Nitric oxide and renal perfusion in humans.
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Endothelium, Vascular↗
Biomedical subjects
Giuseppe Remuzzi
Publications and source records attributed to Giuseppe Remuzzi.
Routine renin-angiotensin system blockade in renal transplantation?
There is ample evidence to support the recommendation of renin-angiotensin system blockade therapy as the standard of care for strategies aimed at preserving renal function in chronic renal disease. Nevertheless, despite the well established antihypertensive effects of these drugs, the use of renin-angiotensin system blockers in renal transplantation has been quite limited so far, nephrologists being afraid of the possibility of inducing renal insufficiency in patients with a single kidney transplant. However, current knowledge of the ability of these agents to control blood pressure and urinary protein excretion, as well as post-transplant erythrocytosis, effectively in kidney transplant recipients suggests that it is now time to apply renin-angiotensin system blockers to the field of renal transplantation.
Angiotensin Receptor Antagonists↗
Halting the progression of chronic nephropathy.
The incidence of end-stage renal disease (ESRD) is increasing worldwide. In the United States alone, there were 372,000 patients requiring renal replacement therapy in the year 2000 and is expected to rise to 650,000 by the year 2010. The trends in Europe and Japan are forecasted to follow a similar path. These increases represent a significant burden to countries worldwide; not only due to the financial costs of providing ESRD care, but also because of lost productivity and significant morbidity and mortality for the affected patients. There is clearly a pressing need for the aggressive identification and early treatment of patients with nephropathy to prevent progression to ESRD. Research in the last 25 yr has made great advances in the understanding of the progression of chronic renal disease in diabetic and nondiabetic proteinuric nephropathy. There are now effective treatment options that can slow the progression of chronic nephropathies in many individuals, and ongoing research has raised the tantalizing prospect of the reversal of renal disease progression.
Chronic Disease↗
How to fully protect the kidney in a severe model of progressive nephropathy: a multidrug approach.
The current therapy for chronic proteinuric nephropathies is angiotensin-converting enzyme inhibitors (ACEi), which slow, but may not halt, the progression of disease, and which may be not effective to the same degree in all patients. In accelerated passive Heymann nephritis (PHN), this study assessed the effect of combining ACEi with angiotensin II receptor antagonist (AIIRA) and with statin that, besides lowering cholesterol, influences inflammatory and fibrogenic processes. Uninephrectomized PHN rats were divided into four groups (n = 10 each) and daily given oral doses of the following: vehicle; 40 mg/L lisinopril; 100 mg/L lisinopril plus L-158,809; 0.3 mg/kg lisinopril plus L-158,809 plus cerivastatin. Treatments started at 2 mo when rats had massive proteinuria and signs of renal injury and lasted until 10 mo. Increases in BP were equally lowered by treatments. ACEi kept proteinuria at levels comparable to pretreatment and numerically lower than vehicle. The addition of AIIRA to lisinopril was more effective, being proteinuria reduced below pretreatment values and significantly lower than vehicle. When cerivastatin was added on top of ACE inhibition and AIIR blockade, urinary protein regressed to normal values and renal failure was prevented. Renal ACE activity was increased threefold in PHN, it was inhibited by more than 60% after ACEi, and decreased below control values with triple therapy. Cerivastatin inhibited ACE activity by 30%. Glomerulosclerosis, tubular damage and interstitial inflammation were ameliorated by ACEi alone or combined with AIIRA, and prevented by addition of statin. TGF-beta(1) mRNA upregulation in PHN kidney was partially reduced after ACEi or combined with AIIRA and almost normalized after adding statin. Cerivastatin inhibited TGF-beta(1) gene upregulation by 25%. These data suggest a possible future strategy to induce remission of proteinuria, lessen renal injury, and protect from loss of function in those patients who do not fully respond to ACEi therapy.
Angiotensin Receptor Antagonists↗
Xenotransplantation in the 21st century.
Xenotransplantation, i.e. transplantation across species, is increasingly being viewed a potential solution to the problem of severe shortage of transplant donors. Clinical application of xenotransplantation is, however, limited in large part by the pre-eminent hurdle of the immune response of the recipient against the graft. This immunologic reaction is mediated initially by natural xenoreactive antibodies, complement and natural killer cells, and later by elicited humoral and cellular immune responses that ultimately lead to graft failure. Progress in understanding the cellular and molecular basis of xenograft rejection has characterized the past few years. Additional hurdles to xenotransplantation include physiologic incompatibility of the transplant and the risk of infections. The recent development of novel strategies to overcome xenograft rejection has brought about great optimism that xenotransplantation may be attainable in the near future.
Animals↗
Effect of hemodynamic conditions on arteriovenous fistula for hemodialysis access.
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Arteriovenous Shunt, Surgical↗
Podocyte number in normotensive type 1 diabetic patients with albuminuria.
We estimated glomerular cell number in 50 normotensive type 1 diabetic patients with raised albumin excretion rate (AER) and investigated any change after 3 years in a subgroup of 16 placebo-treated patients. Biopsies from 10 normal kidney donors were used as controls. Mesangial and endothelial cell number was increased in the 50 diabetic patients at the start of the study compared with control subjects. There was no difference in podocyte number. Glomerular volume was increased in diabetic patients, but surface area of glomerular basement membrane (GBM) underlying the podocytes did not differ between groups. AER correlated positively with mesangial cell number in microalbuminuric patients (r = 0.44, P = 0.012) and negatively with podocyte number in proteinuric patients (r = -0.48, P = 0.040). In the 16 placebo-treated patients, glomerular volume increased after 3 years owing to matrix accumulation and increased GBM surface area. Although overall cell number did not differ significantly from baseline, the decrease in podocyte number during follow-up correlated with AER at follow-up (r = -0.72, P = 0.002). In conclusion, cross-sectional analysis of podocyte number in type 1 diabetic patients with raised AER but normal blood pressure shows no significant reduction compared with nondiabetic control subjects. Longitudinal data provide evidence for an association between podocyte loss and AER, but whether cellular changes are a response to, a cause of, or concomitant with the progression of nephropathy remains uncertain.
Adult↗
Hyperhomocysteinemia and increased risk of retinopathy: a cross-sectional, case-control study in patients with type 2 diabetes.
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Age of Onset↗
Protein overload-induced NF-kappaB activation in proximal tubular cells requires H(2)O(2) through a PKC-dependent pathway.
Abnormal traffic of proteins through the glomerular capillary has an intrinsic toxicity that results in tubular dysfunction and interstitial inflammation. It has been previously shown that in porcine proximal tubular cells high concentrations of albumin activated NF-kappaB, which is responsible for the enhanced synthesis of the inflammatory chemokine RANTES. This study investigates whether reactive oxygen species (ROS) served as second messengers in protein overload-induced NF-kappaB activation. Human proximal tubular cells (HK-2) were incubated (5 to 60 min) with human albumin and IgG (1 to 30 mg/ml). Both proteins induced a rapid or significant increase in hydrogen peroxide (H(2)O(2)) production at 5 min and persisting at 60 min. This effect was dose-dependent. The contribution of H(2)O(2) in regulating NF-kappaB activation was evaluated by using the antioxidants dimethyl-thiourea and pyrrolidine dithiocarbamate in protein-overloaded HK-2 cells. Both agents, by preventing H(2)O(2) generation, induced human albumin or IgG inhibited NF-kappaB activation. Stimulation of HK-2 with exogenous H(2)O(2) resulted in the activation of a NF-kappaB subunit pattern similar to that obtained after protein challenge. Specific inhibitors of protein kinase C (PKC) activity significantly prevented H(2)O(2) production and consequent NF-kappaB activation, suggesting that ROS generation in HK-2 cells occurs downstream of PKC activation. Either antioxidants or PKC inhibitor almost completely abolished the upregulation of the monocyte chemoattractant protein-1 gene induced by excess albumin, as evaluated by real-time PCR, thus supporting a role for PKC and ROS as critical signals for the expression of NF-kappaB-dependent inflammatory genes. To identify the enzymatic sources responsible for the increased H(2)O(2) production, the effect of dyphenyleneiodonium, an inhibitor of the membrane NADP(H) oxidase, was studied, as was the effect of rotenone, which blocks complex I of the mitochondrial respiratory chain. It was found that both agents significantly reduced the exaggerated H(2)O(2) induced by protein overload. These data indicate that exposure to excess proteins in proximal tubular cells induces the formation of ROS, which are responsible for NF-kappaB activation and consequent induction of NF-kappaB-dependent inflammatory signals.
Analysis of Variance↗
The renin-angiotensin system in progression, remission and regression of chronic nephropathies.
Chronic proteinuric nephropathies may progress to end-stage renal disease (ESRD) through a series of events relatively independent of the initial insult that causes parenchymal damage when the injury involves a critical number of nephrons. The key event is enhanced glomerular capillary pressure, which, among other effects, impairs glomerular permeability to proteins, which reach the lumen of the proximal tubule. In this pathological process angiotensin II has a central role. Reabsorption of filtered proteins contributes to the interstitial injury by activating intracellular events, including upregulation of vasoactive and inflammatory genes. Both interstitial inflammation and progression of disease can be limited by angiotensin-converting enzyme (ACE) inhibitors that strengthen the glomerular permeability barrier to proteins, thus limiting proteinuria and filtered protein-dependent inflammatory signals. Clinical evidence suggests that remission is now achievable in some patients with chronic nephropathies. The current lag time between starting treatment and remission, however, is such that a substantial proportion of patients still progress to ESRD before their renal function begins to stabilize. A multimodal approach aimed at reducing or abolishing all the risk factors for progression may shorten the time to remission for the majority of patients with proteinuric nephropathies.
Angiotensin II↗
Thrombotic microangiopathy in renal transplantation.
The term thrombotic microangiopathy (TMA) encompasses syndromes of thrombocytopenia, microangiopathic haemolytic anaemia, neurologic deficits, renal dysfunction and variable signs of organ impairment. Childhood cases of TMA with predominant renal failure are usually referred as Haemolytic Uremic Syndrome (HUS), and adult cases with major neurological involvement as Thrombotic Thrombocytopenic Purpura (TTP). Exotoxins, produced in most cases by E. Coli O 157:H7, have been related to diarrhea associated HUS(D + HUS). Anticancer (mitomycin), immunosuppressive drugs (cyclosporin, tacrolimus and OKT3) and as well as some antiplatelet agents (ticlopidine, clopidrogel) have been associated with both HUS and TTP. Defective factor H or vWF protease activity have been found with familiar and recurrent forms. Endothelial damage and dysfunction is most likely the initial event of the pathogenic process that eventually leads to platelet aggregation, microvascular thrombosis and tissue ischemia. TMA may occur de novo in the native kidneys of patients who received a non-kidney transplant or in the transplanted kidney of patients who progressed to ESRD because of a disease other than HUS. Calcineurin inhibitors and vascular rejection are most often involved in these cases. The disease may also recur on the transplanted kidney in patients who progressed to ESRD because of HUS/TTP. The risk of postransplant recurrence is negligible for D + HUS but is close to 100% in familial/recurrent forms associated with low C3 and decreased factor H bioavailability or activity. Withdrawal or treatment of precipitating factors are the most effective approach. Plasma therapy is usually attempted with the rationale to limit the microangiopathic process, but its efficacy for improving graft survival is unproven. The outcome of recurrent forms is almost invariably poor.
Hemolytic-Uremic Syndrome↗
Thymic microchimerism correlates with the outcome of tolerance-inducing protocols for solid organ transplantation.
This study found that pretransplant infusion of donor peripheral blood leukocytes, either total leukocytes (peripheral blood leukocytes) or peripheral blood mononuclear cells (PBMC), under appropriate immunomodulating conditions was more effective than donor bone marrow (BM) in prolonging the survival of rats that received kidney grafts. A higher percentage of MHCII(+) cells was found in donor PBMC than in BM cells, and depletion of MHCII(+) cells from donor PBMC abolished their tolerogenic potential. By the analysis of microchimerism in rats infused with donor cells and killed at different time points thereafter, the better tolerogenic potential of leukocyte infusion related to a higher capability of these cells to engraft the recipient thymus. PCR analysis on OX6-immunopurified cells revealed the presence of donor MHCII(+) cells in the thymus of these animals. The role of intrathymic microchimerism was reinforced by findings that thymectomy at the time of transplant prevented tolerance induction by donor leukocytes. Donor DNA was found in the thymus of most long-term graft animals that survived, but in none of those that rejected their grafts. The presence of intrathymic microchimerism correlated with graft survival, and microchimerism in other tissues was irrelevant. PCR analysis of DNA from thymic cell subpopulations revealed the presence of donor MHCII(+) cells in the thymus of long-term surviving animals. Thus, in rats, donor leukocyte infusion is better than donor BM for inducing graft tolerance, defined by long-term graft survival, donor-specific T cell hyporesponsiveness, and reduced interferon gamma production. This effect appears to occur through migration of donor MHCII(+) cells in the host thymus.
Animals↗
ACE inhibitors to prevent end-stage renal disease: when to start and why possibly never to stop: a post hoc analysis of the REIN trial results. Ramipril Efficacy in Nephropathy.
In this post hoc, secondary analysis of the Ramipril Efficacy In Nephropathy (REIN) trial, an angiotensin-converting enzyme (ACE) inhibition risk/benefit profile was assessed in 322 patients with nondiabetic, proteinuric chronic nephropathies and different degrees of renal insufficiency. The rate of GFR decline (Delta GFR) and the incidence of end-stage renal disease (ESRD) during ramipril or non-ACE inhibitor treatment were compared within three tertiles of basal GFR. Delta GFR was comparable in the three tertiles, whereas the incidence of ESRD was higher in the lowest tertile than in the middle and highest tertiles. Ramipril decreased Delta GFR by 22%, 22%, and 35% and the incidence of ESRD by 33% (P < 0.05), 37%, and 100% (P < 0.01) in the lowest, middle, and highest tertiles, respectively. Delta GFR reduction was predicted by basal systolic (P < 0.0001), diastolic (P = 0.02), and mean (P < 0.001) BP and proteinuria (P < 0.0001) but not by basal GFR (P = 0.12). ESRD risk reduction was predicted by basal proteinuria (P < 0.01) and GFR (P < 0.0001) and was strongly dependent on treatment duration (P < 0.0001). Adverse events were comparable among the three tertiles and within each tertile in the two treatment groups. Thus, disease progression and response to ACE inhibition do not depend on severity of renal insufficiency. The risk of ESRD and the absolute number of events saved by ACE inhibition is highest in patients with the lowest GFR. However, renoprotection is maximized when ACE inhibition is started earlier and when long-lasting treatment may result in GFR stabilization and definitive prevention of ESRD.
Adult↗
The molecular basis of familial hemolytic uremic syndrome: mutation analysis of factor H gene reveals a hot spot in short consensus repeat 20.
The aim of the present study was to clarify whether factor H mutations were involved in genetic predisposition to hemolytic uremic syndrome, by performing linkage and mutation studies in a large number of patients from those referred to the Italian Registry for Recurrent and Familial HUS/TTP. PCR and Western blot analyses were conducted to characterize the biochemical consequences of the mutations. Five mutations in the factor H gene were identified. Three, identified in two families and in a sporadic case, are heterozygous point mutations within the most C-terminal short consensus repeat 20 (SCR20) of factor H, resulting in single amino acid substitutions. The other two mutations introduce premature stop codons that interrupt the translation of factor H. A heterozygous nonsense mutation was identified in SCR8 in one family, and a homozygous 24-bp deletion within SCR20 was identified in a Bedouin family with a recessive mode of inheritance. Reverse transcription-PCR analysis of cDNA from peripheral blood leukocytes from the Bedouin family showed that the deletion lowered factor H mRNA levels. Although heterozygous mutations were associated with normal factor H levels and incomplete penetrance of the disease, the homozygous mutation in the Bedouin family resulted in severe reduction of factor H levels accompanied by very early disease onset. These data provide compelling molecular evidence that genetically determined deficiencies in factor H are involved in both autosomal-dominant and autosomal-recessive hemolytic uremic syndrome and identify SCR20 as a hot spot for mutations in the disease. The mutations identified here give an important hint to the relevance of the C-terminus of factor H in the control of the alternative complement activation pathway.
Amino Acid Sequence↗
Blocking angiotensin II synthesis/activity preserves glomerular nephrin in rats with severe nephrosis.
Angiotensin-converting enzyme inhibitors restore size-selective dysfunction of the glomerular barrier in experimental animals and humans with proteinuric nephropathies, although the structural and molecular determinants of such an effect are not completely understood. This study used an accelerated model of experimental nephrosis to assess nephrin gene and protein expression in the kidney and the possible modulating effect of drugs that block angiotensin II (AII) synthesis/activity. Passive Heymann nephritis (PHN) and control animals were studied at day 7, month 4, and month 8. Additional PHN rats were treated with lisinopril or AII receptor blocker L-158,809 and studied at 8 mo. Lisinopril and L-158,809 controlled BP, prevented proteinuria, and protected PHN animals from renal injury. An intense signal of nephrin mRNA was detected in glomeruli of control animals mainly restricted to podocytes. In PHN rats, nephrin staining progressively and remarkably decreased with time. Lisinopril and L-158,809 fully prevented the decrease in nephrin transcripts to levels comparable to those of control rats. Consistent with nephrin mRNA expression, immunostaining of the protein showed a progressive decrease in kidneys from PHN rats that was completely abolished by lisinopril and L-158,809. In summary, progressive renal injury was associated with downregulation of nephrin gene that was totally prevented by angiotensin-converting enzyme inhibitor and AII receptor blocker, suggesting that renoprotection afforded by drugs that interfere with AII synthesis/activity was related to an effect on nephrin assembly.
Angiotensin II↗
Combined treatment with mycophenolate mofetil and an angiotensin II receptor antagonist fully protects from chronic rejection in a rat model of renal allograft.
Antigen-dependent and antigen-independent factors have been implicated in the pathophysiology of chronic allograft rejection, but their relative role is not well established. In the Fisher 344-->Lewis rat kidney transplant model, we sought (1) to compare the relative efficacy of the novel immunosuppressant, mycophenolate mofetil (MMF), with that of the AT1 receptor blocker, losartan, in preventing the development of chronic graft rejection when given for 52 wk; (2) to examine whether combining MMF with losartan affords better protection than each of the drugs alone. For comparison, the effect of cyclosporine (CsA) to control chronic graft rejection was also assessed. Administration of MMF alone or losartan alone to the kidney allografted rats resulted in a partial decrease in the amount of proteinuria, preservation of glomerular and tubulo-interstitial graft structure, limitation of intragraft cell infiltration, and improvement of graft survival compared with corresponding parameters in untreated, transplanted control rats. Combined treatment with MMF and losartan completely prevented the development of proteinuria, largely reduced glomerular and tubulointerstitial injury, and suppressed intragraft cell infiltration, and all animals survived at the end of the follow-up. Similarly, CsA treatment largely prevented graft injury but failed to achieve 100% animal survival. We have shown that MMF synergizes with the angiotensin II receptor antagonist, losartan, in simultaneously targeting complementary pathways of chronic allograft rejection. Combining MMF and angiotensin II receptor blocker offers superior long-term renoprotection as compared with CsA. Together, these findings provide the basis to prevent chronic injury and progressive dysfunction after renal transplantation.
Angiotensin Receptor Antagonists↗
Chronic proteinuric nephropathies. II. Outcomes and response to treatment in a prospective cohort of 352 patients: differences between women and men in relation to the ACE gene polymorphism. Gruppo Italiano di Studi Epidemologici in Nefrologia (Gisen)
In the Ramipril Efficacy in Nephropathy study, ramipril decreased the rate of GFR decline (deltaGFR) and progression to end-stage renal disease (ESRD) in 352 patients with proteinuric chronic nephropathies. This study investigated whether in these patients disease outcome and response to treatment were affected by gender or insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene. deltaGFR (0.43 +/- 0.05 versus 0.48 +/- 0.08 ml/min per 1.73 m2) and incidence of ESRD (23 and 22%, respectively) were comparable in male and female patients. However, compared to conventional treatment, ramipril decreased deltaGFR (-52% versus -19%) and progression to ESRD (-74% versus -40%) more effectively in women than in men. Thus, the relative risk (95% confidence interval [CI]) of events (ESRD) between conventional and ramipril treatment was 5.52 (1.59 to 19.17, P = 0.003) in women, but only 1.80 (1.08 to 2.97, P = 0.02) in men. This gender-related effect of ramipril was associated with more reduction in proteinuria (-7.8 +/- 4.2% versus -21.9 +/- 5.7%, P = 0.05) and was still evident even after correction for potentially confounding factors such as baseline GFR, daily sodium intake, ramipril dose, BP control, and concomitant treatment with diuretics or dihydropyridinic calcium channel blockers (adjusted RR [95% CI]: women, 5.07 [1.26 to 20.38], P = 0.02; men, 1.44 [0.85 to 2.44], P = 0.17). Ramipril uniformly decreased deltaGFR and incidence of ESRD in women with either DD (-39% and - 100%) or II + ID (-71% and -82%) genotype, and in men (-25% and -50%) with the DD genotype, but had no beneficial effect in men with the II + ID genotype (+18% and +34%). Thus, the relative risk of events (ESRD) between conventional and ramipril-treated men was higher in subjects with the DD genotype (1.85; 0.69 to 4.94) and lower in those with the II +/- ID genotype (0.71; 0.28 to 1.80). Again, in parallel with deltaGFR and events, proteinuria decreased in women with DD (-23.3 +/-8.0%) or II + ID (-16.0 +/- 9.5%) genotype and in men with the DD genotype (-14.8 +/- 7.0%), but did not change in men with II + ID genotype (+ 1.0 +/- 7.8%). Of note, the ACE genotype-related effect of ramipril was still evident even after correction for the above potentially confounding factors (adjusted RR [95% CI]: DD, 2.52 [0.83 to 7.63], P = 0.10; II + ID, 0.35 [0.12 to 1.01], P = 0.05). Thus, among patients with chronic proteinuric nephropathies, men are at increased risk of progression due to their lower response to ACE inhibitor treatment. ACE inhibition is uniformly renoprotective in women regardless of the ACE polymorphism, and in men with the DD genotype, but is virtually devoid of beneficial effects in men with the II or ID genotype. This information may help to guide therapeutic interventions in clinical practice and to interpret the results of prospective trials in chronic renal disease.
Adolescent↗
Effect of angiotensin-converting enzyme inhibition on glomerular basement membrane permeability and distribution of zonula occludens-1 in MWF rats.
The mechanism(s) by which angiotensin-converting enzyme (ACE) inhibitors prevent glomerular membrane loss of permselective function is still not understood. In male MWF rats, which develop spontaneous proteinuria with age, ACE inhibitors prevent proteinuria and increase glomerular ultrafiltration coefficient. These renoprotective effects are not associated with ultrastructural changes of capillary wall components. This study was undertaken to investigate whether ACE inhibitors modulate functional properties of glomerular basement membrane (GBM) and/or of epithelial cells, both of which have been suggested to play a role in the maintenance of the glomerular filtration barrier. The hydraulic and macromolecular permeability of the GBM were determined, by an in vitro filtration system, in untreated or lisinopril-treated rats and in Wistar rats taken as controls. By indirect immunofluorescence and immunoelectron microscopy, glomerular distribution of the tight junction protein zonula occludens- (ZO-1), a component of the slit diaphragm, was also studied. Results document that spontaneous proteinuria in MWF rats develops without significant changes in the permeability of the GBM to water and albumin, or in the ultrastructure of the podocyte foot processes, but is associated with an important alteration in the distribution of ZO-1 at the glomerular level. Lisinopril, which prevented proteinuria, also prevented glomerular redistribution of the protein. Thus, renoprotective effects of ACE inhibitors are not associated with changes in intrinsic functional properties of GBM, or ultrastructural changes of the epithelial cells, but rather with preservation of glomerular ZO-1 distribution and slit diaphragm function, which are essential for maintaining the filtration barrier.
Angiotensin-Converting Enzyme Inhibitors↗