Percentage Of Glomerulosclerosis Research Articles

FINERENONE TREATMENT PREVENTS GLOMERULAR DAMAGE AND RENAL INTERSTITIAL INFLAMMATION IN TYPE 1 DIABETIC RATS WITH CHRONIC KIDNEY DISEASE

Objective: Finerenone (FIN), a non-steroidal mineralocorticoid receptor antagonist, has shown a protective effect on kidney and cardiovascular damage progression in type 1 diabetic Munich Wistar Frömter rats with established chronic kidney disease (CKD). The gradual decline in kidney function in diabetic CKD is due to a thickening of glomerular and Bowman capsule basement membranes, mesangial matrix expansion, and tubulointerstitial fibrosis. In this study we aimed to characterize whether the renal protection of FIN is related to a decrease in kidney damage through histomorphological changes in diabetic MWF rats. Design and method: Diabetes was induced by a streptozotocin injection (15 mg/Kg, i.p.) together with exposure to a high fat/high sucrose (HF/HS) diet (MWF-D) for 6 weeks. The MWF-D-FIN group was additionally treated with 10 mg/Kg/day of FIN included in the HF/HS diet (n = 6/group). Morphometrical analysis of renal structural changes was performed under hematoxylin and eosin staining, and light microscopy. Matrix metalloproteinases (MMP)-2 and MMP-9 activities were determined by zymography. Results: MWF-D and MWF-D-EP rats exhibited significantly elevated glycemia, water intake, urine volume, glucosuria, and kidney weight compared to control MWF. Histological examination of kidney samples of MWF and MWF-D rats showed hypertrophic glomeruli with an increase of the glomerular tuft and the Bowman's space. These pathological alterations were prevented by FIN treatment. The percentage of glomerulosclerosis was significantly higher in MWF and MWF-D rats and 59% lower in the MWF-D-FIN group (p<0.001) whereas the glomerulosclerosis index was reduced to 33% by FIN (p<0.001). Moreover, MWF-D rats showed an increased interstitial inflammation index compared to MWF rats (p<0.001) which was reduced to 44% (p<0.001) in the MWF-D-FIN group. Since an increase in MMP-2 and MMP-9 activities are associated with fibrosis development, these were determined by zymography in kidney samples of all groups. Both MMP-2 and MMP-9 were significantly higher in MWF-D compared to MWF and decreased by FIN treatment. Conclusions: In conclusion FIN prevents the development of diabetic kidney damage due to a reduction in glomerular alterations and interstitial inflammation associated to an inhibition of MMP-2 and MMP-9 activities.

Association of Implantation Biopsy Findings in Living Donor Kidneys With Donor and Recipient Outcomes

Some living donor kidneys are found to have biopsy evidence of chronic scarring and/or glomerular disease at implantation, but it is unclear if these biopsy findings help predict donor kidney recovery or allograft outcomes. Our objective was to identify the prevalence of chronic histological changes and glomerular disease in donor kidneys, and their association with donor and recipient outcomes. Retrospective cohort study. Single center, living donor kidney transplants from January 2010 to July2022. Chronic histological changes, glomerular disease in donor kidney implantation biopsies. For donors, single-kidney estimated glomerular filtration rate (eGFR) increase, percent total eGFR loss,≥40% eGFR decline from predonation baseline, and eGFR<60mL/min/1.73m2 at 6 months after donation; for recipients, death-censored allograft survival. Biopsies were classified as having possible glomerular disease by pathologist diagnosis or chronic changes based on the percentage of glomerulosclerosis, interstitial fibrosis/tubular atrophy, and vascular disease. We used logistic regression to identify factors associated with the presence of chronic changes, linear regression to identify the association between chronic changes and single-kidney estimated glomerular filtration rate (eGFR) recovery, and time-to-event analyses to identify the relationship between abnormal biopsy findings and allograft outcomes. Among 1,104 living donor kidneys, 155 (14%) had advanced chronic changes on implantation biopsy, and 12 (1%) had findings suggestive of possible donor glomerular disease. Adjusted logistic regression showed that age (odds ratio [OR], 2.44 per 10 years [95% CI, 1.98-3.01), Hispanic ethnicity (OR, 1.87 [95% CI, 1.15-3.05), and hypertension (OR, 1.92 [95% CI, 1.01-3.64), were associated with higher odds of chronic changes on implantation biopsy. Adjusted linear regression showed no association of advanced chronic changes with single-kidney eGFR increase or relative risk of eGFR<60mL/min/1.73m2. There were no differences in time-to-death-censored allograft failure in unadjusted or adjusted Cox proportional hazards models when comparing kidneys with chronic changes to kidneys without histological abnormalities. Retrospective, absence of measured GFR. Approximately 1 in 7 living donor kidneys had chronic changes on implantation biopsy, primarily in the form of moderate vascular disease, and 1% had possible donor glomerular disease. Abnormal implantation biopsy findings were not significantly associated with 6-month donor eGFR outcomes or allograft survival. Kidney biopsies are the gold standard test to identify the presence or absence of kidney disease. However, kidneys donated by healthy living donors-who are extensively screened for any evidence of kidney disease before donation-occasionally show findings that might be considered "abnormal," including the presence of scarring in the kidney or findings suggestive of a primary kidney disease. We studied the frequency of abnormal kidney biopsy findings among living donors at our center. We found that about 14% of kidneys had chronic abnormalities and 1% had findings suggesting possible glomerular kidney disease, but the presence of abnormal biopsy findings was not associated with worse outcomes for the donors or their recipients.

Resistive index and kidney biopsy: what correlation in chronic kidney disease?

Introduction. Chronic kidney disease (CKD) represents a global public health problem. Its progression to the end stage is based on the existence and severity of histological lesions, especially interstitial fibrosis and vascular lesions, and exposes a high risk of mortality and cardiovascular events. Renal biopsy remains the reference examination allowing an accurate evaluation of the importance of fibrosis and remains an invasive and risky examination. The assessment of the risk of progression of CKD by a non-invasive examination would be of capital interest to the nephrologist in order to reinforce nephroprotection measures to delay the progression of renal disease and reduce the risk of cardiovascular events, which represents the first cause of mortality in this population. The value of the resistive index (RI), measured by an echo-doppler, seems to be important. The primary objective of this work was to evaluate the correlation between the value of the RI and the severity of the histological lesions. Secondary objectives were to evaluate the correlation of RI with CKD progression, cardiovascular mortality, and to define a prognostic threshold for progression. Material and method. This is a prospective monocentric study including 104 patients hospitalized in the nephrology department of the regional military university hospital of Constantine during the period April 2014-January 2019, presenting with CKD and scheduled for a renal biopsy for diagnostic purposes. RI measurement was performed 24-48 hours before this procedure. Results. We showed that there is a positive and statistically significant correlation of RI with age (r=0.38, p &lt; 103), the number of cardiovascular risk factors (r=0.39, p &lt; 103),systolic blood pressure (r=0.39 , p &lt; 103) and pulse pressure ( r=0.51 , p &lt; 103), percentage of glomerulosclerosis (r=0.51, p &lt; 103), percentage of interstitial fibrosis ( r=0.43 , p &lt; 103) and vascular damage (p &lt; 103). While there is a negative correlation with initial eGFR (r= -0.52 , p &lt; 103) and to a lesser degree with the combined size of the two kidneys (r= -0.26 , p &lt; 103), no correlation was observed with diastolic blood pressure, proteinuria (proteinuria / creatinuria ratio) and the use of antiproteinuric treatment. Switching to renal replacement therapy (RRT) and cardiovascular mortality were associated with the highest RI. Beyond a threshold value of 0.65, histological lesions are more pronounced with a worse evolution of CKD. Conclusion. This study underlines that RI is a non invasive marker of progression and the interest to propose it as a prognostic criterion in the management of chronic kidney disease.

Prognostic Implications of a Morphometric Evaluation for Chronic Changes on All Diagnostic Native Kidney Biopsies.

Semiquantitative visual inspection for glomerulosclerosis, interstitial fibrosis, and arteriosclerosis is often used to assess chronic changes in native kidney biopsies. Morphometric evaluation of these and other chronic changes may improve the prognostic assessment. We studied a historical cohort of patients who underwent a native kidney biopsy between 1993 and 2015 and were followed through 2021 for ESKD and for progressive CKD (defined as experiencing 50% eGFR decline, temporary dialysis, or ESKD). Pathologist scores for the percentages of globally sclerosed glomeruli (GSG), interstitial fibrosis and tubular atrophy (IFTA), and arteriosclerosis (luminal stenosis) were available. We scanned biopsy sections into high-resolution images to trace microstructures. Morphometry measures were percentage of GSG; percentage of glomerulosclerosis (percentage of GSG, ischemic-appearing glomeruli, or segmentally sclerosed glomeruli); percentage of IFTA; IFTA foci density; percentage of artery luminal stenosis; arteriolar hyalinosis counts; and measures of nephron size. Models assessed risk of ESKD or progressive CKD with biopsy measures adjusted for age, hypertension, diabetes, body mass index, eGFR, and proteinuria. Of 353 patients (followed for a median 7.5 years), 75 developed ESKD and 139 experienced progressive CKD events. Visually estimated scores by pathologists versus morphometry measures for percentages of GSG, IFTA, and luminal stenosis did not substantively differ in predicting outcomes. However, adding percentage of glomerulosclerosis, IFTA foci density, and arteriolar hyalinosis improved outcome prediction. A 10-point score using percentage of glomerulosclerosis, percentage of IFTA, IFTA foci density, and any arteriolar hyalinosis outperformed a 10-point score based on percentages of GSG, IFTA, and luminal stenosis >50% in discriminating risk of ESKD or progressive CKD. Morphometric characterization of glomerulosclerosis, IFTA, and arteriolar hyalinosis on kidney biopsy improves prediction of long-term kidney outcomes.

P0348THE DUAL ENDOTHELIN ETA AND ANGIOTENSIN AT1 RECEPTOR BLOCKER SPARSENTAN PROTECTS AGAINST THE DEVELOPMENT OF ALBUMINURIA AND GLOMERULOSCLEROSIS IN THE GDDY MOUSE MODEL OF IGA

Abstract Background and Aims gddY mice are an IgA nephropathy (IgAN)-prone mouse model that develops albuminuria by 8 weeks (wks) of age with glomerular IgA, IgG, and C3 deposits and progressive mesangioproliferative glomerulonephritis. A previous study in the ddY mouse model, the more genetically heterogeneous predecessor of gddY mice, using the endothelin type A receptor (ETAR) antagonist FR139317 resulted in amelioration of proteinuria and preservation of kidney function. Treatment of ddY mice with the angiotensin II type 1 receptor (AT1R) blocker valsartan resulted in significant protection from glomerulosclerosis (GS) without a significant prevention in proteinuria. Here we examined the effect of sparsentan (SP), a dual ETAR and AT1R blocker, currently in phase 3 trials for focal segmental glomerulosclerosis and IgAN, on the development of albuminuria and GS in gddY mice. Method gddY mice at 4 wks of age were fed with control (C) chow (n=5) or chow containing 900 ppm (n=10) or 1800 ppm (n=10) SP (approximately 180 and 360 mg/kg/day) for 8 wks. Albuminuria (U-Alb) was assessed at 4, 6, 8, and 12 wks of age and plasma levels of SP were determined at 8 am and 4 pm at wks 6, 8, and 12. Kidney biopsies were taken at the end of the study at 12 wks of age for processing and 30 glomeruli per animal were scored for the percentage of GS. Results gddY mice fed SP in the diet for 8 wks from 4 wks of age demonstrated significantly (*P&amp;lt;0.05) decreased U-Alb compared to mice fed the C diet in a dose-dependent manner (Figure 1). The development of GS in mice fed the diet containing 1800 ppm SP was significantly (*P&amp;lt;0.05) attenuated compared to C diet (Figure 2). Plasma levels of SP taken at 8 am and 4 pm after 8 wks of treatment were (mean±SD) 281±107 and 105±62 ng/ml for 900 ppm SP respectively, and 774±674 and 304±176 ng/ml for 1800 ppm SP, respectively. Weight gain in mice fed SP was not different from mice that received C diet. Conclusion Eight weeks of treatment with SP attenuated increases in albuminuria and GS associated with the development of IgAN in gddY mice. If translated to the clinic, these data support SP as a new approach to the treatment of IgAN.

Degree of Glomerulosclerosis in Procurement Kidney Biopsies from Marginal Donor Kidneys and Their Implications in Predicting Graft Outcomes.

Background: This study aimed to assess the association between the percentage of glomerulosclerosis (GS) in procurement allograft biopsies from high-risk deceased donor and graft outcomes in kidney transplant recipients. Methods: The UNOS database was used to identify deceased-donor kidneys with a kidney donor profile index (KDPI) score > 85% from 2005 to 2014. Deceased donor kidneys were categorized based on the percentage of GS: 0–10%, 11–20%, >20% and no biopsy performed. The outcome included death-censored graft survival, patient survival, rate of delayed graft function, and 1-year acute rejection. Results: Of 22,006 kidneys, 91.2% were biopsied showing 0–10% GS (58.0%), 11–20% GS (13.5%), >20% GS (19.7%); 8.8% were not biopsied. The rate of kidney discard was 48.5%; 33.6% in 0–10% GS, 68.9% in 11–20% GS, and 77.4% in >20% GS. 49.8% of kidneys were discarded in those that were not biopsied. Death-censored graft survival at 5 years was 75.8% for 0–10% GS, 70.9% for >10% GS, and 74.8% for the no biopsy group. Among kidneys with >10% GS, there was no significant difference in death-censored graft survival between 11–20% GS and >20% GS. Recipients with >10% GS had an increased risk of graft failure (HR = 1.27, p < 0.001), compared with 0–10% GS. There was no significant difference in patient survival, acute rejection at 1-year, and delayed graft function between 0% and 10% GS and >10% GS. Conclusion: In >85% KDPI kidneys, our study suggested that discard rates increased with higher percentages of GS, and GS >10% is an independent prognostic factor for graft failure. Due to organ shortage, future studies are needed to identify strategies to use these marginal kidneys safely and improve outcomes.

SUN-035 A MODIFIED – ‘MODIFIED PONTICELLI’ REGIMEN - FOR IDIOPATHIC MEMBRANOUS NEPHROPATHY

Idiopathic membranous nephropathy (IMN) is one of the most common causes of nephrotic syndrome in adults worldwide. Treatment using cyclical cyclophosphamide and steroids (‘modified Ponticelli’ regimen) has been the standard of care for decades, however potential therapy-related adverse effects are a significant concern. At our center, we have used lower-than-standard dose intravenous pulse steroid based modification of the conventional ‘modified Ponticelli’ regimen to minimize steroid-related adverse effects (Figure 1). The aim of this study was to assess the efficacy and safety of this regimen in IMN. This was a case-record based retrospective analysis conducted at our center over a period of nine years (January 2008-December 2017). All treatment-naive patients with primary MN fulfilling the following criteria: (1) biopsy proven MN and (2) initiated with a lower-than-standard dose pulse steroid-based modification of the conventional ‘modified Ponticelli’ regimen (Figure 1) were included. Clinical and laboratory parameters of all patients were recorded. Remission rates (both complete and partial) and adverse effects of therapy at the end of 6 months of therapy were studied. Follow-up data up was also collected. The study definitions used are as follows: Complete remission: Proteinuria < 0.3g/day or UPCR <0.3 mg/mg, with normalization of serum albumin (≥3.5g/dL) Partial remission: Reduction of 24 hour urine protein (or UPCR) to < 50% of baseline to < 3.5g/day (or UPCR <3.5mg/mg), but > 0.3g/day (or UPCR > 0.3mg/mg) Relapse: Proteinuria >3.5g/day or >3500mg/g urine creatinine after remission has been attained. Analysis was carried out using SPSS version 18. A total of 41 patients were included. Baseline characteristics are shown in Table 1. All patients received either angiotensin converting enzyme inhibitors/ angiotensin receptor blockers (ACEi/ARBS) as supportive therapy. Immunosuppression was stopped prior to completion of six months for four patients due to infection, while six patients were lost to follow-up. Of the 31 patients who completed six months of therapy, 71% (n=22) responded to therapy [complete remission in 25.8% (n=8), partial remission in 45.2% (n=14)] and 29% (n=9) failed to respond (Table 2). Most common complications seen during therapy were infections in 25.7% (n=9/35, of which immunosuppression was discontinued for four patients), steroid induced diabetes mellitus in 40% (n=14/35), and leucopenia in 8.5% (n=3/35).[R[1] The relapse rate during follow-up (mean follow-up period: 35.6 months) was 29% (n=9). Anti-PLA2R titers and percentage of glomerulosclerosis at presentation were significantly associated with response at 6 months (p<0.05).View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT) Use of lower-than-standard dose pulse steroid and cyclophosphamide is effective in achieving remission in idiopathic membranous nephropathy. Further large randomized control trials with longer follow-up are needed to confirm the same.

In vitro Comparison of Ethanol Metabolism in Precision Cut Liver Slices from C57Bl/6, Balb/c, DBA/2J and 129S1/SvlmJ Mice

Percutaneous biopsy is a key diagnostic tool for both native and allograft kidney diseases. Adequacy criteria vary, but at a minimum, a biopsy should allow the pathologist to reach a diagnosis and provide prognostic information such as the degree of interstitial fibrosis and tubular atrophy (IF/TA) and percentage of glomerulosclerosis. Whereas most studies use glomerular counts as a surrogate for biopsy adequacy, the amount and preservation of tubulointerstitium is equally important, considering IF/TA is a major prognostic parameter for most medical renal diseases. Many studies have compared the diagnostic adequacy of different gauge needles; however few have investigated performance differences between same gauge needles. In this study, we retrospectively analyzed 235 renal biopsies performed at a single center in Canada over 2 years to compare the utilization, safety, diagnostic and prognostic performance of two 18-gauge needles in native and allograft kidney biopsies. We found no significant difference in needle utilization between native and allograft kidneys, or between trainees and staff radiologists. The total tissue yielded area, glomerular counts, percentage of inadequate biopsies and number of passes were similar; however the number of cases in which IF/TA evaluation was deemed not possible was higher for biopsies using disposable instrument needles (4.3% vs. 0%; p = 0.01). These also showed greater number of tissue fragments (median 4 for reusable vs 3 for disposable; p = 0.04). We postulate that the increased tissue fragmentation might have impaired the pathologists ability to accurately assess interstitial fibrosis and tubular atrophy in biopsies obtained with the disposable instrument needles.

Effectiveness and safety of two 18-gauge needle types on native and allograft renal biopsies.

Percutaneous biopsy is a key diagnostic tool for both native and allograft kidney diseases. Adequacy criteria vary, but at a minimum, a biopsy should allow the pathologist to reach a diagnosis and provide prognostic information such as the degree of interstitial fibrosis and tubular atrophy (IF/TA) and percentage of glomerulosclerosis. Whereas most studies use glomerular counts as a surrogate for biopsy adequacy, the amount and preservation of tubulointerstitium is equally important, considering IF/TA is a major prognostic parameter for most medical renal diseases. Many studies have compared the diagnostic adequacy of different gauge needles; however few have investigated performance differences between same gauge needles. In this study, we retrospectively analyzed 235 renal biopsies performed at a single center in Canada over 2years to compare the utilization, safety, diagnostic and prognostic performance of two 18-gauge needles in native and allograft kidney biopsies. We found no significant difference in needle utilization between native and allograft kidneys, or between trainees and staff radiologists. The total tissue yielded area, glomerular counts, percentage of inadequate biopsies and number of passes were similar; however the number of cases in which IF/TA evaluation was deemed not possible was higher for biopsies using disposable instrument needles (4.3% vs. 0%; p=0.01). These also showed greater number of tissue fragments (median 4 for reusable vs 3 for disposable; p=0.04). We postulate that the increased tissue fragmentation might have impaired the pathologists ability to accurately assess interstitial fibrosis and tubular atrophy in biopsies obtained with the disposable instrument needles.

Influence of Normo- and Hypogonadal Condition, Hyperuricemia, and High-Fructose Diet on Renal Changes in Male Rats.

Background. There is a gender disparity in the incidence, prevalence, and progression of renal disease. The object of this paper is to evaluate the presence and type of renal lesion in normogonadic and hypogonadic male rats in a mild hyperuricemia induced condition and exposed to a high-fructose diet. Methods. 56 adult male Wistar rats were used. Animals were divided into two groups, one normogonadic (NGN) and one hypogonadic (HGN), and each group was divided into four subgroups in accordance with the treatment: control with only water (C), fructose (F), oxonic acid (OA), and fructose + oxonic acid (FOA). Renal changes were evaluated by measuring glomerulosclerosis, fibrosis, and arteriolar media/lumen (M/L) ratio. Results. The OA and FOA groups presented significantly hypertension (p < 0.001). The OA group significantly increased (p < 0.05) the percentage of glomerulosclerosis as well as the FOA group (p < 0.001). When comparing NGN versus HGN, we observed a trend to a lower glomerulosclerosis in the latter. A higher arteriolar M/L ratio was observed in the OA (p < 0.05) and FOA (p < 0.001). Conclusion. Hyperuricemia conditions and a high-fructose diet favor blood pressure increase together with changes in the arteriolar media/lumen ratio and renal glomerular damage. These changes were more apparent in normogonadic animals.

Clinicopathological characteristics of patients with immunoglobulin A nephropathy showing acute exacerbations after favorable long-term clinical courses.

Sometimes, acute and progressive proteinuria increases occur in patients with IgA nephropathy (IgAN) after favorable long-term clinical courses of >10 years, but their clinical and histological characteristics are not well understood. We retrospectively selected 20 IgAN patients who had been followed for >10 years after their initial biopsies ((1st)Bx) and underwent second biopsies ((2nd)Bx), because their proteinuria increased to >1 g/day. Eight patients with acute exacerbations (Group A) showed acute proteinuria increases after long periods of mild proteinuria. Their clinicopathological characteristics were analyzed as a case series and were compared with those in Group B that comprised 12 patients with persistent proteinuria. Group A experienced acute proteinuria increases and significant hematuria increases compared with the -1-year (P = 0.006) and -3-year (P = 0.010) time points before the (2nd)Bx, which contrasted to the clinical course in Group B. In Group A, glomerulosclerosis (GS) and the arteriosclerosis score did not differ between the (2nd)Bx and the (1st)Bx, and most patients (88 %) showed cellular and/or fibrocellular crescents within the (2nd)Bx. Compared with Group B, the (2nd)Bx revealed that the percentage of cellular and/or fibrocellular crescents (P = 0.001) was significantly higher, whereas the percentage of GS (P = 0.012) and the arteriosclerosis score (P = 0.020) were significantly lower in Group A. Rapid proteinuria and hematuria increases, and acute histological lesions characterize acute exacerbations in IgAN after favorable long-term clinical courses.

PP.27.28

Objective: Uric acid is associated with high blood pressure, cardiovascular and renal disease. Our main goal is to study in patients with hypertension, the relationship of uric acid with renal arteriolar involvement and secondly their relationship with cardiovascular disease(CVD). Design and method: We performed a retrospective analysis of 68 patients with hypertension and who a renal biopsy (BR) was realized between 2010–2011 and followed up within four years. 5 patients were excluded from the study because insufficient material of renal biopsy. The characteristics of our sample are: Men 58% (37patients), mean age 60.3 ± 14.9 years of Hypertension 9.8 ± 6.4, diabetes 33.3% (21patients), CVD 17.5% (11 patients). 44.4% was under diuretics and 19% with hypouricemic drugs. We collected an anthropometric, laboratory data, new cardiovascular events and the characteristics of the arterioles and glomerulosclerosis in renal biopsy. Results: We detected a relationship without reaching significance comparing the hyperuricemia with the classification of renal arteriolopathy in different stages (mild / moderate / severe): 6.9 ± 2.2; 7.3 ± 1.2; 8.1 ± 2,1 mg / dl, respectively (p = 0.201). Uric acid is positively correlated with the percentage of glomerulosclerosis (R = 0.300, p = 0.018) and negatively correlated with diastolic blood pressure (R = -0,272, p = 0.031) and the MDRD (R = -0,447, p < 0.0001). No differences were detected between the diuretic and hypouricemic therapy among patients with mild / moderate / severe Arteriolopathy. Conclusions: Our results show that elevated uric acid levels are associated with increased arteriolar involvement and glomerulosclerosis. In addition, we found negative correlation with diastolic blood pressure and MDRD. It is concluded that uric acid may contribute to renal vascular involvement.

Machine Perfusion: Initial Results in an Expanded Criteria Donor Kidney Transplant Program

BackgroundDelayed graft function (DGF) negatively impacts graft survival. Expanded criteria donors (ECD) show a higher rate of DGF. Hypothermic machine perfusion (HMP) has shown a DGF decrease and an increase of survival at 1 year. Several authors found that renal resistance (RR) at the end of machine perfusion was an independent risk factor for the development of DGF and poorer graft survival. The objective of this study was to analyze HMP results in the context of an ECD program and assess the impact of donor parameters and resistance index (RI) during perfusion in graft survival after kidney transplantation. MethodsDonor age, terminal creatinine, machine perfusion time, percentage of glomerulosclerosis, and RI at the end of the perfusion were considered as risk predictors. Univariate and multivariate Cox regression analysis was constructed to find independent risk factors of DGF. Finally, diagnostic validity for RR was determined by sensitivity, specificity, and positive and negative predictive values. ResultsTwenty-three percent of patients developed DGF. We found no difference in the ability of flow or RI to predict the development of DGF. The predictive accuracy of RI for DGF by receiver operator characteristic curve was poor, with a c-statistic of 0.66 (95% CI, 0.50–0.81; P = .046). Our analysis did not identify risk factors that predicted graft survival at 1 year. Patient and graft survival were 98.8% and 89.7%, respectively. ConclusionsHMP has reduced the rate of DGF in our cohort of recipients of ECD grafts compared with historical data (23.3% vs 38.0%). Analysis did not identify risk pretransplant factors for graft survival at 1 year.

DTI for the assessment of disease stage in patients with glomerulonephritis--correlation with renal histology.

To investigate whether DTI allows assessment of renal impairment and pathology in patients with chronic glomerulonephritis. Seventy-five patients and 20 healthy volunteers were enrolled in this study. Renal function and kidney biopsies were evaluated. For DTI, a respiratory-triggered coronal EPI sequence was performed (TR, 1400 ms; TE, 76 ms; diffusion direction, 6; NEX, 4; b values, 0 and 600 s/mm2; slices thickness, 6 mm, with no intersection gap). Renal ADC and FA values were calculated and compared between the groups. Correlations between ADC/FA and histopathology were evaluated. ADC values decreased with increased stages. ADC differences in renal parenchyma at different disease stages were found, with the exception of the control group compared with stage 1 patients; similar results were obtained for FA. ADC values in the cortex and medulla in stage 1-3 patients were both statistically different, similar to the FA values. A significant negative correlation was found between the percentage of glomerulosclerosis and FA in the renal cortex (r = -0.74), similar to the degree of tubulointerstitial fibrosis with FA in the medulla (r = -0.76). ADC and FA values are correlated with the degree of renal impairment, the percentage of glomerulosclerosis, and area of interstitial fibrosis. • DTI can be used to assess renal function impairment in patients with chronic glomerulonephritis. • ADC and FA values were correlated with tubulointerstitial fibrosis and glomerulosclerosis. • Identification of renal impairment is helpful for timely treatment. • DTI can be used for non-invasive assessment of renal pathology.

Hypertension, glomerular hypertrophy and nephrosclerosis: the effect of race

BackgroundAfrican Americans have more severe hypertensive nephrosclerosis than white Americans, possibly at similar levels of blood pressure. Glomerular volume is increased in African Americans relative to whites, but it is uncertain how this relates to nephrosclerosis and whether it contributes to or compensates for glomerulosclerosis.MethodsStereological disector/fractionator estimates of glomerular number (Nglom) and average glomerular volume (Vglom) were obtained on autopsy kidneys of 171 African Americans and 131 whites. Eighty-eight African Americans and 49 whites were identified as hypertensive. Nephrosclerosis was measured morphometrically as the percentage of glomerulosclerosis, proportion of cortical fibrosis and interlobular artery intimal thickness, and analyzed with Vglom by age, race, gender, body mass index (BMI) and blood pressure.ResultsAfrican Americans were more frequently hypertensive (58.5%) than whites (35.8%) and when hypertensive had higher levels of blood pressure (P = 0.02). Nglom was significantly lower in hypertensive compared with non-hypertensive subjects among white women (P = 0.02) but not white males (P = 0.34) or African American females (P = 0.10) or males (P = 0.41). For each race and gender, glomerulosclerosis, cortical fibrosis and arterial intimal thickening were statistically correlated with age (P < 0.001) and hypertension (P < 0.001) and increased Vglom with hypertension (P < 0.001) and BMI (P < 0.001). In multivariate analysis, African American race was associated with increased Vglom (P = 0.01) and arterial intimal thickening (P < 0.01), while interactions between race and blood pressure indicated that the severity of nephrosclerosis including increased Vglom was linked most directly to hypertension without significant contributions from race. The hypertension-associated enlargement of Vglom was present with mild degrees of glomerulosclerosis and changed little as the severity of glomerulosclerosis increased.ConclusionsGlomerular hypertrophy was identified as an integral feature of hypertensive nephropathy and appeared to precede rather than compensate for glomerulosclerosis. An effect of race on Vglom and arterial intimal thickening seemed to be related to the more frequent and more severe hypertension among African Americans.

Histopathologic Evaluation of Pretransplant Biopsy as a Factor Influencing Graft Function After Kidney Transplantation: A 1-Year Observation

Introduction Many factors affect long-term results in kidney transplantation including histologic damage as a independent predictor, such as chronic allograft/nephropathy in protocol biopsies and age-dependent lesions. Histopathologic findings correlate with the incidence of delayed graft function, renal function, and allograft survival, allowing a rather precise prediction of graft outcome. Materials and Methods We analyzed 92 renal thick needle preimplantation and 29 postexplantation biopsies. Biopsies were preserved in 4% formalin and immersed in paraffin. Optimal biopsies contained at least 10 glomeruli and at least 2 cross-sections of arteries. We analyzed tubulitis, intensity of acute tubular necrosis, inflammatory infiltration, glomerulonephritis, arterial hyalinization, arteritis, fibrosis, tubular atrophy, arterial intimal fibrosis, increase of mesangial matrix, and percentage of glomerulosclerosis. During the postoperative course we analyzed patients condition, exigency of postoperative dialysis, urine output, as well as serum concentrations of creatinine, urea, uric acid, and ions. During a 1-year observation period, we analyzed living recipients, graft loss, death with a functioning graft, incidence of nephropathy (CAN), and acute rejection episodes (ARE). Results We observed a significant correlation between immediate graft function (IGF) and lack of ATN in the pre-0 biopsy. We observed no correlation between renal function and arterial hyalinization and fibrosis, inflammatory infiltration, tubular atrophy. In the postoperative period, we observed a significant correlation between IGF and lack of interstitial fibrosis with significantly lower levels of creatinine, urea, and potassium and higher urine output early after transplantation. IGF and better function of the right kidney was correlated with shorter time to reach a creatinine level of 2 mg%. In the postoperative periods, we also observed a difference between renal function depending on gender. The presence of acute tubular necrosis, arterial fibrosis, lack of inflammatory infiltration in the pre-0 biopsy correlated with worse late renal function. Among explantation biopsies 65.5% showed signs of CAN, and 37.93%, histologic marks of ARE.

Inhibition of p38 Mitogen-Activated Protein Kinase and Transforming Growth Factor-β1/Smad Signaling Pathways Modulates the Development of Fibrosis in Adriamycin-Induced Nephropathy

Inflammation and fibrogenesis are the two determinants of the progression of renal fibrosis, the common pathway leading to end-stage renal disease. The p38 mitogen-activated protein kinase (MAPK) and transforming growth factor (TGF)-beta1/Smad signaling pathways play critical roles in inflammation and fibrogenesis, respectively. The present study examined the beneficial renoprotective effect of combination therapy using the p38 MAPK pathway inhibitor (SB203580) and a TGF-beta receptor I (ALK5) inhibitor (ALK5I) in a mouse model of adriamycin (ADR) nephrosis. The p38 MAPK and TGF-beta1/Smad2 signaling pathways were activated in ADR-induced nephropathy in a sequential time course manner. Two weeks after ADR injection, the combined administration of SB203580 (1 mg/kg/24 hours) and ALK5I (1 mg/kg/24 hours) markedly reduced p38 MAPK and Smad2 activities. Moreover, the co-administration of SB203580 and ALK5I to ADR-injected mice resulted in a down-regulation of total and active TGF-beta1 production, reduced myofibroblast accumulation, and decreased expression of collagen type IV and fibronectin. In these mice, retardation in the development of glomerulosclerosis and interstitial fibrosis was observed. In conclusion, although p38 MAPK and TGF-beta1/Smad signaling pathways are distinct they coordinate the progression of renal fibrosis in ADR nephrosis. The co-administration of a p38 MAPK inhibitor and an ALK5 inhibitor may have potential applications in the treatment of renal fibrosis.

MRNA Expression of Target Genes in the Urinary Sediment as a Noninvasive Prognostic Indicator of CKD

Study of messenger RNA (mRNA) expression of target genes in urinary sediment was suggested as a noninvasive marker of renal damage in patients with chronic kidney diseases (CKDs). We studied the relationship between urinary mRNA expression of target genes and risk for renal function deterioration in patients with CKD. We studied 131 patients with CKD with kidney biopsy. mRNA expression of 11 target genes in urinary sediment was measured by means of quantitative polymerase chain reaction. Patients then were followed up for 27.4 +/- 10.1 months. The primary end point is doubling of serum creatinine concentration or end-stage renal disease. Thirty-six patients (27.5%) reached the primary end point during follow-up. Univariate analysis showed that sex, age, proteinuria, estimated glomerular filtration rate, histological diagnosis, degree of tubulointerstitial scarring, percentage of glomerulosclerosis, and urinary mRNA expression of hepatocyte growth factor (HGF) were predictors of the primary end point. At 24 months, event-free survival rates were 90.9% and 64.3% for patients with low and high urinary HGF expression, respectively (log rank test, P = 0.002). After adjusting for other confounding factors by using a Cox proportional hazard model, urinary HGF expression remained an independent predictor of the primary end point, and a 1-fold increase in expression was associated with a 4.0% (95% confidence interval, 0.5 to 7.5; P = 0.024) increase in risk. In the target genes examined, urinary HGF expression is an independent prognostic indicator of CKD after adjusting for confounding clinical and histological factors. Measurement of urinary HGF mRNA expression may be a useful noninvasive tool for risk stratification of patients with CKD.

The Perfusion Pressure in Non–Heart-Beating Donors May Expand the Glomeruli

Introduction We have observed expanded glomeruli in biopsies of kidneys from non–heart-beating donors (NHBDs). We sought to determine the differences in glomerular size between NHBDs and brain-dead donors and to assess whether glomerular size impacted graft outcome. Methods We estimated the glomerular area using the maximal planar area (MPA) method in 198 pretransplant biopsies from 119 donors: 54 (45.4%) NHBDs and 65 (54.6%) brain-dead donors. Donor data and graft outcomes were correlated with MPA and percentage of glomerulosclerosis. The range of follow-up was 1 to 3 years. Uni- and multivariate analyses were performed. Results MPA was larger among NHBDs. MPA and GS both significantly correlated with donor age. The association between MPA and age was independent of nephron loss (ie; GS). Increased glomerular size was only observed among donors younger than 50 years. Graft survival and function were not independently associated with MPA. Donor age was a better predictor of graft outcome. Conclusions The perfusion pressure used in NHBDs may expand the glomeruli, but this maneuver does not have any effect on graft outcome. Among donors without severe changes, glomerular size increment shows a limit around the sixth decade of life. In our study, MPA was not an independent predictor of graft survival or function.

Importance of kidney biopsy in graft selection

Pretransplantation biopsies of kidney grafts have become a key to select organs suitable for transplantation from marginal donors. The main microscopic features to be evaluated are as follows: percentage of glomerulosclerosis, interstitial fibrosis and vascular pathology. Although the percentage of glomerulosclerosis prognosticates kidney outcome, it has not yet been established what the age limit and type of kidney injury absolutely forbid the use of a particular organ. The principal reason for the controversy about the real value of the biopsy is due to the limited knowledge of the impact of age on the morphology of renal injuries. We reviewed 50 autopsies of patients older than 65 years, and 75 kidney biopsies showing renal disease. The percentage of glomerulosclerosis was always <15% in autopsy material, and <20% in kidney biopsies. We consider that improvement of the predictive value of pretransplantation renal biopsies may be achieved with the following guidelines: sufficient size of wedge biopsies (1.5 cm deep), not limited to the subcapsular area; never having <25 glomeruli; and a fast paraffin embedding technique that allows an objective evaluation of percentage of glomeruli and arterial-arteriolar damage. Transplantation is contraindicated when there is >20% of glomerulosclerosis accompanied by arteriolar damage.