Aliskiren: the first direct renin inhibitor available for clinical use

The idea of blocking the renin-angiotensin system (RAS) with the inhibition of the enzymatic activity of renin has been pursued for half a century, but it became a reality only recently, with the synthesis of aliskiren, the first direct renin inhibitor available for clinical use. The upstream blockade of the system induced by aliskiren, in combination with its unique pharmacological properties (inhibiting potency, high plasma concentration, long half-life and preferential partitioning in the kidney) makes this compound the ideal tool to achieve a complete blockade of the RAS. Consistent with expectations, present evidence indicates that aliskiren, at the licensed dosages of 150-300 mg/day, lowers blood pressure to the same extent as other first-line antihypertensive agents, with the additional advantage of a longer duration of action which persists for several days after the cessation of treatment. Moreover, aliskiren was found to act synergically not only with diuretics but also with other drug classes, including angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists. In addition, results of recent clinical trials have shown that aliskiren possesses cardiovascular and renal protective properties which may contribute to the beneficial effects of this drug beyond the reduction of blood pressure. Finally, aliskiren has an excellent, placebo-like tolerability profile, a feature which is very relevant for improving compliance of patients.     

Update on role of direct renin inhibitor in diabetic kidney disease

Background: Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD). Renin–angiotensin–aldosterone system (RAAS) plays a critical role in the development of DKD with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) being the mainstay of treatment. Systemic RAAS activity has been implicated in the pathogenesis of DKD, but lately interest has shifted to intrarenal RAAS effect. With the discovery of the (pro)renin receptor and ACE independent pathways of angiotensin II production, our understanding of role of renin in end organ damage has improved significantly. Summary: We summarize our current understanding of ACE dependent and independent pathways in the development of DKD and the preclinical models demonstrating renal effects of direct renin inhibitors (DRIs). We then review clinical studies and trials performed so far evaluating the efficacy of aliskiren on renal outcomes and safety in DKD. Key message: At present, there is little evidence for renal benefit of aliskiren in DKD beyond that offered by ACEIs or ARBs. Combining aliskiren with ACEI or ARB in DKD did not significantly improve renal outcomes in comparison with ACEI or ARB monotherapy in clinical trials. Slightly more adverse events including hyperkalemia, acute kidney injury and hypotension were observed in the combination therapy as compared to the monotherapy. Thus, current evidence suggests that aliskiren, because of its antihypertensive and antiproteinuric effects, maybe used as monotherapy in DKD and considered an equivalent alternative to ACEIs or ARBs. Careful monitoring for renal adverse effects would allow safe clinical use of DRI.     

Local delivery of a direct renin inhibitor into the kidney ameliorates progression of experimental glomerulonephritis

Background

Increasing evidence indicates that locally blocking renin–angiotensin system activity exerts a beneficial effect on glomerulonephritis (GN) progression leading to irreversible glomerulosclerosis. This is the first study on the pharmacological effect of the renal delivery of aliskiren, a direct renin inhibitor, in a progressive model of anti-Thy-1 GN.

Methods

Local blockade of renin activity was accomplished by subrenal capsular implantation of a collagen sponge with aliskiren. The pharmacological effect was evaluated by semiquantitative and quantitative analysis of immunohistological findings and by analysis of glomerular microcirculation using an intravital microscope system.

Results

Quantitative mesangial matrix analysis showed that local treatment with aliskiren significantly suppressed mesangial matrix expansion and ameliorated the glomerular sclerotic index in the progressive model of ATS GN. Immunofluorescent studies revealed that renin expression at the juxtaglomerular region was enhanced in the ATS?+?aliskiren group, and pathological expressions of α-smooth muscle cell actin and type I collagen in ATS GN were remarkably decreased by local treatment with aliskiren. Furthermore, local delivery of aliskiren significantly improved glomerular blood flow levels.

Conclusion

This study revealed that renally delivered aliskiren has a renoprotective effect on potentially progressive glomerulosclerosis.     

Low peripheral plasma renin activity as a critical marker in pediatric hypertension

In evaluating hypertensive children and adolescents, the etiological considerations should include a set of inherited disorders that share very low plasma renin activity (PRA) as a common feature. In particular among these disorders, glucocorticoid remediable aldosteronism (GRA) appears to be emerging as an important etiology of hypertension in the pediatric population. We report the evaluation of a 9-year-old Caucasian girl who presented with severe hypertension and a strong family history of early-onset hypertension. Her suppressed PRA, her family history, and her failure to respond to conventional antihypertensive therapy raised GRA as a potential etiology. The diagnosis was confirmed by an elevated ratio of urinary 18-oxotetrahydrocortisol to urinary tetrahydroaldosterone and genetic testing, which demonstrated the chimeric gene duplication. The molecular pathogenesis of GRA and the clinical implications are reviewed. Received May 15, 1996; received in revised form and accepted September 16, 1996     

BK virus infection,replication, and diseases in pediatric kidney transplantation

Polyomavirus-associated nephropathy is diagnosed in 2–8% of pediatric renal transplants and often precedes renal allograft dysfunction. Without intervention, however, significant graft dysfunction is observed in more than 50% of cases, although progressive early graft loss is reported in only three of 32 (9%) of cases. No specific treatment is available, but early decrease in immunosuppression is followed by declining human polyomavirus type 1 (BK virus) replication and improved outcome. The data suggest differences between pediatric and adult kidney transplantation. Possibly, pediatric patients might be able to mount a more vigorous BK virus-specific immune response than adult patients under similar modulation of immunosuppression. Also the role of cidofovir and leflunomide is still unresolved in pediatric patients. Larger prospective trials are needed to better define the impact of BK virus immunity for replication and disease as well as the role of reducing immunosuppression with or without cidofovir or leflunomide in pediatric transplant patients.     

Effect of renin inhibitor (ES-1005) on expression of the kidney renin gene in sodium-depleted marmosets

Effect of renin inhibitor ES-1005 or captopril on the renin synthesis by the kidney was investigated in sodium-depleted marmosets. The level of kidney renin mRNA was measured after 2-hour (acute study) and one-week (chronic study) administrations of the two agents. Relative amounts of kidney renin mRNA were measured by densitometric Northern blot analysis using an alpha-32P-labelled human renin cDNA fragment as a hybridization probe. In the acute study, treatment with captopril significantly increased plasma renin activity (PRA) (p less than 0.05), but did not change the level of kidney renin mRNA. In the chronic study, treatment with captopril markedly increased PRA as well as the level of kidney renin mRNA (4.7-fold and 6.3-fold increases, respectively). In contrast, treatment with ES-1005 completely inhibited PRA and significantly suppressed the level of kidney renin mRNA in both acute and chronic studies (about one-third of the normal control, p less than 0.05). These results suggest that renin inhibitor ES-1005 not only inhibits plasma renin activity but also suppresses the synthesis of renin by the kidney.     

Idiopathic intracranial hypertension immediately after kidney transplantation in a pediatric recipient

Idiopathic intracranial hypertension, characterized by headache, visual disturbance, papilledema, and increased intracranial pressure in the absence of space-occupying lesions, has been reported in pediatric recipients several months to years following kidney transplantation (KTx). We describe the development of idiopathic intracranial hypertension in a 10-year-old girl in the first few hours after KTx. We hypothesize that this event was associated with thymoglobulin administration, perhaps on the background of growth hormone therapy. Awareness of this possibility could lead to earlier diagnosis and treatment of children with similar risk factors.     

The role of the kidney in salt-sensitive hypertension

Primary hypertension is one of the leading risk factors for cardiovascular disease. Although the pathogenesis is not completely understood, an imbalance of sodium and chloride homeostasis seems to be relevant both in the induction and in the maintenance of salt-sensitive hypertension. Besides individual renal phenotypes, salt intake is one of the most important environmental determinants of this condition. The Milan hypertensive strain (MHS) of rats is an interesting model to investigate the molecular mechanisms underling the development of salt-sensitive hypertension. In young MHS rats, hypertension is anticipated by a phase of increased salt reabsorption localized along the medullary thick ascending limb associated with the up-regulation of the apical sodium−potassium−chloride cotransporter (NKCC2). Later, the frank hypertensive status of adult MHS rats is accompanied by the activation of the luminal and basal lateral transporters of sodium chloride (NaCl) in the distal convoluted tubule (DCT). Several lines of evidence have proven the key role of DCT in the maintenance of hypertension in MHS rats; more importantly, hypertensive patients carrying a mutation of α-adducin (resembling the MHS model) have a high sensitivity to thiazides, suggesting that the Na⁺–Cl⁻ cotransporter also plays a pivotal role in humans.     

Cytomegalovirus infection in the first year after pediatric kidney transplantation

Cytomegalovirus is common in adult recipients (prevalence of 40–90%). Children are typically seronegative but immunosuppression may prone to primary-infection or viral reactivation, with potentially severe consequences. CMV infection incidence in pediatric kidney transplant recipients has seldom been investigated. The aim of our study was to evaluate the incidence and timing of CMV infection during the first year after renal transplantation. We assembled a retrospective cohort of 136 children who had received a kidney transplant between 2003 and 2014 with a year follow-up. The patients were classified regarding CMV infection as high risk (D+/R?), intermediate risk (R+) or low risk (D?/R?). CMV infection was defined by the viral replication remaining asymptomatic whereas CMV disease concerned viral replication with clinical and/or biological symptoms. Oral valganciclovir was used as prophylaxis for high-risk recipients. A total of 38 patients (27.9%) developed CMV infection, 13 (40.6%) of the 32 D+/R?, 24 (45.3%) of the 53 R+ and 1 (2.0%) of the 51 D?/R?. Of these 38 infected patients, 10 developed tissue-invasive disease. During the first year after kidney transplantation, 27.9% of recipients developed CMV infection. This study confirms the influence of donor and recipient CMV status on infection propensity and highlights the importance of adequate follow-up for intermediate risk patients.     

Early-onset coronary artery disease after pediatric kidney transplantation: implicating the angiogenesis inhibitor, endostatin

Pediatric kidney transplant recipients have a higher rate of coronary artery disease (CAD) as adults. The angiogenesis inhibitor, endostatin, has been implicated in the development of atherosclerosis. Endostatin levels will vary between adult patients who received a kidney transplant as a child. We conducted a study in young adult patients who had undergone pediatric kidney (n = 12) or liver transplantation (n = 8). Coronary arterial calcification was measured using electron beam CT. Values were compared with age-matched control subjects from an epidemiologic database. Serum endostatin levels were measured using enzyme-linked immunosorbent assay. Risk factors for atherosclerosis were assessed. Kidney transplant recipients had a higher rate of CAD compared with liver transplant recipients (33 vs 0%, P = 0.03). Mean (± standard error of mean) serum endostatin levels were higher in kidney transplant recipients compared with liver transplant recipients (26 ± 7 vs 14 ± 3 ng/mL, P = 0.04) and control subjects (26 ± 7 vs 11 ± 1 ng/mL, P = 0.01). Pediatric kidney transplantation is associated with a higher rate of adult-onset CAD compared with liver transplantation. Endostatin levels were greater in kidney transplant recipients compared with liver transplant recipients and healthy control subjects. Endostatin may play a role in the development of atherosclerosis after kidney transplantation and may serve as a biomarker for atherosclerotic disease.     

Genetic kidney diseases in the pediatric population of southern Israel

Genetic kidney diseases (GKDs) are an important and well-known entity in pediatric nephrology. In the past decade advances in genetic and molecular approaches have enabled elucidation of the underlying molecular defects in many of these disorders. Herein we summarize the progress that has been made over the past decade in disclosing the molecular basis of several novel GKDs, which were characterized in our area and include Bartter syndrome type IV, type II Bartter syndrome and transient neonatal hyperkalemia, cystinuria and mental retardation, familial hypomagnesemia with secondary hypocalcemia, infantile nephronophthisis, familial hemolytic uremic syndrome with factor H deficiency, and non-cystic autosomal dominant nephropathy. Retrospective analysis of our data reveals that GKDs are over-represented among the pediatric population in southern Israel. GKDs are seen four-times more often than end-stage renal disease (ESRD) and comprise 38% of all cases of ESRD in our area. This high rate of GKDs is mainly due to the high frequency of consanguineous marriages that prevails in this area. Understanding of the genetic and molecular background of these diseases is a result of a fruitful collaboration between the pediatric nephrologists and scientists, and has a direct implication on the diagnosis and treatment of the affected families.     

Pathophysiology of essential hypertension: role of the pump, the vessel, and the kidney.

Essential hypertension is characterized by significant and persistent elevations in arterial pressure. Hypertension is a multifactorial disorder that may involve abnormalities in the functions of the heart pump, the blood vessels, and the kidneys. Short-term and long-term regulation of arterial pressure is influenced by changes in cardiac function, the peripheral vascular resistance, and the renal control mechanisms of plasma electrolytes and volume. Increases in the heart rate and stroke volume lead to increases in the cardiac output and could contribute to increases in arterial pressure particularly in relatively young individuals. Vascular endothelial cell dysfunction could lead to reduction in endothelium-derived relaxing factors such as nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor, or increased production of contracting factors such as endothelin-1 and thromboxane A2. Also, increased activity of signaling pathways of vascular smooth muscle contraction such as [Ca(2+)]i, protein kinase C, mitogen-activated protein kinase, and Rho kinase could enhance vasoconstriction. The decreased vascular relaxation and excessive vasoconstriction lead to significant increases in the peripheral vascular resistance and arterial pressure over time, particularly with aging. Alterations in body fluid regulation by the kidneys could lead to salt and water retention, increased plasma volume, and cardiac output. Also, activation of the renin-angiotensin system increases the levels of angiotensin II in the plasma, leading to generalized vasoconstriction, or locally in the kidneys, leading to salt and water retention. Individual changes in cardiac, vascular, or renal function seldom occur separately, and, if so, they may lead to mild or moderate increases in arterial pressure. Combined alterations in cardiac, vascular, and renal functions are more common and are often associated with pathologic increases in arterial pressure and established hypertension.     

The kidney in the pathogenesis of hypertension: the role of sodium

In this review, we first summarize the evidence which indicates that the inability of the kidney to excrete salt and water normally, particularly when combined with increased salt intake, is frequently associated with hypertension. We then concentrate on the link between sodium and water retention and hypertension. The increase in blood pressure probably results from the increase in volume rather than from the increase in salt. Recent evidence suggests that an increase in volume in the lesser circulation stimulates the release of a sodium pump inhibitor, probably the putative natriuretic hormone, from the hypothalamus. This agent appears to affect cardiac and vascular smooth muscle by suppressing Na+,K+-ATPase, and hence Na+-K+ pump activity in both muscle cells and adrenergic nerve terminals. The sodium pump inhibitor is a heat stable small molecule but its chemical structure is still unknown. It is clearly different from atrial natriuretic factor. We conclude the review with speculations on the possible role of renotropin and various growth and growth inhibitory factors in the vascular structural changes.     

Cardiovascular diseases in kidney transplant recipients: the role of anemia

Cardiovascular diseases are among the leading causes of mortality and death associated graft loss in kidney transplant recipients. Recently, there has been an increased awareness of the potential role of nontraditional risk factors such as anemia in contributing to the increased burden of cardiovascular diseases in kidney transplant recipients. Studies that are primarily based on retrospective data analyses have shown an association between anemia and cardiovascular outcomes. These findings underscore the need for prospective studies to better understand these risks and to implement management strategies that would have a positive impact on patient and graft outcomes. On the basis of the available data, this article reviews the magnitude of cardiovascular diseases and anemia in kidney transplant recipients with a focus on the role of anemia on cardiovascular outcomes in these patients.     

Graft outcomes in pediatric kidney transplantation: focus on the role of race

While significant racial disparities in graft outcome persist among adult and pediatric kidney transplant recipients in the US, some international studies do not show these differences. The aim of this study is to examine predictors of graft outcomes and the impact of race in our pediatric kidney transplant cohort. Records of 109 pediatric kidney transplant recipients performed at our institution between 7/99 and 4/07 were studied. Patients were grouped based on race: African-American (AA) vs. non-AA. Fifty-five AA (12 ± 5 years) and 54 non-AA patients (11 ± 6 years) were studied. There were more females, pre-emptive transplants and living donors in the non-AAs. Survival analysis showed significantly higher rejection rates in AAs, P = 0.02, and lower unadjusted graft survival (P = 0.09). Cox Proportional Hazards Survival Regression Analysis revealed biopsy-proven acute rejection and delayed graft function contributed to worse graft survival, while pre-emptive transplantation had a favorable effect. Race was not an independent risk factor for decreased graft survival in the final model. In conclusion, our cohort showed several modifiable risk factors that can partially account for poorer graft survival in pediatric AA kidney transplant recipients.     

The kidney in the pathogenesis of hypertension: the role of renal nerves

The intrinsic efferent innervation of the kidney consists of exclusively noradrenergic fibers that innervate the preglomerular and postgomerular vasculature, all elements of the juxtagomerular apparatus and virtually all segments of the nephron in both cortical and medullo-papillary regions. Increases in efferent renal sympathetic nerve activity produce renal vasoconstriction, release of renin, catecholamines, prostaglandins and other vasoactive substances, and increases in renal tubular sodium reabsorption; these responses are graded and differentiated. The intrinsic afferent innervation of the kidney consists of mechanoreceptors and chemoreceptors which participate in reno-renal and reno-systemic reflexes that modulate sympathetic neural outflow in an organ-specific differentiated pattern. Therefore, alterations in efferent and afferent renal nerve activity produce changes in several important renal functions known to contribute to the development and maintenance of hypertension.     

Xenotransplantation of the kidney: a pediatric perspective

The major factor limiting the application of allotransplantation for the treatment of renal failure is a severe shortage of donor organs. One approach to overcoming this limitation is the use of kidneys from animals for clinical transplantation, that is xenotransplantation. Although of interest for many years, the application of xenotransplantation has been prevented because of the devastating immune responses of the recipient against the graft. Research conducted in recent years has elucidated the immune mechanisms underlying the rejection of xenografts and has led to the development of incisive therapeutic strategies, including the genetic engineering of donor animals. Success in dealing with the xenogeneic immune response has encouraged the view that xenotransplantation might be feasible in the near future. It also raises consideration of two additional hurdles, the potential limitations of xenogeneic kidneys as physiological replacement for human kidneys and the possibility that the animal organ might transfer infectious organisms to the recipient and to the wider population. This paper reviews recent progress in the field of xenotransplantation of the kidney and offers a perspective on the hurdles to clinical application that remain. Received: 8 December 1998 / Revised: 4 February 1999 / Accepted: 8 February 1999