Glomerular Structural Changes Research Articles

Correlation of light and electron microscopic morphometric parameters of glomerular capillaries with serum creatinine and proteinuria

ABSTRACT Waste products in the bloodstream are filtered by the glomerular capillaries in the kidneys and excreted into the urine. When making a differential diagnosis of kidney diseases, structural assessment of glomeruli using histological, ultrastructural, and immunological studies is crucial. This study assessed the microscopic and ultrastructural morphometric parameters of glomerular capillaries and examined their correlation with serum creatinine and proteinuria. A total of 60 kidney biopsy cases received by the transmission electron microscope (TEM) laboratory for diagnosis were included in the study. Toluidine blue stained 300 nm thick sections of TEM tissue blocks were scanned for glomerular morphometry by a whole slide imaging system, and the estimation of Bowman’s capsule (BC) area, glomerular capillary lumen diameter (GCLD), glomerular capillary density (GCD), glomerular capillary surface area density (GCSA), and percentage of glomerular capillary lumen space (%GCLS) was performed with QuPath software. TEM images of 70 nm thick sections were used for the evaluation of endothelial fenestration diameter (EFD), glomerular basement membrane (GBM) thickness, and podocyte foot process (PFP) effacement. Proteinuria and serum creatinine showed positive correlations with GBM thickness and PFP effacement. Negative correlations of serum creatinine were observed with EFD, %GCLS, and GCSA. Hence, glomerular filtration is greatly affected by the total area of the glomerular capillary surface and structural changes of GBM. Reduction of glomerulus filtration due to foot process effacement and thickening of GBM results in damage to the filtration barrier leading to the leakage of plasma protein into urine.

Gold nanoparticles reduce tubule-interstitial injury and proteinuria in a murine model of subclinical acute kidney injury

Subclinical acute kidney injury (subAKI) is characterized by tubule-interstitial injury without significant changes in glomerular function. SubAKI is associated with the pathogenesis and progression of acute and chronic kidney diseases. Currently, therapeutic strategies to treat subAKI are limited. The use of gold nanoparticles (AuNPs) has shown promising benefits in different models of diseases. However, their possible effects on subAKI are still unknown. Here, we investigated the effects of AuNPs on a mouse model of subAKI. Animals with subAKI showed increased functional and histopathologic markers of tubular injury. There were no changes in glomerular function and structure. The animals with subAKI also presented an inflammatory profile demonstrated by activation of Th1 and Th17 cells in the renal cortex. This phenotype was associated with decreased megalin-mediated albumin endocytosis and expression of proximal tubular megalin. AuNP treatment prevented tubule-interstitial injury induced by subAKI. This effect was associated with a shift to an anti-inflammatory Th2 response. Furthermore, AuNP treatment preserved megalin-mediated albumin endocytosis in vivo and in vitro. AuNPs were not nephrotoxic in healthy mice. These results suggest that AuNPs have a protective effect in the tubule-interstitial injury observed in subAKI, highlighting a promising strategy as a future antiproteinuric treatment.

Inhibition of SGLT2 co-transporter by dapagliflozin ameliorates tubular proteinuria and tubule-interstitial injury at the early stage of diabetic kidney disease

Diabetic kidney disease (DKD) is characterized by progressive impairment of kidney function. It has been postulated that tubule-interstitial injury, associated with tubular albuminuria, precedes glomerular damage in the early stage of DKD. Here, we wanted to determine if the development of tubule-interstitial injury at the early stage of DKD implies modulation of megalin-mediated protein reabsorption in proximal tubule epithelial cells (PTECs) by SGLT2-dependent high glucose influx. Rats with streptozotocin (STZ)-induced diabetes were treated or not with dapagliflozin (DAPA) for 8 weeks. Four experimental groups were generated: (1) CONT, control; (2) DAPA, rats treated with DAPA; (3) STZ, diabetic rats; (4) STZ + DAPA, diabetic rats treated with DAPA. No changes in glomerular structure and function were observed. The STZ group presented proteinuria and albuminuria associated with an increase in the fractional excretion of proteins. A positive correlation between glycemia and proteinuria was found. These phenomena were linked to a decrease in luminal and total megalin expression and, consequently, in albumin reabsorption in PTECs. We also observed tubule-interstitial injury characterized by an increase in urinary tubular injury biomarkers and changes in tubular histomorphometry parameters. In addition, inverse correlations were found between cortical albumin uptake and tubule-interstitial injury or glycemia. All these modifications were attenuated in the STZ + DAPA group. These results suggest that SGLT2-dependent high glucose influx into PTECs promotes a harmful effect on the PTECs, leading to the development of tubular albuminuria and tubule-interstitial injury preceding glomerular damage. These results expand current knowledge on the renoprotective effects of gliflozins.

Фактори ризику, асоційовані з діабетичною нефропатією та їх клінічне значення

The purpose of the study was to highlight the most studied risk factors associated with the development and/or progression of diabetic nephropathy, with an emphasis on some important aspects that should be kept in mind by the physician. Materials and methods. Research materials are publications of national and foreign authors. The methods used were: system approach and system theoretical retrospective analysis of selected materials; generalization; medical and statistical method. Results and discussion. Timely diagnostics of diabetic nephropathy and elimination of risk factors of its development and progression are emphasized to be a difficult task of clinics of internal diseases particularly in conditions when amount of these risk factors is constantly growing. The most investigated risk factors associated with development and progression of diabetic nephropathy such as age, arterial hypertension, disorders of carbohydrate and lipid exchange, proteinuria are discussed in the article. Some peculiarities of correction of metabolic risk factors such as hyperglycemia and dyslipidemia as well as hemodynamic risk factors such as arterial hypertension and intraglomerular hypertension participated in development and progression of diabetic nephropathy are discussed with consideration of acting recommendations. Some aged and gender peculiarities of change of glomerular filtration rate as well as a role of arterial hypertension in progression of diabetic nephropathy through albuminuria are considered. A significance of glycosylated hemoglobin level as an independent risk factors of microalbuminuria is demonstrated. A role of secondary lipid exchange disorders due to type 2 diabetes mellitus in reduction of glomerular filtration rate and elevation of albumin/creatinine ratio as well as albuminuria presence is emphasized. A necessity of urinal detection of nephrin and podocin levels for an early diagnostics of diabetic nephropathy and monitoring of renal glomerular dysfunction in diabetes mellitus is discussed. Some risk factors related to appearance of albuminuria as well as association of albuminuria and proteinuria with glomerular and tubular structural changes in kidney are considered. A clinical significance of albumin/creatinine ratio calculation as an alternative to daily urinal protein concentration measuring for diabetic nephropathy screening is emphasized. Some risk factors related to close positive correlation with this ratio are considered. A role of genetic factors in the development of diabetic nephropathy with a participation of known today some genes candidates and a necessity of genealogical anamnesis definition to reveal a patient’s susceptibility to development of diabetic nephropathy is discussed. Conclusion. The contemporary recommendations for control of glycemia, correction of dyslipidemia and arterial hypertension which allow significantly reduce a risk of kidney impairment in diabetes mellitus or inhibit a progression of diabetic nephropathy in patients with albuminuria and proteinuria are given. A significance of detailed investigation of principles of development and progression of diabetic nephropathy for collaboration of effective diagnostic, treatment and preventive measures is emphasized

Proton pump inhibitor-induced risk of chronic kidney disease is associated with increase of indoxyl sulfate synthesis via inhibition of CYP2E1 protein degradation

Proton pump inhibitors (PPIs) are widely used to treat acid-related disorders in the gastrointestinal tract; however, PPI use increases the risk of chronic kidney disease (CKD) through unclear mechanisms. Considering that PPIs disturb the gut microbiome balance, which is involved in the precursor of gut-derived uremic toxin accumulation, and that gut-derived uremic toxins aggravate CKD progression, the aim of this study is to elucidate whether PPIs affect gut-derived uremic toxin metabolism, including indoxyl sulfate (IS), p-cresyl sulfate, and trimethylamine-N-oxide, as a mechanism for causing CKD. The present study showed that 3 week-treatment of PPIs (omeprazole, lansoprazole, and pantoprazole at 30 mg/kg) in mice only increased IS plasma levels among the above three gut-derived uremic toxins. Additionally, lansoprazole increased IS plasma concentrations along with increased exposure dose (7.5–30 mg/kg) and duration (1–3 weeks). However, nephrotoxicity with mild changes in glomerular structure and signs of fibrosis were observed only in groups exposed to a 3-week treatment of PPIs (30 mg/kg). As the concentrations of indole (the precursor of IS from gut metabolism) in the colon were only increased in the pantoprazole-treated group, the mechanism of increased IS exposure remains unclear. Further studies revealed that PPIs (omeprazole and lansoprazole; but not pantoprazole) increased IS production from indole in primary mouse hepatocytes in a concentration-dependent manner. Additionally, the increased protein levels of hepatic CYP2E1 (the key enzyme mediating IS formation) due to suppressed degradation resulted in an increase in IS levels. Although omeprazole and lansoprazole significantly inhibited IS uptake in hOAT1/3 in vitro, 3 weeks of PPI treatment did not reduce IS renal excretion in mice. In conclusion, PPIs induced IS synthesis via increased hepatic CYP2E1 protein level, subsequently leading to increased IS exposure. These findings present a plausible biological mechanism to explain the association of PPI use with the increased risk of CKD.

Assessment of glomerular morphological patterns by deep learning algorithms

BackgroundCompilation of different morphological lesion signatures is characteristic of renal pathology. Previous studies have documented the potential value of artificial intelligence (AI) in recognizing relatively clear-cut glomerular structures and patterns, such as segmental or global sclerosis or mesangial hypercellularity. This study aimed to test the capacity of deep learning algorithms to recognize complex glomerular structural changes that reflect common diagnostic dilemmas in nephropathology.MethodsFor this purpose, we defined nine classes of glomerular morphological patterns and trained twelve convolutional neuronal network (CNN) models on these. The two-step training process was done on a first dataset defined by an expert nephropathologist (12,253 images) and a second consensus dataset (11,142 images) defined by three experts in the field.ResultsThe efficacy of CNN training was evaluated using another set with 180 consensus images, showing convincingly good classification results (kappa-values 0.838–0.938).Furthermore, we elucidated the image areas decisive for CNN-based decision making by class activation maps. Finally, we demonstrated that the algorithm could decipher glomerular disease patterns coinciding in a single glomerulus (e.g. necrosis along with mesangial and endocapillary hypercellularity).ConclusionsIn summary, our model, focusing on glomerular lesions detectable by conventional microscopy, is the first sui generis to deploy deep learning as a reliable and promising tool in recognition of even discrete and/or overlapping morphological changes. Our results provide a stimulus for ongoing projects that integrate further input levels next to morphology (such as immunohistochemistry, electron microscopy, and clinical information) to develop a novel tool applicable for routine diagnostic nephropathology.

409-P: Arteriolar Hyalinosis Is Associated with the Rate of eGFR Decline and Predicts the Onset of Macroalbuminuria and eGFR<60 Ml/min/1.73 M2 in Patients with Type 2 Diabetes and Normo-microalbuminuria Regardless of Microalbuminuria Grade

Microalbuminuria is thought to be a risk factor for progression to macroalbuminuria, an indicator of renal functional decline in patients with type 1 or 2 diabetes. However, it remains unknown which renal histological factors predict the onset of macroalbuminuria or eGFR<60 mL/min/1.73 m2 (chronic kidney disease, CKD) during early diabetic nephropathy. Therefore, we sought to determine which histological factors, including index of arteriolar hyalinosis (IAH), are predictors for onset of macroalbuminuria and CKD. The study population consisted of 35 patients with type 2 diabetes (25 men; age, 47±9 years; eGFR, 92.7±18.0 mL/min/1.73 m2) with normoalbuminuria or microalbuminuria who underwent percutaneous renal biopsy. We followed these patients for at least 5 (18±6) years. The study endpoint was the onset of macroalbuminuria or CKD, or by March 2020. Light and electron microscopy-based morphometric analyses were performed to quantitatively evaluate glomerular and interstitial structural changes. During the observation period, 9 of 35 patients progressed to macroalbuminuria and 15 had CKD. The annual rate of eGFR decline was significantly related to IAH (r=-0.40, p=0.016), but not any other histological parameters. Kaplan-Meier analysis revealed that arteriolar hyalinosis and mesangial expansion are associated with a significantly higher risk of onset of macroalbuminuria and CKD, and microalbuminuria grade is associated with the onset of macroalbuminuria, but not the onset of CKD. Conclusions: Aggravated arteriolar hyalinosis is a histological risk factor for renal functional decline and predicts the onset of macroalbuminuria and CKD in patients with type 2 diabetes, normo-microalbuminuria, and normal renal function regardless of microalbuminuria grade. This finding might reflect initial changes in early diabetic nephropathy. Disclosure T. Moriya: None. A. Hayashi: None. A. Suzuki: None. M. Matsubara: None. M. Ouchi: None.

Association of urinary C-megalin with albuminuria and renal function in diabetes: a cross-sectional study (Diabetes Distress and Care Registry at Tenri [DDCRT 21]).

A urinary biomarker sensitive to glomerular functional or structural changes in diabetic kidney disease is required. This study examined whether urinary C-megalin reflects renal function or albuminuria in diabetes. This was a cross-sectional study involving 1576 patients with type 1 or 2 diabetes. The exposure variables were estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR), and the outcomes were urinary C-megalin excretion and concentration. Two-part models were used to examine the associations between eGFR and UACR with urinary C-megalin excretion or concentration. The UACR was linearly associated with urinary C-megalin excretion (per 100mg/gCr of UACR; 11.8 fM/gCr [95% CI 8.9-14.7]). There was no association between decreasing eGFR and increasing urinary C-megalin excretion. The UACR was also linearly associated with the urinary C-megalin concentration (per 100mg/gCr of UACR, 7.7 fM/L [95% CI 5.8-9.6]). At eGFR values > 60mL/min/1.73 m2, the eGFR and urinary C-megalin concentration were inversely linearly related (per 10mL/min/1.73 m2 decline, 7.7 fM/L [95% CI 0.2-15.1]). Urinary C-megalin excretion as well as concentration levels are potentially useful biomarkers to detect early changes in diabetic kidney disease.

Role of VEGF-A and LRG1 in Abnormal Angiogenesis Associated With Diabetic Nephropathy.

Diabetic nephropathy (DN) is an important public health concern of increasing proportions and the leading cause of end-stage renal disease (ESRD) in diabetic patients. It is one of the most common long-term microvascular complications of diabetes mellitus that is characterized by proteinuria and glomerular structural changes. Angiogenesis has long been considered to contribute to the pathogenesis of DN, whereas the molecular mechanisms of which are barely known. Angiogenic factors associated with angiogenesis are the major candidates to explain the microvascular and pathologic finds of DN. Vascular endothelial growth factor A (VEGF-A), leucine-rich α-2-glycoprotein 1, angiopoietins and vasohibin family signal between the podocytes, endothelium, and mesangium have important roles in the maintenance of renal functions. An appropriate amount of VEGF-A is beneficial to maintaining glomerular structure, while excessive VEGF-A can lead to abnormal angiogenesis. LRG1 is a novel pro-angiogenic factors involved in the abnormal angiogenesis and renal fibrosis in DN. The imbalance of Ang1/Ang2 ratio has a role in leading to glomerular disease. Vasohibin-2 is recently shown to be in diabetes-induced glomerular alterations. This review will focus on current understanding of these angiogenic factors in angiogenesis and pathogenesis associated with the development of DN, with the aim of evaluating the potential of anti-angiogenesis therapy in patients with DN.

Experimental study on embolization of rabbit renal artery with gelatin sponge microspheres.

The objective of this study was to evaluate the degradation characteristics and embolic effect of gelatin microspheres (GMSs) produced domestically in China through an experimental study comparing the embolization of rabbit renal arteries using GMSs and tris-acryl microspheres. Sixteen healthy adult New Zealand white rabbits were randomly divided into two groups. Group A was embolized with GMSs produced in China with a diameter of 150-200 μm (n = 8), and Group B was embolized with tris-acryl microspheres with a diameter of 100-200 μm (n = 8). The renal arteries were embolized through femoral artery puncture and catheterization. Renal artery angiography rechecks and hematoxylin and eosin staining of tissue sections were performed at 1 day, 4 days, 7 days, and 14 days after embolization, respectively, to observe vascular recanalization, degradation of microspheres, and embolic effect. Group A: Digital subtraction angiography showed complete recanalization at 14 days. The changes in embolic necrotic areas at different time points after embolization were similar in the two groups. At 4 days after embolization, changes in glomerular structure were observed in the kidney on the embolic side. At 7 days after embolization, atrophy, degeneration, and necrosis of the glomeruli, as well as degeneration and inflammatory cell infiltration of the renal tubules, were observed in the kidney on the embolic side. At 14 days after embolization, extensive atrophy and hyalinization of the glomeruli were observed, and local renal tissue showed patchy fibrosis with calcification of internal tissue. Hyperplasia of fibrillar connective tissue was observed in the renal interstitium. The GMSs produced domestically in China can be completely degraded after embolizing blood vessels for 14 days. The GMSs are similar to tris-acryl microspheres in arterial embolization effect and are safe and effective.

Implementing Reverse Phase Protein Array Profiling as a Sensitive Method for the Early Pre-Clinical Detection of Off-Target Toxicities Associated with Sunitinib Malate.

The tyrosine kinase inhibitor (TKI) sunitinib is a multi-targeted agent approved across multiple cancer indications. Nevertheless, since approval, data has emerged to describe a worrisome side effect profile including hypertension, hand-foot syndrome, fatigue, diarrhea, mucositis, proteinuria, and (rarely) congestive heart failure. It has been hypothesized that the observed multi-parameter toxicity profile is related to "on-target" kinase inhibition in "off-target" tissues. To interrogate off-target effects in pre-clinical studies, a reverse phase protein array (RPPA) approach is employed. Mice are treated with sunitinib (40mgkg-1 ) for 4 weeks, following which critical organs are removed. The Zeptosens RPPA platform is employed for protein expression analysis. Differentially expressed proteins associated with damage and/or stress are found in the majority of organs from treated animals. Proteins differentially expressed in the heart are associated with myocardial hypertrophy, ischaemia/reperfusion, and hypoxia. However, hypertrophy is not evidenced on histology. Mild proteinuria is observed; however, no changes in renal glomerular structure are visible via electron microscopy. In skin, proteins associated with cutaneous inflammation, keratinocyte hyper-proliferation, and increased inflammatory response are differentially expressed. It is posited that pre-clinical implementation of a combined histopathological/RPPA approach provides a sensitive method to mechanistically elucidate the early manifestation of TKI on-target/organ off-target toxicities.

Serial renal biopsies in normo- and microalbuminuric patients with type 2 diabetes demonstrate that loss of renal function is associated with a reduction in glomerular filtration surface secondary to mesangial expansion

AimsThe aim of the present study was to explore the relationship between changes in renal structure in patients with type 2 diabetes at an early stage of diabetic nephropathy using serial renal biopsies, and change in renal function. MethodsThe study population comprised 10 patients with type 2 diabetes with normo- or microalbuminuria at baseline. Light and electron microscopy-based morphometric analyses were performed to quantitatively evaluate glomerular and interstitial structural changes. Urinary albumin excretion (UAE) and glomerular filtration rate (GFR) were measured annually. A second renal biopsy was performed after a mean of 6.1 ± 2.4 years of follow-up. ResultsUAE, GFR, blood pressure and severity of diabetic retinopathy (DR) did not change between the baseline and follow-up. The annual decrease in the surface density of the peripheral glomerular basement membrane (GBM) (Sv[PGBM/glom]) was correlated with the rate of loss of GFR during the six-year follow-up period. The annual change in the Sv(PGBM/glom) was negatively correlated with the change in mesangial volume fraction. ConclusionsDecreases in the GFR in patients with type 2 diabetes with normo- or microalbuminuria at baseline were associated with a decreased glomerular filtration surface, as a result of mesangial expansion during a mean six years of observation. These findings confirm ongoing pathological progression of glomerulopathy despite no significant change in albuminuria or retinopathy status.

Protective effect of Yiqi Huoxue decoction on kidney in diabetic GK rats

To investigate the protective effect of Yiqi Huoxue decoction on the kidney in diabetic goto-Kaizaki (GK) rats. Eight Wistar rats were used as normal control group. According to body weight and blood glucose, 16 GK rats were randomly divided into model control group and Yiqi Huoxue group, with 8 rats in each group. Drugs were administrated for 6 weeks. The rats were weighed and fasting blood glucose (FBG) were measured weekly; the glycosylated hemoglobin (HbALc) and 24 h metabolic rate were measured at the end of third and sixth weeks, at the same time, urine was collected to measure urinary glucose (U-GLU), urinary creatinine (U-CREA) and total proteinuria (U-TP) by biochemical method and calculate 24 h protein excretion rate (UAER). At the end of treatment, rats were sacrificed in anesthesia, and creatinin (CREA), uric acid (UA) and cholesterol (CHOL) were detected by biochemical method and glutathione peroxidase (GSH-Px) was detected by manual method with the blood drawn from heart. Both kidneys were taken and weighed to calculate the renal hypertrophy index. The kidneys were placed into neutral formalin and observed under light microscope for pathological change after Periodic Acid-Schiff (PAS) staining. The results showed that as compared with the normal control group, FBG, HbALc, 24 h Metabolic rate, U-GLU, UAER, serum CREA, UA and CHOL levels, as well as renal hypertrophy index were significantly increased (P<0.05) in the model group, while the body weight growth rate, serum GSH-Px level were significantly reduced(P<0.05); in addition, renal glomerular injury and structural changes were observed in the model group. As compared with the model group, serum GSH-Px level was significantly increased (P<0.05) in the Yiqi Huoxue group, While FBG, HbALc, 24 h Metabolic rate, U-GLU, UAER, serum CREA, UA and CHOL levels, as well as renal hypertrophy index were significantly reduced (P<0.05); meanwhile, renal glomerular injury and structural changes were improved in the Yiqi Huoxue group. The results showed that Yiqi Huoxue decoction can significantly increase serum GSH-Px level, reduce FBG, HbALc, 24 h metabolic rate, U-GLU, UAER, serum CREA, UA and CHOL levels, as well as renal hypertrophy index, and improve renal pathology in diabetic GK rats.

Arteriolar Hyalinosis Predicts Increase in Albuminuria and GFR Decline in Normo- and Microalbuminuric Japanese Patients With Type 2 Diabetes

This study investigated the association between renal histology, as assessed by morphometric analysis using light (LM) and electron (EM) microscopy, and changes in urinary albumin excretion (UAE) and glomerular filtration rate (GFR) in Japanese people with type 2 diabetes in the early stages of diabetic nephropathy. We performed percutaneous renal biopsies in 29 patients with type 2 diabetes (22 men, mean ± SD age 49 ± 10 years and GFR 119 ± 27 mL/min/1.73 m2, with 15 normoalbuminuric [UAE <20 μg/min] and 14 microalbuminuric [UAE 20-200 μg/min]) to clarify which histological factors were associated with changes in UAE and GFR during 8.0 ± 3.5 years' follow-up. Glomerular structural changes including mesangial volume fraction [Vv(Mes/glom)] were estimated using EM, whereas the index of arteriolar hyalinosis (IAH) score was assessed by LM. Patients underwent annual measurement of GFR using iohexol injection with simultaneous urine collections for UAE. Vv(Mes/glom) was negatively correlated with baseline and follow-up GFR but not with UAE. The IAH score was positively correlated with UAE and negatively correlated with GFR at follow-up, but it was not correlated with either UAE or GFR at baseline. GFR at follow-up was significantly decreased from baseline in patients with IAH scores ≥2.0 and significantly lower than in patients with IAH scores <2.0. Patients with IAH scores <2.0 showed no significant change in GFR during follow-up. Arteriolar hyalinosis is an additional histological predictor for albuminuria increase and GFR decline in normo- and microalbuminuric Japanese people with type 2 diabetes.

Aldosterone effects on glomerular structure and function

Experimental evidence suggests that aldosterone directly contributes to organ damage by promoting cell growth, fibrosis, and inflammation. Based on these premises, this work aimed to assess the glomerular effects of aldosterone, alone and in combination with salt. After undergoing uninephrectomy, 75 rats were allocated to five groups: control, salt diet, aldosterone, aldosterone + salt diet, aldosterone + salt diet and eplerenone, and they were all studied for four weeks. We focused on glomerular structural, functional, and molecular changes, including slit diaphragm components, local renin-angiotensin system activation, as well as pro-oxidative and profibrotic changes. Aldosterone significantly increased systolic blood pressure, led to glomerular hypertrophy, mesangial expansion, and it significantly increased the glomerular permeability to albumin and the albumin excretion rate, indicating the presence of glomerular damage. These effects were worsened by adding salt to aldosterone, while they were reduced by eplerenone. Aldosterone-induced glomerular damage was associated with glomerular angiotensin-converting enzyme (ACE) 2 downregulation, with ACE/ACE2 ratio increase, ANP decrease, as well as with glomerular pro-oxidative and profibrotic changes. Aldosterone damages not only the structure but also the function of the glomerulus. ACE/ACE2 upregulation, ACE2 and ANP downregulation, and pro-oxidative and profibrotic changes are possible mechanisms accounting for aldosterone-induced glomerular injury.

Tenofovir during pregnancy in rats: a novel pathway for programmed hypertension in the offspring.

To evaluate the occurrence of systemic and renal abnormalities in the offspring of Wistar rats exposed to tenofovir disoproxil fumarate (DF) during pregnancy. Female Wistar rats received a standard diet, with or without addition of tenofovir DF (100 mg/kg diet), 1 week before mating and during pregnancy. Offspring from the tenofovir DF group were placed with an untreated foster mother during breastfeeding and compared with offspring from rats maintained on a standard diet during mating and pregnancy (control). Control and tenofovir DF were followed up at 3 and 6 months of age. Monthly body weight and systolic blood pressure (SBP), glomerular counts, renal function, biochemical parameters, angiotensin II, renal renin angiotensin aldosterone system (RAAS) and renal sodium transporters were analysed. Tenofovir DF offspring showed lower birth weight compared with the control group. After the third month, growth among the tenofovir DF group experienced a rapid catch-up. SBP increased progressively after the second month of age in the tenofovir DF group. Nephron number did not differ between the groups; however, the tenofovir DF group showed glomerular structural changes. Plasma aldosterone was higher in the tenofovir DF group, associated with a significant increase in renal expression of RAAS. The tenofovir DF rats showed up-regulation of renal sodium transporters and consequently lower urinary sodium excretion. This is the first demonstration using an experimental model that maternal exposure to tenofovir DF during gestation results in overactivation of RAAS, up-regulation of renal sodium transporters and hypertension in the offspring.

The glomerular endothelium emerges as a key player in diabetic nephropathy

The effects of diabetes on glomerular structure and particularly that of the glomerular capillary wall have been extensively documented. By correlation with clinical measurements, Weil and colleagues provide important insights into the functional significance of glomerular structural changes in type 2 diabetes. Podocyte detachment correlates with albumin-to-creatinine ratio, but less strongly than does loss of endothelial fenestrations, which also correlates with reduced glomerular filtration rate. The role of the glomerular endothelium in diabetic nephropathy demands further scrutiny.

Morphologic Features of Declining Renal Function in Type 1 Diabetes

Progressive renal dysfunction is a major complication of type 1 diabetes. Studying relationships between evolution of diabetic nephropathy lesions and renal functional alterations (structural-functional relationships) helps to better understand the natural history of diabetic nephropathy. The focus of this review is our current understanding of the interplay between morphologic changes of diabetic nephropathy and glomerular filtration rate (GFR) loss. These morphologic changes often may not progress in parallel to each other or to the decline in GFR or increase in albumin excretion rate (AER). Quantitative measures of renal (mainly glomerular) structural changes can predict a substantially larger fraction of AER variability compared with that of GFR, especially using linear correlation analyses. However, nonlinear models better fit the structural-functional relationships across a wide range of GFRs and AERs. Currently, there are insufficient longitudinal data to show which structural changes predict the slope of GFR decline in type 1 diabetic patients. Based on cross-sectional studies, however, such a predictor would be about 10% more robust in patients whose GFR was 45 mL/min/1.73 m(2) or greater if comprised of a composite of glomerular, tubular, and interstitial parameters versus glomerular changes alone. For a slowly progressive disease, such as diabetic nephropathy, in which, especially in the earlier stages, it takes a long time for GFR to decline substantially, such predictors are much needed and, if sufficiently precise, could potentially serve as a surrogate of renal functional decline in clinical trials.

A Photo Shoot of Proteinuria

Diseases of the renal glomerulus, the site of plasma filtration and the production of primary urine, account for a majority of chronic renal diseases.[1][1] The prevention of ESRD would require therapies that specifically interfere with the pathogenesis of the various underlying glomerular diseases

Early glomerular alterations in genetically determined low nephron number

An association between low nephron number and subsequent development of hypertension in later life has been demonstrated. The underlying pathomechanisms are unknown, but glomerular and postglomerular changes have been discussed. We investigated whether such changes are already present in prehypertensive "glial cell line-derived neurotrophic growth factor" heterozygous mice (GDNF+/-) with lower nephron number. Twenty-six-week-old mice [22 GDNF+/-, 29 C57B6 wild-type control (wt)] were used for in vivo experiments with intra-arterial and tail cuff blood pressure measurements. After perfusion fixation, kidneys were investigated with morphological, morphometric, stereological, and immunohistochemical techniques and TaqMan PCR analysis. As expected at this age, blood pressure was comparable between GDNF+/- and wt. Nephron number per kidney was significantly lower in GDNF+/- than in wt (-32.8%, P < 0.005), and mean glomerular volume was significantly higher (+49.5%, P < 0.001). Renal damage scores, glomerular and tubular proliferation, analysis of intrarenal arteries and peritubular capillaries, expression of relevant tubular transporter proteins, as well as gene expression of profibrotic, proinflammatory, or prohypertensive markers were not significantly different between GDNF+/- and wt. Compensatory glomerular hypertrophy in GDNF+/- was accompanied by higher numbers of endothelial and mesangial cells as well as PCNA-positive glomerular cells, whereas podocyte density was significantly reduced. Further electron microscopic analysis showed marked thickening of glomerular basement membrane. In conclusion, lower nephron number is associated with marked early glomerular structural changes, in particular lower capillary supply, reduced podocyte density, and thickened glomerular basement membrane, that may predispose to glomerular sclerosis.