Azmi Al-Najjar

Early Low-Grade Proteinuria: Causes, Short-Term Evolution and Long-Term Consequences in Renal Transplantation

Proteinuria 1 year after transplantation is associated with poor renal outcome. It is unclear whether low‐grade (<1 g/24 h) proteinuria earlier after transplantation and its short‐term change affect long‐term graft survival. The effects of proteinuria and its change on long‐term graft survival were retrospectively assessed in 484 renal transplant recipients. One‐ and 3‐month proteinuria correlated with donor age, donor cardiovascular death, prolonged cold and warm ischemia times and acute rejection. One‐ and 3‐month proteinuria (per 0.1 g/24 h, hazard ratio (HR): 1.07 and 1.15, p < 0.0001)—especially low‐grade proteinuria (HR: 1.20 and 1.26, p < 0.0001)—were powerful, independent predictors of graft loss. Its short‐term reduction correlated with arterial pressure (AP) (the lower the 3‐month diastolic and 12‐month systolic AP, the lower the risk of increasing proteinuria during 1–3 months and 3–12 months periods, respectively: Odds ratio (OR) per 10 MmHg: 0.78, p = 0.01 and 0.85, respectively, p = 0.02), and was associated with decreased long‐term graft loss (per 0.1 g/24 h: HR: 0.88 and 0.98, respectively, p < 0.0001), independently of initial proteinuria. Early low‐grade proteinuria due to pre‐transplant renal lesions, ischemia‐reperfusion and immunologic injuries is a potent predictor of graft loss. Short‐term reduction in proteinuria is associated with improved long‐term graft survival.

Urinary albumin excretion and the risk of graft loss and death in proteinuric and non-proteinuric renal transplant recipients

Background: Microalbuminuria and macroalbuminuria constitute risk factors for ESRD and death in non‐transplanted populations. Whether microalbuminuria (especially in non‐proteinuric patients) and macroalbuminuria constitute risk factors for graft loss and death is presently unknown in renal transplantation.

Respective Predictive Role of Urinary Albumin Excretion and Nonalbumin Proteinuria on Graft Loss and Death in Renal Transplant Recipients

Proteinuria is constituted by urinary albumin (UAE) and nonalbumin proteins (NAP). UAE was shown to predict ESRD and death. Whether NAP predicts graft or patient outcome is unknown in renal transplantation. We retrospectively analyzed the impact of UAE and NAP respectively on end‐stage renal disease (ESRD) and death in 616 renal transplant recipients. In subjects with proteinuria <0.25 g/day, 76% of urine proteins were NAP; in those with >1 g/day, 44% of the urine proteins were NAP. Determinants of UAE and NAP were partly different: fasting glucose, body weight, donor cause of death and cyclosporine were significantly associated with NAP (but not UAE); panel reactive antibodies (PRA) and rapamycine were significantly associated with UAE (but not with NAP). NAP expressed as a continuous (HR: per g/day: 4.00 [2.85–5.63], p < 0.0001) or a categorical (presence vs. absence, HR = 29.09[8.80–96.20], p < 0.0001) parameter and UAE (per g/day, HR = 1.86 [1.24–2.78], p < 0.0001) were risk factors for graft loss in univariate analyses. NAP remained significant even after adjustment on UAE. The presence of NAP (HR: 5.37 [2.55–11.34], p < 0.0001) and macroalbuminuria (HR: 4.12 [1.65–10.29], p = 0.0024) were risk factors for death. Proteinuria is made of various proportions of UAE and NAP in renal transplantation; these two parameters provide different information on graft/patient survival.

TRANSPLANT RENAL ARTERY STENOSIS: POTENTIAL ROLE OF ISCHEMIA/REPERFUSION INJURY AND LONG-TERM OUTCOME FOLLOWING ANGIOPLASTY

PURPOSE We assess long-term arterial pressure, renal function, and patient and graft survival in recipients of cadaveric kidney transplant with or without transplant renal artery stenosis. We also evaluate the risk factors for transplant renal artery stenosis. MATERIALS AND METHODS We reviewed and analyzed baseline clinical, immunological and outcome data for 26 patients with transplant renal artery stenosis before and after angioplasty, and 72 without stenosis on angiography. We also analyzed graft and patient survival in 304 cases in which angiography was not performed. RESULTS The incidence of transplant renal artery stenosis was 6.6% (26 of 402 patients). Acute rejection episodes (42 versus 22%, p <0.05) and delayed graft function (50 versus 32%, p <0.10) were more frequent, and mean cold ischemia time plus or minus standard error (29.2+/-1.7 versus 24.8+/-1.3 hours, p <0.01) was longer in patients with than without transplant renal artery stenosis. The technical success of angioplasty was 92.3%. Restenosis was documented in 6 of 26 patients (23.1%). Revascularization resulted in a decrease in arterial pressure and better renal function. The 8-year patient (100, 98.6 and 95.7%, respectively) and graft (88.1, 88.9 and 89.3%, respectively) actuarial survival rates were similar among patients with or without transplant renal artery stenosis, and those who did not undergo angiography. CONCLUSIONS Transplant renal artery stenosis had no detectable influence on long-term arterial pressure control, renal function, and patient and graft survival rates, which were similar to those in patients without stenosis. Long cold ischemia time may have a role in the development of transplant renal artery stenosis through ischemia/reperfusion injury.

Early Pulse Pressure and Low-Grade Proteinuria as Independent Long-Term Risk Factors for New-Onset Diabetes Mellitus After Kidney Transplantation

Risk factors for new‐onset diabetes after transplantation (NODAT) need to be assessed in large cohorts.

Immunosuppressive medications, clinical and metabolic parameters in new-onset diabetes mellitus after kidney transplantation.

New‐onset diabetes after transplantation (NODAT) is a growing concern in transplantation. All modifiable risk factors are not yet identified. We assessed the relationship between baseline clinical and biochemical parameters and NODAT. Eight‐hundred and fifty‐seven in‐Caucasian renal transplant recipients were included. Charts were individually reviewed. The follow‐up was 5.3 years (ranges: 0.25–20.8; 5613 patient‐years). The incidence of NODAT was 15.0%, 18.4% and 22.0% at 10, 15 and 20 years following transplantation. Age, body mass index (BMI), glucose (all P < 0.0001) and triglycerides [hazard ratio (HR) per 1 mmol/l: 1.44 [1.17–1.77], P = 0.0006] were potent risk factors whereas steroid withdrawal (HR: 0.69 [0.47–1.01], P = 0.0601) reduced the risk. As compared to cyclosporine, sirolimus (HR: 3.26 [1.63–6.49], P = 0.0008) and tacrolimus (HR: 3.04 [2.02–4.59], P < 0.0001) were risk factors for NODAT. The risk of NODAT was comparable for sirolimus (HR: 2.35 [1.06–5.19], P = 0.0350) and tacrolimus (HR: 2.34 [1.46–3.75], P = 0.0004) after adjustments on age, BMI, glucose and steroid withdrawal; however, unlike sirolimus, tacrolimus remained significant after adjustment on triglycerides. The risk of NODAT appeared similar, but its pathophysiology seemed different in sirolimus‐ and tacrolimus‐treated patients; this observation needs confirmation. However, main independent risk factors were age, BMI, initial glucose and triglycerides.

Association between a polymorphism in the human programmed death-1 (PD-1) gene and cytomegalovirus infection after kidney transplantation

Background Cytomegalovirus (CMV) infection is the most frequent infectious disease following organ transplantation. Strategies to prevent this infection remain a matter for debate, and discovering genetic risk factors might assist in adapting preventive strategies. By inhibiting IFNγ production, programmed death 1 (PD-1) has a crucial role in anti-CMV immune response. A single nucleotide polymorphism (SNP) within intron 4 of the gene (rs11568821), called PD-1.3, has recently been reported to be clinically relevant in several immune disorders. However, its association with CMV infection has never been reported. Methods In this study, the risk of CMV infection according to PD-1.3 genotype was investigated in 469 kidney graft recipients transplanted between 1995 and 2005. Results It was found that the A allele was associated with the risk of CMV infection in seropositive patients who did not receive CMV prophylaxis (OR=2.60, p=0.006). Multivariate analysis including other risk factors for CMV infection showed that this allele was independently associated with CMV infection (OR=2.54; p=0.010). Interestingly, combined analysis of PD-1.3 with the IL12B 3′UTR SNPs (previously shown to be associated with CMV infection) revealed that patients with the PD-1.3 A allele had a much higher risk of CMV infection compared to those having neither risk allele (OR=3.76; p=0.0003). Conclusion This study identified a new genetic risk factor for CMV infection after kidney transplantation and suggests that an adjustment of CMV prophylaxis based on genetic markers would merit further investigation.

Enalapril/amlodipine combination in cyclosporine-treated renal transplant recipients: a prospective randomized trial

Abstract:  Background:  Most hypertensive renal transplant recipients require two or more antihypertensive medications to achieve blood pressure control. However, which medications must be combined is still a matter of debate.

Renal resistive index as a new independent risk factor for new‐onset diabetes mellitus after kidney transplantation

Pulse pressure and urinary albumin excretion were recently identified as risk factors of new‐onset diabetes after renal transplantation (NODAT), suggesting that microvascular injury may be implicated in NODAT. However, the relationship between of microvascular injury and NODAT is unknown. In the present long‐term (median follow‐up: 5.7 years; observation period: 4908 patient‐years) retrospective study in 656 renal transplant recipients, the association between baseline renal resistance index (RI, used as a marker of widespread microvascular damage) and the incidence of NODAT was assessed. The incidence of NODAT was 11.2% and 14.6% at 5 and 10 years, respectively, after transplantation. RI at 3 months was a risk factor for NODAT [hazard ratio (HR) per 0.1: 2.19 (1.55–3.09), P < 0.0001]. RI >0.75 (vs. 0 ≤ 0.75) was a potent a predictor of NODAT [HR: 3.29 (1.91–5.67), P < 0.0001], even after adjustments [HR: 3.29 (1.50–7.24), P = 0.0030] on age, weight, glucose, nephropathy, and arterial pressure. Similar results were observed when RI was measured at 1 month [HR per 0.1:1.74 (1.33–2.27), P < 0.0001] and 12 months [HR per 0.1:1.74 (1.33–2.27), P < 0.0001] after transplantation. High RI early after renal transplantation is a long‐term risk factor for NODAT, and could be used to refine the individual risk of NODAT.

Routine Determination of GFR in Renal Transplant Recipients by HPLC Quantification of Plasma Iohexol Concentrations and Comparison With Estimated GFR

Estimated glomerular filtration rate (eGFR) methods are not sufficiently reliable in renal transplant recipients (RTR) and should be replaced by iohexol plasma clearance measurement. However, this method has poor availability in health centers. The aim of our study was to develop a high‐performance liquid chromatography (HPLC) method for plasma iohexol measurement in routine practice and to evaluate its plasma clearance as a reference of GFR. We developed an HPLC method using UV detection. We evaluated sample storage conditions to provide recommendations for routine practice. Then, we compared GFRbased on plasma iohexol clearance (GFR‐iohexol) to eGFR using modification of diet in renal disease, Cockcroft and Gault, and CDK‐EPIequations in 40 RTR. The method was validated over a concentration range of 15–300 μg/l. Excellent linearity (r > 0.998), inter‐ and intraday precision (CV < 3.3%), and accuracy (>96.8%) were complied with ICH guidelines. We also demonstrated excellent samples stability (9 days). Although eGFR methods are not references in RTR, we found a correct concordance between eGFR and GFR‐iohexol in our population. To conclude, our method is simple, rapid, accurate, and reliable for routine clinical and research use especially in RTR. J. Clin. Lab. Anal. 26:376‐383, 2012.