. Blood pressure, body weight and routine laboratory tests - including
      liver function tests - will be evaluated also at 1 and 2 weeks of rosiglitazone therapy, at
      month 1 and then every month up to study end. Albuminuria will also be evaluated at month 2
      of rosiglitazone therapy.

      No major change in diet and immunosuppressive, antihypertensive and other concomitant
      treatments will be introduced throughout the whole study period. A low salt (2 grams of Na+
      per day) and a controlled dietary protein intake (0.8 g/kg/body weight per day) will be
      recommended to all patients. Should any evidence of clinically relevant water retention or of
      liver toxicity occur throughout the treatment period, rosiglitazone will be back-titrated to
      the initial dose or withdrawn as deemed clinically appropriate.
    

Intervention name(s): Rosiglitazone
Intervention type(s): Drug
Intervention MeSH terms: Rosiglitazone
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment