Chronic Renal Transplant Dysfunction Research Articles

Insulin resistance as putative cause of chronic renal transplant dysfunction

Transplantation is the preferred organ replacement therapy for most patients with end-stage renal disease. Despite impressive improvements over recent years in the treatment of acute rejection, approximately half of all grafts will loose function within 10 years after transplantation. Chronic renal transplant dysfunction, also known as transplant atherosclerosis, is a leading cause of late allograft loss. To date, no specific treatment for chronic renal transplant dysfunction is available. Although its precise pathophysiology remains unknown, it is believed that it involves a multifactorial process of alloantigen-dependent and alloantigen-independent risk factors. Obesity, posttransplant diabetes mellitus, dyslipidemia, hypertension, and proteinuria have all been identified as alloantigen-independent risk factors. Notably, these recipient-related risk factors are well-known risk factors for cardiovascular disease, which cluster within the insulin resistance syndrome in the general population. Insulin resistance is considered the central pathophysiologic feature of this syndrome. It is therefore tempting to speculate that it is insulin resistance that underlies the recipient-related risk factors for chronic renal transplant dysfunction. Recognition of insulin resistance as a central feature underlying many, if not all, recipient-related risk factors would not only improve our understanding of the pathophysiology of chronic renal transplant dysfunction, but also stimulate development of new treatment and prevention strategies.

ANGIOTENSINOGEN AND PLASMINOGEN ACTIVATOR INHIBITOR‐1 GENE POLYMORPHISM IN RELATION TO CHRONIC ALLOGRAFT DYSFUNCTION

Chronic allograft dysfunction (CAD) is the most common cause of allograft failure in the long‐term, and current immunologic strategies have little effect on this condition. The renin‐angiotensin system (RAS) plays important roles in hypertension and progression of chronic renal disease. It is thought that plasminogen activator inhibitor‐1 (PAI‐1) functions in the RAS, in addition to involvement in thrombotic risk and fibrosis. This study investigated possible links between angiotensinogen (AGT) genotypes (M235T/MM, MT, TT) and PAI‐1 genotypes (4G4G, 4G5G, 5G5G) and CAD assessments of both types of polymorphism were performed in 82 renal allograft recipients (47 males and 35 females; mean age 34.87±11.22 years). One hundred healthy subjects (54 males and 46 females; mean age 35.54±10.26 years) were also investigated for AGT polymorphism, and 80 healthy subjects (45 males and 35 females; mean age 36.54±12.41) for PAI‐1 polymorphism. Genotypes were determined using polymerase chain reaction sequence‐specific primers, and polymerase chain reaction followed by restriction fragment length polymorphism analysis.Kidney recipients with CAD had significantly lower frequencies of the MM genotype and the M allele than those without CAD. (P<0.05 and P<0.001, respectively) Presence of the MT genotype was significantly associated with CAD, and this genotype introduced a 3.5‐fold risk of CAD compared with the MM genotype (P<0.05; 95% confidence interval: 1.21–10.20). The transplant recipients with CAD also had significantly lower frequencies of the 5G/5G genotype and the 5G allele than those without CAD (P<0.001 and P<0.05, respectively). Presence of the 4G allele introduced a 1.94‐fold risk of CAD compared with the 5G allele (95% confidence interval: 1.05–3.66). Determination of AGT M235T and PAI‐1 genotypes before transplantation may help identify patients who are at risk for chronic renal transplant dysfunction.

Erythropoietin therapy may retard progression in chronic renal transplant dysfunction.

Recent data suggests that erythropoietin therapy may actually retard the progression of chronic kidney disease (CKD). Transplant recipients with evidence of chronic allograft dysfunction could respond in a similar manner to erythropoietin. We evaluated 166 individuals who initiated erythropoietin therapy after at least 18 days of transplant function. One hundred and nine individuals received erythropoietin between days 18 and 294 of transplant function (group 1-early epoietin alfa) while 57 individuals received erythropoietin on or after day 294 of transplant function (group 2-late epoietin alfa). The slope of serum creatinine (Scr) (Deltaslope Scr) prior to and following the start of erythropoietin therapy and calculated glomerular filtration rates (GFR) were used to assess renal function over time. The average haematocrit rose 6.6% in group 1 patients and 2.1% in group 2 patients during the first 100 days of erythropoietin therapy. The Deltaslope Scr was not significantly altered in group 1 patients. However, for group 2 individuals who continued to have graft function (n=35), the Deltaslope Scr became negative during erythropoietin treatment. This indicated a deceleration in the rate of loss of renal function (day 200 Deltaslope Scr -0.0033, P=0.00091; day 300 Deltaslope Scr -0.0014, P=0.05; day 400 Deltaslope Scr -0.0066, N.S., P=0.066). GFR remained stable in both cohorts. Finally, group 2-late epoietin alfa patients treated with erythropoietin demonstrated a marked trend towards longer graft survival than a group of similar control patients (N.S., P=0.064). The data in a group of renal transplant recipients with chronic allograft dysfunction reinforce data from the CKD realm suggesting that erythropoietin may be of benefit in slowing the rate of loss of function over time. However, this renal response is not evident in all patients. Prospective studies of erythropoietin or erythropoietin-like medications are warranted in this population to better discriminate those who may respond well to administration of these drugs.

Angiotensin gene polymorphism as a determinant of posttransplantation renal dysfunction and hypertension.

Polymorphism of the genes associated with angiotensin, including angiotensin-converting enzyme (ACE), angiotensinogen (AGT), and the type 1 (AT1) and type 2 (AT2) angiotensin II receptors, has been implicated in the pathophysiology of hypertension, ischemic heart disease, and progression of chronic renal disease. We investigated the impact of the ACE, AGT, AT1, and AT2 genotypes on renal allograft function in 148 patients (77 men, 71 women) who underwent transplantation over a 5-year period. Patients were genotyped using polymerase chain reaction sequence-specific primers and polymerase chain reaction followed by restriction fragment length polymorphism analysis. ACE (D) and AGT (A/A) genotypes were associated with poorer chronic renal transplant function and more rapid chronic progression, defined as an increase of serum creatinine level with time. In addition, mean diastolic blood pressure at 3 years was significantly (P<0.02) correlated with C gene dose of AT1 (A-->C, 1166), with levels of 79+/-10 mmHg, 82+/-8.6 mmHg, and 95+/-8.3 mmHg for the A/A, A/C, and C/C genotypes, respectively. An apparent AT2 homozygote disadvantage could be an epiphenomenon because AT2 maps to the X chromosome, and males are homozygous for just one of the AT2 alleles (A/- or G/-). Pretransplantation testing of the ACE, AGT, and AT1 genotypes may assist clinicians in identifying patients at risk for chronic renal transplant dysfunction and hypertension.

The role of transforming growth factor beta in chronic renal allograft nephropathy.

The role of transforming growth factor beta in chronic renal allograft nephropathy.

RANTES and MCP-1 chemokine plasma levels in chronic renal transplant dysfunction and chronic renal failure

Objectives: Procedures to diagnose renal allograft rejection depend on detection of graft dysfunction due to the presence of mononuclear leukocytic infiltrates. Design and methods: In our study, we pursued an immunodiagnostic approach utilizing an ELISA method on plasma samples to monitor patients waiting to undergo transplantation in order to evidence prognostic developments in renal transplantation and, at least, to diagnose renal chronic transplant dysfunction. We analyzed blood levels of two chemokines, RANTES and MCP-1, which are normally overexpressed locally in renal chronic rejection. Results: Our results showed that patients affected by chronic renal failure (and waiting for kidney transplant), as well as kidney-grafted patients affected by chronic transplant dysfunction, had plasma levels of RANTES significantly higher than those of controls (patients without acute or chronic pathologies). Conclusions: Our data suggest a simple method to evaluate the plasmatic presence of RANTES, which could be involved in long-term kidney graft failure.

Accelerated atherosclerosis in the transplant recipient: role of hypertension.

An accelerated atherosclerosis may occur in the native arteries of a transplant recipient as well as in arteries of transplanted kidneys or hearts. The dominating cause of patient mortality are cardiovascular diseases, where ischaemic heart disease is predominant. The accelerated form of arteriosclerosis which takes place in transplanted kidneys and hearts, has a complex pathogenesis, which includes both immunological and nonimmunological factors. Hypertension is one such factor which has been claimed to be an independent risk factor of chronic renal transplant dysfunction, usually characterised by transplant arteriosclerosis. Whether a more intense treatment of hypertension or a more selective use of antihypertensive drugs would have a beneficial effect upon the progression rate of chronic rejection is still an open question.