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Background: Blood pressure is an important and modifiable cardiovascular risk factor. Ambulatory blood pressure monitoring (ABPM) provides valuable prognostic information in patients with chronic kidney disease (CKD), yet little is known about the association of various types of BP measurements with target organ damage (TOD) in patients with primary glomerular disease. The goal of this study was to investigate whether ambulatory blood pressure is better associated with TOD than clinic blood pressure in patients with primary glomerular disease., Methods: 1178 patients with primary glomerular disease were recruited in this cross-sectional study. TOD were assessed by the following 4 parameters: left ventricular mass index (LVMI or LVH, left ventricular hypertrophy), estimated glomerular filtration rate (eGFR< 60 ml/min/1.73m 2 ), albumin-to-creatinine ratio (ACR ≥ 30 mg/g) and carotid intima-media thickness (cIMT) or plaque. Receiver operating characteristic (ROC) curve and multivariate logistic regression analyses were used to evaluate the relationship between ambulatory or clinic systolic blood pressure (SBP) indexes and TOD., Results: Among 1178 patients (mean age, 39 years,54% men), 116, 458, 1031 and 251 patients had LVH, eGFR < 60 ml/min/1.73m 2 , ACR ≥ 30 mg/g and cIMT≥0.9 mm or plaque respectively. Area under ROC curves for TOD in ambulatory SBP, especially nighttime SBP, was greater than that in clinic SBP (P < 0.05). Multivariate logistic regression analyses showed that 24 h SBP, daytime SBP and nighttime SBP were significantly associated with LVH, eGFR< 60 ml/min/1.73m 2 and ACR ≥ 30 mg/g after adjustment for clinic SBP, while the association of clinic SBP was attenuated after further adjustment for nighttime SBP., Conclusions: Ambulatory blood pressure, especially nighttime blood pressure, is probably superior to clinic blood pressure and has a significant association with TOD in primary glomerular disease patients.

Purpose of Review: The recent years have been marked by the publication of several articles highlighting the pathophysiological role of glomerular parietal epithelial cells (PEC) and refining their phenotypic heterogeneity., Recent Findings: The present review synthetizes recent findings on (i) the potential regenerative role of PEC in glomerular diseases, and (ii) the mechanisms and signaling of leading to PEC pathogenic involvement in crescentic glomerulonephritis (CGN) and focal segmental glomerulosclerosis (FSGS)., Summary: The debate is still open regarding the podocyte regenerative properties of PEC in glomerular disease, whereas the pathogenic involvement of PEC activation in glomerular disease is increasingly admitted. Recent highlights on the podocyte regenerative role of PEC, on one hand, and on their pathological function, on the other hand, for sure will feed the debate in the kidney community for the next years. Nevertheless, from a therapeutic perspective, the two options, boosting cellular regeneration and blocking PECs pathogenicity, should not be seen as antagonistic but, rather, complementary.

Collapsing glomerulopathy (CG) is a rare entity as a glomerular disease. Although it has been considered as a variant of focal segmental glomerulosclerosis, the fact is that the podocyte lesions show different features with respect to the typical focal segmental glomerulosclerosis, an aspect that has been attributed to a type of podocytopathy. In CG, the podocyte lesion is typically characterised by a dysregulated podocyte phenotype, reflected by the loss of expression of mature podocyte markers. CG can be a primary disease or it can be associated with several causal factors that develop a common histopathological entity. The clinical expressiveness of CG is often characterised by the presence of a nephrotic syndrome and a rapid deterioration of the renal function than other variants of the focal segmental glomerulosclerosis. The prognosis of these patients is a rapid progression towards end-stage renal disease with poor response to treatment., (Copyright © 2018 Elsevier España, S.L.U. All rights reserved.)

Background: The increase of circulating urokinase plasminogen activator receptor (suPAR) was demonstrated in various diseases showing its prognostic value as well as the link to the inflammatory reaction. In glomerular diseases, suPAR was considered a causative factor of proteinuria. In the present study we aimed to evaluate serum concentration of suPAR in children with primary and secondary glomerulonephritis (GN) and its association with disease severity., Methods: The study involved 22 children with minimal change disease (MCD), nine with primary focal segmental glomerulosclerosis (FSGS), seven with Henoch-Schönlein nephritis, seven with lupus nephritis (LN) and 16 controls., Results: Serum suPAR was significantly higher in children with FSGS and LN than controls (4.47±1.39 ng/mL vs. 3.23±0.76 ng/mL; P=0.011 and 6.17±1.12 ng/mL vs. 3.23±0.76 ng/mL, respectively; P<0.0001). Further, suPAR was increased in LN when compared to FSGS (P=0.031). In the total group suPAR showed negative correlation with eGFR, serum complement C3 and positive with left ventricular mass index. In children with MCD and FSGS the inverse association of suPAR with eGFR was also shown., Conclusions: In children with primary and secondary glomerulonephritis suPAR levels are not associated with proteinuria. In primary GN elevated suPAR levels may result from reduced eGFR reflecting renal damage. In LN circulating suPAR can be increased further indicating both multi-organ involvement and systemic inflammation reflecting disease severity.

Objective: To study the clinical features and treatment of focal segmental glomerulosclerosis (FSGS) after renal transplantation in a child with ANCA-associated glomerulonephritis. Method: The clinical and pathological data of the patient treated in the Department of Pediatrics as well as in the Department of Organ Transplantation in November 2015 in the First Affiliated Hospital of Sun Yat-sen University, who was diagnosed with de novo FSGS after renal transplantation with a primary disease ANCA-associated glomerulonephritis, was analyzed retrospectively. Reports on "ANCA-associated glomerulonephritis" "(renal OR kidney) transplantation" "focal segmental glomerular sclerosis" were searched and reviewed. Result: A ten years old female was definitely diagnosed with ANCA-associated glomerulonephritis on the 81 st day after the onset of primary ANCA associated glomerulonephritis. Because of progressive decline of renal function, a hemodialysis period for 7 months was administered following the pulsed methylprednisolone as well as cyclophosphamide treatment. The renal transplantation was then carried out 18 months later, the renal function recovered 7 days later while proteinuria reappeared 28 days after renal transplantation. Based on the anti-rejection treatment, 3 times pulsed methylprednisolone administration did not make difference on reducing the proteinuria and then a renal biopsy was conducted and the transplanted kidney proved to be a newly developed FSGS. Consequently, plasma exchange therapy was administrated. When the plasma exchange course finished, the proteinuria decreased significantly (from 3.270 g/24 h to 0.370 g/24 h). No reports were retrieved either in Chinese databases or at PubMed as well as Medline databases. Conclusion: FSGS appears in transplanted kidney in patient with a primary renal disease as ANCA associated glomerulonephritis with early proteinuria after transplantation as well as negative P-ANCA and MPO. Pathology of renal biopsy revealed FSGS while the pathology of other recipient was not FSGS. The patient had no response to pulsed methylprednisolone therapy. Instead, plasma exchange therapy was an alternative also effective treatment for de novo FSGS in transplanted kidney.

Glomerulonephritis is the primary cause of end-stage renal failure in 30-50% of kidney transplant recipients and recurrence of the initial disease is an important determinant of long-term graft outcome after transplantation. Although renal transplantation remains the best treatment option for patients with end stage renal diseases in most cases, diagnosis and management of recurrences of glomerulopathies are critical for the optimization and improvement of long-term kidney transplant graft survival and provide a unique opportunity to explore the pathogenesis of native kidney disease. This review aims to update knowledge for a large panel of recurrent primary and secondary glomerulonephritis after kidney transplantation, excluding diabetic nephropathy including primary focal and segmental glomerulosclerosis, membranous nephropathy, IgA nephropathy, membranoproliferative glomerulonephritis, lupus, vasculitis but also less usual secondary nephropathy related to sarcoidosis, AA and AL amyloidosis, monoclonal immunoglobulin deposition disease, and fibrillary glomerulonephritis., (© 2012 The Authors. Transplant International © 2012 European Society for Organ Transplantation.)

In animal models, interstitial angiotensin II (ang II) and AT1 receptor (AT1R) are key mediators of renal inflammation and fibrosis in progressive chronic nephropathies. We hypothesized that these molecules were overexpressed in patients with progressive glomerulopathies. In this observational retrospective study, we described the expression of ang II and AT1R by immunohistochemistry in kidney biopsies of 7 patients with minimal change disease (MCD) and in 25 patients with progressive glomerulopathies (PGPs). Proteinuria, serum albumin, and serum creatinine were not statistically different between MCD and PGP patients. Total expression of ang II and AT1R was not statistically different between MCD (108.7+/-11.5 and 73.2+/-13.6 cells/mm(2), respectively) and PGN patients (100.7+/-9.0 and 157.7+/-13.8 cells/mm(2), respectively; p>0.05). Yet, interstitial expression of ang II and AT1R (91.6+/-16.0 and 45.6+/-5.4 cells/mm(2), respectively) was higher in patients with PGN than in those with MCD (22.0+/-4.1 and 17.9+/-2.9 cells/mm(2), respectively, p<0.05), as was the proportion of interstitial fibrosis (11.0+/-0.7% versus 6.1+/-1.2%, p<005). In patients with MCD, ang II and AT1R expressions predominate in the tubular compartment (52% and 36% of the positive cells, respectively). In those with PGP, the interstitial expression of ang II and AT1R predominates (58% and 45%, respectively). In conclusion, interstitial expression of ang II and AT1R is increased in patients with progressive glomerulopathies. The relationship of these results and interstitial fibrosis and disease progression in humans warrants further investigations.

Background: Studies comparing the impact of sex in primary glomerular disease have reported conflicting results., Methods: We analysed 395 membranous (MGN), 370 focal and segmental glomerulosclerosis (FSGS) and 542 IgA nephropathy patients to determine the impact of the patients' sex on outcome. We assessed initial and follow-up blood pressure, proteinuria, anti-hypertensive and immunosuppressive therapy, rate of renal function decline and survival from renal failure or a 50% decrease in creatinine clearance (combined event)., Results: Women accounted for one-third of the cohort. At presentation they were on average 2 years younger than men, and over follow-up received no more immunosuppression or anti-hypertensive agents than their male counterpart. Their mean arterial pressure (MAP) overall was 2 mmHg lower. Proteinuria at presentation and during follow-up in women compared to men was 50% and 30% lower in MGN and FSGS, while no differences were seen in IgA nephropathy. The rate of renal function decline and outcome favoured women over men in MGN (hazard ratios of a combined event of 0.63, 95% CI 0.40-1.00, P = 0.05) and in FSGS (HR 0.67, 95% CI 0.48-0.95, P = 0.02) but not in IgA nephropathy. These differences were not independent of blood pressure and proteinuria, indicating that these sex-dependent risk factors accounted for most of the hazards seen in men. However, the quantitative effect of proteinuria on the rate of progression was distinct and modified by sex in MGN and FSGS with higher proteinuria levels having less impact on progression rate in women. This interaction was independent of blood pressure., Conclusions: Women have a better outcome than men in MGN and FSGS but not in IgA nephropathy. These benefits are mostly mediated through both lower proteinuria and blood pressure at presentation and throughout follow-up, although females did have an independent advantage at higher levels of proteinuria.

Background: Little data are available concerning post-transplantation glomerulonephritis (PTx-GN) and its prognostic factors associated with graft outcomes., Methods: We retrospectively evaluated patients with de novo and recurrent PTx-GN to identify the factors associated with their negative impact on graft and patient outcomes. PTx-GN was diagnosed in 55 patients, wherein 17 (31%) had recurrent glomerulonephritis (GN) and 16 (29%) had de novo., Results: Our enrolled population consisted of 34 +/- 13.7-yr-old male patients (72%), on hemodialysis for a median of 18 months (0-204) and mainly grafted from living donors (76%). The median onset time of proteinuria and hematuria was 50 d (10-2160) and 30 d (4-1170), respectively. One-yr graft survival rates after PTx-GN diagnosis was 64%. The most frequent de novo GN was membranous GN (26%), while focal segmental glomerulosclerosis was the most frequent recurrent GN (41%), with a very early onset (median of three months). One-yr graft survival was better in the recurrent disease than in the de novo patients, 76% vs. 55% (p = 0.24). The best predictor factors that correlated with graft survival were: proteinuria <3.5 g [relative risk (RR) = 0.24, p = 0.017], serum creatinine below 2.0 mg/dL (RR = 0.06, p = 0.016) at the time of biopsy and the use of angiotensin-converting enzyme inhibitors (ACEI) (RR = 0.12, p = 0.005). The use of ACEI markedly improved one-yr graft survival rates (92% vs. 47%, p < 0.001)., Conclusion: PTx-GN has a strong negative impact on kidney graft survival. De novo GN appears to have a poorer prognosis than the recurrent type. Patients who used ACEI showed a better survival rate in the follow-up.

Background: We previously demonstrated that chronic hypoxia has pivotal roles in the progression of tubulointerstitial injury from the early stage of the uninephrectomized Thy1 nephritis model. We have also shown that pretreatment of cobalt confers renoprotection in the ischemia/reperfusion (I/R) injury, in association with the up-regulation of hypoxia-inducible factor (HIF)-regulated genes. Here, we tested the hypothesis that cobalt administration not only attenuates acute ischemic insult, but also ameliorates tubulointerstitial injury secondary to chronic hypoxia., Methods: We applied sustained cobalt treatment to the uninephrectomized Thy1 nephritis model at 3 to 5 weeks, when tubular hypoxia appeared. Histologic evaluation, including glomerular and peritubular capillary networks, was made at 8 weeks. HIF activation was confirmed by real-time polymerase chain reaction (PCR) analyses for HIF-regulated genes, such as erythropoietin (EPO), vascular endothelial growth factor (VEGF), and heme oxygenase 1 (HO-1). Up-regulation of HIF-1alpha and HIF-regulated genes was also verified by Western blotting analysis. To elucidate responsible mechanisms of cobalt in the amelioration of tubuloniterstitial injury, terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) staining was conducted at 5 weeks. A combination therapy with angiotensin receptor blocker (ARB), olmesartan, was also challenged., Results: Although the intervention did not change glomerular structural damage or urinary protein excretion rate, tubulointerstitial injury was improved in cobalt-treated animals when compared with the vehicle-treated group. The amelioration was associated with the parallel up-regulation of renoprotective, HIF-regulated gene expression. TUNEL staining revealed that the number of apoptotic cells was reduced in the cortex by cobalt administration, suggesting that renoprotection was achieved partly through its antiapoptotic properties. Furthermore, it was demonstrated that cobalt treatment exerts additional renoprotective effects with the ARB treatment in this model., Conclusion: Maneuvers to activate HIF in the ischemic tubulointerstitium will be a new direction to future therapeutic strategies.

Immune glomerulonephritis (GN) initially develop as a result of inappropriate immune response, either inadequately directed to self-antigens, or unable to effectively eliminate a foreign antigen. This abnormal immune response leads to the formation of circulating immune complexes, auto-antibodies or self-reactive effector T cells that target glomerular antigens or to the inappropriate regulation of IgA producing lymphocytes (Berger disease) or helper T lymphocyte sub populations (minimal change nephrotic syndrome). In most of the cases, the initial immune injury induces an inflammatory response. However, it is the extent of the interstitial fibrosis which is genetically controlled, that conditioned the evolution of the initial glomerular injury to glomerular sclerosis and progressive renal failure. Recent data on the pathogenesis of the most frequent GN are reported: IgA nephropathy, membranous nephropathy and minimal change nephrotic syndrome. Recent significant advances in the pathophysiology of those glomerular diseases have shed considerable light on the understanding of the underlying disease even if they do not have immediate therapeutic implications.

Background: The urinary excretion of N-acetyl-beta-glucosamynidase (NAG) is increased in subjects exposed to substances toxic for renal tubular cells. In experimental and human glomerular diseases, its increased excretion is probably due to the dysfunction of tubular epithelial cells induced by increased traffic of proteins in the tubular lumen. The first aim of this study was to evaluate whether NAG excretion is correlated not only with the amount of proteinuria but also with some proteinuric components which reflect both glomerular capillary wall damage (IgG) and an impairment of tubular reabsorption of microproteins (alpha(1) microglobulin). The second aim was to assess whether NAG excretion has a predictive value on functional outcome and response to therapy., Methods: In 136 patients with primary glomerulonephritis [74 with idiopathic membranous nephropathy (IMN), 44 with primary focal segmental glomerulosclerosis (FSGS) and 18 with minimal change disease (MCD)] urinary NAG excretion was measured by a colorimetric method and expressed in units per gram of urinary creatinine., Results: Using univariate linear regression analysis NAG excretion in all 136 patients was significantly dependent on IgG excretion, 24-h proteinuria, fractional excretion of alpha(1) microglobulin (FE alpha(1)m) and diagnosis. Using multiple linear regression analysis, NAG excretion was significantly dependent only on IgG excretion and 24-h proteinuria. Limiting the analysis to 67 patients with nephrotic syndrome (NS) and baseline normal renal function, by multiple linear regression, NAG excretion was significantly dependent on IgG excretion (P=0.0004), 24-h proteinuria (P=0.0067) and FE alpha(1)-m (P=0.0032) (R(2)=0.63). In 66 patients with NS and normal baseline renal function (MCD 10 patients; FSGS 20 patients; IMN 36 patients), according to values below or above defined cut-offs (IMN, 18 U/g urinary Cr; FSGS and MCD, 24 U/g urinary Cr), NAG excretion predicted remission in 86 vs 27% of IMN patients (P=0.0002) and 77 vs 14% of FSGS patients (P=0.005). Progression to chronic renal failure (CRF) was 0 vs 47% in IMN patients (P=0.001) and 8 vs 57% in FSGS patients (P=0.03). Using Cox model, in IMN patients only NAG excretion (P=0.01, RR 5.8), but not 24-h proteinuria, predicted progression to CRF. All MCD patients had NAG excretion values below the chosen cut-off, and 90% of them developed remission. Response to immunosuppressive therapy was significantly different in patients with NAG excretion values below or above the cut-offs., Conclusion: Urinary NAG excretion can be considered as a reliable marker of the tubulo-toxicity of proteinuria in the early stage of IMN, FSGS and MCD; the excretion values show a significant relationship with 24-h proteinuria, IgG excretion and FE alpha(1)m. Its determination may be a non-invasive, useful test for the early identification of patients who will subsequently develop CRF or clinical remission and responsiveness to therapy.

116 children with different variants of acute glomerulonephritis have been found to have predominantly sympaticotonic symptoms. Results of the analysis of cardiointervalography parameters have shown an increase of tension of sympatoadrenal mechanisms of the vegetative nervous system, especially manifest in a mixed variant of acute glomerulonephritis and relatively minimal in the nephritic one. Achievement of clinical-and-laboratory remission is manifested by KyriHpoBamie of priority activity of sympatoadrenal mechanisms. Expressiveness of the above changes dynamics is less pronounced in those patients presenting with the mixed variant and is more adequate in the nephritic variant of the condition. Evident clinical-and-laboratory manifestations of the disease stabilization forestall the state of full normalization of the vegetative-visceral maintenance of homeostasis, that can form the basis for aggravation of the illness or be a threat of development of the chronic course of the pathology in question.

Improving accuracy in predicting outcome in the idiopathic glomerulopathies requires standard clinical and laboratory data observed over time and the application of certain basic biostatistical tests. In our initial model we examined categories of glomerular disease that progress i.e. membranous, membranoproliferative, diffuse proliferative, focal sclerosing and IgA nephropathy. We determined that a combination of severity and persistence of proteinuria above certain levels over fixed time frames plus the knowledge of any change in glomerular filtration rate during these periods resulted in slopes of creatinine clearances that were the same across this histologic spectrum. This modeling of disease was then applied in a more rigorous fashion to our patients with idiopathic membranous nephropathy (IMGN). Multivariate logistic regression analyses was used to test all other potential clinical and laboratory predictors of chronic renal failure. These additional factors did not improve our ability to predict outcome. This algorithm was subsequently validated on two independent IMGN data bases. Overall accuracy of prediction estimated within 6 months of presentation was maintained at > 85%. The role of this type of evaluation in both clinical practice and research is discussed.

Diabetic nephropathy tends to develop more readily in patients with a family history of hypertension and/or disturbances in sodium transport across the plasma membrane. This prompted us to study the renal effects of diabetes mellitus in a rat strain which is predisposed to develop salt-sensitive hypertension, the Dahl salt-sensitive rat. Diabetes is associated with several aberrations in the renal handling of sodium, such as elevation of tubular Na+, K+ATPase activity. This effect was more pronounced in Dahl salt-sensitive than in Dahl salt-resistant rats. Severe renal lesions, characteristic of the advanced phase of diabetic nephropathy are very rarely observed in rats with streptozotocin diabetes. However, 2 months after induction of diabetes, the Dahl salt-sensitive rats had morphological signs of advanced glomerular disease. The urinary albumin concentration was very high, but did not correlate with the blood pressure. Non-diabetic Dahl salt-sensitive rats as well as Dahl salt-resistant diabetic and non-diabetic rats had little or no signs of glomerular disease and consistently very low urinary albumin concentrations.

TGF-beta is a multifunctional regulatory peptide which plays a key role in embryogenesis, tissue repair and immune response. One of the most important properties of TGF-beta is its widespread effects on extracellular matrix. TGF-beta stimulates the synthesis of individual matrix components and reduces the matrix degradation by proteases. It also modulates the expression of integrin receptors that mediate cell-matrix interactions. Moreover it has been demonstrated that TGF-beta may be involved in the pathogenesis of diseases characterized with an excessive matrix accumulation. In this review we summarize data from experimental studies which link the action of TGF-beta with the pathological matrix deposition in glomerulonephritis. We also present compelling evidence that the sustained expression of TGF-beta contributes to the development of glomerulosclerosis and progressive kidney fibrosis. Finally we discuss prospects of anti-TGF-beta therapy in treating renal diseases associated with overproduction of TGF-beta.

Intrarenal hemodynamic and tubular function has been assessed in 16 patients who presented clinically with hypertension, hematuria and severe renal functional impairment. Twelve of these 16 patients had histopathologic classification as DPGN (3 cases), MPGN (3 cases) and FSGS (6 cases). The initial assessment of intrarenal hemodynamics in 11 patients revealed strikingly increased afferent (RA) and efferent arterioles (RE), filtration fraction (FF), intraglomerular capillary hydrostatic pressure (PG), whereas, there was marked reduction in renal plasma flow (RPF), in ultrafiltration coefficient (KFG) and in glomerular filtration rate (GFR). Tubular transporting defect as being reflected by enhanced fractional excretions of solutes was also observed. Both enhanced TXB2 production and diminished PGI2 may be in part responsible for the marked reduction of RPF and elevated intrarenal resistance. In light of the preceding intrarenal hemodynamics alteration, therapeutic intervention with vasodilators consisting of dipyridamole, calcium channel blocker and angiotensin convertase inhibitor has been accomplished with clinical improvement in glomerular and tubular functions following the improvement in intrarenal hemodynamics. Thus, this abnormal intrarenal hemodynamics renders a supportive view of the hemodynamically mediated glomerulo-tubulo-interstitial injury to be central to the pathogenetic mechanism.

Renal biopsies in which immunohistologic examination had shown the presence of glomerular focal segmental IgM were reviewed in order to investigate the histology and clinical course in these patients. Among 19 such biopsies, 12 had focal segmental glomerulosclerosis (FSGS), whereas seven had only so-called glomerular tip lesions (GTL). GTL also occurred moreover in four of the patients with FSGS. Clinical data suggest a somewhat milder course of disease in the seven patients with GTL as the sole lesion than in the patients of the FSGS group. The nature of GTL is at present unclear. We suggest that GTL may be an initial stage of FSGS, being a lesion that may or may not develop towards FSGS in its typical form. Regardless of its origin, attention is directed to the GTL as a characteristic histologic glomerular lesion, which may be the only significant histologic change in the renal biopsy from a patient with nephrotic syndrome or severe proteinuria.

Clinical progress and outcomes of 151 pregnancies have been evaluated in 123 patients with chronic primary glomerulonephritis (GN). The incidence of gestational and neonatal complications was evaluated for a relationship with preconception findings of proteinuria, hematuria, arterial pressure, blood creatinine and, in 45 women, histological patterns of disease. Major preconception proteinuria (over 3 g/day), hypertension, decreased renal function and especially clustering of these findings were prognostically poor. Gestational progress and outcomes in mesangiocapillary GN were worse as compared with mesangial proliferative GN.

In order to investigate the effects of atrial natriuretic polypeptides (ANP) on hypertensive glomerular lesions, ANP was administered intravenously by osmotic minipumps to 20 15-week-old male spontaneously hypertensive rats (SHRs) in a sustained hypertensive stage. ANP was infused at the rate of 100 ng/hour/rat (the ANP group). Saline was similarly administered to 19 age-matched SHRs (the control group). The rats were sacrificed on the seventh day. Semiquantitative evaluation of the renal tissue revealed no significant difference in glomerular sclerosis between the 2 groups. However, segmental hyalinosis in glomeruli was more accentuated in the ANP group than in the control group. As it is suggested that hyalinosis in glomeruli is related to the elevated intracapillary pressure, the results of the present work were in accordance with reports that ANP increases glomerular capillary pressure by preglomerular vasodilation and postglomerular vasoconstriction. It should be determined whether endogenous ANP works as an aggravating factor for glomerular injuries in the natural course of hypertension.

The following results were obtained in a long-term retrospective study including 250 patients with focal sclerosing glomerulonephritis: 1. The renal survival rate (RSR) was 90% at 5 years and 67% at 10 years, the average period of observation being 4.7 years. 2. Univariate analysis revealed that the following morphologic and clinical parameters are associated with an increased risk of terminal renal failure or death due to renal causes: a) Tubulointerstitial changes in the form of interstitial fibrosis, with or without acute renal failure; b) Advanced glomerular lesions; c) Advanced vascular alterations; d) Nephrotic syndrome present at the time of the biopsy; e) Elevated serum creatinine concentration at the time of the biopsy; f) Arterial hypertension at the time of the biopsy; g) Greater age at diagnosis; h) Male sex. 3. Multivariate survivorship analysis showed that tubulointerstitial changes and the presence of nephrotic syndrome at the time of biopsy are the only variables with significant independent predictive value for the outcome. Assessment of these factors thus allows the pathologist to make a relevant statement concerning the probable course and prognosis of the disease at the time of the diagnostic biopsy.

To study the influence of hypertension on the progression of focal glomerulosclerosis (FGS), we produced an experimental model of FGS in spontaneously hypertensive rats (SHRs) by the combined administration of puromycinaminonucleoside (AMNS) and protamine sulfate (PS). SHRs and normotensive Wistar Kyoto rats as a control strain were given daily injections of subcutaneous AMNS (1 mg/100 gm body weight) and intravenous PS (two separated doses of 2.5 mg/100 mg body weight) for 4 days; they were killed on day 80 after three series of injections at 10-day intervals. The levels of urinary protein, serum creatinine, and urea nitrogen in SHRs given AMNS and PS were elevated throughout the experiment and were significantly higher than these levels in other control groups on day 80. Histology in SHRs given AMNS and PS showed advanced FGS associated with glomerular hypertrophy and widespread interstitial fibrosis. Most small arteries and arterioles showed "onion peel" thickening and fibrinoid necrosis of the intima, which is characteristic of malignant arteriosclerosis. We observed that the gradient of glomerulosclerosis increased from superficial to deep cortical zones; this phenomenon had often been reported in human FGS. However, these distinguished lesions were not found in control groups. Therefore, it is suggested that systemic hypertension is one of the deleterious factors enhancing histologic and functional deterioration in FGS.

We studied the clinical features, pathologic findings, and course of 18 patients who were found to have glomerular disease at the time of hospitalization with manifestations of acquired immunodeficiency syndrome or acquired immunodeficiency syndrome-related complex at New York University Medical Center, New York, NY, during 1984 through 1987. Focal glomerulosclerosis, characterized by segmental and/or global collapse of capillary walls, was observed in 15 of these patients; mesangial proliferation in 2, and membranous nephropathy in 1. Those with focal glomerulosclerosis typically demonstrated heavy proteinuria without edema or hypertension and progressed rapidly to renal failure in less than 1 year from the time of discovery. This form of focal glomerulosclerosis is characterized by a fulminant course, the collapse type of sclerosis, and the frequent occurrence of uremia without advanced glomerular obliteration. The absence of widespread glomerular sclerosis and the rapid course suggest that unique renal hemodynamic mechanisms may be responsible for the progression.

We previously described the development of glomerulosclerosis in mice transgenic for large T-antigen, a gene whose in vitro expression markedly increases proliferation of cultured cells. In the current study we sought to determine the effect of unilateral nephrectomy on these sclerosis-prone animals which have a genetically defined potential for increased renal growth. In comparison with sham nephrectomy animals, nephrectomized transgenic female mice had significantly larger kidneys, larger glomeruli (5886 mu2 npx vs. 3796 mu2 sham), more cells per glomerulus and more severe glomerulosclerosis. Nephrectomized transgenic male animals had variable increases in kidney size, no significant increase in glomerular size (4750 mu2 npx vs. 4502 mu2 sham) or cellularity, and no worsening of glomerulosclerosis. In non-transgenic female animals nephrectomy induced an increase in kidney size but not in glomerular size (2640 mu2 npx vs. 2625 mu2 sham) and failed to induce glomerular lesions. A close correlation (r = 0.91) was found between glomerular size and severity of glomerulosclerosis in these animals. This finding supports the hypothesis that a pathophysiologic link exists between glomerular enlargement and glomerulosclerosis. We also found that increases in total kidney size and glomerular size did not consistently parallel each other, that is, renal hypertrophy may occur without an increase in glomerular size. This finding suggests that total kidney growth and glomerular growth may be independently regulated or may have different thresholds for activation following unilateral nephrectomy.

Similarities between atherosclerosis and glomerulosclerosis suggest that hyperlipidaemia may contribute to glomerular injury. Dietary supplementation with 4% cholesterol + 1% cholic acid was administered to rats 4 weeks after 1 1/3 nephrectomy and continued for 7 weeks. There was a significant increase in serum cholesterol (peak = 11.52 +/- 1.09 mmol l-1 vs. 4.73 +/- 0.31 on control diet, P less than 0.001) and triglyceride concentrations (peak = 2.31 +/- 0.27 mmol l-1 vs. 1.41 +/- 0.29, P less than 0.05) and a marked increase in beta-migrating lipoproteins. The severity of hypercholesterolaemia was significantly correlated with proteinuria (control diet: r = 0.600, cholesterol diet: r = 0.672, P less than 0.0001) as was hypertriglyceridaemia (control diet: r = 0.544, cholesterol diet: r = 0.678, P less than 0.0001). The percentage of glomeruli containing lipid deposits was increased from 21% to 60% (P less than 0.05). The kidney total cholesterol content was increased from 29.2 +/- 0.8 to 47.7 +/- 3.3 mumols g-1 dry weight (P less than 0.0001), with esterified cholesterol increasing from 7.5 +/- 0.4% to 14.5 +/- 2.1% of total (P less than 0.01). Serum cholesterol concentration was significantly correlated with both glomerular lipid deposition (rs = 0.7195, P less than 0.0001) and tissue total cholesterol content (rs = 0.6053, P less than 0.001). Lipid vacuolation was prominent in the paramesangium and within mesangial cells. Despite these changes hypertension, uraemia, proteinuria and glomerulosclerosis were not significantly increased on the cholesterol diet. Cholesterol deposition in the glomeruli occurs secondary to hyperlipidaemia in rats following subtotal nephrectomy but over 7 weeks no exacerbation of glomerulosclerosis is detectable.

The effect of exercise on the progression of experimental renal disease was studied in adriamycin (ADR)-treated rats, a model of sclerosing glomerulonephritis with nephrotic syndrome. Two hours of daily swimming exercise was carried out for 20 weeks in ADR-treated male Lewis rats fed with either an ad libitum intake of regular chow (group 1) or a restricted amount of food (group 3), which was equal to the amount of food freely ingested by ADR-treated rats not undergoing swimming exercise (group 2). Group 3 resulted in a significantly lower serum creatinine, higher inulin clearance and lower glomerular sclerosis index compared to group 2. The progress of renal dysfunction did not differ significantly between group 1 and group 2. Hyperlipidemia, especially, hypertriglyceridemia was significantly lower in the exercise groups than in the sedentary group. Among all the rats, inulin clearance was inversely correlated with either cholesterol (r = 0.560, p less than 0.01) or triglyceride (r = 0.423, p less than 0.05) and the glomerular sclerosis index correlated positively with cholesterol (r = 0.599, p less than 0.005). Systolic blood pressure was 10 mm Hg lower in group 3 than in group 2 and the difference was significant. It is concluded that swimming exercise with a relative restriction of food intake can improve hyperlipidemia and prevent progressive renal dysfunction in ADR-induced nephritic rats.

Fetal outcome was retrospectively studied in 217 pregnancies observed during the past two decades in 93 patients, 34 suffering from IgA nephropathy (IgAGN, 69 pregnancies), 53 from reflux nephropathy (RN, 137 pregnancies), and six from focal glomerular sclerosis (FGS, 10 pregnancies). Overall incidence of live births was 175 in 217 (81%). Fetal loss, corrected for induced abortions, was 10 in 66 (15%) in IgAGN, 18 in 129 (14%) in RN, and 2 in 10 in FGS. Renal failure and hypertension preexisting prior to conception or developing early in pregnancy were the most important factors associated with unsuccessful fetal outcome whereas urinary tract infection had limited effects in RN patients. Influence of pregnancy on the course of maternal renal disease was evaluated in the same groups of patients. An abnormally rapid deterioration of renal function was observed in three of the women with IgAGN and in one of the RN patients (with an additional case among 46 further female RN patients) but in none in the FGS group. All five women experiencing functional deterioration had a serum creatinine (SCr) level of greater than or equal to 200 mumol/L (2.3 mg/dL) and hypertension at conception. Hypertension in pregnancy was highly predictive of recurrence of hypertension in subsequent pregnancy and of the remote development of permanent hypertension in IgAGN patients. We conclude that when renal function is preserved, pregnancy is usually successful and no deleterious effects on maternal renal disease are to be expected in patients with IgAN, RN, and probably FGS.(ABSTRACT TRUNCATED AT 250 WORDS)

To examine the effect of age on a compensatory renal growth, adaptive renal hemodynamics and renal histology in solitary kidney, unilateral nephrectomy was performed in young rats at 4 weeks of age (group 4-UN) or in adult rats at 10 weeks of age (group 10-UN). Urinary protein was measured every 4 weeks until the 48th week. Serial changes in kidney weight, glomerular filtration rate (GFR), renal plasma flow (RPF) and renal histology were investigated at weeks 4, 8, 24 and 48 after the uninephrectomy. Increase in proteinuria was significantly greater in group 4-Un than in group 10-UN from weeks 32-48 after uninephrectomy. The remnant kidney showed a compensatory enlargement which was more marked in group 4-UN than in group 10-UN at weeks 24 and 48. GFR or RPF in group 4-UN was significantly greater than that in group 10-UN at weeks 4, 8, and 24. Focal and segmental glomerular sclerosis was evident at week 24 or later in the uninephrectomized rats, being more severe in group 4-UN than in group 10-UN at week 48. We conclude that uninephrectomy in young rats leads to augmented compensatory renal growth and glomerular hyperperfusion, resulting in extensive glomerular sclerosis compared to that in adult rats.

A model of chronic progressive glomerular sclerosis in experimental antiglomerular basement membrane (anti-GBM) glomerulonephritis was developed in Wistar rats. Wistar rats given the accelerated form of anti-GBM anti-body glomerulonephritis initially developed significant proteinuria and renal insufficiency associated primarily with a decrease in glomerular filtration rate (GFR) with normal renal clearance of para-aminohippuric acid and with markedly reduced filtration fraction. The glomerular functional abnormalities were associated with marked glomerular hypercellularity due to leukocytic infiltration as well as proliferation of intrinsic glomerular cells with crescent formation. Late in the course of the disease, by day 21, GFR had fallen further, associated with a parallel decrease in the clearance of para-aminohippuric acid and a normal filtration fraction. At this stage, glomerular hypercellularity had diminished and was replaced by glomerular sclerosis. The model appears to be a reproducible form of chronic glomerulosclerosis and demonstrates that the chronic phase of glomerular basement membrane (GBM) glomerulonephritis is distinctly different from that of the acute phase. It provides a controllable setting to study the glomerular sclerotic process independent of the initial inflammatory changes.

This is the first report on the recurrence of a glomerular disease in renal transplant in Hungary. The primary disease of the girl died at the age of 13 was focal sclerosing glomerulonephritis with slight mesangial cell proliferation. The first symptoms appeared at the age of 6.5 and they progressed rapidly. Four years later, because of the severe nephrotic syndrome and chronic renal failure, renal transplantation was performed with the synchronous removal of the patient's own kidneys. In the latter an interesting immunohistological finding has been observed: beside the usual positivities, the basement membrane of the distal tubule at the opposite side of the macula densa showed a strong reaction with anti IgM and a somewhat weaker positivity with anti C3 sera. The primary disease recurred very soon. A mesangial cell proliferation, however did not develop, in contrary to the primary disease, which contradicts the theory that the mesangioproliferative form would be a distinct clinicopathological entity.

The response of lymphocytes to Concanavalin A (Con A) was measured in patients with the nephrotic syndrome due to minimal change nephropathy (11 patients), focal glomerulosclerosis (15 patients) and membranous nephropathy (21 patients); autologous serum was not used in these studies. There was a significant reduction in lymphocyte transformation in each group of patients compared to normal controls (p less than 0.01 for each group), but there was no significant difference between the individual groups of patients. Impaired lymphocyte transformation to Con A appears therefore to be a general feature of the nephrotic syndrome and is not exclusive to minimal change nephropathy. Measurements of suppressor cell function in 4 patients with minimal change nephropathy, 9 patients with focal glomerulosclerosis and 12 patients with membranous nephropathy were performed at the same time as the above studies. In each group suppressor cell function was decreased, indicating that the impaired lymphocyte response to Con A is not due to increased suppressor cell activity. These findings do not support the hypothesis that an abnormality of lymphocyte function peculiar to minimal change nephropathy is pathogenetic in that disease and not in other causes of the nephrotic syndrome; it seems more likely that the abnormalities described are secondary to the nephrotic state.

To investigate the possible relationship between disturbance of mesangial function and segmental localization of glomerular sclerosis, five uninephrectomized male Wistar rats and five sham-operated controls received colloidal carbon intravenously. At 4 months 8.4 +/- 2.5% of the glomeruli of the nephrectomized rats showed focal sclerosis. Glomeruli of nephrectomized rats contained significantly more carbon than glomeruli of controls. Glomeruli with focal sclerosis contained significantly more carbon than normal glomeruli in the same kidneys with a preferential tracer localization within the lesions. In another experiment carbon injections were given before surgery. At 4 months 12.6 +/- 4.1% of the glomeruli of the nephrectomized rats showed focal sclerosis, an incidence not significantly different from that of the first experiment. Glomerular carbon content was equal in experimental and control rats and no preferential localization of the tracer within the lesions was found. From these results we conclude that the preferential localization of carbon in the glomerular lesions in rats nephrectomized before injection of carbon is caused by the increased delivery of tracer shortly after injection to those glomerular areas where sclerosis will develop at a later time. The development of focal sclerosis may be related to the local deposition of harmful substances from the circulation.

Proteinuria and progressive glomerulosclerosis are commonly associated with nephron loss. We studied the pathogenesis of these lesions by examining the role of changes in specific glomerular capillary wall permeability properties in uninephrectomized rats. The development of altered capillary permselectivity to macromolecules and loss of glomerular basement membrane anionic charge were measured by the dextran fractional clearance and ferritin tracer probe methods, respectively. In addition, the protective effect of dietary protein restriction and an angiotensin I-converting enzyme inhibitor (captopril) were studied in eight groups of male Sprague-Dawley rats. Four groups of rats underwent sham-nephrectomy or left nephrectomy and were fed an 8.5% protein diet (sham-nephrectomy and low protein, nephrectomy and low protein) or a 30% protein diet, respectively (sham-nephrectomy and high protein, nephrectomy a high protein). Four other groups of rats underwent sham-nephrectomy or left nephrectomy and were treated with captopril (50 mg/kg/day) while receiving a 8.5% protein diet (sham-nephrectomy, low protein and captopril, nephrectomy, low protein and captopril) or a 30% protein diet, respectively (sham-nephrectomy, high protein and captopril, nephrectomy, high protein and captopril). Rats were nephrectomized at 21 days of age and were functionally tested and sacrificed at 7 months of age. The nephrectomy and high protein rats had significantly greater proteinuria and higher fractional clearance of neutral dextrans in the 30 to 42 A range compared with that of sham-nephrectomy and high protein, nephrectomy and low protein, and nephrectomy, high protein and captopril rats. The nephrectomy and high protein rats also had a significantly lower labeling of the glomerular basement membrane with cationic ferritin tracer molecules compared with the nephrectomy and low protein and nephrectomy, high protein and captopril rats. Of the eight treatment groups, the nephrectomy and high protein rats had the most severe glomerular lesions. In general, nephrectomized rats fed low dietary protein and nephrectomized rats treated with captopril had significantly less proteinuria, glomerular lesions, and milder changes in the glomerular capillary wall porosity and glomerular basement membrane anionic charge.(ABSTRACT TRUNCATED AT 400 WORDS)

By 2 to 3 months of age, many fawn-hooded rats, particularly males, had indirect systolic blood pressures of greater than 145 mm Hg; by 4 months of age, most males had persistent elevations in blood pressure (greater than 160 mm Hg). Female fawn-hooded rats developed hypertension at 4-5 months of age. Concurrently, fawn-hooded rats develop a severe form of focal glomerular sclerosis. The causes of the hypertension and focal glomerular sclerosis are yet not known, nor has a relation been found between these abnormalities.

A retrospective analysis of the progression of renal failure was performed in 6 children and 5 adults with idiopathic nephrotic syndrome unresponsive to steroids and immunosuppressants and with histological findings of focal glomerulosclerosis. We analyzed the linear regression of Ccr and of their logarithmic transformation vs time (months) starting from the time when the first abnormal value was observed (t = 0). The regression analysis was performed at three different times, when Ccr was: 30-20, 20-25 and 10-15 ml/min/1.73 sqm. Extrapolation of each of these lines on the x axis predicted when renal function would be zero. The difference in months, between the predicted and actual time of starting dialysis was prediction error. "r" values were always elevated and statistically significant for both linear and logarithmic regression; there was a large intersubject variability in the rate of loss of renal function but the mean prediction error at various levels of Ccr was within limits clinically acceptable. Moreover its magnitude did not significantly decrease by prolonging the time of observation. This indicates that in this disease the decay of Ccr enters a track which proceeds linearly or logarithmically after the onset of renal failure and no major deviation from the predicted line is to be expected. The good predictability in our study may be attributed to the fact that our patients were homogeneous for a number of factors which may be relevant to progression of the disease. It confirms the view supported by Gretz et al. [1983] that there is a need for stratification of patients in large cohort studies on the predictability of loss of renal function.

Injury of the glomerular microvasculature by nonimmunologic processes is often the underlying mechanism of progressive deterioration of renal function in patients with a variety of renal disorders. The structural hallmark of this injury is focal and segmental glomerulosclerosis, often accompanied by entrapment of hyalin. Although such lesions are quite characteristic for diseases that primarily affect the glomerular podocyte, similar damage occurs in association with functional and structural adaptive changes that develop as a consequence of a significant loss of functioning nephrons or other systemic disorders. Experimental studies have revealed that such functional adaptations include intrarenal vasodilatation that through increases in glomerular capillary pressure and plasma flow leads to a significant compensatory hyperfiltration. This functional state is accompanied by a parallel increase in glomerular volume, attained chiefly by expansion of matrix components and an increase in the number of endothelial and mesangial cells, but not of podocytes. The persistence of the adaptive changes results in endothelial, mesangial, and epithelial cell dysfunction revealed clinically by proteinuria and structurally by the development of microthrombosis, microaneurysms, mesangial expansion, and occlusion of capillaries by hyalin accumulation. Although all these pathologic processes can lead to segmental collapse of the capillary tuft, it is the progressive hyalin deposition in capillaries with defective or detached podocytes that represents the major mechanism in the development of segmental and eventually global glomerulosclerosis. The inability of the highly differentiated podocyte to replicate in response to systemic or locally released trophic factors ultimately results in imperfections of the capillary wall that set the stage for permeability defects amplified and accentuated by greatly augmented hydrodynamic forces. These structural and functional microvascular changes acting in concert not only facilitate the transcapillary convection of macromolecules that results in albuminuria, but can also be anticipated to play a key role in the entrapment and accumulation of larger macromolecules in front of the lamina densa in the form of hyalin material. Continuing damage to the glomerular microvasculature exacerbates the adaptive changes in surviving nephrons, closing a positive-feedback loop that culminates in end-stage renal failure.

In a variety of recent studies in animals with chronic renal diseases, investigators have found a tight correlation between the elevation in glomerular pressures and flows versus glomerular hypertrophy. To investigate a possible causal link between the glomerular hyperfunction and hypertrophy, we studied the functional and morphological sequelae of nephrectomy and those of unilateral ureteral diversion (UD) into the peritoneal cavity (that is, removal of renal clearance function while keeping the kidney tissue in situ). In all nine experimental groups of 54 Munich-Wistar rats, 2/3 of the renal mass was removed from the left kidney by ligation of two or three branches of the left renal artery. In addition, right nephrectomy (NPX) was performed in Groups 1B, 2B and 3B or UD in Groups 1C, 2C and 3C. The right kidney was left untouched in control groups, Groups 1A, 2A and 3A. Micropuncture measurements and histological studies were performed at four days (Groups 1A, 1B and 1C), two weeks (Groups 2A, 2B and 2C) or four weeks (Groups 3A, 3B and 3C). At both four days and two weeks, NPX and UD groups had marked and comparable degrees of glomerular hypertension, hyperperfusion and hyperfiltration compared to the control group in the left kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal failure was induced in 15 normal Beagle dogs by ligation of approximately 5/6 of the renal arteries of the left kidney and contralateral nephrectomy in order to determine how: (a) 11/12 reduction in total renal mass influences urine protein excretion and renal morphology in dogs, and (b) dietary protein intake influences renal function, urine protein excretion, and renal morphology in canine renal failure. Dogs were fed a reduced protein diet for 12 weeks after induction of renal failure, while compensatory renal hypertrophy developed. Renal function was then evaluated and dogs were distributed into 2 groups with approximately equal degrees of renal dysfunction. One group was fed a high protein diet (42% protein) and a second group was fed moderately restricted protein diets (18% protein). After 8 weeks, renal function, magnitude of proteinuria, and renal morphology were re-evaluated. Inulin clearance increased in all dogs fed the 42% protein diet and 3 of 10 dogs fed the 18% protein diets. Proteinuria was significantly greater in dogs fed the high protein diet than dogs fed the reduced protein diets. Compared with previously nephrectomized contralateral control kidneys, glomerular sclerosis and renal interstitial lesions had developed in all dogs, regardless of severity of renal dysfunction or diet fed. Although reduced dietary protein intake did not prevent development of renal lesions, renal lesions were significantly more severe in the 5 dogs fed the 42% protein diet and 3 dogs fed the 18% protein diets in which inulin clearance increased, than in 7 dogs fed the reduced protein diets in which inulin clearance did not increase.

Systemic hypertension complicates the course of most patients with chronic renal failure and accelerates the progression of experimental and clinical glomerular disease. Based on recent experimental studies, it is suggested that at similar levels of systemic hypertension, glomerular injury only develops when pre-glomerular resistances are ineffective, thus allowing the development of glomerular hypertension. The mechanisms by which the hemodynamic stress of elevated intracapillary flows and pressures leads to progressive glomerular damage, particularly to the development of focal glomerulosclerosis is currently unknown. Endothelial cell injury, increased mesangial traffic or trapping of macromolecules and epithelial cell injury, or a combination, appear to occur early, followed by in situ inflammatory and microthrombotic mechanisms. This may explain why various therapeutic approaches, whether dietary or pharmacologic, can have salutory effects despite their diverse mechanisms of action.

Assessment of tubular functions by mean of concentration, urinary sodium excretion and urinary acidification following a short ammonium-chloride-loading test were studied in 18 minimal-change nephrotics (MC-NS), in 12 nephrotics associated with focal segmental glomerulosclerosis (FSG), in 5 nephrotics associated with membranoproliferative glomerulonephritis (MPGN) and in 10 patients with lupus nephritis. Normal tubular functions in respect to maximal urinary concentration (U/P osmolar ratio greater than 2.5), value of FENa of less than 1.0, and maximal urinary acidification were observed in the MC-NS group. In contrast, defects in maximal urinary concentration and urinary acidification were documented in the nephrotics associated with FSG and MPGN. Submaximal urinary acidification was also noted in lupus nephritis. The mean value of FENa were also higher than 1.0 in MPGN and lupus nephritis.