Hyperuricemia, Hypertension, and Chronic Kidney Disease: an Emerging Association.

Uric acid is a product of purine metabolism and has been linked to gout and kidney calculi. Chronic kidney disease (CKD) and hypertension (HTN) are two major public health problems, and both are associated with increased risk of cardiovascular events. Emerging evidence suggests a pathogenic role of hyperuricemia in the development of HTN and CKD, in addition to progression of CKD, by inducing renal inflammation, endothelial dysfunction, and activation of the renin-angiotensin system. In addition, several epidemiological studies have linked hyperuricemia with an increased risk of HTN and CKD. A few clinical trials have assessed the use of uric acid-lowering therapies such as allopurinol and febuxostat in the management of HTN and delaying progression of CKD. To date, most of these trials are short-term with a small sample size; however, their results are encouraging and provide a rationale for larger randomized controlled trials to establish the role of uric acid-lowering therapies in the management of HTN, in addition to prevention of CKD progression and cardiovascular events.

Calcineurin inhibitors: 40 years later, can't live without ...

Calcineurin inhibitors (CNIs) revolutionized the field of organ transplantation and remain the standard of care 40 years after the discovery of cyclosporine. The early impressive results of cyclosporine in kidney transplant recipients led to its subsequent use in other organ transplant recipients and for treatment of a variety of autoimmune diseases as well. In this review, we examine the discovery of CNIs, their mechanism of action, preclinical and clinical studies with CNIs, and the usage of CNIs in nontransplant recipients. We review the mechanisms of renal toxicity associated with CNIs and the recent efforts to avoid or reduce usage of these drugs. Although minimization strategies are possible, safe, and of potential long-term benefit, complete avoidance of CNIs has proven to be more challenging than initially thought.

Identifying predictors of blood pressure control in the Lebanese population - a national, multicentric survey -- I-PREDICT.

BACKGROUND: Blood Pressure (BP) is not well controlled and factors that predict BP control are not well identified in Lebanon. Improvement of hypertension management requires an understanding of patients' characteristics and factors associated with uncontrolled BP. This national, multicentric, observational prospective study was designed to determine the predictors of BP control in patients followed up to 6 months. METHODS: I-PREDICT study was conducted on 988 patients with newly diagnosed or uncontrolled hypertension. Socio-demographic and clinical characteristics were analyzed. The level of agreement between doctors' perceptions on BP control status and JNC VII guidelines was analyzed. RESULTS: The predictor associated with poor BP control was diabetes (OR = 0.17, CI = 0.10-0.28 at month-1; OR = 0.15, CI = 0.10-0.24 at month-6). The predictors associated with better BP control at month-6 were the early control of BP at month-1 (OR = 10.39, CI = 6.18-17.47) and combination therapy prescribed at baseline and month-1 (OR = 15.14, CI = 1.09-208.46, P = 0.04). In the sub-group of diabetes, the predictors that were associated with better BP control at 6 months were following diet at V1 (OR = 2.27, CI = 1.01 to 5.12) and BP control at V2 (OR = 7.34, CT = 3.83 to 14.07). The predictors that were associated with poor BP control at 6 months were middle economic class (OR = 0.036, CI = 0.16-0.94) and upper economic class (OR = 0.036; CI = 0.13-0.93).The rate of BP control was significantly higher at month 6 versus month 1 (67.52% vs 44.08%, P = 0.001). Additional analysis showed poor agreement between the doctors' perceptions on BP control status and the guidelines. CONCLUSIONS: Reaching an early BP control and combination therapy were significant predictors of better BP control, whereas diabetes was a significant predictor of poor BP control. A poor agreement between JNC VII guidelines and clinical practice was observed. I-PREDICT study identified factors that can be targeted for improving BP control.

Dual renin-angiotensin system inhibition for prevention of renal and cardiovascular events: do the latest trials challenge existing evidence?

Circulatory and tissue renin-angiotensin systems (RAS) play a central role in cardiovascular (CV) and renal pathophysiology, making RAS inhibition a logical therapeutic approach in the prevention of CV and renal disease in patients with hypertension. The cardio- and renoprotective effects observed with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) monotherapy, together with the availability of a direct renin inhibitor (DRI), led to the investigation of the potential benefits of dual RAS inhibition. In small studies, ARB and ACE inhibitor combinations were shown to be beneficial in patients with CV or renal disease, with improvement in surrogate markers. However, in larger outcome trials, involving combinations of ACE inhibitors, ARBs or DRIs, dual RAS inhibition did not show reduction in mortality in patients with diabetes, heart failure, coronary heart disease or after myocardial infarction, and was in fact, associated with increased harm. A recent meta-analysis of all major trials conducted over the past 22 years involving dual RAS inhibition has clearly shown that the risk-benefit ratio argues against the use of dual RAS inhibition. Hence, the recent evidence clearly advocates against the use of dual RAS inhibition, and single RAS inhibition appears to be the most suitable approach to controlling blood pressure and improving patient outcomes.

What is a preferred angiotensin II receptor blocker-based combination therapy for blood pressure control in hypertensive patients with diabetic and non-diabetic renal impairment?

Hypertension has a major associated risk for organ damage and mortality, which is further heightened in patients with prior cardiovascular (CV) events, comorbid diabetes mellitus, microalbuminuria and renal impairment. Given that most patients with hypertension require at least two antihypertensives to achieve blood pressure (BP) goals, identifying the most appropriate combination regimen based on individual risk factors and comorbidities is important for risk management. Single-pill combinations (SPCs) containing two or more antihypertensive agents with complementary mechanisms of action offer potential advantages over free-drug combinations, including simplification of treatment regimens, convenience and reduced costs. The improved adherence and convenience resulting from SPC use is recognised in updated hypertension guidelines. Despite a wide choice of SPCs for hypertension treatment, clinical evidence from direct head-to-head comparisons to guide selection for individual patients is lacking. However, in patients with evidence of renal disease or at greater risk of developing renal disease, such as those with diabetes mellitus, microalbuminura and high-normal BP or overt hypertension, guidelines recommend renin-angiotensin system (RAS) blocker-based combination therapy due to superior renoprotective effects compared with other antihypertensive classes. Furthermore, RAS inhibitors attenuate the oedema and renal hyperfiltration associated with calcium channel blocker (CCB) monotherapy, making them a good choice for combination therapy. The occurrence of angiotensin-converting enzyme (ACE) inhibitor-induced cough supports the use of angiotensin II receptor blockers (ARBs) for RAS blockade rather than ACE inhibitors. In this regard, ARB-based SPCs are available in combination with the diuretic, hydrochlorothiazide (HCTZ) or the calcium CCB, amlodipine. Telmisartan, a long-acting ARB with preferential pharmacodynamic profile compared with several other ARBs, and the only ARB with an indication for the prevention of CV disease progression, is available in two SPC formulations, telmisartan/HCTZ and telmisartan/amlodipine. Clinical studies suggest that in CV high-risk patients and those with evidence of renal disease, the use of an ARB/CCB combination may be preferred to ARB/HCTZ combinations due to superior renoprotective and CV benefits and reduced metabolic side effects in patients with concomitant metabolic disorders. However, selection of the most appropriate antihypertensive combination should be dependent on careful review of the individual patient and appropriate consideration of drug pharmacology.

Interleukin-10-592C/A, -819C/T and -1082A/G promoter variants affect the susceptibility to nephropathy in Tunisian type 2 diabetes (T2DM) patients.

BACKGROUND: The Interleukin (IL)-10 polymorphic variants -1082G/A, -819C/T and -592C/A were linked with obesity, metabolic syndrome, and type 2 diabetes (T2DM). We investigated the hypothesis that IL-10 promoter polymorphisms may be associated with the progression of diabetic nephropathy (DN). DESIGN: Case-controlled study. PATIENTS: Study subjects comprised of 515 DN patients, and 402 normoalbuminuric (DWN) T2DM patients. MEASUREMENTS: IL-10 genotyping was done by PCR-based assays, and the contributions of the IL-10 polymorphic variants to DN were analysed by haplotype analysis and multivariate regression analysis. RESULTS: Decreased prevalence of (mutant) -819T allele and -819C/T genotype was seen in DN patients; neither the -1082G/A nor the -592C/A polymorphism was associated with DN. Three-loci haplotype (-1082GA/-819CT/-592CA) analysis identified GTC as DN-protective haplotype. Multivariate regression analysis confirmed the association of GTC haplotype (P = 0.045; OR = 0.56, 95% CI: 0.31-0.99), and in addition identified GTA haplotype (P = 0.044; OR = 0.54, 95% CI: 0.30-0.98) as independent predictors of DN after controlling for a number of covariates (age, sex, BMI; hypertension, glucose, HbA1c, DN duration, total cholesterol, medications). CONCLUSION: This study suggests that IL-10 promoter polymorphism influence the risk of nephropathy in Tunisian T2DM patients.

Renal pseudoaneurysm formation post allograft biopsy: a case report.

Renal pseudoaneurysm (PSA) is a rare complication post kidney transplant biopsy that accounts for less than 1% of allograft dysfunction. Imaging guidelines in the diagnosis of renal PSA have not yet been developed owing to the low occurrence and limited data availability. However, contrast-enhanced CT and magnetic resonance angiography (MRA) are the preferred modalities in detecting PSA owing to the high contrast and spatial resolution. However, magnetic resonance angiography is preferred since non-contrast imaging techniques can see blood flow patterns in renal PSA without the use of contrast media that may alter renal function. We present a rare complication in a 48-year-old male receiving a living related kidney transplant and found to have renal PSA post allograft biopsy. We review the clinical features, imaging and treatment outcome with the developed PSA in the transplanted kidney post allograft biopsy.

CMV and BKPyV Infections in Renal Transplant Recipients Receiving an mTOR Inhibitor-Based Regimen Versus a CNI-Based Regimen: A Systematic Review and Meta-Analysis of Randomized, Controlled Trials.

BACKGROUND AND OBJECTIVES: The objective of this meta-analysis is to compare the incidences of cytomegalovirus and BK polyoma virus infections in renal transplant recipients receiving a mammalian target of rapamycin inhibitor (mTOR)-based regimen compared with a calcineurin inhibitor-based regimen. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a comprehensive search for randomized, controlled trials up to January of 2016 addressing our objective. Other outcomes included acute rejection, graft loss, serious adverse events, proteinuria, wound-healing complications, and eGFR. Two review authors selected eligible studies, abstracted data, and assessed risk of bias. We assessed quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation methodology. RESULTS: We included 28 randomized, controlled trials with 6211 participants classified into comparison 1: mTOR inhibitor versus calcineurin inhibitor and comparison 2: mTOR inhibitor plus reduced dose of calcineurin inhibitor versus regular dose of calcineurin inhibitor. Results showed decreased incidence of cytomegalovirus infection in mTOR inhibitor-based group in both comparison 1 (risk ratio, 0.54; 95% confidence interval, 0.41 to 0.72), with high quality of evidence, and comparison 2 (risk ratio, 0.43; 95% confidence interval, 0.24 to 0.80), with moderate quality of evidence. The available evidence neither confirmed nor ruled out a reduction of BK polyoma virus infection in mTOR inhibitor-based group in both comparisons. Secondary outcomes revealed more serious adverse events and acute rejections in mTOR inhibitor-based group in comparison 1 and no difference in comparison 2. There was no difference in graft loss in both comparisons. eGFR was higher in the mTOR inhibitor-based group in comparison 1 (mean difference =4.07 ml/min per 1.73 m2; 95% confidence interval, 1.34 to 6.80) and similar to the calcineurin inhibitor-based group in comparison 2. More proteinuria and wound-healing complications occurred in the mTOR inhibitor-based groups. CONCLUSIONS: We found moderate- to high-quality evidence of reduced risk of cytomegalovirus infection in renal transplant recipients in the mTOR inhibitor-based compared with the calcineurin inhibitor-based regimen. Our review also suggested that a combination of a mTOR inhibitor and a reduced dose of calcineurin inhibitor may be associated with similar eGFR and rates of acute rejections and serious adverse events compared with a standard calcineurin inhibitor-based regimen at the expense of higher incidence of proteinuria and wound-healing complications.

Free versus Fixed Combination Antihypertensive Therapy for Essential Arterial Hypertension: A Systematic Review and Meta-Analysis.

BACKGROUND: In a free drug combination, each Blood pressure (BP)-lowering drug is administered as a separate pill, while in a fixed drug combination several BP-lowering agents are combined in a single pill. Using a single pill may enhance compliance and simplify treatment, which would translate into better clinical outcomes. The objective of this meta-analysis is to compare the effects of using a fixed combination versus free combination of BP-lowering agents in the management of patients with essential hypertension. METHODS: We searched Cochrane CENTRAL, MEDLINE, and EMBASE for randomized clinical trials (RCTs) addressing the objective of the review and assessing at least one of the following outcomes: BP-lowering efficacy, rapidity in achieving BP target, compliance, incidence of side effects, mortality, and morbidity. Two review authors independently selected eligible studies, abstracted data, and assessed risk of bias of included trials. The primary meta-analyses used a random-effects model. RESULTS: We identified seven RCTs with a total of 397 participants. Meta-analysis of efficacy in controlling BP showed a non-significant reduction of mean systolic BP of 0.81 mmHg (95% CI -3.25, 1.64) favoring the fixed combination group. As for adverse events, results showed a non-significant 13% risk reduction favoring the free combination (risk ratio 1.13, 95% CI 0.85, 1.5). Low quality of evidence was noted for both outcomes. Rapidity in achieving BP target was assessed in only one trial, and the results favored the fixed combination. Adherence to treatment was assessed in three trials, no pooled analysis was possible for this outcome. None of the included trials assessed mortality and morbidity. CONCLUSION: The available low quality evidence does not confirm or rule out a substantive difference between fixed combination and free combination therapy in the management of HTN. Well designed RCTs with a long duration of follow-up and assessment of morbidity and mortality outcomes are needed.

Rituximab use in adult primary glomerulopathy: where is the evidence?

Rituximab is a chimeric anti-CD20 antibody that results in depletion of B-cell lymphocytes. It is currently used in the treatment of a variety of autoimmune diseases, in addition to CD20-positive lymphomas. The use of rituximab in the treatment of the adult primary glomerular diseases has emerged recently, although not yet established as first-line therapy in international guidelines. In patients with steroid-dependent minimal change disease or frequently relapsing disease, and in patients with idiopathic membranous nephropathy (IMN), several retrospective and prospective studies support the use of rituximab to induce remission, whereas in idiopathic focal and segmental glomerulosclerosis (FSGS), the use of rituximab has resulted in variable results. Evidence is still lacking for the use of rituximab in patients with immunoglobulin A nephropathy (IgAN) and idiopathic membranoproliferative glomerulonephritis (MPGN), as only few reports used rituximab in these two entities. Randomized controlled trials (RCTs) are warranted and clearly needed to establish the definitive role of rituximab in the management of steroid-dependent and frequently relapsing minimal change disease, IMN, both as first-line and second-line treatment, and in MPGN. We await the results of an ongoing RCT of rituximab use in IgAN. Although current evidence for the use of rituximab in patients with idiopathic FSGS is poor, more RCTs are needed to clarify its role, if any, in the management of steroid-resistant or steroid-dependent FSGS.

Salmonella typhi in a child with urinary tract infection and urolithiasis.

Salmonella species are a rare cause of urinary tract infections in children. They have been associated with a higher incidence of structural abnormalities or immunosuppressive status. We report the case of an 11-year-old girl with urinary tract infection (UTI) secondary to Salmonella typhi and associated with urolithiasis. A review of the subject is then discussed.

Cutaneous aspergillosis in a renal transplant recipient.

Aspergillosis is a serious infection in renal transplant patients especially if dissemination occurs. We report a case of primary cutaneous aspergillosis, an extremely rare entity described in only four cases in renal transplant. It should be sought when surgical wound shows a rapidly growing necrotizing features early post transplant and without evidence of hematogeneous or contiguous tissue or organ involvement. Early suspicion, diagnosis, extensive surgical debridement as well as rapid institution of Amphotericin B can minimize the risk of dissemination.

Current perspectives on combination therapy in the management of hypertension.

Hypertension (HTN) is a worldwide health problem and a major preventable risk factor for cardiovascular (CV) events. Achieving an optimal blood pressure (BP) target for patients with HTN will often require more than one BP-lowering drug. Combination therapy is not only needed, but also confers many advantages such as better efficacy and a better tolerability. A better compliance and simplicity of treatment is noted with the single-pill combination (SPC). In addition, for those patients who do not achieve BP target when receiving dual combinations, triple SPCs are now available, and their efficacy and safety have been tested in large clinical trials. BP-lowering drugs used in combination therapy should have complementary mechanisms of action, leading to an additive BP-lowering effect and improvement in overall tolerability, achieved by decreasing the incidence of adverse effects. On the basis of large, outcome-driven trials, preferred dual combinations include an angiotensin receptor antagonist (ARB) or an angiotensin converting enzyme inhibitor (ACEI) combined with a calcium channel blocker (CCB), or an ARB or ACEI combined with a diuretic. Acceptable dual combinations include a direct rennin inhibitor (DRI) and a CCB, a DRI and a diuretic, a beta-blocker and a diuretic, a CCB and a diuretic, a CCB and a beta-blocker, a dihydropyridine CCB and a non-dihydropyridine CCB, and a thiazide diuretic combined with a potassium-sparing diuretic. Some combinations are not recommended and may even be harmful, such as dual renin angiotensin aldosterone system inhibition. Currently available triple SPCs combine a renin angiotensin aldosterone system inhibitor with a CCB and a diuretic. Combination therapy as an initial approach is advocated in patients with a systolic BP more than 20 mmHg and/or a diastolic BP more than 10 mmHg above target and in patients with high CV risk. In addition, using SPCs has been stressed and favored in recent international guidelines. Recently, triple SPCs have been approved and provide an attractive option for patients not achieving BP target on dual combination. The effect of such a strategy in the overall management of HTN, especially on further reducing the incidence of CV events, will have to be confirmed in future clinical and population-based studies.

Potential mechanisms for renal damage in beta-thalassemia.

Improvement of survival in patients with ß-thalassemia has allowed several clinical morbidities to manifest, including renal complications. Patients may experience proximal tubular dysfunctions and abnormalities in glomerular filtration rate. Several risk factors have been proposed. Hypoxia may lead to renal damage with resulting proximal tubular epithelial cell dysfunction and interstitial fibrosis, while anemia induces renal hemodynamic changes. Iron overload secondary to regular transfusion therapy can also result in an increase in oxidative stress and direct cytotoxicity to the kidney. Moreover, the use of certain iron-chelating agents is associated with a transient, nonprogressive increase in serum creatinine levels. However, most available evidence comes from small, cross-sectional studies. Longitudinal follow-up of patients is needed to better understand the mechanisms of renal abnormalities in this patient population.