Early diagnosis of chronic kidney disease in patients with diabetes in France: multidisciplinary expert opinion, prevention value and practical recommendations.

Diabetes is the leading cause of end-stage kidney disease (ESKD), accounting for approximately 50% of patients starting dialysis. However, the management of these patients at the stage of chronic kidney disease (CKD) remains poor, with fragmented care pathways among healthcare professionals (HCPs). Diagnosis of CKD and most of its complications is based on laboratory evidence. This article provides an overview of critical laboratory evidence of CKD and their limitations, such as estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), Kidney Failure Risk Equation (KFRE), and serum potassium. eGFR is estimated using the CKD-EPI 2009 formula, more relevant in Europe, from the calibrated dosage of plasma creatinine. The estimation formula and the diagnostic thresholds have been the subject of recent controversies. Recent guidelines emphasized the combined equation using both creatinine and cystatin for improved estimation of GFR. UACR on a spot urine sample is a simple method that replaces the collection of 24-hour urine. Albuminuria is the preferred test because of increased sensitivity but proteinuria may be appropriate in some settings as an alternative or in addition to albuminuria testing. KFRE is a new tool to estimate the risk of progression to ESKD. This score is now well validated and may improve the nephrology referral strategy. Plasma or serum potassium is an important parameter to monitor in patients with CKD, especially those on renin-angiotensin-aldosterone system (RAAS) inhibitors or diuretics. Pre-analytical conditions are essential to exclude factitious hyperkalemia. The current concept is to correct hyperkalemia using pharmacological approaches, resins or diuretics to be able to maintain RAAS blockers at the recommended dose and discontinue them at last resort. This paper also suggests expert recommendations to optimize the healthcare pathway and the roles and interactions of the HCPs involved in managing CKD in patients with diabetes.

Diabetic kidney disease versus non-diabetic kidney disease in type 2 diabetic patients on dialysis: An observational cohort.

BACKGROUND: All chronic kidney diseases in diabetic patients are not diabetic kidney diseases. The objective was to compare the clinical characteristics, survival and access to transplantation in diabetic patients starting dialysis and classified either as diabetic kidney disease (DKD) or non-diabetic kidney disease in diabetic patients (NDKD). METHODS: We used the nationwide French REIN registry to analyse baseline clinical characteristics at dialysis inception and outcomes defined as kidney transplantation, deaths and their causes. The probability of death or transplantation was analysed using a multivariate Cox model and the Fine and Gray competing for risk model (sdHT). RESULTS: We included 65,136 patients from January 2009 to December 2015 with a median follow-up of 31 months. The cumulative incidence of kidney transplantation over eight years was 46.9% (44.8-48.9) in non-diabetic patients (ND), higher than the 19.3% (17.5-21.2) in the DKD group and 22.2% (18.4-26.7) in the NDKD group. The risk of death was significantly higher in the NDKD group than in the DKD group, even after accounting for the competing risk of transplantation (NDKD/sdHR 1.22; 95%CI 1.18-1.27; p < 0.005 vs. DKD/sdHR 1.12; 95%CI 1.08-1.16; p < 0.005 with adjustment for age, sex, major adverse cardiovascular events, cancer and chronic respiratory failure, compared to ND). CONCLUSIONS: In diabetic patients starting dialysis, patients in the DKD group had reduced access to kidney transplantation. NDKD patients had a higher risk of mortality than DKD. The distinction between DKD and NDKD should be accounted for in the plan of care of diabetic patients starting dialysis.

Evaluation of a predictive model of end-stage kidney disease in a French-based cohort.

BACKGROUND: The risk of ESKD is highly heterogeneous among renal diseases, and risk scores were developed to account for multiple progression factors. Kidney failure risk equation (KFRE) is the most widely accepted, although external validation is scarce. The objective of this study was to evaluate the usefulness of this score in a French case-control cohort and test the pertinence of the proposed thresholds. METHODS: A retrospective case-control study comparing a group of patients starting renal replacement therapy (RRT) to a group of patients with CKD stages 3-5. Multivariate analysis to assess the predictors of ESKD risk. Discrimination of 4-, 6- and 8-variable scores using ROC curves and compared with eGFR alone and albumin/creatinine ratio (ACR) alone. RESULTS: 314 patients with a ratio of 1 case for 1 control. In multivariate analysis, increasing age and higher eGFR were associated with a lower risk of ESKD (OR 0.62, 95% CI 0.48-0.79; and OR 0.72, 95% CI 0.59-0.86, respectively). The log-transformed ACR was associated with a higher risk of ESKD (OR 1.25 per log unit, 95% CI 1.02-1.55). The 4-variable score was significantly higher in the RRT group than in the CKD-ND group, and was more efficient than the eGFR (AUROC 0.66, 95% CI 0.60-0.72, p = 0.018) and the log-transformed ACR (AUROC 0.63 95% CI 0.60-0.72, p = 0.0087) to predict ESKD. The 6-variable score including BP metrics and diabetes was not more discriminant as the 4-variable score. The 8-variable score had similar performance compared with the 4-score (AUROC 8-variable score: 0.70, 95% CI 0.64-0.76, p = 0.526). A 40% and 20% score thresholds were not superior to eGFR < 15 and 20 mL/min/1.73 m2, respectively. A 10% threshold was more specific than an eGFR < 30 mL/min/1.73 m2. CONCLUSION: KFRE was highly discriminant between patients progressing to ESKD vs those non-progressing. The 4-variable score may help stratify renal risk and referral in the numerous patients with stage 3 CKD. Conversely, the proposed thresholds for creating vascular access or preemptive transplantation were not superior to eGFR alone.

Effect of emergency start and central venous catheter on outcomes in incident hemodialysis patients: a prospective observational cohort.

BACKGROUND: Unfavorable conditions at hemodialysis inception reduce the survival rate. However, the relative contribution to outcomes of predialysis follow-up, symptoms, emergency start or central venous catheter (CVC) is unknown. METHODS: We analyzed the determinants of survival according to dialysis initiation conditions in the nationwide REIN registry, using two methods based either on clinical classification or data mining. We divided patients into four groups according to dialysis initiation (emergency vs planned, symptoms or not, previous follow-up). "Followed planned starters" began dialysis as outpatients and with an arteriovenous fistula (AVF). "Followed symptomatic non-urgent starters" were patients who started earlier because of any non-urgent symptomatic event. "Followed urgent starters" had seen a nephrologist before inception but started dialysis in an emergency condition. "Unknown urgent starters" were patients without any follow-up and who had a CVC at inception. RESULTS: "Followed urgent" starters had the lowest 2-year survival rate (66.8%) compared to "followed planned" (77.3%), "followed symptomatic non urgent" (79.2%), and "unknown urgent" (71.7%). Compared to other groups, the risk of mortality was lower in followed symptomatic non urgent (HR 0.86 95% CI 0.75-0.99) and higher in followed urgent starters (HR 1.05 (95% CI 0.94-1.18). In data mining Classification And Regression Tree regrouping in five categories, the lowest 2-year survival (52.3%) was in over 70-year-old starters with a CVC. The survival was 93.2% in under 57-year-old patients without active cancer, 82.5% in 57-70-year-old individuals without cancer, 72.4% in over 70-year-old patients without CVC and 61.4% in under 70-year-old subjects with cancer. The hazard ratio of data mining categories varied between 2.12 (95% CI 1.73-2.60) in 57-70-year-old subjects without cancer and 4.42 (95% CI 3.64-5.37) in over 70-year-old patients with CVC. Therefore, regrouping incident patients into five data mining categories, identified by age, cancer, and CVC use, could discriminate the 2-year survival in patients starting hemodialysis. CONCLUSIONS: Although each classification captured different prognosis information, both analyses showed that starting hemodialysis on a CVC has more dramatic outcomes than emergency start per se.

Prevalence of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis and Spatial Association With Quarries in a Region of Northeastern France: A Capture-Recapture and Geospatial Analysis.

OBJECTIVE: Silica is an environmental substance strongly linked with autoimmunity. The aim of this study was to assess the prevalence of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and renal limited vasculitis, in a northeastern region of France and to evaluate whether there was a geospatial association between the localization of quarries in the region and the prevalence of these AAVs. METHODS: Potential AAV patients were identified using 3 sources: hospital records, immunology laboratories, and the French National Health Insurance System. Patients who resided in the Alsace region of France as of January 1, 2016 and who fulfilled the American College of Rheumatology criteria for GPA or the 2012 Chapel Hill Consensus Conference definitions for GPA or MPA were included. Incomplete case ascertainment was corrected using a capture-recapture analysis. The spatial association between the number of cases and the presence of quarries in each administrative entity was assessed using regression analyses weighted for geographic region. RESULTS: Among 910 potential AAV patients, we identified 185 patients fulfilling inclusion criteria: 120 patients with GPA, 35 patients with MPA, and 30 patients with renal limited vasculitis. The number of cases missed by any source as estimated by capture-recapture analysis was 6.4 (95% confidence interval [95% CI] 3.6-11.5). Accordingly, the estimated prevalence in Alsace in 2016 was 65.5 GPA cases per million inhabitants (95% CI 47.3-93.0), 19.1 MPA cases per million inhabitants (95% CI 11.3-34.3), and 16.8 renal limited vasculitis cases per million inhabitants (95% CI 8.7-35.2). The risk of AAV was significantly increased in communities with quarries (odds ratio 2.51 [95% CI 1.66-3.80]), and geographic-weighted regression analyses revealed a significant spatial association between the proximity to quarries and the number of GPA cases (P = 0.039). In analyses stratifying the AAV patients by ANCA serotype, a significant association between the presence of quarries and positivity for both proteinase 3 ANCAs (P = 0.04) and myeloperoxidase ANCAs (P = 0.03) was observed. CONCLUSION: In a region with a high density of quarries, the spatial association between the presence of and proximity to quarries and the prevalence of AAVs supports the idea that silica may have a role as a specific environmental factor in this disease.

Impact of the dialysate acid component on haemodialysis mortality rates.

BACKGROUND: No prospective study has evaluated the long-term effect on mortality of the new acid concentrates added to bicarbonate dialysate. The aim of this pharmacoepidemiological study was to evaluate the association between hydrochloric or citric acid-based dialysate and mortality on haemodialysis (HD). METHODS: This study included 117 796 patients with 3 723 887 months on HD recorded in the national French Renal Epidemiology and Information Network registry. Dialysate acid components were retrospectively reconstructed for each facility. All patients on HD were associated each month with an exposure based on that at their facility of treatment. We took each patient's time-varying exposure into account to calculate the monthly mortality rates for each exposure. Incidence rate ratios (IRRs) for mortality were calculated with a Poisson regression, with acetic acid as the reference. Regressions were adjusted for initial clinical characteristics (age, gender, previous cardiovascular events, active malignancy, diabetes, pulmonary disease, mobility), dialysis technique and location (in-centre, outpatient centre, self-care unit) and ESRD vintage, updated monthly. RESULTS: The crude mortality rate per 1000 patient-months with citric acid {11.5 [95% confidence interval (CI) 11.1-12.0]} was lower than with either acetic acid [12.9 (95% CI 12.8-13.1)] or hydrochloric acid [12.8 (95% CI 12.2-13.5)]. For the 2014-17 period, the IRR for mortality with citric acid [adjusted IRR 0.94 (95% CI 0.90-0.99)] and with hydrochloric acid [adjusted IRR 0.86 (95% CI 0.79-0.94)] were significantly lower than with acetic acid. CONCLUSION: This post-marketing study of long-term exposure to dialysate acidifiers at the patient level found the use of citric and hydrochloric acid-based dialysates, compared with acetic acid, was associated with lower mortality.

CERA conversion to darbepoetin alfa in 154 hemodialysis patients.

PURPOSE: Anemia is a common complication in dialysis patients, usually treated with erythropoietin (EPO). Among available EPOs and analogs, continuous erythropoietin receptor activator (CERA) and darbepoetin alfa (DA) are the only two agents with a long duration of action, although they have almost never been formally compared in terms of efficacy. We took advantage of an accidental disruption in CERA supply to study the effect of its replacement with DA in the same patients. METHODS: The clinical and biological characteristics of 154 hemodialysis patients were retrospectively reviewed during the last 3 months on CERA compared to the first 4 months after replacement by DA, both ASE being administered by IV route. The comparison included EPO doses, hemoglobin levels, factors interfering with anemia (iron status assessment, iron doses, inflammation, quality of treatment) and was performed under the Bayesian paradigm. RESULTS: We found no significant differences between the two EPOs in terms of doses or hemoglobin concentrations. Factors that could potentially influence hemoglobin concentrations also did not differ under CERA or DA. The stability of hemoglobin was identical with both EPOs. We provide a conversion factor which allows comparison of cost according to local prices. CONCLUSIONS: We conclude that, in this observational "real life" study, the two EPOs are to be considered as equivalent.

Cardiovascular Safety and All-Cause Mortality of Methoxy Polyethylene Glycol-Epoetin Beta and Other Erythropoiesis-Stimulating Agents in Anemia of CKD: A Randomized Noninferiority Trial.

BACKGROUND AND OBJECTIVES: Erythropoiesis-stimulating agents correct anemia of CKD but may increase cardiovascular risk. We compared cardiovascular outcomes and all-cause mortality associated with monthly methoxy polyethylene glycol-epoetin beta with those of the shorter-acting agents epoetin alfa/beta and darbepoetin alfa in patients with anemia of CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a multicenter, open-label, noninferiority trial in which patients were randomized to receive methoxy polyethylene glycol-epoetin beta or reference erythropoiesis-stimulating agents, stratified by maintenance or correction treatment status and C-reactive protein level. The trial had a prespecified noninferiority margin of 1.20 for the hazard ratio (HR) for the primary end point (a composite of all-cause mortality, nonfatal myocardial infarction or stroke, adjudicated by an independent blinded committee). This trial is registered with ClinicalTrials.gov, number NCT00773513. RESULTS: In total, 2818 patients underwent randomization, received methoxy polyethylene glycol-epoetin beta or a reference agent, and were followed for a median of 3.4 years (maximum, 8.4 years). In the modified intention-to-treat analysis, a primary end point event occurred in 640 (45.4%) patients in the methoxy polyethylene glycol-epoetin beta arm, and 644 (45.7%) in the reference arm (HR 1.03; 95% confidence interval [95% CI], 0.93 to 1.15, P=0.004 for noninferiority). All-cause mortality was not different between treatment groups (HR 1.06; 95% CI, 0.94 to 1.19). Results in patient subgroups on dialysis or treated in the correction or maintenance settings were comparable to the primary analysis. CONCLUSIONS: In patients with anemia of CKD, once-monthly methoxy polyethylene glycol-epoetin beta was noninferior to conventional, shorter-acting erythropoiesis-stimulating agents with respect to rates of major adverse cardiovascular events or all-cause mortality.

French law: what about a reasoned reimbursement of serum vitamin D assays?

The number of serum 25-hydroxyvitamin D (25OHD) assays has increased tenfold in France in less than 10 years, sometimes for invalidated reasons. In 2013, the French National Authority for Health (Haute autorité de santé, or HAS) limited the indications for serum 25OHD measurements to rickets/osteomalacia, older adults with recurrent falls, monitoring of kidney transplant in adults, and surgical treatment of obesity in adults. Our aim here was to note that other indications for serum 25OHD measurements are supported by previous literature and by a number of national and international recommendations, in particular the following: any situation of bone fragility, any chronic renal failure <45 mL/min/1.73m2, any situation of malabsorption, clinical signs consistent with vitamin D deficiency or vitamin D overload, and calcium phosphorus evaluation. We suggest that the measurement of serum 25OHD concentration should remain reimbursed as part of these extended indications.

Mutation Update of the CLCN5 Gene Responsible for Dent Disease 1.

Dent disease is a rare X-linked tubulopathy characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressive renal failure, and variable manifestations of other proximal tubule dysfunctions. It often progresses over a few decades to chronic renal insufficiency, and therefore molecular characterization is important to allow appropriate genetic counseling. Two genetic subtypes have been described to date: Dent disease 1 is caused by mutations of the CLCN5 gene, coding for the chloride/proton exchanger ClC-5; and Dent disease 2 by mutations of the OCRL gene, coding for the inositol polyphosphate 5-phosphatase OCRL-1. Herein, we review previously reported mutations (n = 192) and their associated phenotype in 377 male patients with Dent disease 1 and describe phenotype and novel (n = 42) and recurrent mutations (n = 24) in a large cohort of 117 Dent disease 1 patients belonging to 90 families. The novel missense and in-frame mutations described were mapped onto a three-dimensional homology model of the ClC-5 protein. This analysis suggests that these mutations affect the dimerization process, helix stability, or transport. The phenotype of our cohort patients supports and extends the phenotype that has been reported in smaller studies.

Percutaneous cryoablation for tuberous sclerosis-associated renal angiomyolipoma with neoadjuvant mTOR inhibition.

BACKGROUND: Renal angiomyolipomas (AMLs) are frequent in tuberous sclerosis and are responsible for a significant proportion of the morbidity in adulthood, mainly from bleeding complications, which are correlated to the size of the AMLs. We describe the case of a 19-year-old female with multiple bilateral renal angiomyolipomas. CASE PRESENTATION: The renal AMLs measured up to 6 cm in size. She was first treated with a low dose of the mammalian target of rapamycin (mTOR) inhibitor sirolimus (up to 3 mg/day over a 12-month period) and following significant AML size reduction, percutaneous cryoablation was performed. No side-effects of either treatment were reported. At 12 months post-cryoablation, no recurrence of the AML was noted. CONCLUSION: This is the first report of this treatment strategy and the case study reveals that combining a low dose of an mTOR inhibitor with percutaneous cryoablation to treat small tumors mitigates the side-effects while providing a good clinical outcome. This therapeutic approach is a novel tool for the clinician involved in the management of patients with tuberous sclerosis.

Impaired platelet P2Y12 inhibition by thienopyridines in chronic kidney disease: mechanisms, clinical relevance and pharmacological options.

Patients with chronic kidney disease (CKD) represent an increasing proportion of the population undergoing percutaneous coronary intervention (PCI) and up to 40% of the patients treated for acute coronary syndrome (ACS). Several studies and registries in the setting of ACS and elective PCI have reported a negative association between CKD and mortality, stent thrombosis, post-procedural ischaemic events and bleeding events. Pharmacological inhibition of the adenosine diphosphate receptor by thienopyridines or ticagrelor and disruption of the cyclooxygenase pathway by aspirin constitute the current standards of care to prevent thrombotic complications following stent-based PCI. In CKD patients, the avoidance of anti-platelet therapy may be driven by the lack of clinical trial data to support its efficacy, by errors or omissions, or by a reluctance to use this therapy in a population characterized by its enhanced bleeding risk. However, there is growing evidence to suggest that a severely decreased glomerular filtration rate per se, independent of the presence of diabetes mellitus, is an important determinant of high residual platelet reactivity under a clopidogrel maintenance dose. Recent reports have emphasized that the impact of impaired platelet inhibition by thienopyridines is of paramount importance in CKD patients, with an enhanced mortality rate in low-responder patients. Pharmacodynamic studies indicate the phosphodiesterase 3 inhibitor, cilostazol, the third generation thienopyridine prasugrel and the reversible P2Y12 antagonist ticagrelor to be potent strategies to overcome this biological resistance. In clinical practice, platelet function testing should be considered in CKD patients undergoing PCI, especially in those who experience thrombotic events despite dual therapy. Newer agents should be contemplated in patients who display higher residual platelet aggregability after standard treatment. Among these, the non-thienopyridine P2Y12 receptor antagonist ticagrelor, which does not require biotransformation, could be the drug of choice in CKD patients with ACS. In this population, ticagrelor has been found to reduce mortality and ischaemic events with an acceptable bleeding risk.

Safety of meglumine gadoterate (Gd-DOTA)-enhanced MRI compared to unenhanced MRI in patients with chronic kidney disease (RESCUE study).

OBJECTIVE: To prospectively compare the renal safety of meglumine gadoterate (Gd-DOTA)-enhanced magnetic resonance imaging (MRI) to a control group (unenhanced MRI) in high-risk patients. METHODS: Patients with chronic kidney disease (CKD) scheduled for MRI procedures were screened. The primary endpoint was the percentage of patients with an elevation of serum creatinine levels, measured 72 ± 24 h after the MRI procedure, by at least 25 % or 44.2 µmol/l (0.5 mg/dl) from baseline. A non-inferiority margin of the between-group difference was set at -15 % for statistical analysis of the primary endpoint. Main secondary endpoints were the variation in serum creatinine and eGFR values between baseline and 72 ± 24 h after MRI and the percentage of patients with a decrease in eGFR of at least 25 % from baseline. Patients were screened for signs of nephrogenic systemic fibrosis (NSF) at 3-month follow-up. RESULTS: Among the 114 evaluable patients, one (1.4 %) in the Gd-DOTA-MRI group and none in the control group met the criteria of the primary endpoint [Δ = -1.4 %, 95%CI = (-7.9 %; 6.7 %)]. Non-inferiority was therefore demonstrated (P = 0.001). No clinically significant differences were observed between groups for the secondary endpoints. No serious safety events (including NSF) were noted. CONCLUSION: Meglumine gadoterate did not affect renal function and was a safe contrast agent in patients with CKD. KEY POINTS: • Contrast-induced nephropathy (CIN) is a potential problem following gadolinium administration for MRI. • Meglumine gadoterate (Gd-DOTA) appears safe, even in patients with chronic kidney disease. • Gd-DOTA only caused a temporary creatinine level increase in 1/70 such patients. • No case or sign of NSF was detected at 3-month follow-up.

Association of estimated GFR with platelet inhibition in patients treated with clopidogrel.

BACKGROUND: The reasons that decreased glomerular filtration rate (GFR) might alter the clinical efficacy of clopidogrel are poorly understood. STUDY DESIGN: In this study, we sought to evaluate whether decreased GFR alters platelet response to clopidogrel in patients receiving a maintenance dose of clopidogrel (75 mg/d for at least 8 days). SETTINGS & PARTICIPANTS: 126 consecutive patients categorized by estimated GFR: stages 1-2 (>60 mL/min/1.73 m(2); n = 29), stage 3a (45-59 mL/min/1.73 m(2); n = 21); stage 3b (30-44 mL/min/1.73 m(2); n = 26), stage 4 (15-29 mL/min/1.73 m(2); n = 14), and stage 5 (<15 mL/min/1.73 m(2); n = 36) were prospectively enrolled. PREDICTOR: Residual platelet reactivity, defined in the VASP (Vasodilator Stimulated Phosphoprotein) flow cytometry test as platelet reactivity index (PRI) ≥61% and in the VerifyNow turbidimetric-based assay as a value >235 PRU (adenosine diphosphate receptor reaction units) or percentage of platelet inhibition <15%. OUTCOMES: We examined factors associated with low response to clopidogrel using logistic regression. RESULTS: A significant relationship between estimated GFR, PRI, PRU, and percentage of inhibition was found. The prevalence of residual platelet reactivity was highest in patients with GFR stage 5. PRI ≥61% occurred in 52.8% of patients with stage 5 versus 30.8% of stage 3b and 24.1% of stages 1-2 (P = 0.1). PRU >235 was found in 63.6% of patients with stage 5 versus 36.8% of stage 3b and 17.2% of stages 1-2 (P = 0.005). Inhibition <15% affected 66.7% of patients with stage 5 versus 21.1% of stage 3b and 17.2% of stages 1-2 (P < 0.001). In the multivariable model, GFR stage 5 (adjusted prevalence ratio [PR], 3.10; 95% CI, 1.23-9.43; P = 0.02), and obesity (adjusted PR, 1.92; 95% CI, 1.34-2.23; P = 0.004) were the sole predictors of residual platelet reactivity. LIMITATIONS: Interference of hemodialysis with the pharmacokinetics of clopidogrel could not be excluded. CONCLUSION: GFR stage 5 is associated with substantial impairment of platelet inhibition independently of diabetes mellitus.

[Hypertensive nephrosclerosis]. / Néphroangiosclérose.

Hypertensive nephrosclerosis is the leading cause of end stage renal disease (ESRD) in France, however, in prospective clinical trials of hypertension, ESRD accounts only for a small fraction of all events (incidence rate 0.2 to 0.4% by year). Hypertensive nephrosclerosis is characterized histologically by a series of vascular injury, none of which is truly specific and that can be observed also in obesity or normal aging. Hypertensive nephrosclerosis is mildly symptomatic, but the prognosis is never benign, due to cardiovascular and renal burden. This unspecific presentation may explain why the diagnosis of hypertensive nephrosclerosis is easily carried by excess, the main differential diagnoses are atherosclerotic ischemic renal disease, poorly symptomatic primitive nephropathies or the sequelae of unnoticed malignant hypertensive nephrosclerosis. The very high prevalence of hypertensive nephrosclerosis in populations from African ancestry has suggested a genetic predisposition. MYH9/APOL1 gene variants have recently been identified and are strongly associated with hypertensive nephrosclerosis, however the pathophysiological link between these variants and renal disease is still unclear. The treatment is mainly based on blocking the renin angiotensin system, especially when proteinuria is present. The target blood pressure is less firmly established, the latest data from the AASK study, however, do suggest a benefit on progression of lower values < 135/80 or even < 130/80 mmHg, especially in patients with proteinuria.

Simultaneous development of lymphoma in recipients of renal transplants from a single donor: donor origin confirmed by human leukocyte antigen staining and microsatellite analysis.

BACKGROUND: Posttransplant lymphoproliferative disorders (PTLD) occur in 0.5% to 2.5% of cases in renal-transplant recipients. Epstein-Barr virus (EBV) is usually detected in the tumor cells, suggesting a role for this virus as an agent of B-cell proliferation. It is unusual for patients receiving allografts from the same donor to develop PTLD simultaneously. METHODS: we describe two patients who received renal allografts from the same donor and developed PTLD simultaneously. The presence of EBV in both tumors was confirmed. In this report, the origin of tumor cells was determined by immunohistochemical human leukocyte antigen (HLA) typing and microsatellite analysis. Clonality was studied by immunoglobulin gene rearrangement analysis. RESULTS: Our results suggest that the tumor originated from donor cells in both patients but, because immunoglobulin gene rearrangements were different, this could mean that lymphoid cells proliferate independently in each recipient. CONCLUSIONS: We propose the following pathogenesis: immortalization of passenger B lymphocytes by EBV, proliferation of these cells, and development of PTLD by means of immunosuppression, antigenic stimulation, and HLA mismatch.

Comparison of cystatin C, creatinine and creatinine clearance vs. GFR for detection of renal failure in renal transplant patients.

BACKGROUND: Serum cystatin C (Scyst) has been suggested as an alternative index of glomerular filtration rate (GFR) and could be useful in renal transplant patients. METHODS: In a 60-subject cohort (40 +/- 12 years old), we compared the simultaneous measurements of Scyst, serum creatinine (Screat), creatinine clearance (Ccreat), Cockcroft and Gault's estimated clearance (Ccg) and GFR measured using inulin clearance (Cin). Receiver operating characteristic (ROC) analysis was performed using two Cin cut-off (60 and 90 mL/min/1.73 m2). RESULTS: A significant correlation was found among Cin on one hand and 1/Scyst, Ccreat, 1/Screat and Ccg on the other hand. Best fits (sensitivity/specificity) at 90 mL/min/1.73 m2 were 1.18 mg/L (0.72/0.80) for Scyst, 1.32 mg/dL (0.67/0.90) for Screat, 77 mL/min (0.80/0.70) for Ccg and 104 mL/min (0.88/0.80) for Ccreat. The areas under the ROC curves were not significantly different. CONCLUSIONS: This study provides cut-off values for Screat and Ccg for detection of renal failure in renal transplant patients. However, the results also suggest that Scyst is not a more sensitive marker than Screat or Ccg for detecting renal failure in renal transplant patients.

Hormonal, renal, hemodynamic responses to acute neutral endopeptidase inhibition in heart transplant patients.

We investigated the hemodynamic, renal, and hormonal responses to neutral endopeptidase (NEP) inhibition during a 6-h, double-blind, randomized, placebo-controlled study in seven chronic, stable heart transplant patients. Baseline characteristics were similar during both experiments, and no significant changes were observed after placebo. NEP inhibition increased circulating endothelin-1 (from 2.01 +/- 0.1 to 2.90 +/- 0.2 pmol/l; P < 0.01), atrial natriuretic peptide (ANP; from 21.5 +/- 2.7 to 29.6 +/- 3.7 pmol/l; P < 0.01), and the ANP second messenger cGMP. Noteworthy, systemic blood pressure did not increase. Renal plasma flow and glomerular filtration rate remained unmodified after NEP inhibition. Filtration fraction (33 +/- 13%), diuresis (196 +/- 62%), and natriuresis (315 +/- 105%) increased significantly in relation to ANP and cGMP. A strong inverse relationship was observed between excreted cGMP and sodium reabsorption (r = -0.71, P < 0.0001). Thus, despite significantly increasing endothelin-1, NEP inhibition did not adversely influence systemic or renal hemodynamics in transplant patients. ANP, possibly through a tubular action, enhances the natriuresis observed after NEP inhibition.