Beatriz Bayés

Disseminated varicella infection in adult renal allograft recipients: role of mycophenolate mofetil

Disseminated varicella zoster virus (VZV) infection is a rare complication after renal transplantation in adults. We report 4 cases diagnosed in our transplant patients. One of which was a primary infection (chicken pox) with multivisceral involvement (hepatitis, pneumonitis, myocarditis, and disseminated intravascular coagulation). The other 3 patients VZV-seropositive before transplantation suffered from disseminated zoster. No immunosuppressive drug was significantly associated with a higher risk of disseminated VZV infection. However, from our experience, we believe that mycophenolate mofetil (MMF), plays a part in the clinical presentation of the disease. Early treatment with high doses of acyclovir is fundamental in infection control. It is essential to perform a pretransplantation serological VZV study on all patients.

Prediabetes in patients receiving tacrolimus in the first year after kidney transplantation: a prospective and multicenter study.

Background. Tacrolimus-based immunosuppression, the most widely used regimen in kidney transplantation, increases the risk of new onset diabetes after transplantation (NODAT). However, the prevalence, evolution and risk factors of different prediabetic alterations: impaired fasting glucose, impaired glucose tolerance, and provisional diabetes, have not been established. Methods. In this multicenter and prospective study we evaluated 154 nondiabetic kidney transplant recipients receiving tacrolimus, mycophenolate mofetil and low dose steroids. An oral glucose tolerance test was performed 3 and 12 months after transplantation and prediabetes was defined by American Diabetes Association criteria. Results. Prediabetes was highly prevalent and showed little variation between 3 and 12 months (36% and 33%, respectively). Impaired glucose tolerance was the most frequent abnormality observed (23% and 25%, respectively) observed. In addition, 20% of recipients showed NODAT by 1 year. Multivariate analysis showed that age (odds ratio [OR]: 1.07, 95% confidence interval [CI]: 1.004–1.14), pretransplant body mass index (OR: 1.3, CI: 1.09–1.6) and triglyceride/high density lipoprotein-cholesterol ratio, a marker of insulin resistance, (OR: 1.4, CI: 1.05–1.9) were independent risk factors for prediabetes. Conclusion. One in two recipients with tacrolimus-based immunosuppresion showed prediabetes or NODAT by 1 year posttransplantation when properly investigated. Older age and high pretransplant body mass index and triglyceride/high density lipoprotein-cholesterol ratio were risk factors for prediabetes. These findings may help applying early interventions to prevent the disorder.

Is there a need for changes in renal biopsy criteria in proteinuria in type 2 diabetes

Criteria for renal biopsy in proteinuric type 2 diabetes mellitus (T2DM) patients have been not defined. Usually criteria for renal biopsy in type 1 diabetes mellitus (T1DM) are used (microhaematuria, absence of diabetic retinopathy (DR), uncharacteristic change in renal function or immunological abnormalities). The aim of this study was to reconsider the indications for renal biopsy in T2DM using T1DM criteria, to determine whether they are useful in identifying patients with potentially treatable lesions. We studied 127 proteinuric patients with T2DM. Renal biopsy was performed in 35 who met the criteria for biopsy. Biopsy revealed diabetic glomerulopathy (DG) in 29 (83%) (in three associated with nondiabetic renal disease), immunoglobulin A (IgA) glomerulonephritis in three, focal glomerulosclerosis in one and normal glomeruli in two. DG was diagnosed in 17 (74%) of the patients without DR, in 18 (78%) of the patients with microhaematuria and in 10 (67%) of the patients with microhaematuria and without DR. All patients with DR had DG alone, except three with sudden unexpected changes in renal function. We conclude that DG is the most commonly found renal lesion in T2DM patients with proteinuria biopsied according to T1DM criteria, even in patients with microhaematuria or without retinopathy. Thus, these biopsy criteria are not useful in identifying patients with potentially treatable other renal diseases.

Adiponectin and risk of new-onset diabetes mellitus after kidney transplantation.

Background. New-onset diabetes mellitus after transplantation (NODAT) is a severe complication of kidney transplantation (KTx) with negative effects upon patient and graft survival. Several risk factors for NODAT have been described; however, the search for an early predictive marker is ongoing. It has recently been demonstrated that high concentrations of adiponectin (APN), which is an adipocyte-derived peptide with antiinflammatory and insulin-sensitizing properties, protect against future development of type 2 diabetes in healthy individuals. The purpose of this report was to study pretransplant insulin resistance and analyze pretransplant serum leptin and APN levels as independent risk factors for the development of NODAT. Methods. A total of 68 KTx patients were studied [mean age, 48±11 years; 70% males; body mass index (BMI), 25±3 kg/m2]; 31 KTx patients with NODAT and 37 KTx patients without NODAT (non-NODAT) with similar age, sex, BMI, immunosuppression, and posttransplant time were studied. All patients received prednisone and calcineurin inhibitors (75% tacrolimus and 25% cyclosporine A), and 76% of patients received mycophenolate mofetil. Family history of diabetes mellitus was recorded. Pretransplant homeostasis model assessment for insulin resistance (HOMA-IR) index was calculated from fasting plasma glucose and insulin. Pretransplant serum leptin and APN levels were determined by radioimmunoassay. Results. NODAT patients showed higher pretransplant plasma insulin concentrations [NODAT, 13.4 (11–22.7) &mgr;IU/mL; non-NODAT, 10.05 (7.45–18.4) &mgr;IU/mL; P=0.049], HOMA-IR index [NODAT, 4.18 (2.49–5.75); non-NODAT, 2.63 (1.52–4.68); P=0.043], and lower pretransplant serum APN concentration [NODAT, 8.78 (7.2–11.38) &mgr;g/mL; non-NODAT, 11.4 (8.56–15.27) &mgr;g/mL, P=0.012]. Inverse correlations between APN and BMI (r=−0.33; P=0.014) and APN and HOMA-IR index (r=−0.39; P=0.002) and between APN and NODAT (r=−0.31; P=0.011) were observed. Multiple logistic regression analysis showed the patients with lower pretransplant APN concentrations to be those at greater risk of developing NODAT [Odds Ratio=0.832 (0.71–0.96); P=0.01]. Conclusion. Pretransplant serum APN concentration is an independent predictive factor for NODAT development in kidney-transplanted patients.

Obesity, inflammation, and kidney disease

Obesity and extreme obesity are associated with a wide range of well known comorbidities (cardiovascular disease, dyslipidemia, hypertension, diabetes mellitus, metabolic syndrome). Recently, the association between obesity and renal involvement has been accepted since several epidemiological and pathological studies support this relationship. However, the physiopathological mechanism of this association is not completely understood. Different mechanisms have been implicated in the production of these renal lesions. Between them, metabolic alterations and inflammatory adipocytokines have been suggested. This paper is a review of the association between inflammatory adipocytokines or metabolic syndrome with renal involvement. We also briefly report our experience in a cohort of extremely obese patients.

Pretransplant pregnancy-associated plasma protein-A as a predictor of chronic allograft nephropathy and posttransplant cardiovascular events

Background. Cardiovascular disease and chronic allograft nephropathy (CAN) are two of the main complications observed in patients after renal transplantation. Both appear to be manifestations of the same process, in which inflammation plays a determinate role. Pregnancy-associated plasma protein A (PAPP-A) has been shown to be a marker of acute coronary syndrome and cardiovascular pathology. The objective of this study was to demonstrate whether or not serum concentration of pretransplant PAPP-A is a marker of CAN and a predictor of posttransplant cardiovascular events. Methods. In all, 178 renal transplants (65% males; 53±12 years of age) followed up over the course of 49.3±33.6 months were used in this study. During the follow-up period, 19 patients developed CAN (diagnosed by renal biopsy) and 27 patients had a cardiovascular event. Previous to transplantation, the following were determined: ultrasensitive C-reactive protein (CRP) (nephelometry); interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) (immunofluorimetric automatized method), and ultrasensitive PAPP-A (ELISA). Results. A positive correlation was found between PAPP-A and the inflammatory markers (PAPP-A vs. CRP, r=0.218; P=0.004; PAPP-A vs. IL-6, r=0.235; P<0.001; PAPP-A vs. TNF-α, r=0.372; P<0.001). The multiple regression analysis showed PAPP-A (relative risk [RR]: 6.4; 95% confidence interval [CI]:1.24-33.11; P=0.027) and CRP (RR: 6.05; 95% CI:1.21-29.74; P=0.028) to be predictors of posttransplant cardiovascular events and PAPP-A (RR: 4.27; 95% CI: 1.03-17.60; P=0.044) and TNF-α (RR: 5.6; 95% CI: 1.43-21.83; P=0.013) to be predictors of CAN. Conclusions. PAPP-A correlated with the inflammatory markers studied (CRP, IL-6 and TNF-α). Pretransplant serum concentration of PAPP-A is a predictor of posttransplant cardiovascular events and CAN.

Validation of estimated renal function measurements compared with the isotopic glomerular filtration rate in an HIV-infected cohort

We performed a cross-sectional study to determine the best method for estimating the glomerular filtration rate (GFR) in HIV-infected subjects. Isotopic GFR was correlated with 24-h urine creatinine clearance, cystatin C levels, and 3 creatinine-based equations-the Modification of Diet in Renal Disease (MDRD), Cockcroft-Gault (CG), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)-in 15 patients. Cystatin C showed the strongest correlation with isotopic GFR (r=-0.760, p=0.001). When cystatin C was used as the reference variable for all 106 patients, CKD-EPI proved to be superior to the other equations (r=-0.671, p<0.001). Time with HIV infection, unsuppressed viral load, low CD4 T-cell counts, and use of protease inhibitors are related to an increased risk of renal impairment, leading us to recommend early initiation of antiretroviral therapy accompanied by a regular renal study.

Unmasking Glucose Metabolism Alterations in Stable Renal Transplant Recipients: A Multicenter Study

BACKGROUND AND OBJECTIVES Emerging information indicates that glucose metabolism alterations are common after renal transplantation and are associated with carotid atheromatosis. The aims of this study were to investigate the prevalence of different glucose metabolism alterations in stable recipients as well as the factors related to the condition. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A multicenter, cross-sectional study was conducted of 374 renal transplant recipients without pre- or posttransplantation diabetes. A standard 75-g oral glucose tolerance test was performed. RESULTS Glucose metabolism alterations were present in 119 (31.8%) recipients: 92 (24.6%) with an abnormal oral glucose tolerance test and 27 (7.2%) with isolated impaired fasting glucose. The most common disorder was impaired glucose tolerance (17.9%), and an abnormal oral glucose tolerance test was observed for 21.5% of recipients with a normal fasting glucose. By multivariate analysis, age, prednisone dosage, triglyceride/high-density lipoprotein cholesterol ratio, and beta blocker use were shown to be factors related to glucose metabolism alterations. Remarkably, triglyceride levels, triglyceride/high-density lipoprotein cholesterol ratio, and the proportion of recipients with impaired fasting glucose were already higher throughout the first posttransplantation year in recipients with a current glucose metabolism alteration as compared with those without the condition. CONCLUSIONS Glucose metabolism alterations are common in stable renal transplant recipients, and an oral glucose tolerance test is required for its detection. They are associated with a worse metabolic profile, which is already present during the first posttransplantation year. These findings may help planning strategies for early detection and intervention.

Uromodulin and α1-Antitrypsin Urinary Peptide Analysis to Differentiate Glomerular Kidney Diseases

Background/Aims: Glomerular kidney disease (GKD) is suspected in patients based on proteinuria, but its diagnosis relies primarily on renal biopsy. We used urine peptide profiling as a noninvasive means to link GKD-associated changes to each glomerular entity. Methods: Urinary peptide profiles of 60 biopsy-proven glomerular patients and 14 controls were analyzed by combining magnetic bead peptide enrichment, MALDI-TOF MS analysis, and ClinProTools v2.0 to select differential peptides. Tentative identification of the differential peptides was carried out by HPLC-MS/MS. Results: The HPLC-MS/MS results suggest that uromodulin (UMOD; m/z: 1682, 1898 and 1913) and α1-antitrypsin (A1AT; m/z: 1945, 2392 and 2505) are differentially expressed urinary peptides that distinguish between GKD patients and healthy subjects. Low UMOD and high A1AT peptide abundance was observed in 80–92% of patients with GKD. Proliferative forms of GKD were distinguished from nonproliferative forms, based on a combination of UMOD and A1AT peptides. Nonproliferative forms correlated with higher A1AT peptide levels – focal segmental glomerulosclerosis was linked more closely to high levels of the m/z 1945 peptide than minimal change disease. Conclusion: We describe a workflow – urinary peptide profiling coupled with histological findings – that can be used to distinguish GKD accurately and noninvasively, particularly its nonproliferative forms.

Posttransplant Inflammation Associated With Onset of Chronic Kidney Disease

BACKGROUND Chronic allograft nephropathy (CAN), a major complication in renal transplant patients, is an important cause of graft loss. Inflammation as measured in the pretransplant and posttransplant phases, using various markers, has been associated with worse renal function and a greater risk of cardiovascular disease and of long-term graft loss. OBJECTIVE The objective of our study was to evaluate whether worsening inflammation in the first 3 months postoperatively was a risk factor for developing CAN. PATIENTS AND METHODS We performed a cross-sectional study in 207 patients. The following markers of inflammation (MIF) were determined pretransplant and at 3 months after grafting: C-reactive protein (CRP) (mg/L), interleukin (IL)-6 (pg/mL), IL-10 (pg/mL), tumor necrosis factor (TNF)-α (pg/mL), and its soluble receptor (ng/mL), soluble-IL2R (UI/mL), pregnancy-associated plasma protein A (PAPP-A; mUI/L), and IL-4 (pg/mL). We also calculated the ratio at 3 months versus the pre value of MIF. RESULTS CAN was diagnosed after the first year in 23 patients (11.3%) always by renal biopsy performed for clinical indications. Patients with CAN showed worse inflammation, eg, MIF ratios over one, with statistically significant differences for the ratios of TNF-α and PAPP-A (P=.032 and P=.051 respectively). Upon multivariate logistic regression analysis, using CAN as the dependent variable and age, sex, donor age, months on dialysis, acute tubular necrosis, acute rejection, and MIF ratios as covariates, we observed that an acute rejection episode (OR=13.03; CI=2.8-60.9; P=.001), CRP ratio (OR=1.36; CI=1.07-1.73; P=.013), and PAPP-A ratio (OR=1.80; CI=0.92-3.53; P=.005) were independent markers of CAN. CONCLUSIONS Among other factors, inflammation may determine the onset of CAN as diagnosed by renal biopsy.