Tubulointerstitial Index Research Articles

Ca antagonist ameliorates glomerular injury via suppression of glomerular hypertrophy in spontaneously hypertensive rats

Summary: A study was conducted to determine whether calcium blockers (CCB) have renoprotective effects, and if so to elucidate the mechanisms of such effects.A total of 30 uninephrectomized (UNX) spontaneously hypertensive rats (SHR), 5 weeks of age, were divided into three groups. Group 1 was fed a diet containing 0.01% manidipine and 8% NaCl, while groups 2 and 3 were fed diets containing only 8 and 0.5% NaCl, respectively. Feeding of these diets began 7 days after UNX (experimental day 0). Bodyweight, urinary protein /24 h, urinary sodium excretion/24 h, and food intake were measured at certain time intervals.At time of death (day 9 or 21), estimations of inulin clearance (Cin) and morphological evaluations, determination of glomerular sclerosis index (GSI), tubulointerstitial index (TII) and glomerular volume were performed.Urinary protein was significantly higher in groups 1 and 2 than in group 3 from day 7 onward, but did not differ between the former two groups. Cin in group 2 was higher than in groups 1 and 3 on day 9, but declined to lower levels than in groups 1 and 3 by day 21. There was no difference in Cin between group 1 and group 3 on day 21. Morphometry (GSI and TII) revealed that renal lesions were more progressive in group 2 than in group 1. Glomeruli in group 2 were markedly larger than those in group 1, but no difference in glomerular volume was noted between groups 1 and 3.Our findings suggest that CCB prevent progression of renal injury induced by accelerated hypertension in UNX SHR. the mechanisms of prevention may, at least in part, be related to suppression of glomerular hypertrophy. Inhibition of renal injury can be achieved without significant reduction of proteinuria.

Tubulointerstitial lesions in human membranous glomerulonephritis: Relationship to proteinuria

Recent studies in experimental glomerular disease suggest that proteinuria may be involved in the pathogenesis of accompanying tubulointerstitial (TI) lesions. To investigate whether there is a relationship between proteinuria and TI damage in membranous glomerulonephritis, 78 biopsy specimens with no or mild vascular disease and 10% or less obsolete glomeruli were examined and evaluated quantitatively. Extent of TI damage was represented by the TI index (TII) obtained for each biopsy specimen by dividing the morphometrically measured area of cortical damage by the total cortical area and multiplying the result by 1,000. The TII increased with stage of glomerular disease, but only the difference between stages 3 and 1 was significant ( P < 0.016). The TII showed significant individual correlation with 24-hour urinary protein ( r = 0.435, P < 0.0001), serum albumin ( r = −0.327, P = 0.0045), and percent of glomeruli with visceral epithelial cell protein absorption droplets ( r = 0.419, P = 0.0001), but not with age, serum creatinine, or percent obsolete glomeruli. With multivariate analysis TII correlated significantly with urinary protein ( r = 0.286, P = 0.0146) and percent glomeruli with visceral epithelial cell protein droplets ( r = 0.304, P = 0.0058). The results are consistent with the hypothesis that proteinuria is involved in the development of TI injury in glomerular disease.

The ameliorative effect of probucol on adriamycin (ADR) induced nephrotic rats

This paper reports the ameliorative effect of Probucol (Pb) on ADR-induced nephrotic rats. Male Wistar rats underwent unilateral nephrectomy followed by one-week subsequent intravenous injection of 4.0 mg/kg of ADR. The rats were then divided into 3 groups: Pb-treated, non-treated and the control. The control group received 0.9% saline (vehicle) by injection. The 24-hr urinary protein excretion was measured for 24 weeks. When the animals were sacrificed at weeks 4, 12, and 24, respectively, blood samples were collected for biochemical study and the kidneys were extracted for measurement of malondialdehyde (MDA). In the morphological study, glomerular volume, glomerular sclerosis in dex (GSI), and tubulointerstitial index (TII) were calculated. Pb treatment lowered the serum lipid level and 24-hr urinary protein excretion. Total cholesterol was closely correlated with the urinary protein. However, there was no difference in terms of glomerular volume, kidney weight and GSI between the two groups. Pb treatment suppressed the kidney tissue MDA and TII significantly, the values of which were mutually correlated. The 24-hr protein excretion was significantly correlated with TII, but not with GSI. The decreased proteinuria was explained on the basis of suppression of enhancement of intraglomerular pressure induced by interstitial lesion. The findings suggest that renoprotection of Pb may derive from the amelioration of interstitial lesions.

The Time‐Dependence of Long‐Term Prediction in Lupus Nephritis

To assess the clinical, laboratory, and renal biopsy predictors of long-term outcome in lupus nephritis and to investigate the time-dependence of these predictors. Eighty-seven lupus nephritis patients were studied retrospectively for the outcomes renal failure and fatality due to renal involvement. In addition to a conventional Cox model analysis, a new generalized time-dependent analytic approach was developed and used to assess the time-dependence of a predictor variable's importance. The mean followup time was 11.9 years. Renal failure (n = 19) was significantly predicted by measures of renal function (abnormal serum creatinine levels, proteinuria, duration of prior renal disease) and immunologic activity (elevated DNA binding, hypocomplementemia, and thrombocytopenia), by overall lupus disease activity measures (le Riche index, Lupus Activity Criteria Count), and by the activity index, the tubulointerstitial index, and the amount of subepithelial deposits on renal biopsy. In general, the laboratory predictors were significantly better prognostic markers in the early years after biopsy, the disease activity measures were best in the later years, and the biopsy variables were significant predictors over the entire observation period. In contrast to the renal failure outcome, the best predictors for death not directly related to lupus nephritis (n = 17) were the extent of comorbid diseases (principally vascular diseases), older age, and the chronicity index. All three predicted well over the extended observation period. The major predictor variables for renal outcomes and nonrenal outcomes are distinct. The time-dependence of the predictive ability of some variables may be important in managing individual patients. The new generalized time-dependent analytic technique may have widespread application in studies to identify prognostic factors for established disease or risk factors for the development of disease.

The early effects of dietary restriction on the pathogenesis of chronic renal disease in Sprague-Dawley rats at 12 months.

This study evaluated the effects of different diets and dietary regimens on the pathogenesis of chronic renal disease (CRD) in Sprague-Dawley rats at 52 wk and correlated these data with survival at 106 wk. A commercial diet (5002) was compared to a modified diet (5002-9) with less protein, fat, and energy and more fiber. Both diets were fed by ad libitum (AL) or dietary restriction (DR) regimens. The glomerular area (GA), glomerular sclerotic index (GSI), tubulo-interstitial index (TII), and tubular labeling index (tubular LI) were measured. The 5002-9 diet fed AL did not decrease the severity of CRD or increase survival, nor did the 5002 diet fed 6.5 hr/day. Both diets fed by DR did improve CRD and survival. Both AL groups had higher indices, and the 5002 AL males had the highest GA and GSI. These data indicate that the initial events in CRD occur as glomerular hypertrophy. Because the TII and tubular LI were only increased with advanced CRD, tubulo-interstitial damage did not occur until the glomerular changes were established. The 52-wk glomerular indices correlated with survival at 106 wk. Increased GA at 52 wk predicted low survival rates at 106 wk. These findings support a hypothesis that glomerular sclerosis and tubulo-interstitial damage occur secondary to early initial glomerular hypertrophy that is mitigated by caloric restriction.

The pathogenesis and prognosis of lupus nephritis: Information from repeat renal biopsy

Of an inception cohort of 87 patients with lupus nephritis who underwent a renal biopsy, 42 underwent second biopsies a median of 25 months later. From first to second biopsy, focal and diffuse proliferative nephritis (World Health Organization classes III and IV) became less frequent, and mesangial hypercellularity (class II) and a membranous pattern (class V) increased. The National Institutes of Health activity index and mesangial and subendothelial deposits declined while the chronicity index, a tubulointerstitial index, and subepithelial deposits increased. The biopsy improvement in urinary protein excretion was best explained by decreases in the activity index score and the amount of subendothelial deposits. A decrease in the amount of subendothelial deposits tended to predict an improvement in the serum creatinine level from first to second biopsy. With follow-up from second biopsy in excess of 7 years, the best predictors of long-term outcome were the ultrastructural variables mesangial, subendothelial and subepithelial deposits. When the change in biopsy predictors from first to second biopsy was evaluated, a decrease in the amount of mesangial or subendothelial deposits was best at predicting a lower risk of renal impairment, renal insufficiency, and mortality. The results confirm the importance of immune complex deposition as measured by electron microscopy in the pathogenesis of lupus nephritis and suggest that control of this process may alter renal function and prognosis.

Differential effects of calorie restriction on glomeruli and tubules of the remnant kidney.

We have previously shown that 40% calorie restriction (CR) prevents renal injury 21 weeks after 5/6 nephrectomy (Nx) in rats, regardless of whether protein intake was concurrently restricted or not. Growth retardation appeared to be a necessary prerequisite for the protective effects of CR. To further study these mechanisms, we performed 5/6 Nx in male F344 rats and pair-fed them with a control diet (ad lib group) or a high protein diet restricted by 40% so that protein intake was similar, but calorie consumption was reduced (CR group). Four weeks after 5/6 Nx, when glomerulosclerosis had not yet developed, we compared various parameters as follows in both dietary groups and sham operated rats: urinary protein excretion (uPr), GFR (14C inulin clearance), mean nephron GFR (MNGFR; GFR divided by total number of glomeruli), glomerular volume (VG), tubulointerstitial index (TII), a measure of tubular damage kidney weight (kidney wt), kidney IGF-I content by RIA, and IGF-I immunohistochemistry. CR ameliorated the increase of MNGFR, but not glomerular hypertrophy. TII, kidney wt and kidney IGF-I content were increased in the ad lib Nx group; these changes were alleviated by CR. Two weeks after 5/6 Nx, immunohistochemistry for IGF-I showed increased staining in superficial distal nephrons in the ad lib group, and this was also suppressed by CR. The occurrence of tubulointerstitial pathology prior to glomerulosclerosis, and the beneficial effects of CR on all parameters except Vg indicate a dissociation of mechanisms which result in tubular versus glomerular hypertrophy and damage.(ABSTRACT TRUNCATED AT 250 WORDS)