Nephropathy of type-2 diabetes mellitus.
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Diabetes Mellitus, Type 2↗
Biomedical subjects
G Remuzzi
Publications and source records attributed to G Remuzzi.
The antiproteinuric effect of angiotensin antagonism in human IgA nephropathy is potentiated by indomethacin.
Evidence is available from animal and human studies that protein traffic through the glomerular capillary has a pathogenetic role in subsequent renal damage and that angiotensin-converting enzyme (ACE) inhibitors appear superior to other drugs in lowering proteinuria and the rate of renal function decline. This study compares the effect of ACE inhibition or angiotensin II (AngII) receptor blockade on urinary protein excretion and renal hemodynamics in 20 patients with IgA glomerulonephritis randomized to receive enalapril (20 mg/d) or irbesartan (100 mg/d) for 28 d in a double-blind study with two parallel groups. This study also evaluated whether addition of indomethacin (75 mg twice a day) to each of the two treatments resulted in a more potent antiproteinuric effect. Enalapril alone reduced total protein excretion (61% change from baseline) and fractional clearance of albumin without changes in GFR and minor elevation in renal plasma flow. Also, patients randomized to receive the AngII receptor antagonist irbesartan for 28 d had lower proteinuria (55% change from baseline) and fractional clearance of albumin at the end of the treatment period with similar renal hemodynamic changes. When indomethacin was added to enalapril treatment, a further significant reduction in urinary proteins and fractional albumin clearance was observed. In patients given irbesartan, the addition of indomethacin further reduced proteinuria and fractional clearance of albumin. The combined therapy with enalapril or irbesartan and indomethacin did not significantly affect GFR and renal plasma flow compared with baseline. These findings indicate that in patients with IgA glomerulonephritis the antiproteinuric effect of blocking AngII activity by either ACE inhibitors or AngII receptor antagonists is potentiated by indomethacin, an effect that occurred without impairment of renal function.
Adult↗
The nephropathy of non-insulin-dependent diabetes: predictors of outcome relative to diverse patterns of renal injury.
Nephropathy of non-insulin-dependent diabetes mellitus (NIDDM) is the most common cause of end-stage renal failure (ESRF) in Western countries. This study investigates the clinical and histologic putative predictors of disease progression, with the final goal to identify patients at risk who may benefit from early diagnosis and intervention. It examines by repeated measurements of BP, blood glucose, serum creatinine, and urinary protein excretion rate 65 consecutive NIDDM patients with clinical, persistent proteinuria and biopsy-documented typical diabetic glomerulopathy (class I; n = 30), predominant nephroangiosclerosis (class II; n = 23), or nondiabetic type glomerulopathy (class III; n = 12), whose severity of renal tissue involvement was precisely quantified by a global histologic score. Baseline parameters and progression to renal end points, i.e., doubling of baseline serum creatinine, dialysis, or transplantation, were univariately and multivariately correlated by proportional hazards regression models. The median kidney survival time in the overall study population was 3.07 yr. Thirty-seven percent of patients reached an end point during a median (range) follow-up of 1.8 yr (0.4 to 5.7 yr). By univariate and multivariate analysis, kidney survival significantly correlated with baseline urinary protein excretion rate (P = 0.04 and P = 0.04, respectively) and renal tissue injury score (P = 0.0001 and P = 0.02, respectively), but not with the histologic classes. Patients with a urinary protein excretion rate < or = 2 g/24 h, or > 2 g/24 h with a histologic score < 7, never reached an end point. All patients with urinary protein excretion > 2 g/24 h and a histologic score > 13 progressed to ESRF over a median of 1.6 yr. No differences in other baseline parameters or in BP and diabetes control during follow-up accounted for these different outcomes. In NIDDM as well as in nondiabetic chronic renal disease, quantification of urinary protein excretion rate--independent of the pattern of underlying glomerular involvement--reliably discriminates progressors from nonprogressors and, combined with precise quantification of renal tissue injury, reliably predicts risk of ESRF. This information may be used to set guidelines for early diagnosis and appropriate intervention to reduce the number of diabetic patients who will need renal replacement therapy in years to come.
Adult↗
Precision of plasma clearance of iohexol for estimation of GFR in patients with renal disease.
The choice of the optimal method for the measurement of renal function is based on the accuracy and the precision of the technique. The plasma clearance of nonradioactive iohexol has been proposed as a reliable alternative to renal clearance of inulin for estimation of GFR. However, the precision of this method in estimating GFR in patients with renal disease has not been determined so far. This issue was assessed by determining plasma clearance of iohexol on three different occasions during a 12-d period in 24 patients with renal disease and a wide range of renal function (creatinine clearance: 14 to 104 ml/min per 1.73 m2). Overall, the mean intraindividual coefficient of variation was 5.59%, and the reproducibility was 6.28%. The precision of the method also applied to the subgroup of patients with moderate-to-severe renal insufficiency, because a low coefficient of variation (5.71%) and a high reproducibility (6.57%) were found in patients with GFR < or =40 ml/min per 1.73 m2. It was also shown that the precision of GFR measurement by the plasma clearance of iohexol is not affected by the gender. These findings indicate that the method of plasma clearance of iohexol allows a good precision in the estimation of GFR in patients with normal renal function and different degrees of renal dysfunction.
Adult↗
Upregulation of renal and systemic cyclooxygenase-2 in patients with active lupus nephritis.
In lupus nephritis (LN), renal thromboxane A2 (TXA2) production is increased, and inhibition of TXA2 activity improves renal function. In patients with LN, renal function depends very much on vasodilatory prostaglandins, and indeed inhibiting the prostaglandin-forming enzyme cyclooxygenase (COX) with aspirin or related compounds was detrimental on renal hemodynamics in these patients. There are no data so far on whether the excessive TXA2 production in LN derives from upregulation of type I or type II isoforms of COX. It was found that TXB2 synthesis and COX-2 gene expression were higher in peripheral blood mononuclear cells from patients with active LN compared to patients in the inactive form of the disease and to healthy subjects. Unlike COX-2, levels of COX-1 mRNA were comparable in lupus patients and control subjects and were not influenced by the disease activity. Immunoperoxidase studies on kidney biopsies showed COX-1 staining in glomerular arterioles and other renal vessels, with no evident difference between lupus biopsies and control specimens taken from either individuals who were free of renal disease or patients with non-lupus nephropathies. In contrast, COX-2 staining was definitely stronger in specimens from patients with active LN than control specimens. In active LN, COX-2-specific staining was localized mainly in the glomeruli, with a weaker signal on tubuli and in the interstitium. Double-staining studies with an antibody against the macrophage marker CD68 and an anti-COX-2 antibody definitely showed that COX-2 and CD68 often colocalized on the same cell, with only occasional glomerular COX-2-stained mesangial areas. Patients with non-lupus nephropathies had no increase in renal COX-2 expression. These results indicate that COX-2 upregulation is a specific finding of active LN and that monocytes infiltrating the glomeruli contribute to the exaggerated local synthesis of TXA2. If this is correct, COX-2 may soon become a target for therapeutic intervention in this disease.
Adult↗
In progressive nephropathies, overload of tubular cells with filtered proteins translates glomerular permeability dysfunction into cellular signals of interstitial inflammation.
Progression to end-stage renal failure is the final common pathway of many forms of glomerular disease, independent of the type of initial insult. Progressive glomerulopathies have in common persistently high levels of urinary protein excretion and tubulointerstitial lesions at biopsy. Among the cellular mechanisms that may determine progression regardless of etiology, the traffic of excess proteins filtered from glomerulus in renal tubule may have functional importance by initiating interstitial inflammation in the early phase of parenchymal injury. This study analyzes the time course and sites of protein accumulation and interstitial cellular infiltration in two different models of proteinuric nephropathies. In remnant kidneys after 5/6 renal mass ablation, albumin and IgG accumulation by proximal tubular cells was visualized in the early stage, preceding interstitial infiltration of MHC-II-positive cells and macrophages. By double-staining, infiltrates developed at or near tubules containing intracellular IgG or luminal casts. This relationship persisted thereafter despite more irregular distribution of infiltrate. Similar patterns were found in an immune model (passive Heymann nephritis), indicating that the interstitial inflammatory reaction develops at the sites of protein overload, regardless of the type of glomerular injury. Osteopontin was detectable in cells of proximal tubules congested with protein in both models at sites of interstitial infiltration, and by virtue of its chemoattractive action this is likely mediator of a proximal tubule-dependent inflammatory pathway in response to protein load. Protein overload of tubules is a key candidate process translating glomerular protein leakage into cellular signals of interstitial inflammation. Mechanisms underlying the proinflammatory response of tubular cells to protein challenge in diseased kidney should be explored, as well as ways of limiting protein reabsorption/deposition to prevent consequent inflammation and progressive disease.
Albumins↗
Protecting single-kidney allografts from long-term functional deterioration.
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Angiotensin-Converting Enzyme Inhibitors↗
Progressive glomerular injury in the MWF rat is predicted by inborn nephron deficit.
It has been suggested that a reduced number of nephrons may predispose to systemic hypertension and glomerular injury. Compensatory hemodynamic changes, due to a low number of glomeruli, might be responsible for glomerular functional and structural changes. It is difficult to evaluate this hypothesis in humans because of limitations in estimating the number of nephrons in the living kidney. The aim of the present study was to estimate nephron number, single glomerular hemodynamics, and glomerular volume in male and female MWF rats, a strain that spontaneously develops systemic hypertension, proteinuria, and glomerulosclerosis. Male and female Wistar rats were used as controls. At 12 to 14 wk of age, male MWF rats developed proteinuria, whereas female MWF and Wistar rats showed normal urinary protein excretion rate. Glomerular number was significantly reduced in male and female MWF rats (13,690+/-1,489 and 12,855+/-1,781 gl/ kidney, respectively) compared with Wistar rats (26,955+/-2,171 and 27,166+/-1,754 gl/kidney, respectively). The mean number of nephrons per unit of body weight was also lower in MWF males (88+/-10) compared with MWF females (139+/-20) and compared with male and female Wistar animals (142+/-14 and 221+/-22 gl/g body wt). Whole-kidney hemodynamic parameters and the number of nephrons were used to calculate single-nephron filtration rate and plasma flow. Both measures were markedly elevated in male MWF rats relative to values obtained in the other three groups. Similarly, glomerular volume was significantly greater in MWF males than in other animals. These results suggest that an inborn deficit of nephrons may be responsible for spontaneous development of later-in-life hypertension and renal dysfunction. The data also indicate the need to investigate the role of this potential pathogenetic factor for human hypertension and kidney disease in humans.
Animals↗
Unselective inhibition of endothelin receptors reduces renal dysfunction in experimental diabetes.
Chronic nephropathies are associated with enhanced renal synthesis of endothelin (ET)-1. A recent study demonstrated that an ET(A) receptor antagonist given to diabetic rats at the moment of disease induction prevented the development of renal injury. Here we investigated whether an unselective ET(A)/ET(B) receptor antagonist, PD 142,893, was renoprotective when given to streptozotocin diabetic rats when animals were already proteinuric. The effect of PD 142,893 was compared with that of an ACE inhibitor, lisinopril, known to retard progressive renal disease in experimental and human diabetes. PD 142,893 normalized systemic blood pressure, reduced urinary protein and albumin excretion, and ameliorated renal blood flow in diabetic rats, but it did not affect such parameters in control rats. Lisinopril had a renoprotective effect comparable to PD 142,893, although lisinopril controlled systemic blood pressure better. Northern blot analysis of ET-1 mRNA revealed upregulation of ET-1 gene in the diabetic kidney. Similar results were obtained by in situ hybridization in glomeruli and tubuli of diabetic rats. Both treatments remarkably attenuated exaggerated renal ET-1 gene expression. These data suggest that ET-1 is a contributory mediator of kidney damage in diabetes and indicate that ET receptor antagonists may represent a new therapeutic mean for treatment of progressive diabetic nephropathy.
Albuminuria↗
Cadaver kidney allocation in the north Italy transplant program on the eve of the new millennium.
The identification of parameters impacting on cadaver kidney graft outcome is of paramount importance to ensure proper organ allocation, a process that must take into account ethical, biological, social and administrative factors. This is particularly critical in countries where organ procurement is largely insufficient. In the present chapter we report the results of studies carried out to determine the impact of 17 factors on graft survival and function at 4 years posttransplant in 2,917 recipients transplanted from January 1990-September 1997 in the North Italy Transplant program (NITp). Patient and graft survival rates at 4 years (+/- SEM) were 93.5 +/- 0.5% and 81.4 +/- 0.8%, respectively. Excellent graft function at 4 years was shown by 69.8% of recipients. Younger donor age, absence of pretransplant transfusions, patient dialysis center in the NITp area and level of HLA match showed a statistically significant positive association with graft survival. Younger donor age and male donor gender showed a statistically significant association with excellent graft function at 4 years. These global outcomes were confirmed when the analysis was limited to the subset of the 2,617 adult recipients and to the subset of 1,211 cases for whom both donor and recipient HLA-DRB1 types were available before transplant. The results were used to develop a computer-assisted, refined version of the NITp adult kidney allocation algorithm that was named NITK3. A preliminary evaluation of 472 transplants allocated in 12 months with NITK3 compared with 459 transplants allocated in the preceding 12 months according to the previous algorithm (NITK2) showed a significantly higher proportion of recipients who had been on the waiting list for more than 3 years (33.1% vs 21.1%). The use of NITK3 was also associated with a significantly increased ability to transplant alloimmunized patients (17.7% vs 9.5% with NITK2) and recipients with 0-1 HLA mismatches (21.2% vs 13.5% with NITK2). Differences in 6-month graft survival rates and in the percentage of patients with excellent function at 6 months were not statistically significant in recipients transplanted with NITK3 versus NITK2. Survival rates were 96.9% and 92.4%, respectively. Percentages of patients with excellent renal function were 68.3% and 70.5%, respectively. These preliminary data suggest that NITK3 improves HLA match and reduces the number of patients on the waiting list for 3 or more years without determining significant modifications of 6-month graft survival and function. Moreover, it facilitates the achievement of a fair local balance between organs retrieved and transplanted, the compliance of operators with objective allocation rules and the documentation of the whole allocation process.
Adolescent↗
Primary prevention of renal failure in diabetic patients: the Bergamo Nephrologic Diabetes Complication Trial.
BACKGROUND: Microalbuminuria is an early marker of diabetic nephropathy, and its prevention can be considered to be the primary prevention of diabetic nephropathy. Angiotensin converting enzyme inhibitors and non-dihydropyridinic calcium antagonists have specific renoprotective properties in diabetes, and preliminary evidence is available that their combination can delay the onset and limit the progression of nephropathy in experimental diabetes more effectively than either of the two agents alone. DESIGN OF CLINICAL TRIAL: The Bergamo Nephrologic Diabetes Complication Trial is a prospective, randomized, double-blind, parallel-group study aimed at evaluating the possibility of preventing the onset of nephropathy in 2400 hypertensive non-insulin-dependent diabetes mellitus patients who have a normal albumin excretion rate. During phase A of the study, patients will be randomized to one of the following treatments for 3 years: a non-dihydropyridinic calcium antagonist (slow-release verapamil 240 mg/day), an angiotensin converting enzyme inhibitor (trandolapril 2 mg/day), the combination of these drugs (verapamil 180 mg/day plus trandolapril 2 mg/day) and placebo. Other antihypertensive agents will be allowed in order to achieve and maintain systolic and diastolic blood pressures consistently below 140 and 90 mmHg, respectively, in all patients. The primary efficacy variable of phase A will be progression to microalbuminuria. In phase B progression to macro-albuminuria will be evaluated in patients who became microalbuminuric in phase A. These patients will be randomized to 2 years of treatment with trandolapril (2 mg/day) alone or combined with verapamil (180 mg/day).
Angiotensin-Converting Enzyme Inhibitors↗
Nitric oxide/endothelin balance after nephron reduction.
Nitric oxide (NO), an L-arginine derivative, is implicated in neuronal transmission, immune response and vasodilation, besides acting as a platelet function modulator. A number of recent studies in the experimental model of renal mass reduction (RMR) in rats have proposed the hypothesis that abnormalities of the NO synthetic pathway could have a key role in mediating the complex hemodynamic and hemostatic disorders associated with the progression of renal disease. Thus, renal NO generation is lower than normal in rats with RMR seven days after surgery, and progressively worsens with time in close correlation with signs of renal injury. This abnormality is due to a strong defect of inducible NO synthase (iNOS) content in the kidney. In the same model, administration of either the NO precursor, L-arginine, or a NO-releasing compound reduces proteinuria, slows renal disease progression and prolongs survival. On the other hand RMR is associated with a progressive increase of renal synthesis of the potent vasoconstrictor peptide, endothelin-1 (ET-1), whose mRNA is expressed in excessive amounts in cortical tubules early after surgical ablation. In this setting, a marked reduction of NO, in the face of continuous local generation of ET-1, may well contribute to intraglomerular capillary hypertension and cell proliferation. Actually, administration of a selective ETA receptor antagonist to RMR rats reduced abnormal permeability to proteins and prevented renal function deterioration. In the same model the ETA receptor antagonist also corrected the impaired renal NO synthesis, suggesting that excessive ET-1 bioactivity might also be responsible for the progressive reduction of renal NO. In keeping with this possibility are recent in vitro data that ET-1 inhibits iNOS transcription, a process mediated by interaction of the peptide with subtype A receptors. Nitric oxide and ET-1 have profound and opposite effects on glomerular and tubular function. Thus, abnormalities of renal NO and ET-1 synthetic pathways, as documented in the RMR model, likely have major and complementary roles in promoting alteration in renal hemodynamics and functions in progressive nephropathies.
Animals↗
The hemolytic uremic syndrome.
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Acute Kidney Injury↗
How to convert from traditional cyclosporine to the microemulsion formulation in stable renal transplant patients?
How to convert from traditional cyclosporine (CsA) to the microemulsion formulation in stable renal transplant patients is still a matter of debate. The present study was designed to evaluate the effects of changeover from traditional Sandimmune to Neoral formulation at two dose-ratio conversions on CsA pharmacokinetics, safety and tolerability particularly in terms of renal function. Thirty outpatients regularly followed at our Clinical Research Center were randomized to 1:1 or 1:0.75 dose-ratio conversion and assigned to the two groups according to a comparable renal function and time post-transplant. Patients underwent CsA pharmacokinetic evaluation and renal function measurements (GFR and RPF) before, at day 15, and at month 6 after conversion to Neoral formulation. More consistent CsA concentration-time profiles with Neoral than traditional formulation were obtained at the two time points of evaluation after conversion. At 1:1 dose-ratio conversion an increased absorption rate, reflected by a shorter time to maximum blood CsA concentration (Tmax), and a greater bioavailability, as shown by an increase in the peak CsA concentration (Cmax) and the 12-h exposure to drug defined by the area under the time-concentration curve (AUC0-->12 h) was found 15 d and 6 months after conversion to Neoral formulation. A similar AUC as compared with traditional Sandimmune was observed in those patients randomized to receive a 25% lower dose of Neoral formulation. All of patients defined as 'low' absorbers became 'high' absorbers as early as 15 d after conversion to Neoral formulation at 1:1 or 0.75 dose-ratio regimen. Overall mean GFR was unchanged in both conversion regimens during the 6 months of follow-up. However, there was a tendency to lower GFR even in some patients randomized to 1:0.75 conversion but mostly in those with 1:1 conversion. A limited sampling strategy utilizing three blood samples (0, 1, 3 h post-dosing of Neoral formulation) provided an excellent correlation with actual drug exposure (r = 0.977). Enhanced CsA absorption with the microemulsion formulation results in increased drug exposure that may reduce GFR in some patients who undergo 1:1 dose-ratio conversion. The Neoral formulation that permits a more effective, consistent, and predictable absorption of CsA may represent a great advantage in order to prevent acute and possibly chronic rejections. Efforts have to be made to find optimal therapeutic range and dosing schedule for this new formulation, which may be facilitated by using the limited sampling approach to predict AUC after only three-point sampling.
Administration, Oral↗
Mechanism of progression of renal disease: growth factors and related mechanisms.
Several studies have consistently indicated a close association between altered glomerular permeability to proteins and renal damage. Dietary and pharmacologic manipulations that restore the selectivity of the glomerular barrier to macromolecules stop progressive renal injury. We propose that abnormal traffic of proteins through the glomerular capillary has an intrinsic renal toxicity because of protein over-reabsorption by proximal tubular cells. Protein overload induces functional alterations of tubular cells, including overexpression of vasoactive and proinflammatory mediators such as endothelin-1. This review examines the role of endothelin-1 as a trigger of renal damage, both in vitro and in vivo, and summarizes relevant supporting data.
Animals↗
Fluid shear stress modulates von Willebrand factor release from human vascular endothelium.
Fluid shear stress generated by blood flow on arterial wall may play a role in the process of atherosclerosis, not only affecting the mass transport phenomena that take place in blood, but also by modulation of synthesis and secretion of humoral factors released by vascular endothelium that mediate platelet-vessel wall interactions. The present study was designed to investigate whether shear stress, induced by laminar flow, modulates von Willebrand factor (vWF) release from cultured human umbilical vein endothelial cells (HUVEC) and whether this physical stimulation can affect vWF synthesis. Monolayers of HUVEC were exposed to laminar flow of varying magnitude (from 2 to 12 dynes/cm2) using a cone-and-plate device. The release of vWF in cell supernatant and in extracellular matrix by cells exposed to flow or maintained in static conditions was evaluated by enzyme-linked immunosorbent assay. HUVEC exposed to laminar flow released higher amounts of vWF into the cell supernatant within few hours of exposure and vWF secretion was dependent on shear stress magnitude. vWF released in extracellular matrix was also higher in cell monolayers exposed to shear than in static controls. vWF mRNA expression in HUVEC was not affected by exposure of cells to laminar flow, indicating that shear-induced vWF release reflected enhanced secretion without de novo protein synthesis. Immunofluorescence studies showed that the release of vWF is due to exocytosis from Weibel-Palade bodies, the storage organelles of vWF. These data indicate a novel mechanism by which local hemodynamic shear forces modulate endothelial cell function and may play a role in development of arterial thrombotic events.
Cells, Cultured↗
Dearing--a report to be embraced.
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Education↗
Nonviral gene delivery to the rat kidney with polyethylenimine.
The aim of this study was to establish a nonviral method for gene delivery to the rat kidney. To this purpose, a panel of reagents was tested, including a monocationic lipid, DOTAP, a polycationic lipid, DOGS (or Transfectam), and three different forms of the cationic polymer polyethylenimine (PEI). A comparison among these compounds was performed in vivo, using luciferase as reporter gene. Complexes containing 10 microg of DNA were injected into the left renal artery of rats and allowed to remain in contact with the kidney for 10 min. Forty-eight hours later, luciferase expression levels in kidney extracts were measured. Kidneys injected with DNA complexed to the branched, 25-kD PEI polymer (PEI 25k) yielded activity levels significantly higher than control, sham-operated kidneys (2.7 x 10(4) vs. 5.2 x 10(3) RLU/kidney, respectively), whereas the other transfecting agents did not yield significant activity over controls. PEI 25k was therefore chosen for further optimization of transfection conditions. Dose-dependent luciferase expression was shown for 10, 50, and 100 microg of PEI-complexed DNA, reaching maximal levels of 2.4 x 10(5) RLU/kidney at 100 microg DNA. The optimal PEI nitrogen/DNA phosphate molar ratio was 10 equivalents. Luciferase activity peaked at 2 days, was still significantly higher than controls at 7 days, and was undetectable at 14 days post-injection. Using beta-galactosidase (beta-Gal) as a reporter, transgene expression was localized almost exclusively in proximal tubular cells.
Animals↗