Well-preserved Renal Function Research Articles

Clinical Significance of Apela in Acute Cardiorenal Insuffiency of Chronic Heart Failure

Introduction: Apela has a wide range of biological effects on the cardiovascular system, but the changes and significance of endogenous Apela in patients with chronic heart failure (CHF) and acute deterioration of cardiac and renal function are unclear. Methods: A total of 69 patients with stable CHF combined with well-preserved renal function were enrolled and followed for 12 months. The effects of Apela on human renal glomerular endothelial cells (hRGEC), human glomerular mesangial cells (hMC), and human renal tubular epithelial cells (HK-2) were observed. Results: Serum Apela concentration was positively correlated with NYHA class (r = 0.711) and N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration (r = 0.303) but negatively correlated with left ventricular ejection fraction (LVEF) (r = −0.374) and 6-min walk distance (r = −0.860) in patients with stable CHF. Twenty-one patients experiencing deterioration of renal and cardiac function were diagnosed with cardiorenal syndrome (CRS) during the follow-up period. In addition, the serum Apela, as well as the difference in Apela between stable and worsening phases (ΔApela), was correlated with the estimated glomerular filtration rate (eGFR) and ΔeGFR in patients with CRS. Apela significantly inhibited the upregulated expression of MCP-1 and TNF-α induced by angiotensin II (AngII) in hRGEC, hMC, and HK-2 cells. Apela inhibited the adhesion of THP-1 cells to hRGEC and promoted the tubular formation of hRGEC. Moreover, Apela enhanced the expression of MMP-9 in hMC but inhibited the upregulated expression of α-SMA and vimentin in HK-2 cells by AngII. Conclusion: This study suggests that the level of Apela can be used to diagnose heart failure and assess the severity of cardiac dysfunction in patients with stable CHF, and its dynamic changes can be used to evaluate the damage to renal function in patients with CRS. Apela plays multiple protective effects on renal cells, highlighting its clinical application prospect in the prevention and treatment of CRS.

Effect of hematuria on the kidney disease progression in IgA nephropathy patients with mild proteinuria and well-preserved renal function

ObjectiveTo investigate whether hematuria is a risk factor in IgA nephropathy (IgAN) patients with mild proteinuria and well-preserved renal function. MethodsThis retrospective study included a total of 63 IgAN patients, with complete clinical data available for 50 patients. Hematuria assessment was conducted using two methods: 1) an automated method using a urine particle analyzer, and 2) a manual method performed by a skilled examiner to examine microscopic urine sediment. ResultsThe results of hematuria measurement using both automated and manual methods showed a strong linear correlation (r = 0.78, P < 0.001). In IgAN patients, those with high urinary red blood cell count (U-RBCs) exhibited higher serum IgA levels compared to patients with low U-RBCs. Additionally, patients with crescent formation had higher levels of proteinuria compared to those without crescents. Patients who received immunosuppressive treatment displayed higher levels of systolic blood pressure (SBP) and mean arterial pressure (MAP), as well as lower levels of serum hemoglobin and albumin. They also had a higher prevalence of T1 lesions compared to patients who did not undergo immunosuppression. Furthermore, among patients with crescent formation, those who received immunosuppressive agents exhibited higher levels of SBP, diastolic blood pressure (DBP), MAP, and U-RBCs, as well as lower levels of albumin and proteinuria at the time of renal biopsy. No composite kidney endpoint events were observed in these groups of patients. The U-RBCs level was not identified as a risk factor influencing the decline of estimated glomerular filtration rate (eGFR) in IgAN. ConclusionsThe presence of hematuria at the time of biopsy was not found to be associated with kidney disease progression in IgAN patients who had mild proteinuria and well-preserved renal function. This suggests that it is possible that these patients may not derive significant benefits from immunosuppressive therapy.

#2841 AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD) PATIENT CHARACTERISTICS ASSOCIATED WITH BETTER RESPONSE TO TOLVAPTAN TREATMENT

Abstract Background and Aims Tolvaptan treatment is indicated in patients with rapidly progressive ADPKD. The factors associated with a favorable medication response are not completely analyzed. We looked into the characteristics of ADPKD patients who responded better to tolvaptan treatment after three years of treatment. Method Forty-one (41) patients, 18 females, 23 males, with rapidly progressive ADPKD (Mayo Clinic Imaging Category, MCIC, 1C, 1D and 1E, mean (SD) age 42.5 (8.6) years and estimated-glomerular filtration rate (e-GFR) &amp;gt; 25 ml/min) who completed three years treatment with tolvaptan, were included in the study. Total kidney volume (TKV) was measured using Magnetic Resonance Imaging at the initiation of the study and 3 years post treatment. The expected e-GFR decline at 3 years without treatment was calculated using the Mayo Clinic formula (Irazabal MV et al., JASN, 2015) and compared to the e-GFR found after three years of tolvaptan treatment (e-GFR measured after 3 years of treatment versus expected e-GFR). Based on the same formula, the End Stage Renal Disease (ESRD) prediction was calculated, before and after 3 years of treatment (i.e. we focused on the difference between the ESRD prediction calculated prior to treatment initiation and the prediction calculated with the data measured after 3 years of treatment). The above mentioned differences in e-GFR and ESRD prediction were used as response to treatment markers and correlated with a series of patient characteristics (age, sex, age at ADPKD diagnosis, presence of hypertension (HTN) and age at HTN onset, age at ESRD of the affected parent, TKV, MICI, etc) using univariate and multivariate statistical analysis. Results The median (IQR) difference between e-GFR measured after three years of tolvaptan treatment and the expected without treatment was 5.3 (-1.3, 8.7) ml/min (i.e. more than the expected at 3 years without treatment). The median (IQR) prediction of ESRD had been prolonged by 1 (0, 2) years (more than the expected prediction calculated prior to treatment initiation). In univariate analysis, the baseline e-GFR (immediately before treatment) and the age at which the affected parent had developed ESRD were both positively associated with the e-GFR improvement and ESRD prediction prolongation (p = 0.02, 0.047, 0.01, and 0.02, respectively). In multivariate analysis, e-GFR improvement was associated with the age of the patient at treatment initiation (β = -0.9, 95%CI: -1.52 - 0.29, p = 0.006), the age of the patient at hypertension diagnosis (β = 0.88, 95%CI: 0.25 - 1.52, p = 0.008) and the age at which the affected parent had developed ESRD (β = 0.57, 95%CI: 0.16 - 0.98, p = 0.008). In addition, ESRD prediction prolongation was associated with the initial e-GFR (p = 0.001), the age at which the affected parent had developed ESRD (p = 0.013) and the MCIC (β = 1.93, 95%CI 0.46 – 3.39, p = 0.013) (i.e. greater ESRD prediction prolongation for patients at MCIC 1E than at 1C). Conclusion Tolvaptan treatment seems to be more efficient in younger patients with rapidly progressing ADPKD, well-preserved renal function, a less severe family history, and a shorter chronicity of hypertension.

Pregnancy in Women With Preexisting Glomerular Diseases: A Single-Center Experience.

AimWomen with glomerular diseases are often of childbearing age. Besides lupus nephritis, data regarding pregnancy in patients with glomerular diseases are limited, posing a challenging task to attending nephrologists. This study aimed to investigate the pregnancy outcomes and the impact on the underlying glomerular disease among women followed in our institution.MethodsA single-center retrospective cohort study of women with biopsy-proven glomerular diseases who experienced pregnancy between 2010 and 2020. We analyzed data before, during, and after gestation.ResultsA total of 22 women, 13 women with primary and 9 women with secondary glomerular diseases, were included in this study. Most patients (82%) had received immunosuppressive treatment at various times before pregnancy. All the women were in remission, either complete (62%) or partial (38%), with well-preserved renal function (82%) before conception. A total of 30 live births and 1 stillbirth were recorded; the rate of preterm delivery was 23%. Renal function and proteinuria remained stable during pregnancy. Preeclampsia was observed in 6.7% of patients and disease relapse in 6.9% of the pregnancies.ConclusionPregnancy was associated with a low frequency of adverse events in women with underlying glomerular diseases, provided they have quiescent disease and preserved renal function.

Early Everolimus-Facilitated Reduced Tacrolimus in Liver Transplantation: Results From the Randomized HEPHAISTOS Trial.

Everolimus‐facilitated reduced‐exposure tacrolimus (EVR + rTAC) at 30 days after liver transplantation (LT) has shown advantages in renal preservation. This study evaluated the effects of early initiation of EVR + rTAC in de novo LT recipients (LTRs). In HEPHAISTOS (NCT01551212, EudraCT 2011‐003118‐17), a 12‐month, multicenter, controlled study, LTRs were randomly assigned at 7 to 21 days after LT to receive EVR + rTAC or standard‐exposure tacrolimus (sTAC) with steroids. The primary objective was to demonstrate superior renal function (assessed by estimated glomerular filtration rate [eGFR]) with EVR + rTAC versus sTAC at month 12 in the full analysis set (FAS). Other assessments at month 12 included the evaluation of renal function in compliance set and on‐treatment (OT) patients, efficacy (composite endpoint of graft loss, death, or treated biopsy‐proven acute rejection [tBPAR] and individual components) in FAS, and safety. In total, 333 patients (EVR + rTAC, 169; sTAC, 164) were included in the FAS. A high proportion of patients was nonadherent in maintaining tacrolimus trough levels (EVR + rTAC, 36.1%; sTAC, 34.7%). At month 12, the adjusted least square mean eGFR was numerically higher with EVR + rTAC versus sTAC (76.2 versus 72.1 mL/minute/1.73 m2, difference: 4.1 mL/minute/1.73 m2; P = 0.097). A significant difference of 8.3 mL/minute/1.73 m2 (P = 0.03) favoring EVR + rTAC was noted in the compliance set. Incidence of composite efficacy endpoint (7.7% versus 7.9%) and tBPAR (7.1% versus 5.5%) at month 12 as well as incidence of treatment‐emergent adverse events (AEs) and serious AEs were comparable between groups. A lower proportion of patients discontinued EVR + rTAC than sTAC treatment (27.2% versus 34.1%). Early use of everolimus in combination with rTAC showed comparable efficacy, safety, and well‐preserved renal function versus sTAC therapy at month 12. Of note, renal function was significantly enhanced in the compliance set.

P0215EXCESSIVE TISSUE SODIUM STORAGE IN PATIENTS WITH NON-DIALYSIS DEPENDENT CARDIO-RENAL SYNDROME IS COMPARABLE TO HEMODIALYSIS PATIENTS

Abstract Background and Aims Both CKD and heart failure (HF) are characterized by a propensity to retain sodium. Renal dysfunction worsens the progression of heart failure and is associated with worse outcomes. This may be a result of synergistic aggravation of sodium retention by the two conditions. We aimed to compare tissue Na storage in skin and muscle between cardiorenal (CR) patients and patients with a range of renal dysfunction, including those requiring hemodialysis (HD). Method Proton and 23Na images of the lower limb were acquired on a 3T MRI. We studied 9 CR patients, 7 matched CKD 2-5 patients (without HF) and 31 established HD patients. Regions of interest including skin and soleus were drawn on images to provide a quantitative sodium measurement and these tissue concentrations compared between groups. Blood samples were drawn at each scan in all patients. Spot urine samples were collected for CR patients. Results For CR patients, mean age was 66 ± 8 years, 78% of male, mean estimated glomerular filtration rate (eGFR) was 52 ± 18 mL/min/1.73m2, urea was 11 ± 6 mmol/L. For HD patients, mean age was 66 ± 8.7 years, 68% of male and mean dialysis vintage was 38 ± 37 months for HD patients. Mean age was 63 ± 8, 71 % of male, eGFR 45 ± 29 mL/min/1.73m2 for CKD patients. CR patients displayed an increased amount of salt in skin (32.5 ± 13 mmol/L) and muscle (26 ±4 mmol/L) with levels significantly higher than that seen in GFR matched controls (without HF) and comparable to HD patients (31 ±12 and 28 ± 6 mmol/L p=0.9 and p=0.3 respectively) without meaningful residual renal function. Conclusion The combination of HF and CKD is associated with intense tissue Na storage; resulting in tissue Na accumulation in CR patients (with reasonably well-preserved renal function) similar to CKD patients requiring HD.

Kidney Transplantation Utilising Donors After Circulatory Death – The First Report from the African Continent

Introduction At Groote Schuur Hospital, the number of deceased donors have declined over the last two decades, necessitating more liberal donor selection. In 2007, measures to expand the deceased kidney donor pool were implemented, including a HIV positive to positive transplant program, the utilisation of Extended Criteria Donors (ECD) as well as a Donation after Circulatory Death (DCD) program (Figure 1). Despite the successful implementation of DCD programs across Europe and the United Sates, other African centres have not adopted this mode of donation. The aim of this study was to report on our institutional experience with DCD kidney transplants and to encourage this approach among other African centres to improve access to transplantation. Materials and methods Retrospective, descriptive study of consecutive DCD renal transplants at Groote Schuur Hospital over a 10 year period (1 January 2007 to 31 December 2016). Data was obtained from donor referral and recipient registries. Primary end-points were defined as 1, 2 and 5 year graft- (censored for death with functioning graft) and patient survival. Kaplan-Meier method was used for survival analysis. Secondary end-points included the incidence of delayed graft function (DGF), 30-day morbidity, length of stay and donor and recipient clinical characteristics. Results 13 DCD procurements were performed, with no kidneys discarded. Utilised donors were young (median age 22 years; IQR 21-32) with well-preserved renal function (median terminal serum creatinine 86 umol/l; IQR 73-181). 26 Renal transplants were performed with a mean cold ischaemic time of 11 hours (IQR 8-14). Cumulative incidence of DGF was 65.4%. The median length of stay was 20 days (IQR 16-28) in those who experienced DGF and 11 days (IQR 9-16) in those who did not. 30-Day morbidity (other than DGF) was 19.2% (Figure 2). Graft survival at 1, 2 and 5 years were 100%, 95.8% (95% CI 73.9% - 99.4%) and 83.6% (95% CI 56.1%-94.8%) respectively (Figure 3). Patient survival at 1, 2 and 5 years was 92.3% (95% CI 72.6-98.0), as no deaths occurred between 1 and 5 years post-transplant (Figure 4). Discussion Long term graft- and patient survival were comparable with international literature. The incidence of DGF was 65,4%. Possible explanations may include a high incidence of donor vasopressor requirements (46.2%), an initial learning curve with procurement technique and relatively long cold ischaemic times. Nevertheless, DCD may present an unique opportunity to expand deceased donation throughout Africa, particularly in areas hampered by a lack of brain death legislation and religious and/or cultural concerns regarding Donation after Brain Death. Conclusion Results from this study reaffirm the potential of DCD to expand deceased donation throughout Africa, in a religiously and culturally sensitive way.

Serum Uromodulin: A Biomarker of Long-Term Kidney Allograft Failure

Background: Uromodulin is a kidney-derived glycoprotein and putative tubular function index. Lower serum uromodulin was recently associated with increased risk for kidney allograft failure in a preliminary, longitudinal single-center ­European study involving 91 kidney transplant recipients (KTRs). Methods: The Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial is a completed, large, multiethnic controlled clinical trial cohort, which studied chronic, stable KTRs. We conducted a case cohort analysis using a randomly selected subset of patients (random subcohort, n = 433), and all individuals who developed kidney allograft failure (cases, n = 226) during follow-up. Serum uromodulin was determined in this total of n = 613 FAVORIT trial participants at randomization. Death-censored kidney allograft failure was the study outcome. Results: The 226 kidney allograft failures occurred during a median surveillance of 3.2 years. Unadjusted, weighted Cox proportional hazards modeling revealed that lower serum uromodulin, tertile 1 vs. tertile 3, was associated with a threefold greater risk for kidney allograft failure (hazards ratio [HR], 95% CI 3.20 [2.05–5.01]). This association was attenuated but persisted at twofold greater risk for allograft failure, after adjustment for age, sex, smoking, allograft type and vintage, prevalent diabetes mellitus and cardiovascular disease (CVD), total/high-density lipoprotein cholesterol ratio, systolic blood pressure, estimated glomerular filtration rate, and natural log urinary albumin/creatinine: HR 2.00, 95% CI (1.06–3.77). Conclusions: Lower serum uromodulin, a possible indicator of less well-preserved renal tubular function, remained associated with greater risk for kidney allograft failure, after adjustment for major, established clinical kidney allograft failure and CVD risk factors, in a large, multiethnic cohort of long-term, stable KTRs.

Early atherosclerosis in normotensive patients with autosomal dominant polycystic kidney disease: the relation between epicardial adipose tissue thickness and carotid intima-media thickness.

Epicardial adipose tissue thickness (EATT) is suggested as a novel marker of subclinical atherosclerosis. Despite increased carotid intima-media thickness (CIMT) in autosomal dominant polycystic kidney disease (ADPKD) patients, the extent of the relationship between CIMT and EATT is unknown. The main purpose of our study was to evaluate the relation between EATT and CIMT in normotensive ADPKD patients with well-preserved renal function. Fifty-five normotensive ADPKD patients with normal renal function and 50 healthy control subjects were included in the study. EATT and CIMT were measured by echocardiography in all subjects. Correlation between EATT and CIMT was evaluated in ADPKD patients, while multivariate linear regression analysis was performed to determine factors predicting EATT and CIMT. ADPKD patients had significantly higher levels CIMT [0.7 (0.4–1.2) vs. 0.5 (0.4–0.8) mm, p < 0.001] and EATT (6.8 ± 2.7 vs. 4.8 ± 1.2 mm, p < 0.001) as compared with control subjects. Significant positive correlation was found between EATT and CIMT (r = 0.58, p < 0.001). Higher CRP levels (OR 54.7, 95 % CI 37.44–72.01, p < 0.001) and having ADPKD (OR 10.2, 95 % CI 2.53–17.86, p = 0.01) were the only independent factors associated with a higher EATT. A higher age (OR 0.35, 95 % CI −0.02 to 0.71, p = 0.06) tended to be independently associated with a higher EATT. In conclusion, our findings suggest that EATT, being simply measured by echocardiography and correlated with CIMT, can be used to detect subclinical atherosclerosis in normotensive ADPKD patients.

Early Initiation of Everolimus After Liver Transplantation: A Single-Center Experience.

Evidence relating to early everolimus use after liver transplantation remains limited. Ninety-one adult patients undergoing liver transplantation at our center during 2007-2012 in whom everolimus therapy was initiated <3 months post-transplant were analyzed retrospectively. Everolimus was started on days 1-5 in 50 patients (group 1) and after day 5 in 41 patients (group 2). Most patients continued to receive low-dose cyclosporine (59.3%, target 50-80 ng/ml) or low-dose tacrolimus (25.3%; target 3-5 ng/ml). Mean follow-up was 4.6 years. One-, three- and five-year patient survival rates were 80.5%, 74.2%, and 70.5%, respectively, and did not differ between groups 1 and 2. Six patients (6.6%) developed biopsy-proven acute rejection after a median of 47 days (range 27-356 days). Everolimus was discontinued due to adverse events in 21 patients (23.1%). Incisional hernia repair occurred in 14.0% and 9.4% of patients in group 1 and 2, respectively. Renal function remained stable during follow-up, despite poor baseline function. Everolimus with very low-dose calcineurin inhibitor given immediately after liver transplantation appears safe and effective, achieving a low rejection rate with well-preserved renal function.

Aloperine Protects Mice against Ischemia-Reperfusion (IR)-Induced Renal Injury by Regulating PI3K/AKT/mTOR Signaling and AP-1 Activity.

Aloperine is a quinolizidine alkaloid extracted from the leaves of Sophora plants. It has been recognized with the potential to treat inflammatory and allergic diseases as well as tumors. In this report, we demonstrate that pretreatment with aloperine provided protection for mice against ischemia-reperfusion (IR)-induced acute renal injury as manifested by the attenuated inflammatory infiltration, reduced tubular apoptosis, and well-preserved renal function. Mechanistic studies revealed that aloperine selectively repressed IL-1β and IFN-γ expression by regulating PI3K/Akt/mTOR signaling and NF-κB transcriptional activity. However, aloperine did not show a perceptible impact on IL-6 and TGF-β expression and the related Jak2/Stat3 signaling. It was also noted that aloperine regulates AP-1 activity, through which it not only enhances SOD expression to increase reactive oxygen species (ROS) detoxification but also promotes the expression of antiapoptotic Bcl-2, thereby preventing tubular cells from IR-induced apoptosis. Collectively, our data suggest that administration of aloperine prior to IR insults, such as renal transplantation, could be a viable approach to prevent IR-induced injuries.

Efficacy and safety of Flos Abelmoschus manihot (Malvaceae) on type 2 diabetic nephropathy: A systematic review.

To evaluate the efficacy and safety of Flos Abelmoschus manihot (Malvaceae) on type 2 diabetic nephropathy (DN). The Cochrane Library, PubMed/MEDLINE, Excerpta Medical Database, Chinese electronic literature databases, and the references of relevant articles were searched in March 2012 for randomized controlled trials (RCTs) that reported the effects of Flos A. manihot on type 2 DN patients with overt but subnephrotic-range proteinuria (500-3,500 mg/24 h). The quality of trials was evaluated using the Cochrane-recommended method. The results were summarized as risk ratios (RRs) for dichotomous outcomes or mean differences (MDs) for continuous outcomes. Seven trials (531 patients) were included. Flos A. manihot significantly decreased proteinuria [MD -317.32 mg/24 h, 95% confidence interval (CI) [-470.48, -164.17],P<0.01]. After excluding a trial that only included patients with well-preserved renal function, Flos A. manihot was associated with a significant decrease in serum creatinine (MD -11.99 μmol/L, 95% CI [-16.95, -7.04],P<0.01). Serious adverse events were not observed. The most common adverse event was mild to moderate gastrointestinal discomfort; however, patients receiving this herb did not have an increased risk for tolerated gastrointestinal discomfort (RR 1.48, 95% CI [0.39, 5.68],P=0.57). Flos A. manihot may be considered as an important adjunctive therapy with the first-line and indispensable therapeutic strategies for type 2 DN. High-quality RCTs are urgently needed to confirm the effect of Flos A. manihot on definite endpoints such as end-stage renal disease.

Cardiovascular abnormalities in patients with autosomal dominant polycystic kidney disease

The autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder in nephrology. Two genes have been implicated in the development of the disease: PKD1 on chromosome 16 (85%) and PKD2 on chromosome 4 (15%). ADPKD is clinically characterized by renal and extrarenal involvement indicated by the onset of cystic and non-cystic manifestations. Since cardiovascular complications are a leading cause of morbidity and mortality, this review aims to analyze cardiac and vascular involvement in ADPKD. Hypertension is a common early symptom, and occurs in approximately 60% of patients before renal dysfunction. The effect of hypertension on the progression to end-stage renal disease makes it the main potentially treatable risk factor in ADPKD. Also, left ventricular hypertrophy occurs frequently in these patients representing another powerful and independent risk factor for cardiovascular morbidity and mortality in ADPKD. Other abnormalities, such as biventricular diastolic dysfunction, endothelial dysfunction, and increased carotid intima-media thickness, are present even in young ADPKD patients with normal blood pressure and well-preserved renal function. Intracranial and extracranial aneurysms, as well as cardiac valvular defects, are other common cardiovascular manifestations in patients with ADPKD. Early treatment of hypertension through the use of renin-angiotensin-aldosterone system blocking agents could play a nephroprotective effect and reduce the occurrence of cardiovascular complications in ADPKD patients.

Analgesia dose prescribing and estimated glomerular filtration rate decline: a general practice database linkage cohort study

ObjectiveWe aimed to quantify the short-term effect of non-steroidal anti-inflammatory drugs (NSAIDs), aspirin and paracetamol analgesia dose prescribing on estimated glomerular filtration rate (eGFR) decline in the general practice population.DesignA...

Prevalence and progression of peripheral vascular calcification in type 2 diabetes subjects with preserved kidney function

AimsTo determine predictors of prevalence and progression of peripheral vascular calcification (VC) in type 2 diabetes (DM) subjects with preserved kidney function. MethodsFifty-eight subjects (age 63±11.6 years) with type 2 DM and serum creatinine <125μmol/l were studied. A CT scan of femoral, posterior tibial and dorsalis pedis arteries was carried out at baseline and at one year. Serum osteoprotegerin (OPG) and RANKL were measured along with routine biochemistry. ResultsSeventy-eight percent of patients had baseline VC, 47% with femoral VC, 49% with VC at two sites – femoral and foot, and 4% foot VC alone. Age, ethnicity, peripheral neuropathy and eGFR were independent predictors of baseline VC. Baseline calcification was the most important predictor of VC progression and was present in all subjects with progression compared to 35% of non-progressors (p<0.001). Exclusion of demographic factors from models revealed neuropathy and serum OPG levels as independent predictors of both; baseline VC and progression. ConclusionsSubjects with type 2 DM and well-preserved renal function had a high prevalence of VC, which was rapidly progressive especially in those with baseline VC. Age, ethnicity, neuropathy, smoking and eGFR were predictors of baseline VC and progression.

Insulin resistance and coronary flow velocity reserve in patients with autosomal dominant polycystic kidney disease

Cardiovascular problems are a major cause of morbidity and mortality in patients with autosomal dominant polycystic kidney disease (ADPKD). The aim of this study was to investigate coronary flow velocity reserve (CFVR) as a marker of endothelial dysfunction, carotid intima media thickness (CIMT) as a marker of subclinical organ damage and insulin resistance (IR) as a cardiovascular risk factor in patients with ADPKD. Twenty-two normotensive ADPKD patients with well-preserved renal function and 19 healthy subjects were included in the study. Creatinine clearances were calculated by the Cockcroft-Gault formula. The homeostasis model of IR (HOMA-IR) was used to measure IR. CIMT was measured by high-resolution vascular ultrasound. CFVR was calculated as the ratio of hyperaemic to baseline diastolic peak velocities by echocardiography. There was no significant difference between the two groups regarding age, gender, body mass index, systolic and diastolic blood pressures, cholesterol and triglyceride levels. However, CIMT and HOMA-IR were significantly increased and CFVR was significantly decreased in patients with ADPKD compared with healthy subjects. The findings of decreased CFVR, increased CIMT and increased IR suggest that cardiovascular risk is elevated even in the early stages of ADPKD.

Renal Function and NODM inDe NovoRenal Transplant Recipients Treated with Standard and Reduced Levels of Tacrolimus in Combination with EC-MPS

Information is lacking concerning concomitant administration of enteric-coated mycophenolate sodium with tacrolimus (EC-MPS+Tac) in renal transplant recipients (RTxR). In this 6-month, prospective, open-label, multicenter study, de novo RTxR were randomized (1 : 1) to low-dose (LD) or standard-dose (SD) Tac with basiliximab, EC-MPS 720 mg bid, and steroids. Primary objective was to compare renal function at 6-month posttransplantation. Secondary objectives were to compare the incidences of biopsy-proven acute rejection (BPAR), graft loss and death, and new-onset diabetes mellitus (NODM). 292 patients (LD n = 151, SD n = 141) were included. Mean Tac levels were at the low end of the target range in standard-exposure patients (SD, n = 141) and exceeded target range in low-exposure patients (LD = 151) throughout the study. There was no significant difference in mean glomerular filtration rate (GFR) between treatments (ITT-population: 63.6 versus 61.0 mL/min). Incidence of BPAR was similar (10.6% versus 9.9%). NODM was significantly less frequent in LD Tac (17% versus 31%; P = 0.02); other adverse effects (AEs) were comparable. EC-MPS+Tac (LD/SD) was efficacious and well tolerated with well-preserved renal function. No renal function benefits were demonstrated, possibly related to poor adherence to reduced Tac exposure.

The foot in type 2 diabetes: Is there a link between vascular calcification and bone mineral density?

AimsTo examine the relationship between vascular calcification in the foot (FVC) and bone mineral density (BMD) in the heel of type 2 diabetes mellitus (DM) subjects. Methods65 subjects with type 2 DM and serum creatinine<125μmol/l underwent CT scanning of the foot to assess FVC and dual energy X ray absorptiometry (DEXA) scan to assess heel BMD. Routine biochemistry including osteoprotegerin (OPG) and Receptor activator of nuclear factor kappa-B ligand (RANKL) was also carried out. ResultsThe proportion of subjects with FVC was 43%, whilst 40% had low BMD (T score<−1.0). Age, neuropathy and 25 hydroxyvitamin D were independent predictors of FVC. Body-weight, eGFR, 25 hydroxyvitamin D, OPG, and total cholesterol were independent predictors of low heel BMD. There was no correlation between albuminuria and BMD or FVC. There was no difference in heel BMD between those with FVC and those without, but those with frank osteoporosis were significantly more likely to have FVC than those with higher BMD. ConclusionsThere is no clear-cut association between FVC and low BMD in type 2 DM with relatively well-preserved renal function. Age, neuropathy, eGFR, hyperlipidemia, body-weight, 25 hydroxyvitamin D and OPG play a complex role in their pathogenesis.

Detection of autosomal dominant polycystic kidney disease by NMR spectroscopic fingerprinting of urine

Autosomal dominant polycystic kidney disease (ADPKD) is a frequent cause of kidney failure; however, urinary biomarkers for the disease are lacking. In a step towards identifying such markers, we used multidimensional-multinuclear nuclear magnetic resonance (NMR) spectroscopy with support vector machine-based classification and analyzed urine specimens of 54 patients with ADPKD and slightly reduced estimated glomerular filtration rates. Within this cohort, 35 received medication for arterial hypertension and 19 did not. The results were compared with NMR profiles of 46 healthy volunteers, 10 ADPKD patients on hemodialysis with residual renal function, 16 kidney transplant patients, and 52 type 2 diabetic patients with chronic kidney disease. Based on the average of 51 out of 701 NMR features, we could reliably discriminate ADPKD patients with moderately advanced disease from ADPKD patients with end-stage renal disease, patients with chronic kidney disease of other etiologies, and healthy probands with an accuracy of >80%. Of the 35 patients with ADPKD receiving medication for hypertension, most showed increased excretion of proteins and also methanol. In contrast, elevated urinary methanol was not found in any of the control and other patient groups. Thus, we found that NMR fingerprinting of urine differentiates ADPKD from several other kidney diseases and individuals with normal kidney function. The diagnostic and prognostic potential of these profiles requires further evaluation.

Calcineurin Inhibitor-Free Immunosuppression in Pediatric Renal Transplantation

The introduction, in the mid-1980s, of calcineurin inhibitors - namely ciclosporin (cyclosporine) and later tacrolimus - has significantly improved short-term renal graft survival by lowering acute rejection rates in both adult and pediatric kidney transplantation. Nonetheless, long-term transplant survival is still not satisfactory, with calcineurin inhibitor-induced chronic nephrotoxicity being one of the main causes of progressive nephron loss and declining renal transplant function. Hence, different immunosuppressant regimens have been proposed to avoid or ameliorate calcineurin inhibitor-induced nephrotoxicity. These comprise the use of non-depleting or depleting antibodies for calcineurin inhibitor minimization, calcineurin inhibitor avoidance, or calcineurin inhibitor withdrawal from mycophenolate mofetil-based immunosuppressant protocols. De novo use of a mammalian target of rapamycin (mTOR) inhibitor (sirolimus or everolimus) or conversion from a calcineurin inhibitor to an mTOR inhibitor may constitute another therapeutic option to avoid or reduce calcineurin inhibitor-induced nephrotoxicity. To date, complete calcineurin inhibitor avoidance seems to be inappropriate because other relatively potent immunosuppressant agents such as lymphocyte-depleting antibodies are needed for rejection prophylaxis, which are frequently accompanied by a higher incidence of infections and an unacceptably high acute rejection rate under calcineurin inhibitor avoidance. In some studies, calcineurin inhibitor withdrawal in adult and pediatric kidney allograft recipients with stable or declining transplant function has been associated with an amelioration of renal function; however, this is attained at the cost of a higher acute rejection rate in 10-20% of patients. It has been frequently stressed that conversion from a calcineurin inhibitor-based regimen to an mTOR inhibitor-based immunosuppressant regimen should be performed early (e.g. 3 or 6 months post-transplant) in patients with well-preserved renal transplant function without significant proteinuria in order to prevent, or at least limit, calcineurin inhibitor-induced tissue damage and provide long-term benefit. It should be borne in mind though that the use of an mTOR inhibitor carries the risk of potential adverse events such as aggravation of proteinuria, hyperlipidemia, myelosuppression, and hypergonadotropic hypogonadism. Even though everolimus may be better tolerated than sirolimus, studies on everolimus for calcineurin inhibitor-free immunosuppression in the pediatric kidney transplant patient population are lacking. At present, the safest therapeutic strategy for pediatric renal allograft recipients with chronic calcineurin inhibitor-induced nephrotoxicity appears to be a mycophenolate mofetil-based regimen with low-dose calcineurin inhibitor therapy and corticosteroids; available published data show that dual immunosuppression with mycophenolate mofetil and corticosteroids, as well as an mTOR inhibitor plus mycophenolate mofetil plus corticosteroid-based regimens, are associated with an increased risk of acute rejection episodes. In individual patients with evidenced chronic allograft dysfunction and over-immunosuppression leading to recurrent infections, dual maintenance immunosuppression with mycophenolate mofetil and corticosteroids may be appropriate. As stated in the annual report issued by the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) Registry, currently the most popular immunosuppressant protocol consists of a calcineurin inhibitor combined with mycophenolate mofetil and corticosteroids: 59.1% and 53.2% of patients with a functioning graft receive a calcineurin inhibitor plus mycophenolate mofetil plus corticosteroid-based immunosuppression at 1 and 5 years post-transplant, respectively. 91.4% and 87.8% of patients are administered a calcineurin inhibitor-containing regimen 1 and/or 5 years after transplantation, respectively. Undoubtedly, the use of calcineurin inhibitor-free immunosuppressant regimens with or without antibody induction, plus an mTOR inhibitor and mycophenolate mofetil, requires more comprehensive long-term investigations to determine whether acceptable rejection rates and conservation of renal function can be achieved.