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Background: Glomerular hyperfiltration (GH) is a hallmark of renal dysfunction in diabetes and obesity. Recent clinical trials demonstrated that SGLT2 inhibitors are renoprotective, possibly by abating hyperfiltration. The present review considers the current evidence for a cause-to-effect relationship between hyperfiltration-related physical forces and the development of chronic kidney disease (CKD). Summary: Glomerular hyperfiltration is associated with glomerular and tubular hypertrophy. Hyperfiltration is mainly due to an increase in glomerular capillary pressure, which increases tensile stress applied to the capillary wall structures. In addition, the increased ultrafiltrate flow into Bowman’s space heightens shear stress on the podocyte foot processes and body surface. These mechanical stresses lead to an increase in glomerular basement membrane (GBM) length and to podocyte hypertrophy. The ability of the podocyte to grow being limited, a mismatch develops between the GBM area and the GBM area covered by foot processes, leading to podocyte injury, detachment of viable podocytes, adherence of capillaries to parietal epithelium, synechia formation and segmental sclerosis. Mechanical stress is also applied to post-filtration structures, resulting in dilation of glomerular and tubular urinary spaces, increased proximal tubular sodium reabsorption by hypertrophied epithelial cells and activation of mediators leading to tubulointerstitial inflammation, hypoxia and fibrosis Key Messages: GH-related mechanical stress leads to both adaptive and maladaptive glomerular and tubular changes. These flow-related effects play a central role in the pathogenesis of glomerular disease. Attenuation of hyperfiltration is thus an important therapeutic target in diabetes and obesity-induced CKD.

Introduction: Extra efferent arterioles, also known as polar vasculosis (PV), are often observed in the glomerular vascular pole and are associated with glomerular hypertrophy, indicating early recurrent diabetic kidney disease (DKD) in renal allografts. However, its significance in patients without diabetes remains uncertain. Methods: A total of 9,004 renal allograft biopsy specimens obtained between January 2007 and December 2017 at Tokyo Women’s Medical University were retrospectively analyzed to examine the clinical and pathological significance of PV in renal allografts. PV was identified in 186 biopsy specimens obtained from 165 patients. The PV group comprised 46 patients; 35 patients without DKD and 11 patients with DKD as the initial cause of ESRD, whose clinical information was available and treated with the calcineurin inhibitor (CNI) tacrolimus. The non-PV group comprising patients with renal allografts matched for age and postoperative day included 93 patients without DKD and 16 patients with DKD as the initial cause of ESRD. Results: In patients with nondiabetic renal allografts, systolic blood pressure was significantly higher in the PV group than in the non-PV group. The trough tacrolimus levels during the overall study period and at 2 weeks, 1 month, and 2 years after transplantation were significantly higher in the PV group compared with the non-PV group. Glomerulomegaly was significantly more common. Moreover, ah and aah scores in Banff score were significantly higher in the PV group than in the non-PV group. In those with diabetic renal allografts, although the clinical parameters and tacrolimus trough levels in all time periods were not significantly different between the PV and non-PV groups, the ah score was significantly higher in the PV group. Conclusion: PV was associated with CNI toxicity in nondiabetic but not in diabetic renal allografts. The pathogenesis of PV in renal allografts is considered to be multifactorial.

Background/Aims: Patients with minimal change disease (MCD) have a high relapse rate, which results in many complications. Identifying the risk factors for relapse is crucial, but little is known about these factors. Therefore, we performed the current study to determine the factors related to relapse in this patient population. Methods: We retrospectively analyzed 51 adult patients with biopsy-proven primary MCD treated between 2003 and 2013. The demographic, physiologic, laboratory and therapeutic data were gathered from the electronic medical records database. Lesions of the glomerulus, tubulointerstitium and vasculature were analyzed for associations with relapse. Results: During a median 50.9 months, 96.1% (49 of 51) of patients had achieved complete remission, and the rest ultimately achieved at least partial remission. A total of 56.9% (29 of 51) patients experienced at least 1 episode of relapse after the first remission. Patients with relapse had a higher rate of glomerular hypertrophy (GH; 34.5%) than those without relapse (9.1%; p < 0.05). After adjusting for confounders, GH was associated with increased odds of relapse (OR 15.992; 95% CI 1.537-166.362; p = 0.02). In a subgroup analysis according to median age, sex and tubulointerstitial (TI) lesions, the association between GH and relapse was evident only in men and in the group with TI lesions. Conclusion: GH is associated with relapse in adult patients with MCD, particularly in men and in those with TI lesions. Frequent monitoring and early intervention are needed in these groups. Future large prospective cohort studies are needed to confirm the study results.

Background/Aims: Arachidonic acid-metabolizing enzyme, 12-lipoxygenase (12-LO), is involved in the glomerular hypertrophy of diabetic nephropathy (DN), in which cyclin-dependent kinase inhibitors (CKIs) play important roles. However, it is unclear whether 12-LO regulates the expression of the CKI p16ink4a in DN. Methods: Primary glomerular mesangial cells (MCs) and glomeruli isolated from rats were used in this study. The rats were fed a high-fat diet and given low-dose streptozotocin to induce type 2 diabetes. The 12-LO product, 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE), was infused through an osmotic minipump. Enzyme-linked immunosorbent assay, Western blot, and morphometric analyses were performed. Results: High glucose (HG) increased the p16ink4a protein expression in MCs, but this increase was prevented by the 12-LO inhibitor, cinnamyl-3,​4-dihydroxy-α-cynanocinnamate (CDC). The levels of p-p38MAPK and p16ink4a in MCs were significantly elevated after the 12(S)-HETE treatment, whereas the p38MAPK inhibitor SB203580 prevented these increases. Compared with levels in control MCs, marked increases in p38MAPK activation and p16ink4a expression were observed in MCs plated on collagen IV, while the CDC treatment prevented these changes. Subcutaneous injection of CDC did not affect glucose levels, but completely attenuated the diabetes-related increases in the 12(S)-HETE content, p16ink4a expression, p-p38MAPK levels, glomerular volume, and the kidney/body weight ratio. Compared with levels in controls, p16ink4a and p-p38MAPK in the glomeruli derived from 12(S)-HETE-treated rats were significantly higher. Conclusions: 12-LO-p38MAPK mediates the upregulation of p16ink4a in HG-stimulated MCs and type 2-diabetic glomeruli, and new therapies aimed at 12-LO inhibition may prove beneficial in ameliorating diabetes-induced glomerular hypertrophy.

A clinicopathological and morphometric analysis of glomerular hypertrophy (GH) was conducted using biopsies obtained from 52 selected pediatric patients with IgA nephropathy (IgAN). Of the 52 patients, consisting of 12 with chronic renal failure (CRF) and 40 without CRF, various clinical and morphometric parameters were compared to 10 controls with benign hematuria. The mean glomerular tuft size, mesangial area, and interstitial area all significantly increased in patients with poor prognosis when compared to the non-CRF-IgAN cases and the control cases. The glomerular capillary loop size was also significantly greater in CRF-IgAN than in non-CRF-IgAn patients (1.37 times) and the controls (1.55 times). The 10-year renal survival rates of patients with ‘large’ loop size (>1.55-fold) were significantly lower (p < 0.001) than those of patients with a smaller capillary loop size. The size of the capillary loops was directly related to the relative interstitial area (Aint) (r2 = 0.43, p < 0.001), to the degree of glomerulosclerosis (GS; r2 = 0.348, p < 0.001) and the mesangial area (r2 = 0.326, p < 0.001). Proteinuria tightly correlated with the capillary loop size (r2 = 0.374, p < 0.001). It was not unexpected that a strong relationship was detected between the serum creatinine level and Aint (r2 = 0.452, p < 0.001) and the percentage of GS (r2 = 0.342, p < 0.001). In IgAN the percentage of GS correlated significantly with Aint (r2 = 0.484, p < 0.001). GH, which was manifested by glomerular capillary loop dilatation, shows a close correlation with the interstitial expansion, degree of GS and mesangial enlargement. These data suggest that both extra- and intraglomerular hemodynamic changes followed by primary glomerular damage thus lead to capillary dilatation of the intact glomeruli as a morphological manifestation of GH and therefore such changes play a key role in the progression of IgAN.

Milan normotensive rats, which spontaneously develop marked proteinuria (PU) and glomerulosclerosis (GS), were either kept on a normal-protein diet, a normal-protein diet with additional low-dose captopril (CAP), which did not affect blood pressure, or on a low-protein diet. After 8 months PU (79 +/- 25 mg/day) GS (3 +/- 2%) and total glomerular volume (TGV; 27.9 +/- 2.9 mm3/kidney) were significantly lower (p0.05) in the low-protein diet group than in both the normal-protein group (PU 583 +/- 210 mg/day, GS 12 +/- 5%, TGV 34.6 +/- 8 mm3/kidney) and the low-CAP group (PU 611 +/- 224 mg/day, GS 16 +/- 6%, TGV 41.8 +/- 8.6 mm3/kidney). In conclusion, the development of glomerular hypertrophy and GS in Milan normotensive rats was reduced by the low-protein diet, but not by low-CAP treatment.

The effects of a high salt diet on glomerular hypertrophy and sclerosis were examined in a focal glomerular sclerosis rat model. Sprague-Dawley rats were injected twice with Adriamycin (ADR, 2.5 mg/kg body weight) and then divided into 3 groups: (1) ADR rats fed a 1% sodium chloride (NaCI) diet (control ADR rats); (2) ADR rats fed an 8% NaC1 diet (ADR-NaC1 group), and (3) ADR rats fed a 10% sodium bicarbonate (NaHCO3) diet (the ADR-NaHCO3 group), and were then observed for 8 weeks. There were no differences in the blood pressure levels between the control ADR and ADR-NaC1 groups. The urinary protein excretion was significantly less in the ADR-NaC1 and ADR-NaHCO3 groups than in the control ADR group. However, a progressive increase in the blood urea nitrogen and serum creatinine associated with extensive glomerular sclerosis and hypertrophy was only observed in the ADR-NaC1 group. An increase in the glomerular diameter preceded the development of glomerulosclerosis in this group. Furthermore, a daily administration of amiloride, a Na+/H+ exchanger inhibitor, to the ADR-NaC1 rats prevented the development of glomerular hypertrophy and sclerosis. These results therefore suggest that the aggravated effect of a high salt diet on glomerular sclerosis may be related to glomerular hypertrophy which is associated with the stimulation of the Na+/H+ exchanger.

Adriamycin (ADR)-induced nephropathy is characterized by focal and segmental glomerulosclerosis and is supposed to be an ideal model of chronic progressive renal disease. The aim of our study was to investigate whether there might be an altered activity of glomerular proteinases in ADR nephropathy, thereby aggravating glomerular protein accumulation as an important initiating hallmark of glomerulosclerosis. In fact, we could demonstrate significantly enhanced levels of intraglomerular protein and DNA content in the experimental animals at week 7, 12 and 22 after administration of ADR. When relating intraglomerular proteinase activity, which was measured in ultrasonically destroyed isolated glomeruli, obtained by differential sieving techniques, to the intraglomerular protein and DNA content, this enzyme activity was significantly reduced throughout the observation period. Based on these data, we suggest that this relatively decreased proteinase activity in glomeruli exposed to ADR might play a pathogenetic role in the development of glomerular hypertrophy, an important harbinger of glomerulosclerosis.

To clarify a role of sex hormones in greater susceptibility of young rats than adults to the development of focal and segmental glomerulosclerosis (FSGS), we castrated animals at different ages and investigated whether the attenuating effect of castration on FSGS is age-dependent in unilaterally nephrectomized male Sprague-Dawley (SD) rats. At 6 weeks of age, all groups received unilateral right nephrectomy (Nx) and group 2 was simultaneously castrated, while group 1 received a sham operation. Group 3 was castrated at 3 months of age, and group 4 at 6 months of age. Body weight, blood pressure, urinary protein and serum constituents were investigated every 2 months from 4 to 14 months of age. At 6 and 14 months of age, rats were studied morphologically. Castration at 6 weeks of age or at 3 months of age significantly inhibited the compensatory glomerular hypertrophy and hyperfunction with regard to the creatinine clearance as seen in Nx rats at 6 months of age and significantly reduced glomerular injury at the end of the experiment, while castration at 6 months produced neither an inhibitory effect on glomerular hypertrophy nor an attenuating effect on glomerular injury. Serum levels of growth hormone (GH) and somatomedin-C (SmC) were decreased by castration to a greater extent when castrated at younger age. These findings indicated that GH and SmC influenced by male sex hormone seem to play a more important role at younger age than in adults in exerting its effect on glomerular growth, leading somehow to glomerular injury in aging, unilaterally nephrectomized male SD rats.

Clincopathological and morphometric analysis of glomerular hypertrophy was conducted using biopsies from 89 patients with minimal change nephrotic syndrome (MCNS). Of the 80 patients, in 69 with complete remission and in 20 with one or more relapses, various clinical and morphometric parameters were compared to 15 normal controls. Proteinuria was more severe and serum creatinine (Cr) concentration significantly higher in patients with relapse of proteinuria. The morphometric analysis showed that the sizes of (1) glomerular tufts and (2) glomerular capillaries were significantly larger in patients in the relapse group than in the remission or control groups, but no difference in the size of Bowman's capsule was found between the two MCNS subgroups. The intertubular capillaries were narrower in patients who failed to reach prompt complete remission. A negative correlation between intra- and extraglomerular capillary size was evident (r = -0.83, p0.001). A definitive correlation was detected between the circumference of glomerular capillary loops and the degree of proteinuria (r = 0.89, p0.001). The mean tubulocapillary diffusion distance was significantly longer in biopsies of the patients in relapse and showed a close significant correlation with serum Cr level (r = -0.87, p0.001) and intertubular capillary size (r = -0.87, p0.001). These data suggest that extra- and intraglomerular hemodynamic alterations in MCNS lead to glomerular hypertrophy, and dilatation of the glomerular capillary loop plays a key role in the relapse of MCNS.

Renal hypertrophy is a characteristic and early manifestation of diabetes in humans and experimental animals. We examined the precise distribution of insulin-like growth factor-I (IGF-I) mRNA and IGF-I receptor mRNA in the experimental diabetic rat kidney using a nonradioactive in situ hybridization technique. No significant difference in the distribution of IGF-I mRNA was found between the diabetic and control rats. IGF-I mRNA-positive cells were found in the collecting ducts and in scattered single cells in the distal tubules. The number of IGF-I mRNA-positive cells was very low in the glomeruli. Expression of IGF-I receptor mRNA was rarely seen in the glomeruli of control rats. IGF-I receptor mRNA was detected after induction of diabetes in glomerular mesangial, visceral epithelial, and parietal epithelial cells. The number of IGF-I receptor mRNA-positive cells in a glomerulus increased significantly, peaking at 4 weeks as compared with the control rats. Overexpression of IGF-I receptor in glomerular cells, especially mesangial and visceral epithelial cells, may contribute to glomerular hypertrophy in diabetic nephropathy.

The accumulation of extracellular matrix (ECM) is an important feature of most forms of progressive glomerular diseases. In order to examine the relationship between ECM synthesis and glomerulosclerosis, we evaluated fibronectin synthesis by glomeruli with the immunoprecipitation of conditioned media from isolated glomeruli in 5/6 nephrectomized spontaneously hypertensive rats (5/6N-SHR). There was no difference in blood pressure between 5/6N-SHR and control SHR throughout the experiment. Two weeks after the nephrectomy, most of the glomeruli were intact and no difference in the synthesis of fibronectin was observed between either groups. Twenty weeks after the nephrectomy, marked glomerulosclerosis associated with an increase in urinary protein was revealed in 5/6N-SHR but no glomerular lesions in control SHR. The synthesis of fibronectin by isolated glomeruli increased in 5/6N-SHR compared to control SHR. The administration of enalapril or hydralazine + reserpine + hydrochlorothiazide markedly attenuated the glomerular sclerosis and urinary protein excretion to a comparable degree, although the later therapy reduced blood pressure more effectively. These antihypertensive therapies also suppressed fibronectin synthesis in the 5/6N-SHR group at week 20. In conclusion, increased synthesis of glomerular fibronectin appeared to contribute to the glomerulosclerosis caused by subtotal nephrectomy and hypertension.

Experimental glomerulosclerosis is associated with hyperlipidaemia and the deposition of lipid in glomeruli. Glomerulosclerosis is typically preceded by glomerular hypertrophy. To investigate a possible pathogenic role of lipids in glomerulosclerosis, glomerular structure and cellular composition were studied in rats fed either a control diet or one supplemented with 4% cholesterol and 1% cholic acid for 21 weeks following unilateral nephrectomy. On the cholesterol diet there were significant increases in glomerular cross-sectional area (13.11 +/- 0.39 x 10(3) vs. 11.13 +/- 0.44 x 10(3) mu 2, p less than 0.01) and mesangial area (1.81 +/- 0.07 x 10(3) vs. 1.50 +/- 0.08 x 10(3) mu 2, p less than 0.02). These changes were significantly correlated with proteinuria, which was significantly greater on the cholesterol diet (mean area under curve for duration of diet = 3.11 +/- 0.38 vs. 1.42 +/- 0.35 g, p less than 0.02). There was a significant increase in glomerular leukocytes on the cholesterol diet (4.10 +/- 0.44 vs 2.86 +/- 0.25 OX-1 positive cells/10(4) mu 2, p less than 0.05). Mesangial foam cells, derived from macrophages, were associated with adhesions to Bowman's capsule. These results demonstrate that hyperlipidaemia exacerbates the development of glomerular hypertrophy and that this may be mediated by factors released during the phagocytosis of lipoprotein deposits by macrophages.