Diabetes-induced microvascular dysfunction in the hydronephrotic kidney: role of nitric oxide.

BACKGROUND: Renal hemodynamics in early diabetes are characterized by preglomerular and postglomerular vasodilation and increased glomerular capillary pressure, leading to hyperfiltration. Despite intensive research, the etiology of the renal vasodilation in diabetes remains a matter of debate. The present study investigated the controversial role of nitric oxide (NO) in the renal vasodilation in streptozotocin-induced diabetic rats. METHODS: In the renal microcirculation, basal tone and response to NO synthase blockade were studied using the in vivo hydronephrotic kidney technique. L-arginine analog N-nitro-L-arginine methyl ester (L-NAME) was administered locally to avoid confounding by systemic blood pressure effects. The expression of endothelial NO synthase (eNOS) was investigated in total kidney by immunocytochemistry and in isolated renal vascular trees by Western blotting. Urinary excretion of nitrites/nitrates was measured. RESULTS: Diabetic rats demonstrated a significant basal vasodilation of all preglomerular and postglomerular vessels versus control rats. Vasoconstriction to L-NAME was significantly increased in diabetic vessels. After high-dose L-NAME, there was no difference in diameter between diabetic and control vessels, suggesting that the basal vasodilation is mediated by NO. Immunocytochemically, the expression of eNOS was mainly localized in the endothelium of preglomerular and postglomerular vessels and glomerular capillaries, and was increased in the diabetic kidneys. Immunoblots on isolated renal vascular trees revealed an up-regulation of eNOS protein expression in diabetic animals. The urinary excretion of nitrites/nitrates was elevated in diabetic rats. CONCLUSION: The present study suggests that an up-regulation of eNOS in the renal microvasculature, resulting in an increased basal generation of NO, is responsible for the intrarenal vasodilation characteristic of early diabetes.     

Limitations to body length/serum creatinine ratio as an estimate of glomerular filtration in children

The ability of the Schwartz formula (C _SCH) to estimate glomerular filtration rate (GFR) accurately was investigated in children with renal disease. ¹²⁵Iodine-iothalamate clearance (C _IO) was used as the reference standard for measuring GFR. Data from 176 C _IO studies performed on 133 children (aged between 1 and 18 years) were compared with the simultaneous estimation of GFR by C _SCH. The overestimation of GFR by C _SCH was inversely proportional to the level of renal function. When C _IO was >90 ml/min per 1.73 m², C _SCH overestimated GFR by only 0.1%±3%, but when C _IO was ≤15 ml/min per 1.73 m², C _SCH overestimated GFR by 164%±42%. When renal function is normal or mildly reduced (GFR >50 ml/min per 1.73 m²), C _SCH overestimated C _IO by only 10.3±3.0%, compared with 90.3±14.5% when renal function was moderately to severely curtailed (GFR ≤50 ml/min per 1.73 m²). We conclude that C _SCH is valid in predicting GFR only in children with normal renal function and mild insufficiency. Received January 30, 1996; received in revised form and accepted May 14, 1996     

Monoclonal antibodies to human glomerular cells: a marker for glomerular epithelial cells

A monoclonal antibody, PHM 5, directed against human glomerular epithelial cells, was prepared after immunisation of a mouse with isolated human glomeruli and fusion of spleen cells with a mouse myeloma. Binding of antibody to isolated glomeruli was detected by radioimmune indirect binding assay, and specificity for glomerular epithelial cells was shown using a four-layer peroxidase-antiperoxidase technique applied to epoxy resin sections of the human kidney cortex. PHM 5 appears to detect a human-specific cell surface carbohydrate antigen not previously described, and can be used to identify epithelial cells in renal biopsy sections and in culture outgrowths of isolated glomeruli.     

Low glomerular filtration rate in normoalbuminuric type 1 diabetic patients: an indicator of more advanced glomerular lesions

Increased urinary albumin excretion rate is widely accepted as the first clinical sign of diabetic nephropathy. However, it is possible that some diabetic patients could first manifest reduced glomerular filtration rate (GFR) or hypertension. Relatively advanced diabetic renal lesions can be present in some diabetic patients with long-standing normoalbuminuria, and this might indicate increased risk of progression to microalbuminuria and then to overt diabetic nephropathy. The aim of this study was to identify a group of normoalbuminuric type 1 diabetic patients with low GFR and compare them with normoalbuminuric patients with normal GFR. Altogether, 105 normoalbuminuric type 1 diabetic patients with at least 10 years of diabetes duration that had a renal biopsy performed for research purposes were studied. Patients were divided according to GFR into groups with normal (>/=90 ml x min(-1) x 1.73 m(-2)) or reduced (<90 ml x min(-1) x 1.73 m(-2)) GFR. Clinical and renal structural parameters were compared between these two groups. Glomerular structural parameters were estimated by electron microscopic morphometry. The 23 patients with reduced GFR had more advanced diabetic glomerular lesions. The finding of reduced GFR was much more common among female patients, particularly if retinopathy and/or hypertension were also present. This report confirms that reduced GFR occurs among long-standing normoalbuminuric type 1 diabetic patients and is associated with more advanced diabetic glomerular lesions and, probably, with increased risk of progression. For these reasons, we suggest that regular measurements of GFR be performed in long-standing normoalbuminuric type 1 diabetic female diabetic patients, especially in those with retinopathy or hypertension.     

An independent indicator of erectile dysfunction is C-reactive protein/albumin ratio

Research has found that, instead of passive lipid-accumulated vascular damage, atherosclerosis which is the primary cause of erectile dysfunction (ED) can be seen as an active inflammatory cycle and that inflammation has a central role in the entire atherosclerotic process. As an inflammatory marker, serum C-reactive protein (CRP)/albumin ratio (CAR) may link to ED and ED severity. The CAR, demographic features and other criteria of 198 patients with ED who visited our outpatient clinic during March 2019–April 2020 were prospectively evaluated. The research also included healthy control subjects without systemic or infectious diseases. The mean difference of CAR between ED and no ED was statistically significant (0.55 ± 0.27 and 0.79 ± 0.49, p = .002 respectively). On the basis of the ROC analysis, CAR has a good ED diagnostic value with an area under the curve (AUC) of 0.63 (95% CI:0.541–0.714) and better diagnostic performance to distinguish ED severity (AUC:0.73, 95% CI:0.620–0.842). Additionally, mean CAR gradually increased with increasing severity of ED (for all p < .001). The CAR has been described as an independent ED indicator in the multivariate analysis (p = .001OR = 8.934; 95% CI:2.449–32.583). Increased CAR is associated with ED severity and increased ED risk. For CAR predicting ED and ED severity, a considerable cut-off point was identified.     

Urinary podocyte loss is a more specific marker of ongoing glomerular damage than proteinuria

Podocyte loss contributes to the development of glomerulosclerosis. Although podocyte detachment has been recognized as a new mechanism of podocyte loss in glomerular diseases, its time course and relationship to disease activity are not known. Urinary excretion of viable podocytes was quantified in two models of transient glomerular injury, i.e., rats with puromycin aminonucleoside-induced nephrosis (PAN) and mesangioproliferative nephropathy (anti-Thy 1.1 nephritis model), as well as in a model of continuous glomerular injury, i.e., hypertensive nephropathy (5/6-nephrectomy model), and in aging rats. The number of glomerular Wilm's tumor (WT)-1-positive podocytes and the glomerular expression of cell-cycle proteins in vivo were assessed. Urinary podocyte loss occurred in both primary (PAN) and secondary (anti-Thy 1.1 nephritis) in parallel to the onset of proteinuria. However, subsequently proteinuria persisted despite remission of podocyturia. In continuous glomerular injury, i.e., after 5/6-nephrectomy, podocyturia paralleled the course of proteinuria and of systemic hypertension, whereas no podocyturia became detectable during normal aging (up to 12 mo). Despite podocyte detachment of varying degrees, no decrease in glomerular podocyte counts (i.e., WT-1 positive nuclei) was noted in either disease model. Podocyturia in the PAN and anti-Thy 1.1 nephritis model was preceded by entry of glomerular podocytes into the cell cycle, i.e., cyclin D1, cdc2, and/or proliferating cell nuclear antigen (PCNA) expression. Podocyturia is a widespread phenomenon in glomerular disease and not simply a reflection of proteinuria because it is limited to phases of ongoing glomerular injury. The data suggest that podocyturia may become a more sensitive means to assess the activity of glomerular damage than proteinuria.     

Cystatin C in heart failure is nothing more than a bystander of glomerular filtration

BACKGROUND: Cystatin is an ubiquitous protease inhibitor involved in degradation of cellular proteins and has recently been associated with increased risk of cardiovascular disease and heart failure independent of renal function. We tested whether cystatin in heart failure is only associated with renal function or also with echocardio-Doppler parameters and factors of myocardial remodeling (C-reactive protein, endothelin, and natriuretic peptides). METHODS: This was an observational study conducted in 100 adult Caucasian outpatients with NYHA class I-II heart function without diabetes and ischemic heart, 50 with idiopathic dilated cardiomyopathy (DCM) and 50 with uremic cardiomyopathy undergoing hemodialysis (HD). Multiple linear regression analysis was performed on cystatin concentration using clinical, laboratory (creatinine, high sensitivity C-reactive protein, endothelin, B-type natriuretic peptide [BNP]) and echocardio-Doppler data as explanatory variables. RESULTS: The heart was more severely involved in DCM patients (worse ejection fraction, diastolic volume index, index of myocardial performance, left ventricular mass index). Mean values of cystatin, creatinine, BNP and C-reactive protein in HD compared with DCM patients were 6, 9, 5 and 3 times higher, respectively. Mean values of endothelin were comparable in both groups. Cystatin significantly correlated with creatinine in both groups (r=0.50 in DCM and r=0.37 in HD, and r=0.95 in pooled groups). In the multiple regression analysis, only disease group and creatinine within groups were significant independent factors that accounted for 94% of the variability of cystatin. CONCLUSION: Renal function was the determinant of cystatin in a concentration range of 6 times regardless of severity of heart involvement.     

Serum cystatin C is a more sensitive marker of glomerular function than serum creatinine

We determined the relationship between the levels of serum cystatin C or creatinine (s-Cr) and the grade of creatinine clearance (CCr) in patients with various glomerular diseases. Serum samples from 96 patients with glomerular diseases were obtained from our hospital. The levels of serum cystatin C were measured using the Dade Behring Cystatin C assay with the automated Dade Behring Nephelometer II (BNII). CCr levels were classified into six groups according to the Guidelines of the Japanese Society of Nephrology as follows: grade 1 (normal renal function); grade 2 (slight decrease of renal function); grade 3 (moderate decrease of renal function); grade 4 (severe decrease of renal function); grade 5 (renal failure), and grade 6 (uremia). The mean levels of serum cystatin C in grade 3 patients were significantly higher than those in grade 1. The mean levels of serum cystatin C in grades 4, 5 and 6 patients were also significantly higher than those in grade 1. However, the mean levels of serum Cr in grade 3 patients were not significantly higher than those in grade 1. The levels of s-Cr in grades 4, 5 or 6 patients were significantly higher than those in grade 1. In this study, an increase of serum cystatin C levels occurred earlier than that of s-Cr in various glomerular diseases. It appears that the levels of serum cystatin C may provide early prognostic marker of patients with various glomerular diseases rather than the levels of s-Cr.     

Evaluation of hematuria using the urinary albumin-to-total-protein ratio to differentiate glomerular and nonglomerular bleeding

BACKGROUND: Depending on the etiology and pathophysiology of hematuria, urinary bleeding is classified as glomerular hematuria or nonglomerular hematuria. Nephritis is usually detected by the presence of proteinuria, especially elevated albumin excretion. In this study, we report on the use of the urinary albumin-to-total-protein ratio to accurately differentiate glomerular and nonglomerular bleeding. METHODS: A total of 143 fresh, random urine specimens demonstrating microscopic hematuria (5 or more red blood cells per high-power field) from patients with the source of the hematuria confirmed by histopathology and/or clinical criteria were included in the study. RESULTS: Of the 143 specimens, 104 were from patients diagnosed with glomerular disease and 39 were from patients with nonglomerular disease. Corrected for urine concentration, the mean total-protein-to-creatinine (Cr) and albumin-to-Cr ratios in the glomerular disease group were 1.67 +/- 2.71 g/g Cr and 1.15 +/- 1.77 g/g Cr, respectively (P < 0.001). In the nonglomerular group, the mean total protein-to-Cr and albumin-to-Cr ratios were 0.19 +/- 0.23 g/g Cr and 0.05 +/- 0.06 g/g Cr, respectively (P < 0.001). However, considerable overlap in the ratios among glomerular and nonglomerular disease groups was observed. In contrast, the mean albumin-to-total protein ratios for glomerular and nonglomerular diseases were 0.72 +/- 0.10 and 0.35 +/- 0.17, respectively (P < 0.001). At a cutoff of 0.59, the albumin-to-total-protein ratio demonstrated a sensitivity of 97.1% (101 of 104 cases) in detecting glomerular disease. CONCLUSIONS: The urinary albumin-to-total-protein ratio is potentially a useful index for the differentiation of glomerular and nonglomerular disease in the presence of microscopic hematuria.     

Risk factors for late renal allograft dysfunction: effects of baseline glomerular size

Background: Both alloantigen dependent and alloantigen independent factors contribute to late allograft dysfunction. Among the latter, the importance of the mass of the donor kidney is an issue of interest. We hypothesized that glomerular hypertrophy is a risk factor for deterioration of allograft function. The goal of this study was to examine the role of glomerular size in predicting late allograft dysfunction. METHODS: All baseline graft biopsies between 1990 and 1998 were reviewed and sections containing at least 15 glomeruli were selected for morphometric analyses. Glomerular size was measured using the maximal profile area (MPA) method. Linear correlations between creatinine clearance (Ccr) and variables were evaluated. Covariates that tended to correlate with Ccr on univariate analysis (p < 0.2) were examined using multivariate analysis to determine the covariates associated with Ccr at 6 months (M) and 1, 2, 3, 4 years (yrs) after transplantation. RESULTS: Eighty-six patients were enrolled. Donor age, MPA, baseline Ccr, percent of global glomerulosclerosis (GS%), cyclosporin nephrotoxicity, cold ischemic time(CIT) and episodes of rejection were significantly correlated with interval Ccr in univariate analyses. MPA was a significant covariate at 6M, 1 yr, 3 yrs and 4 yrs. Other covariates significantly associated with interval Ccr included GS%, baseline Ccr, CIT and number of acute rejection episodes. CONCLUSIONS: Glomerular size in baseline biopsies is predictive of late allograft function, and the presence of hypertrophied glomeruli combined with other factors contributes to chronic renal allograft dysfunction.     

Slope‐only glomerular filtration rate and single‐sample glomerular filtration rate as measurements of the ratio of glomerular filtration rate to extracellular fluid volume

Aims: The Jacobsson single‐sample equation for measuring glomerular filtration rate (GFR) after bolus injection is based on two factors of questionable theoretical validity for correcting the single‐compartment assumption. The aims were to redevelop a more transparent equation, show its fundamental similarity with ‘slope‐only’ GFR and compare it with the original equation and with slope‐only GFR. Methodology: The modified Jacobsson equation is k = (1/t).ln[V(t)/V(0)], where k is the rate constant of the terminal exponential and V(0) and V(t) are distribution volumes at times 0 and t. V(0) exceeds extracellular fluid volume (ECV): that is k′ = (1/t).ln[V(t)/ECV], where k′ > k. Moreover, [GFR/ECV] >k (= k + [15.4.k²]). The ratio k/k′ was determined in 476 patients to calculate single‐sample k (3 or 4 h post‐injection). Slope‐only and single‐sample GFR/ECV were measured using Cr‐51‐EDTA in 105 further studies, multiplied by ECV (estimated from weight), scaled to 1.73 m² and compared with GFR/1.73 m² from the original Jacobsson equation against reference multi‐sample GFR/1.73 m² simultaneously and independently measured with iohexol. Results: The relation between k and k′ was linear. k/k′ was 0.827 at 3 h and 0.864 at 4 h. There was no difference in bias or precision between the original Jacobsson and modified equations. In both, precision was better than slope‐only GFR/BSA. When GFR remained scaled to ECV, slope‐only GFR showed marginally better precision against reference GFR/ECV. Conclusions: Single‐sample and slope‐only techniques give GFR as k. Although the theory of the modified Jacobsson equation is more transparent than the original equation, it gives the same result. It is, however, easier to use.     

Development and validation of a more accurate estimating equation for glomerular filtration rate in a Chinese population

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Conversion from calcineurin inhibitors to sirolimus in chronic allograft dysfunction: changes in glomerular haemodynamics and proteinuria.

BACKGROUND: The study was conducted in order to describe possible intraglomerular haemodynamic changes inducing proteinuria after 14 patients with chronic allograft dysfunction were converted from calcineurin inhibitors (CIs) to sirolimus without changing concomitant immunosuppression or antihypertensive treatment. METHODS: Creatinine, glomerular filtration rate (GFR), proteinuria, renal functional reserve (RFR) and effective renal plasma flow (ERPF) were determined before and 8 months after conversion. Intraglomerular pressure (P(G)), afferent arteriolar resistance (AAR) and efferent arteriolar resistance (EAR) were calculated using Gomez's formula. RESULTS: Creatinine (1.97 vs 2.075 mg/dl; P = 0.270) and GFR (40 vs 43 ml/min; P = 0.505) remained unchanged, proteinuria increased (338 vs 1146 mg/24 h; P = 0.006), RFR decreased (34.84 vs 13.47%; P = 0.019), ERPF (248 vs 310.6 ml/min; P = 0.0625) and P(G) (42.72 vs 46.17 mmHg; P = 0.0625) tendentially increased and AAR tendentially decreased (14.12 vs 10.28 dyne/s/cm(5); P = 0.0625). CONCLUSION: After conversion, P(G) shows a tendency to increase and RFR decreases significantly-characteristics of hyperfiltration, which could possibly partially explain the increase of proteinuria. Therefore, the application of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers seems promising. To avoid hyperfiltration, conversion should be performed early when renal insufficiency is still moderate.