Autosomal Dominant Tubulointerstitial Kidney Disease: Clinical Presentation of Patients With ADTKD-UMOD and ADTKD-MUC1.

RATIONALE & OBJECTIVE: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare underdiagnosed cause of end-stage renal disease (ESRD). ADTKD is caused by mutations in at least 4 different genes: MUC1, UMOD, HNF1B, and REN. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 56 families (131 affected individuals) with ADTKD referred from different Spanish hospitals. Clinical, laboratory, radiologic, and pathologic data were collected, and genetic testing for UMOD, MUC1, REN, and HNF1B was performed. PREDICTORS: Hyperuricemia, ultrasound findings, renal histology, genetic mutations. OUTCOMES: Age at ESRD, rate of decline in estimated glomerular filtration rate. RESULTS: ADTKD was diagnosed in 25 families (45%), 9 carried UMOD pathogenic variants (41 affected members), and 16 carried the MUC1 pathogenic mutation c.(428)dupC (90 affected members). No pathogenic variants were identified in REN or HNF1B. Among the 77 individuals who developed ESRD, median age at onset of ESRD was 51 years for those with ADTKD-MUC1 versus 56 years (P=0.1) for those with ADTKD-UMOD. Individuals with the MUC1 duplication presented higher risk for developing ESRD (HR, 2.24; P=0.03). The slope of decline in estimated glomerular filtration rate showed no significant difference between groups (-3.0mL/min/1.73m2 per year in the ADTKD-UMOD group versus -3.9mL/min/1.73m2 per year in the ADTKD-MUC1 group; P=0.2). The prevalence of hyperuricemia was significantly higher in individuals with ADTKD-UMOD (87% vs 54%; P=0.006). Although gout occurred more frequently in this group, the difference was not statistically significant (24% vs 7%; P=0.07). LIMITATIONS: Relatively small Spanish cohort. MUC1 analysis limited to cytosine duplication. CONCLUSIONS: The main genetic cause of ADTKD in our Spanish cohort is the MUC1 pathogenic mutation c.(428)dupC. Renal survival may be worse in individuals with the MUC1 mutation than in those with UMOD mutations. Clinical presentation does not permit distinguishing between these variants. However, hyperuricemia and gout are more frequent in individuals with ADTKD-UMOD.

Posttransplant Lymphoproliferative Disease and Inhibitors of Mammalian Target of Rapamycin: When a Quick Look Back Can Change the Perspective.

Posttransplant lymphoproliferative disease represents a heterogeneous group of diseases characterized by uncontrolled proliferation of lymphocytes, favored by immunosuppression. Several risk factors for its development have been described, with Epstein-Barr virus infection being a main cause of early-onset forms and chronic antigen stimulation of donors and/or accumulated immunosuppression as key factors of later forms of lymphocyte transformation. The present clinical case presents a patient diagnosed with posttransplant lymphoproliferative disease 3 years after renal transplant who had a potentially lethal complication related to conversion to inhibitors of mammalian target of rapamycin. Because clinical studies that establish the most suitable treatment are lacking, it is recommended to identify the strategy, defining possible risks versus benefits of conversion to inhibitors of mammalian target of rapamycin in cases of posttransplant lymphoproliferative disease, and to maintain a high level of surveillance in case of possible secondary effects that can be verified after their introduction.

Adjustment of Eculizumab Dosage Pattern in Patients with Atypical Hemolytic Uremic Syndrome with Suboptimal Response to Standard Treatment Pattern.

In patients with atypical hemolytic uremic syndrome (aHUS), complement blocking by eculizumab rapidly halts the process of thrombotic microangiopathy and it is associated with clear long-term hematologic and renal improvements. Eculizumab treatment consists of a 4-week initial phase with weekly IV administration of 900 mg doses, followed by a maintenance phase with a 1,200 mg dose in the fifth week and every 14 ± 2 days thereafter. We present three patients with aHUS and suboptimal response to eculizumab treatment at the usual administration dosage who showed hematologic and renal improvements after an adjustment in the eculizumab treatment protocol.

Oxidative stress markers in predicting response to treatment with ferric carboxymaltose in nondialysis chronic kidney disease patients.

BACKGROUND: Nearly half of all non-dialysis chronic kidney disease (CKD) patients respond to iron therapy. Factors affecting anemia response to iron therapy are not well characterized. Oxidative stress (OS) is a recognized factor for anemia in CKD and promotes erythropoiesis stimulating agent (ESA) resistance; however, the influence in predicting response to intravenous (IV) iron has not been evaluated. METHODS: Patients (n = 47) with non-dialysis CKD stages 3 - 5 (mean eGFR: 26 ± 10.4 mL/min/1.73 m2) and iron-deficiency anemia (hemoglobin < 11 g/dL, transferrin saturation (TSAT) index < 20%, and/or ferritin < 100 ng/mL) received a single injection of 1,000 mg of ferric carboxymaltose (FCM) and were observed for 12 weeks. Based on erythropoietic response (defined as ≥ 1 g/dL increase in hemoglobin level), patients were classified as responders or non-responders. Baseline conventional markers of iron status (TSAT and ferritin), inflammatory markers (C-reactive protein and IL-6), OS markers (oxidized LDL, protein carbonyl groups, erythrocyte superoxide dismutase, and glutathione peroxidase (GPx)), and catalase activity were measured. RESULTS: FCM resulted in a significant increase in hemoglobin, TSAT, and ferritin (10 ± 0.7 vs. 11.4 ± 1.3 g/dL, p < 0.0001; 14.6 ± 6.4% vs. 28.9 ± 10%, p < 0.0001; 67.8 ± 61.7 vs. 502.5 ± 263.3 ng/dL, p < 0.0001, respectively). Responders and non-responders were 34 (72%) and 13 (28%), respectively. Age, baseline hemoglobin, estimated glomerular filtration rate, parathyroid hormone, and use of ESA or angiotensin-modulating agents were similar in both groups. Responders showed a tendency towards lower TSAT than non-responders (13.6 ± 6.5% vs. 17.2 ± 5.6%, p = 0.06) but similar ferritin levels. Inflammatory markers were similar in both groups. eGPx activity was lower in non-responders compared to responders (103.1 ± 50.9 vs. 144.9 ± 63.1 U/g Hb, p = 0.01, respectively), although the other proteins, lipid oxidation markers, and enzymatic antioxidants did not differ between the two groups. In the multivariate adjusted model, odds (95% CI) for achieving erythropoietic response to FCM were 10.53 (1.25 - 88.16) in the third tertile of eGPX activity and 3.20 (0.56 - 18.0) in the second tertile compared to those in the lowest tertiles (p = 0.02). CONCLUSIONS: Decreased eGPx activity has adverse influences on response to FCM, suggesting that impaired erythrocyte antioxidant defense may be involved in the response to iron therapy in CKD patients.

Oxidative stress and other risk factors for white matter lesions in chronic hemodialysis patients.

BACKGROUND: Chronic kidney disease (CKD) is a risk factor for cardiovascular disease and promotes oxidative tress (OS), which has been implicated in the pathogenesis of white matter lesions (WML), a form of small-vessel cerebrovascular disease. The relationship between OS and WML in chronic hemodialysis (HD) patients has not yet been studied. METHODS: We studied 67 chronic HD patients, aged 40 - 65 years (average 54 years) without known cerebrovascular disease. All patients underwent brain magnetic resonance imaging and subcortical and periventricular WML were evaluated using semiquantitative measures. Patients were classified into two groups depending on the presence or absence of WML (Fazekas classification), and the WML were scored. Carotid ultrasonography was also performed to evaluate the presence of carotid artery plaques and/or stenosis. Markers of protein and lipid oxidation (protein carbonyl and oxLDL antibodies), the glutathione system, enzymatic antioxidants (superoxide dismutase, glutathione peroxidase, glutathione reductase and catalase) and total antioxidant capacity (ORAC) were measured. OS markers were compared to those of a group of 36 healthy subjects. RESULTS: WML were present in 54% of the total population. Patients who had WML were older and had lower predialysis diastolic blood pressure than patients without WML. Other potential cardiovascular risk factors for WML, including obesity, hyperlipidemia, diabetes mellitus, presence of carotid artery plaques or stenosis, and duration and adequacy of HD were not related to the presence of WML. Compared to controls, HD patients had increased OS and decreased antioxidant capacity. However, OS did not differ between patients with WML and those without, and we found no association between OS markers and mean WML scores. After adjusting for several factors, only age and low predialysis diastolic blood pressure independently predicted an increased risk of WML. CONCLUSIONS: Our results confirm that chronic HD patients have increased OS, but this is not related to the presence or severity of WML.

Acute and sub-acute effect of ferric carboxymaltose on inflammation and adhesion molecules in patients with predialysis chronic renal failure.

BACKGROUND: Treatment with parenteral iron causes oxidative stress, inflammation and endothelial dysfunction. Ferric carboxymaltose (FCM) is a new preparation of non-dextran iron which, due to its pharmacokinetics and stability, may induce less toxicity than other iron molecules. The aim of this study was to analyse the effect of FCM on inflammation and adhesion molecules in chronic kidney disease (CKD). METHODS: Forty-seven patients with predialysis CKD and iron-deficiency anaemia received a single dose of FCM (15 mg/kg, maximum dose 1 gram). At baseline and after 60 minutes (acute effect) and after 3 weeks and 3 months (sub-acute effect), we determined inflammatory markers: C-reactive protein (CRP), interleukin-6 (IL-6) and endothelial dysfunction: intercellular adhesion molecule (ICAM) and vascular adhesion molecule (VCAM). RESULTS: Treatment with FCM was associated with a significant increase in haemoglobin levels: 10 (0.7) vs. 11.4 (1.3)g/dl, p<.0001. CRP, IL-6, ICAM and VCAM levels did not correlate with baseline haemoglobin or ferritin levels and there was no relationship between changes in these markers and those of haemoglobin after administration of FCM. No significant, acute or sub-acute changes occurred in any of the inflammatory or endothelial markers studied. Statin therapy was associated with lower VCAM concentrations. CONCLUSIONS: Treatment with high doses of FCM in patients with predialysis CKD has no proinflammatory effect and does not alter levels of adhesion molecules ICAM and VCAM in this population.

Role of oxidative stress in cardiovascular effects of anemia treatment with erythropoietin in predialysis patients with chronic kidney disease.

BACKGROUND/AIM: Oxidative stress (OS) is involved in left ventricular hypertrophy (LVH). Short-term treatment with erythropoietin (EPO) in chronic kidney disease (CKD) complicated by anemia and LVH is associated with a reduction in left ventricular mass (LVM). We proposed to assess whether the pro-oxidant status of CKD influences these outcomes. METHODS: Predialysis patients (n = 76) with CKD and hemoglobin (Hb) levels < 11 g/dl received EPO for 6 months. The effects of this anemia correction on LVH regression were evaluated using echocardiography. Patients with LVM decrease > 10% were considered "responders" (n = 25) to treatment and those with LVM change < 10% were considered "non-responders" (n = 24). Measurement of OS included plasma and erythrocyte oxidized (GSSG) and reduced (GSH) glutathione, GSH redox ratio (GSSG/GSH), erythrocyte glutathione peroxidase (GPx) and oxidized LDL (Ox- LDL). RESULTS: 49 patients completed the study. With EPO therapy, mean Hb levels increased from 9.9 ± 0.6 to 12.8 ± 1.5 g/ dl (p < 0.0001) and LVM index decreased from 69.2 ± 17.7 to 64.1 ± 19.6 g/m2.7 (p = 0.01). At 6 months, "non-responders" had higher systolic blood pressure, pulse pressure, GSSG and GSH redox ratio and lower GSH than "responders". In multivariate analysis, and following adjustment for confounding variables, systolic blood pressure and GSH redox ratio independently predicted LVH regression. CONCLUSION: Blood pressure and plasma GSH redox ratio (a marker of OS) are important predictors of LVH regression in anemic predialysis patients treated with EPO.

Evaluation of oxidative stress biomarkers in patients with chronic renal failure: a case control study.

BACKGROUND: Oxidative stress is related to several diseases, including chronic renal insufficiency. The disequilibrium in the oxidant-antioxidant balance is the result of several metabolic changes. The majority of studies to-date have evaluated the grade of oxidative stress with a single biomarker, or a very limited number of them. FINDINGS: The present study used several important biomarkers to establish a score relating to oxidative stress status (glutathione S-transferase, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, reduced and oxidized glutathione, thiobarbituric acid reactive substances and hemolysis test). The score of oxidative stress (SOS) was then applied to a group of patients with renal insufficiency not on hemodialysis, and compared to healthy control individuals.The score for patients with chronic renal insufficiency was significantly different from that of the healthy control group (0.62 +/- 1.41 vs. -0.05 +/- 0.94; p < 0.001). The comparison between patients with chronic renal insufficiency and control individuals showed significant differences with respect to changes in the enzymatic antioxidant systems (glutathione S-transferase, glutathione reductase), non-enzymatic antioxidant system (oxidized glutathione) and oxidizability (hemolysis test) indicating significant oxidative stress associated with chronic renal insufficiency. CONCLUSIONS: Patients with chronic renal insufficiency not on hemodialysis are susceptible to oxidative stress. The mechanisms that underlie this status are the consequence of changes in glutathione and related enzymes. The SOS scoring system is a useful biochemical parameter to evaluate the influence of oxidative stress on the clinical status of these patients.

Cystatin C and cardiac hypertrophy in primary hypertension.

INTRODUCTION: Cystatin C is a marker of kidney function and a predictor of cardiovascular morbidity and mortality. It is unknown whether this protein may be related to the cardiac involvement that is common among patients with essential hypertension. PATIENTS AND METHODS: We evaluated the relationship between serum cystatin C, serum creatinine, estimated glomerular filtration rate and cardiac structure assessed by echocardiography, in a group of 49 non-diabetic patients with primary hypertension and normal serum creatinine. RESULTS: Mean cystatin C levels were 0.74 +/- 0.15 mg/l. Age, body mass index, triglycerides and creatinine, estimated glomerular filtration rate and left ventricular mass index were independently associated with cystatin C levels. Seventy three per cent of patients had cardiac hypertrophy. The prevalence of left ventricular hypertrophy was higher in patients who had cystatin C levels above the 70th percentile (0.79 mg/dl) than patients below this percentile (93.3% vs 66.7%, respectively, p = 0.04). Serum cystatin C (beta = 0.48, p = 0.009), but not serum creatinine nor estimated glomerular filtration rate, was independently related to left ventricular mass index in a logistic regression analysis. CONCLUSION: Cystatin C is closely related to left ventricular mass in hypertensive patients, and could be a marker for cardiac hypertrophy in these patients.

[Chronic kidney disease and the heart. Linked pathologies]. / Enfermedad renal crónica y corazón. Un continuo evolutivo.

There is a close relationship between chronic kidney disease and cardiovascular disorders. The observed increase in morbidity and mortality is due, to a certain extent, to the association of traditional cardiovascular risk factors with the progressive decline in renal function. However, prognosis is made even worse by the presence of additional non-traditional risk factors, in particular the development of left ventricular hypertrophy. Substantial research is required to help prevent these conditions resulting in premature death.

Silent cerebral white matter lesions and their relationship with vascular risk factors in middle-aged predialysis patients with CKD.

BACKGROUND: Silent cerebral white matter lesions are observed on magnetic resonance imaging (MRI) scans in elderly people, and they are related to vascular risk factors, particularly hypertension. No data on the prevalence and risk factors of white matter lesions in patients with chronic kidney disease (CKD) are available. The aim is to analyze the prevalence of white matter lesions and their determinants in this population. METHODS: We studied 52 patients without diabetes with CKD (stage 3 or 4) aged 30 to 60 years (average, 49 years) and a group of 32 normotensive control subjects. MRI studies were performed and subcortical and periventricular white matter lesions were evaluated by using semiquantitative measures. Patients were classified into 2 groups depending on the presence or absence of white matter lesions. Echocardiographic studies and measures of markers of systemic inflammation (C-reactive protein and interleukin 6) also were performed. RESULTS: White matter lesions were more prevalent in patients with CKD than controls (33% versus 6%; P = 0.008). Patients with CKD who had white matter lesions were older; had a greater history of cardiovascular disease and vascular nephropathy as a primary cause of renal disease and greater levels of systolic blood pressure, pulse pressure, left ventricular mass index, and C-reactive protein; and were administered more antihypertensive drugs than patients with CKD without white matter lesions. Stage and duration of CKD were not related to the presence of white matter lesions. After adjusting for several factors, only vascular nephropathy (odds ratio, 15.6; 95% confidence interval, 1.27 to 191.54; P = 0.03) independently predicted an increased risk for white matter lesions. CONCLUSION: One third of middle-aged patients with CKD have silent cerebral white matter lesions. Vascular nephropathy seems to be the most important factor related to the presence of these lesions, suggesting that white matter lesions reflect ischemic brain damage caused by generalized vascular damage.

Exercise blood pressure, cardiac structure, and diastolic function in young normotensive patients with polycystic kidney disease: a prehypertensive state.

BACKGROUND: Increased left ventricular mass (LVM) and left ventricular hypertrophy have been found in early stages of autosomal dominant polycystic kidney disease (ADPKD). The mechanisms that lead to an increase in LVM in this population are unknown. The aim of this study is to evaluate blood pressure (BP) response to exercise and very early alterations in cardiac structure and diastolic function in young normotensive patients with ADPKD. METHODS: Color Doppler echocardiography and exercise treadmill testing according to the Bruce protocol were performed in 18 young normotensive patients with ADPKD and 18 healthy subjects. RESULTS: LVM index was greater and isovolumic relaxation time (IVRT) was longer in patients with ADPKD than controls (93.3 +/- 21.4 versus 77.5 +/- 18.6 g/m2; P = 0.02; 100 +/- 20.2 versus 80 +/- 9.7 milliseconds; P = 0.001, respectively). Exercise capacity in metabolic equivalents was similar in both groups. Systolic BP response during exercise and recovery were similar in both groups. Diastolic BP decreased during exercise, but the magnitude of decrease was lower in patients with ADPKD than controls (P = 0.01). During recovery, patients with ADPKD showed a greater sustained diastolic BP than controls (P = 0.02). Patients with ADPKD with an exaggerated systolic BP response had a greater LVM index than those with a normal response (112.1 +/- 10.4 versus 84 +/- 19.2 g/m2; P = 0.001). Multivariate regression analysis showed that exercise systolic BP and diastolic BP were independent predictors of LVM index and IVRT, respectively. CONCLUSION: Young normotensive patients with ADPKD showed increased LVM index and prolonged IVRT, which are related to exercise BP response. Exaggerated diastolic BP response during exercise suggests an impaired capacity for exercise-induced vasodilatation and may indicate a greater risk for the development of future hypertension.