Estimated GFR in autosomal dominant polycystic kidney disease: errors of an unpredictable method.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) causes about 10% of cases of end stage renal disease. Disease progression rate is heterogeneous. Tolvaptan is presently the only specific therapeutic option to slow kidney function decline in adults at risk of rapidly progressing ADPKD with chronic kidney disease (CKD) stages 1-4. Thus, a reliable evaluation of kidney function in patients with ADPKD is needed. METHODS: We evaluated the agreement between measured (mGFR) and estimated glomerular filtration rate (eGFR) by 61 formulas based on creatinine and/or cystatin-C (eGFR) in 226 ADPKD patients with diverse GFR values, from predialysis to glomerular hyperfiltration. Also, we evaluated whether incorrect categorization of CKD using eGFR may interfere with the indication and/or reimbursement of Tolvaptan treatment. RESULTS: No formula showed acceptable agreement with mGFR. Total Deviation Index averaged about 50% for eGFR based on creatinine and/or cystatin-C, indicating that 90% of the estimations of GFR showed bounds of error of 50% when compared with mGFR. In 1 out of 4 cases with mGFR < 30 ml/min, eGFR provided estimations above this threshold. Also, in half of the cases with mGFR between 30 and 40 ml/min, formulas estimated values < 30 ml/min. CONCLUSIONS: The evaluation of renal function with formulas in ADPKD patients is unreliable. Extreme deviation from real renal function is quite frequent. The consequences of this error deserve attention, especially in rapid progressors who may benefit from starting treatment with tolvaptan and in whom specific GFR thresholds are needed for the indication or reimbursement. Whenever possible, mGFR is recommended.

A synergistic association of ACE I/D and eNOS G894T gene variants with the progression of immunoglobulin A nephropathy - a pilot study.

BACKGROUND: Individual variability in the natural history and response to therapy of immunoglobulin A nephropathy (IgAN) suggests a complex multifactorial pathogenesis. We investigated whether single nucleotide polymorphisms (SNPs) involved in the non-immunologic progression of renal disease are related with disease progression. METHODS: This is a pilot historic cohort study of 64 Caucasian patients with biopsy-proven IgAN and a median follow-up of 70 months. Three SNPs of the renin-angiotensin system genes (angiotensin I converting enzyme insertion/deletion (ACE I/D), angiotensinogen (AGT) M235T, and angiotensin II type 1 receptor (AT(1)R) 1166A/C), 2 of the endothelial nitric oxide synthase (eNOS), 4a/b and G894T, and 1 of the bradykinin 1 receptor, G-699C, were genotyped. The primary outcome was 'kidney survival' defined as a 30% decrease of baseline creatinine clearance; annualized decrease of glomerular filtration rate was also calculated. RESULTS: Proteinuria, histological lesions, and mean arterial pressure were related to an unfavorable outcome. The simultaneous presence of the DD and GG variants of the ACE and eNOS genes was related to an unfavorable outcome as compared with other combinations [hazard ratio ranging from 4.7 (95% CI 1.52-14.33) to 8.4 (95% CI 2.45-29.10)] after controlling for proteinuria, mean arterial pressure and baseline histological lesions. CONCLUSION: This study suggests that in our population with IgAN, an interaction between ACE and eNOS polymorphisms may be a prognostic factor for renal function deterioration.

The combined effect of pre-transplant triglyceride levels and the type of calcineurin inhibitor in predicting the risk of new onset diabetes after renal transplantation.

BACKGROUND: Insulin resistance precedes overt diabetes in the general population and hypertriglyceridemia is a reliable marker of the disorder. Thus, patients in the waiting list with hypertriglyceridemia may be at risk for new-onset diabetes after transplantation (NODAT). Objectives. We investigate whether pre-transplant triglyceride (TG) levels are a risk factor for NODAT and whether they exert a combined effect with the type of calcineurin inhibitor (CNI). METHODS: We analysed 314 consecutive non-diabetic recipients [215 cyclosporine A (CsA); 99 tacrolimus (Tacro)] transplanted between 1999 and 2003 with a mean follow-up of 34 months. Outcome was NODAT defined by ADA criteria. RESULTS: NODAT developed in 81 recipients (25.8%). Multivariate analysis which included a propensity score for factors determining CNI allocation showed that age (OR: 1.06; 95% CI: 1.03-1.09), pre-transplant BMI (OR: 1.1; 95% CI: 1.02-1.17),TG levels (OR: 1.3 per 50 mg/dl increment, 95% CI: 1.07-1.6) and treated acute rejection (OR: 4.8, 95% CI: 3-11), but not the type of CNI, were independent risk factors for NODAT. A significant interaction between pre-transplant TG and type of CNI was observed. Using CsA as the reference, the combination of Tacro plus pre-transplant hypertriglyceridemia (>/=200 mg/dl) showed an OR of 3.26 (1.4-7.8) to develop NODAT, contrasting with an OR of 0.75 (0.34-1.6) in Tacro recipients with pre-transplant TG levels <200 mg/dl. CONCLUSION: Pre-transplant hypertriglyceridemia was a risk factor for NODAT only in recipients treated with Tacro; it highlights the importance of pre-transplant insulin resistance in the pathogenesis of NODAT.

Glycated haemoglobin levels are related to chronic subclinical inflammation in renal transplant recipients without pre-existing or new onset diabetes.

BACKGROUND: C-reactive protein (CRP), a marker of chronic subclinical inflammation (CSI), is related to cardiovascular mortality in the general and renal transplant populations. In the general population, high CRP levels are associated with pre-diabetic glucose homeostasis alterations which may contribute to the proatherogenic effect of CSI. METHODS: We studied 134 consecutive renal transplant recipients without pre-existing or new onset diabetes. CRP, oral glucose tolerance test, insulin sensitivity and HbA1c were measured. RESULTS: Among CRP tertiles, fasting glucose and glucose after 120 min were not different. However, HbA1c was higher (4.9+/-0.6; 5.2+/-0.5; 5.4+/-0.5; P=0.005] and insulin sensitivity lower (McAuley index: 7.2+/-2; 6.8+/-2; 6.2+/-1.3; P=0.042) in the third CRP tertile. In addition, HDL-cholesterol was lower and triglycerides and body mass index (BMI) higher in the third tertile. Consequently, metabolic syndrome was more prevalent in the upper CRP tertiles [11 (25%); 19 (43%); 22 (50%); P=0.01). In multivariate analyses, HbA1c was related to higher CRP levels (standardized beta coefficient=0.21, P=0.013), independently of BMI (standardized beta coefficient=0.24, P=0.005) and triglycerides (standardized beta coefficient=0.18; P=0.03). CONCLUSIONS: Subclinical glucose homeostasis alterations are related to chronic inflammation in renal transplant recipients without pre-existing or new onset diabetes and may contribute to their high cardiovascular mortality.

Impact of metabolic syndrome on graft function and survival after cadaveric renal transplantation.

BACKGROUND: The prevalence and consequences of metabolic syndrome after renal transplantation are not well established. Our aims are to analyze in a historic cohort of consecutive renal transplant recipients without diabetes: (1) the prevalence of metabolic syndrome and its evolution to de novo posttransplantation diabetes mellitus (PTDM), and (2) its impact on graft function and graft and patient survival. METHODS: We studied 230 transplant recipients with stable graft function at 1 year (baseline) and at least 18 months of follow-up (assessment date). Metabolic syndrome is defined using the Adult Treatment Panel III criteria with a slight modification. RESULTS: Metabolic syndrome was present in 22.6% of transplant recipients at baseline, increasing to 37.7% at assessment date. Transplant recipients with metabolic syndrome at baseline more frequently developed PTDM during follow-up than those without metabolic syndrome (P < 0.001). In multiple linear regression analysis, metabolic syndrome was an independent risk factor for decreasing inverse serum creatinine (1/Cr) during follow-up (P = 0.038). In Cox proportional analysis, the hazard ratio for a 30% decrease in 1/Cr over time was 2.6 (95% confidence interval, 1.3 to 5.1; P = 0.005). Graft survival was significantly lower in the metabolic-syndrome group (P = 0.008) and remained significant in multivariate Cox analysis (hazard ratios, 3 to 4.5 in different models). Patient survival also was significantly lower in the metabolic-syndrome group (P = 0.02). CONCLUSION: Metabolic syndrome is a prominent risk factor for PTDM, chronic graft dysfunction, graft loss, and patient death in renal transplant recipients. Because metabolic syndrome is a cluster of modifiable factors, prompt intervention may prevent its consequences.

Clinical impact of preexisting vascular calcifications on mortality after renal transplantation.

BACKGROUND: Vascular calcifications (VC) are a well-known cardiovascular risk factor (CVRF) in uremic patients. However, their role on mortality after renal transplantation (RT) is unclear. METHODS: In 1117 RT recipients, we investigated the association between long-term survival and the presence of VC, evaluated by preoperative posteroanterior plain radiography from aorto-iliac region, at the time of RT. The primary study outcome was all-cause mortality. Other perioperative CVRF were also collected. RESULTS: VC were observed in 273 patients (24.4%) before RT; additionally, 132 (12%) patients died during follow-up, due, mainly, to cardiovascular (39%) or infectious (24%) complications. As expected, patients with VC showed a higher age and a greater number of CVRF than those without VC. Overall mortality rate was also higher in VC group (19 vs. 9.5%; P= 0.0001), as well as cardiovascular mortality (9.5 vs. 3.1; P= 0.048). Multivariate Cox model showed that VC were predictor of overall mortality [relative risk (RR) 1.8; 95% CI 1.1-2.8; P= 0.015] and cardiovascular mortality (RR 2.6; 95%CI 1.1-6); P= 0.033), independently of other CVRF. An interaction between the presence of VC and diabetes was found. The effect of VC on mortality was evident in nondiabetic patients, that is, those with VC had a significantly higher mortality rate than patients without VC (21 vs. 9%; P= 0.0001). By contrast, these differences were not observed in diabetic patients (16.5 vs. 14.3%; P= 0.656). CONCLUSION: VC evaluated by a simple and inexpensive plain radiography are an independent predictor of cardiovascular and all-cause mortality following RT. This finding may encourage the implementation of appropriate therapeutic strategies after RT.