Focal Segmental Glomerulosclerosis Lesions Research Articles

Podocyte‐parietal epithelial cell cross‐talk: a role for paracrine KLF4‐STAT3 signaling in parietal epithelial cell proliferation in proliferative glomerulopathies

Podocyte injury contributing to parietal epithelial cell (PEC) proliferation is a dominant histologic feature in both rapidly progressive glomerulonephritis (RPGN) and subtypes of focal segmental glomerulosclerosis (FSGS). Activation of Signal Transducer and Activator of Transcription 3 (STAT3) signaling is critical to the progression of both. We recently showed that podocyte‐specific loss of Krüppel‐Like Factor 4 (KLF4), a zinc‐finger transcription factor, activates STAT3 signaling leading to mitotic catastrophe in podocytes and eventual FSGS, while triggering PEC proliferation.To determine the mechanism by which podocyte‐specific knockdown of KLF4 leads to podocyte loss and triggers PEC proliferation with dysregulated STAT3 signaling, we generated cultured human podocytes with KLF4 knockdown (KLF4‐shRNA) and screened several pharmacological STAT3‐specific inhibitors to determine that S3I‐201 prevented podocyte loss to a higher degree than other STAT3 inhibitors or DMSO‐treated KLF4‐shRNA podocytes. Furthermore, we demonstrated that S3I‐201‐treated PodCre‐KLF4fl/fl mice exhibited less proteinuria and improved renal function as compared to DMSO‐treated PodCre‐KLF4fl/fl mice. We further validated the reno‐protective effects of S3I‐201 in HIV‐1 transgenic mice, a known model of podocyte‐specific Klf4 loss and STAT3 activation, by demonstrating reduced albuminuria, podocyte loss, FSGS lesions, and parietal epithelial cell activation, with improved renal function.We previously demonstrated that supernatant harvested from KLF4‐shRNA podocytes induces PEC proliferation. To elucidate the mechanism by which loss of KLF4 specifically in podocytes triggers PEC activation and proliferation, we performed unbiased quantitative proteomics on the supernatant of KLF4‐shRNA podocytes as compared to EV‐shRNA podocytes. We subsequently cross‐matched proteins upregulated in supernatant of KLF4‐shRNA podocytes with differentially expressed transcripts from RNA‐sequencing of isolated glomeruli from PodCre‐KLF4fl/fl mice as compared to wildtype KLF4fl/fl mice. Enrichment analysis of these differentially expressed targets revealed activation of STAT‐dependent and independent pathways involved in inflammation, extracellular matrix organization, and proliferation. Interestingly, the highest expressed STAT3 downstream targets were Plasminogen Activator Inhibitor 1 (PAI‐1) and Galectin‐1 (LGALS1), which are key mediators of epithelial cell migration and proliferation.Collectively, these findings demonstrate the role of dysregulated KLF4‐STAT3 signaling in proliferative glomerulopathies and identify potential paracrine mediators of podocyte‐PEC cross‐talk.Support or Funding InformationNIH/NIDDK, SBU URECAThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Focal segmental glomerulosclerosis lesion associated with inhibition of tyrosine kinases by lenvatinib: a case report

BackgroundLenvatinib is a tyrosine kinase inhibitor with novel binding ability. It is considered the standard of care for metastatic thyroid cancer; moreover, whether it is indicated for other malignant tumors has been examined. Lenvatinib increases the risk of kidney injury in some patients. In comparison with sorafenib, which is a conventional tyrosine kinase inhibitor (TKI), lenvatinib results in more side effects, including hypertension and proteinuria. We describe a case of secondary focal segmental glomerulosclerosis (FSGS) that developed following treatment of metastatic thyroid cancer with lenvatinib and reviewed the mechanisms of renal impairment.Case presentationWe describe a patient with metastatic thyroid cancer who developed hypertension, nephrotic syndrome, and acute kidney injury after 3 months of lenvatinib treatment. Renal biopsy results revealed that 7 of 16 glomeruli indicated complete hyalinization, and that the glomeruli with incomplete hyalinization showed FSGS due to a vascular endothelial disorder and podocyte damage, which seemed to have been induced by lenvatinib treatment. These findings were similar to those of renal impairment treated with conventional TKIs. Although lenvatinib treatment was discontinued, up to 15 months were required to achieve remission of proteinuria, thus leading to chronic kidney disease with hyalinized lesions.ConclusionsTo the best of our knowledge, this is the first reported case of secondary FSGS by lenvatinib treatment. Renal impairment treated with TKIs is commonly associated with minimal change nephrotic syndrome/FSGS findings, and it is suggested that renal involvement with TKI is different from that with the vascular endothelial growth factor ligand. Overexpression of c-mip due to TKI causes disorders such as podocyte dysregulation and promotion of apoptosis, which cause FSGS. Lenvatinib may result in FSGS by a similar mechanism with another TKI and could cause irreversible renal impairment; therefore caution must be used. It is essential to monitor blood pressure, urinary findings, and the renal function.

Pattern of Glomerular Staining for C4d Immunohistochemistry is Useful for the Diagnosis of Immune Complex Mediated Glomerulonephritis in Renal Allograft Biopsies

Introduction Performance of the C4d stain is required for the adequate evaluation of kidney transplant biopsies (KTBx). Positive C4d staining in the renal peritubular capillaries is very useful for the diagnosis of antibody mediated allograft rejection (AMR) and correlates with poorer graft outcomes. Glomerular C4d staining is common in the chronic phases of AMR but this is not diagnostically useful due to inconsistent distribution and intensity of staining. Deposition of the C4d complement component in immune complex mediated (ICM) glomerulonephritis (GN) is expected but this has not been systematically studied in KTBx. Materials and Methods C4d stain (immunohistochemical method) was applied to 2432 consecutive, paraffin embedded KTBx, over a period of 5 years. In KTBx due to abrupt increase in proteinuria or history of GN in the native kidney, immunofluorescence and electron microscopy studies for standard evaluation of GN were also used for diagnosis. Results and Discussion In this unselected biopsy cohort, 33 KTBx from 27 patients showed recurrent or primary GN: 12 membranous glomerulopathy (MGN), 4 lupus nephritis (SLE), 9 IgA nephropathy and 8 focal segmental glomerulosclerosis (FSGS), Distinctive and consistent glomerular C4d stainining was noted in patients with MGN with a pattern paralleling the IF and EM findings. SImilarly, in recurrnet SLE, glomerular C4d staining corresponded to the histological lupus Class determined by light microscopy, IF and EM. The C4d staining pattern in these GNs was clearly different from that seen in transplant glomerulopathy. C4d staining in IgA nephropathy was inconsistent, mostly mesangial and did not correlate clearly with the strength of IF IgA staining. Only the segmental sclerotic lesions in FSGS were highlighted by the C4d staining in a manner that appeared nonspecific. Conclusions C4d staining is routinely evaluated in transplant biopsies and this stain consistently highlights immune complex deposits in MGN and SLE. Recognition of this distinctive staining pattern is helpful in the diagnosis of these processes and should prompt complete evaluation with IF and EM if these studies were not initially available. The findings in this study are based on C4d stain evaluation of paraffin embedded tissue sections. Since C4d staining corresponds to the classical pathway of complement activation, similar findings are expected with the IF staining method in fresh frozen tissue sections.

Recurrent focal segmental glomerulosclerosis after kidney transplant in adults: A report on various treatment regimens

Aim: Recurrence of focal segmental glomerulosclerosis (FSGS) in the post-transplant setting is variable with high rates of graft loss. Risk factors of recurrence include young age and Caucasian race. Data on outcome of recurrent FSGS from South Asia is scanty. We describe our experience of managing adults with recurrent FSGS with different therapies. Settings and Design: The study was conducted at the Department of Nephrology and Renal transplant surgery, Post Graduate Institute of Medical education and Research Institute, Chandigarh, India, and this was an observational study. Methods: We analyzed outcomes of patients with biopsy-proven recurrent FSGS over the last 5 years (2012–2017). Recurrence was defined as significant proteinuria (albuminuria ≥ 3+) and a demonstrable FSGS lesion on light microscopy and/or electron microscopy suggestive of diffuse foot process effacement. Results: Thirteen patients with 14 recurrences of FSGS post-renal transplant were identified. Mean age of the patients was 33.15 (±8.32) years. Median time to recurrence of FSGS was 45 days. Plasma exchange (PLEX) alone was used in two patients with 50% in remission. Combined PLEX and rituximab were used in six recurrences with remission in 83.3% of them. Five recurrences were treated with only angiotensin-converting enzyme inhibitor/angiotensin receptor blockade (ACEi/ARB) due to financial constraints. Of them, 4 (80%) achieved remission in proteinuria. One patient did not receive any therapy and expired in the 1st month of follow-up. Conclusion: The present series is one of the largest reports of recurrent FSGS from South Asia. Furthermore, the current report strengthens the use of ACEi/ARB in patients with recurrent FSGS.

Focal segmental glomerulosclerosis; why does it occur segmentally?

Podocyte loss is the fundamental basis of glomerulosclerosis. Focal segmental glomerulosclerosis (FSGS) is a progressive glomerular disease, and its glomerular features are a prototype of podocyte loss-driven glomerulosclerosis. The glomerular pathology of FSGS is characterized by a focal and segmental location of the sclerotic lesions in human FSGS; segmental sclerosis often shows simultaneous intra- and extra-capillary changes, including parietal cell migration, capillary collapse, hyaline deposition, and intra-capillary thrombi and occasional hypercellularity. This suggests that local cellular events, initiated by podocyte loss, are the basis of the segmental lesions in FSGS. Using podocyte-specific injury by toxin administration, a series of recent works has identified the cellular basis of the glomerular response to podocyte loss. This review discusses the molecular pathway of the local response to podocyte loss and its progression to sclerosis. Recent results suggest that segmental sclerosis is a physiological tissue response aimed at halting protein leakage from a disrupted filtration barrier.

The Clinical Course of Minimal Change Nephrotic Syndrome With Onset in Adulthood or Late Adolescence: A Case Series

Few studies have examined the treatment and outcome of adult-onset minimal change nephrotic syndrome (MCNS). We retrospectively studied 125 patients who had MCNS with onset in either adulthood or late adolescence. Presenting characteristics, duration of initial treatment and response to treatment, relapse patterns, complications, and long-term outcome were studied. Case series. Patients with new-onset nephrotic syndrome 16 years or older and a histologic diagnosis of MCNS in 1985 to 2011 were identified from pathology records of 10 participating centers. Partial and complete remission, treatment resistance, relapse, complications, renal survival. Corticosteroids were given as initial treatment in 105 (84%) patients. After 16 weeks of corticosteroid treatment, 92 (88%) of these patients had reached remission. Median time to remission was 4 (IQR, 2-7) weeks. 7 (6%) patients initially received cyclophosphamide with or without corticosteroids, and all attained remission after a median of 4 (IQR, 3-11) weeks. 13 (10%) patients reached remission without immunosuppressive treatment. One or more relapses were observed in 57 (54%) patients who received initial corticosteroid treatment. Second-line cyclophosphamide resulted in stable remission in 57% of patients with relapsing MCNS. Acute kidney injury was observed in 50 (40%) patients. Recovery of kidney function occurred almost without exception. Arterial or venous thrombosis occurred in 11 (9%) patients. At the last follow-up, 113 (90%) patients were in remission and had preserved kidney function. 3 patients with steroid-resistant MCNS progressed to end-stage renal disease, which was associated with focal segmental glomerulosclerosis lesions on repeat biopsy. Retrospective design, variable treatment protocols. The large majority of patients who had MCNS with onset in adulthood or late adolescence were treated with corticosteroids and reached remission, but many had relapses. Cyclophosphamide resulted in stable remission in many patients with relapses. Significant morbidity was observed due to acute kidney injury and other complications. Progression to end-stage renal disease occurred in a few patients and was explained by focal segmental glomerulosclerosis.

Steroid-resistant nephrotic syndrome caused by co-inheritance of mutations at NPHS1 and ADCK4 genes in two Chinese siblings.

Hereditary nephrotic syndrome often presents with steroid-resistance and onset within the first year of life. Mutations in genes highly expressed in podocytes have been found in two thirds of these patients, especially NPHS1 and NPHS2 among at least 29 genetic causes that have been discovered. We reported two siblings with steroid-resistant nephrotic syndrome caused by co-inheritance of mutations at NPHS1 (c.1339G>A, p.E447K) and ACDK4 (c.748G>C, p.D250H) genes. The siblings presented with steroid-resistant nephrotic syndrome and pathological lesions of focal segmental glomerulosclerosis (FSGS), while the elder sister also developed hypertension, renal failure and cardiac dysfunction.

Segmental arterial mediolysis with mesangial cell hyperplasia; A review with supplementary comments concerning its pathogenesis

Background: Segmental arterial mediolysis (SAM) a rare arteriopathy causing massive bleeding or ischemic symptoms, is suspected of representing a vascular disease of the peripheral sympathetic nervous system. It is initiated by the supra physiological release of norepinephrine from the efferent branches of the peripheral sympathetic nerves that innervate the large and medial sized muscular arteries targeted in SAM. Recognized stimuli for this response are iatrogenic sympathomimetic agonists and some B-2 agonists. However, these stimuli were not always apparent in published cases of SAM casting doubt on this hypothesis. Methods and findings: SAM, reported in kidneys of slaughtered pigs, was believed to represent a dysfunctional development in a fight and flight response. Additionally some stenotic renal arteries described in cases of pheochromocytomas reportedly were caused by arterial spasm and fibromuscular dysplasia changes found in the evolution of SAM. Varying degrees of mesangial cell hyperplasia accompanied SAM in swine, dog and scattered human cases of SAM. Segmental sclerosis of glomerular loops accompanied the mesangial cell hyperplasia in a few cases of SAM. The hyperplasia was not extensive so that its role in regulating blood flow and urine volume through glomerular capillaries was probably inconsequential. It represented a collateral lesion created by SAM’s norepinephrine driven pathogenesis. Conclusion: These findings provide indirect evidence that SAM additionally may be initiated by conditions causing the adrenal medulla to release supra physiologic levels of circulating norepinephrine. Supra physiologic release of norepinephrine from the peripheral sympathetic nerves also can cause mesangial hyperplasia that can be accompanied with segmental glomerular loop sclerosis-making it another precursor lesion of focal segmental glomerulosclerosis.

What are we missing in the clinical trials of focal segmental glomerulosclerosis?

Focal segmental glomerulosclerosis (FSGS) is a lesion and not a disease. This conundrum is the crux of controversies regarding interventions to alter its natural history. In the broadest sense, the lesion can be primary (idiopathic), or secondary to a process originating outside the kidneys or to a genetic mutation. The organ-based target is the podocyte, and the mechanisms responsible for the podocytopathy are numerous and diverse. Recurrence of primary FSGS in renal allografts provides the best evidence for the existence of a circulating factor or factors, the nature of which remains uncertain. The separation of primary from secondary FSGS clinically and pathologically is challenging, but full-blown nephrotic syndrome and diffuse (universal) foot process effacement are strong signals for a primary form of FSGS. It is imperative that clinical trials designed to investigate therapeutic strategies for patients with a lesion of FSGS pay careful attention to the separation of primary from secondary forms of FSGS. This critical review provides a rationale and a process for helping to ensure that this is accomplished, such that clinical trials provide useful information and treatment responsiveness applicable to the primary forms of FSGS.

Evidence from the Oxford Classification cohort supports the clinical value of subclassification of focal segmental glomerulosclerosis in IgA nephropathy

Focal segmental glomerulosclerosis (FSGS) is a common finding in IgA nephropathy (IgAN). Here we assessed FSGS lesions in the Oxford Classification patient cohort and correlated histology with clinical presentation and outcome to determine whether subclassification of the S score in IgAN is reproducible and of clinical value. Our subclassification of lesions in 137 individuals with segmental glomerulosclerosis or adhesion (S1) identified 38% with podocyte hypertrophy, 10% with hyalinosis, 9% with resorption droplets within podocytes, 7% with tip lesions, 3% with perihilar sclerosis, and 2% with endocapillary foam cells. Reproducibility was good or excellent for tip lesions, hyalinosis, and perihilar sclerosis; moderate for podocyte hypertrophy; and poor for resorption droplets, adhesion only, and endocapillary foam cells. Podocyte hypertrophy and tip lesions were strongly associated with greater initial proteinuria. During follow-up of patients without immunosuppression, those with these features had more rapid renal function decline and worse survival from a combined event compared to S1 patients without such features and those without FSGS. Also in individuals with podocyte hypertrophy or tip lesions, immunosuppressive therapy was associated with better renal survival. In IgA nephropathy, the presence of podocyte hypertrophy or tip lesions, markers of podocyte injury, were reproducible. These features are strongly associated with proteinuria and, in untreated patients, carry a worse prognosis. Thus, our findings support reporting podocytopathic features alongside the S score of the Oxford Classification.

Collapsing glomerulopathy is common in the setting of thrombotic microangiopathy of the native kidney

Thrombotic microangiopathy (TMA) is a poorly recognized cause of collapsing glomerulopathy. The frequency and significance of collapsing glomerulopathy associated with renal TMA have not been specifically studied in native kidney biopsy specimens. Here we retrospectively documented clinicopathologic features of 53 patients withhistologically proven TMA in the native kidney, with special emphasis on changes due to focal segmental glomerulosclerosis (FSGS). Histological TMA was related tohypertensive nephropathy in 21 patients, genetic complement abnormalities in 9, drugs in 7, and to other causes in 16 patients. Almost half (26 patients) presented with arteriolar, 6 with glomerular, and 21 with mixed TMA. Using the Columbia classification system for the 53 patients with histological TMA, 33 had concurrent FSGS lesions with collapsing glomerulopathy the dominant variant in 19 patients (58% of the FSGS cases), not otherwise specified in 9 patients, cellular in 3, and perihilar or tip lesions in 1 patient each. The presence of FSGS was associated with a poor renal prognosis, with no prognostic difference between collapsing glomerulopathy and other FSGS variants. Thus, collapsing glomerulopathy is frequently found in native kidney biopsies with TMA, suggesting that endothelial injury may play an important role in the pathophysiology of FSGS.

Patients With Combined Membranous Nephropathy and Focal Segmental Glomerulosclerosis Have Comparable Clinical and Autoantibody Profiles With Primary Membranous Nephropathy: A Retrospective Observational Study.

Patients with combined membranous nephropathy (MN) and focal segmental glomerulosclerosis (FSGS) have been reported with different clinical significance. Investigations on the possible mechanisms of the combined glomerular lesions are necessary but scarce. Twenty patients with both MN and FSGS lesions were enrolled in the study. Sixty-five patients with primary MN and 56 patients with primary FSGS were used as disease controls. Clinical data on renal biopsy and during follow-up were collected. Circulating anti-phospholipase A2 receptor (PLA2R) antibody, glomerular PLA2R expression, IgG4 deposition, and soluble urokinase receptor (suPAR) levels were detected. We found that patients with combined lesions presented with older age, less proteinuria, higher albumin, and better renal function on biopsy. These were comparable to the patients with primary MN, but differed from the patients with primary FSGS. Patients with combined lesions showed higher stages of MN, no cellular variant on FSGS classification, and more common (100.0%) tubulointerstitial injury than both primary MN and primary FSGS patients. In the patients with combined lesions, 80.0% had circulating anti-PLA2R antibody and 68.4% had IgG4 predominant deposition in glomeruli, which were comparable to primary MN. The patients with combined lesions had significantly lower urinary suPAR concentrations, than the primary FSGS patients (315.6 ± 151.0 vs 752.1 ± 633.9 pg/μmol; P = 0.002), but similar to the primary MN patients (267.9 ± 147.5 pg/μmol). We conclude that patients with combined MN and FSGS may share the same underlying pathogenesis with primary MN. The FSGS lesion might be secondary to primary MN.

Contribution of the TTC21B gene to glomerular and cystic kidney diseases.

The TTC21B gene was initially described as causative of nephronophthisis (NPHP). Recently, the homozygous TTC21B p.P209L mutation has been identified in families with focal segmental glomerulosclerosis (FSGS) and tubulointerstitial lesions. Heterozygous TTC21B variants have been proposed as genetic modifiers in ciliopathies. We aimed to study the causative and modifying role of the TTC21B gene in glomerular and cystic kidney diseases. Mutation analysis of the TTC21B gene was performed by massive parallel sequencing. We studied the causative role of the TTC21B gene in 17 patients with primary diagnosis of FSGS or NPHP and its modifying role in 184 patients with inherited glomerular or cystic kidney diseases. Disease-causing TTC21B mutations were identified in three families presenting nephrotic proteinuria with FSGS and tubulointerstitial lesions in which some family members presented hypertension and myopia. Two families carried the homozygous p.P209L and the third was compound heterozygous for the p.P209L and a novel p.H426D mutation. Rare heterozygous TTC21B variants predicted to be pathogenic were found in five patients. These TTC21B variants were significantly more frequent in renal patients compared with controls (P = 0.0349). Two patients with a heterozygous deleterious TTC21B variant in addition to the disease-causing mutation presented a more severe phenotype than expected. Our results confirm the causal role of the homozygous p.P209L TTC21B mutation in two new families with FSGS and tubulointerstitial disease. We identified a novel TTC21B mutation demonstrating that p.P209L is not the unique causative mutation of this nephropathy. Thus, TTC21B mutation analysis should be considered for the genetic diagnosis of families with FSGS and tubulointerstitial lesions. Finally, we provide evidence that heterozygous deleterious TTC21B variants may act as genetic modifiers of the severity of glomerular and cystic kidney diseases.

Soluble Urokinase Receptor Levels Are Correlated with Focal Segmental Glomerulosclerosis Lesions in IgA Nephropathy: A Cohort Study from China.

BackgroundSoluble urokinase receptor (suPAR) may be involved in the pathological mechanisms of focal segmental glomerulosclerosis (FSGS) changes. However, it remains unclear whether suPAR is correlated with the FSGS-like lesions in IgA nephropathy (IgAN).MethodsWe measured the plasma suPAR levels in 138 patients with IgAN, and then their clinical and pathological relationships were analyzed.ResultsWe found that the plasma suPAR levels were significantly correlated with age and renal function by both univariate and multivariate analysis in our IgAN patient cohort. Female had higher plasma suPAR levels and no significant correlation was observed between plasma suPAR levels and 24-h urine protein and highly sensitive C-reaction protein with multivariate analysis. In our cohort, sixty of these IgAN patients could be diagnosed with a type of FSGS lesions. The plasma suPAR levels were higher in the IgAN patients with FSGS lesions than in the IgAN patients without FSGS lesions by univariate (P < 0.0001) and multivariate (P < 0.001) analysis adjusting for other predictor variables, which might be helpful to differentiate the pathological changes with and without FSGS lesions. And the optimal cutoff value was 1806 pg/ml in this study. The plasma suPAR concentrations were also associated with the degree of tubular atrophy/interstitial fibrosis in both univariate and multivariate analysis. In multivariate analysis, the plasma suPAR levels were correlated with the percentage of crescents, not global sclerosis and arterial lesions.ConclusionsOur study suggested that the plasma suPAR levels were associated with age, gender, renal function, the degree of tubular atrophy/interstitial fibrosis and the percentage of crescent formation. The plasma suPAR might be a potential predictor for the presence of FSGS pathological lesions in Chinese patients with IgAN.

Glomerular endothelial cell injury and focal segmental glomerulosclerosis lesion in idiopathic membranous nephropathy.

BackgroundFocal segmental glomerulosclerosis (FSGS) lesions have often been discussed as a negative predictor in idopathic membranous nephropathy (MN). The mechanism of the development of FSGS lesion in MN is still uncertain.MethodsFrom 250 cases of MN, 26 cases contained FSGS lesion. We compared the clinicopathological characteristics between MN cases with FSGS lesion [MN-FSGS(+)] and MN without FSGS lesion [MN-FSGS(−)], matched for gender, age, stage of MN.ResultsThe glomerular filtration rate (eGFR) was significantly lower in MN-FSGS(+) cases compared to MN-FSGS(−), although nephrotic syndrome, hematuria, and systolic blood pressure levels were not significantly different between the two groups. Pathologically, glomeruli in MN-FSGS(+) cases showed narrowing and loss of glomerular capillaries with separating from GBM or disappearance of CD34+ endothelial cells, and accumulation of extracellular matrix (ECM) in capillary walls, indicating the development of glomerular capillary injury. These findings of endothelial injury were seen even in MN-FSGS(−) cases, but they were more prominent in MN-FSGS(+) than MN-FSGS(−) by computer assessed morphometric analysis. In MN-FSGS(+) cases, 44 out of 534 glomeruli (8.2%) contained FSGS lesions (n = 31, NOS lesion; n = 13, perihilar lesion). Significant thickness of GBM with ECM accumulation was evident in MN-FSGS(+) cases. Podocyte injury with effacement of foot processes was also noted, but the expression of VEGF on podocytes was not different between the two groups, which suggests that the significant thickness of capillary walls may influence the function of VEGF from podocyte resulting in the glomerular capillary injury that contribute to the development of FSGS lesion in MN.ConclusionGlomerular capillary injury was seen in all MN cases. Furthermore, the prominent injuries of glomerular capillaries may be associated with the deterioration of eGFR and the formation of FSGS lesions in MN.

Nephrosclerosis: update on a centenarian.

Nephrosclerosis is an umbrella term defining changes in all compartments of the kidney, changes caused by hypertension and by ageing. Among other lesions, arteriolosclerosis and arteriolohyalinosis play a major role in inducing glomerular ischaemic shrinking and sclerosis along with glomerulomegaly and focal-segmental glomerulosclerosis (FSGS). These lesions are accompanied by tubulointerstitial inflammation and fibrosis that predict the decline of renal function. Nephrosclerosis is a major cause of renal insufficiency in blacks of African descent with a severe, early form of renovasculopathy and a rapid course to renal failure with predominant lesions of FSGS. It seems that in blacks, separate genetic factors independently lead to vascular lesions and to hypertension with a different time-scale of their onset and of their progression, nephroangiosclerosis preceding the onset of hypertension. Conversely, true and histologically identified nephrosclerosis in white Europeans rarely leads to end-stage renal disease in the absence of malignant hypertension. Various animal models demonstrate that renal vascular lesions may exist in the absence of hypertension. These experiments also point to a major role of angiotensin II and of a number of independent and overlapping cellular and molecular pathways in a cascade of inflammatory events that end in renal fibrosis. Two pathophysiologic mechanisms are at work in inducing glomerular lesions and tubulointerstitial fibrosis: a loss of autoregulation of the renal blood flow caused by an arteriolohyalinosis of the glomerular afferent arteriole and ischaemia that fosters the generation of hypoxia inducible-fibrosing factors. Not all antihypertensive drugs equally protect the kidney from nephrosclerosis. Angiotensin II antagonists exert a favourable effect on hyperfiltration. Conversely, dihydropyridine calcium-channel blockers and vasodilators do not withstand the derangement of renal autoregulation.

Older adults with kidney disease-epidemiology and clinicopathologic correlations: a remarkable single-center survey.

The occupants of our globe, on average, are steadily growing older consequent to lower birth rates and longer life expectancy. While the actual tempo of this global aging process varies from region to region, due to the impact of epidemics of disease (e.g. AIDS), reduced infant mortality, hygiene, malnutrition and violence, there is little doubt that the aging of society as a whole will have profound effects on healthcare systems and clinical practice. The discipline of nephrology is not exempt from these events, indeed it has already been and is continuing to be impacted by the aging of society, particularly in income-rich countries. The prevalence of acute and chronic kidney diseases is expected to increase significantly in the next few decades, largely in the older adult population. The specific causes or nature of these diseases are quite heterogeneous and often difficult to categorize on clinical grounds alone. Renal biopsy has been and continues to be a powerful tool to add precision to diagnosis. Many surveys of renal pathology, as it exists in a given population and how it changes over time, have been published, mostly collected in regional renal biopsy registries, but relatively few have focused mainly on the older and elder adult, conventionally defined as having attained the age of 65 years or more [1–3]. The survey by Jin et al. [4] from Jinling Hospital and the Nanjing University School of Medicine in Nanjing, China, published in this issue of Nephrology Dialysis Transplantation is a good example of this kind of morphological/epidemiological investigation. Remarkably, over 29 000 renal biopsies were performed in adults (age 18–81 years) at a single center over a 10-year period, of which ∼850 (2.9%) were performed in older or elder adults. These older subjects had a variety of clinical presentations and indications for performance of renal biopsy, but the actual rate of renal biopsy performance is not precisely known, but a rate of ∼2900 renal biopsies per year would be high by any standard. Undoubtedly, selection pressures such as the referral nature of and the cachement areas sub-served by the center play large roles in the epidemiological observations reported. Not surprisingly, proteinuria (including nephrotic syndrome; NS) with or without hematuria or acute kidney injury (AKI) was commonly the reason for performance of renal biopsy—observed in almost two-thirds of the subjects. Glomerular or vasculitic diseases predominated— slightly over 70% of all biopsies showed lesion of membranous nephropathy (MN), IgA nephropathy (IgA N), minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), small vessel vasculitis (SVV), diabetic nephropathy (DN) or amyloidosis (AM). DN is likely under-represented (at 9.75%) in this series, compared with its actual prevalence in the population as a whole—even though in this series renal biopsies were performed in diabetic subjects with renal involvement and without biopsy ‘contraindications’. It is not clear if the extent of ‘atypical’ characteristics at presentation influenced the decision to perform renal biopsy in diabetic subjects. Among elderly subjects presenting with NS, four lesions (MN, AM, MCD and IgA N) accounted for 80% of those observed. The distribution of these lesions in the elderly is strikingly different from that observed in the ‘control’ younger population. It is also noteworthy that the most common lesion in the very old (>75 years) was MN. Of great interest is the low prevalence of lesions of FSGS in both the young and old subjects alike (5.8 and 4.7%, respectively). Among older patients presenting with NS (with or without AKI) on only 28/851 (3.3%) demonstrated FSGS on renal biopsy. The frequency of FSGS in this and other studies in Asians is much different that seen in non-Asian populations, especially in subjects of African ancestry [5]. This difference is likely explained on a genetic basis (lack of APOL1 risk alleles in Asians), but environmental influences cannot be excluded [6]. The relative rarity of ‘primary’ or ‘idiopathic’membrano-proliferative glomerulonephritis (MPGN) in the elderly is notable (only 7 in 851 cases; 0.82%). These data support the contemporary view that IN F O C U S

Lack of renoprotective effect of chronic intravenous angiotensin-(1-7) or angiotensin-(2-10) in a rat model of focal segmental glomerulosclerosis.

Unopposed angiotensin (Ang) II-mediated cellular effects may lead to progressive glomerulosclerosis. While Ang-II can be locally generated in the kidneys, we previously showed that glomerular podocytes primarily convert Ang-I, the precursor of Ang-II, to Ang-(1-7) and Ang-(2-10), peptides that have been independently implicated in biological actions opposing those of Ang-II. Therefore, we hypothesized that Ang-(1-7) and Ang-(2-10) could be renoprotective in the fawn-hooded hypertensive rat, a model of focal segmental glomerulosclerosis. We evaluated the ability of 8–12 week-long intravenous administration of either Ang-(1-7) or Ang-(2-10) (100–400 ng/kg/min) to reduce glomerular injury in uni-nephrectomized fawn-hooded hypertensive rats, early or late in the disease. Vehicle-treated rats developed hypertension and lesions of focal segmental glomerulosclerosis. No reduction in glomerular damage was observed, as measured by either 24-hour urinary protein excretion or histological examination of glomerulosclerosis, upon Ang-(1-7) or Ang-(2-10) administration, regardless of peptide dose or disease stage. On the contrary, when given at 400 ng/kg/min, both peptides induced a further increase in systolic blood pressure. Content of Ang peptides was measured by parallel reaction monitoring in kidneys harvested at sacrifice. Exogenous administration of Ang-(1-7) and Ang-(2-10) did not lead to a significant increase in their corresponding intrarenal levels. However, the relative abundance of Ang-(1-7) with respect to Ang-II was increased in kidney homogenates of Ang-(1-7)-treated rats. We conclude that chronic intravenous administration of Ang-(1-7) or Ang-(2-10) does not ameliorate glomerular damage in a rat model of focal segmental glomerulosclerosis and may induce a further rise in blood pressure, potentially aggravating glomerular injury.

Detection of Activated Parietal Epithelial Cells on the Glomerular Tuft Distinguishes Early Focal Segmental Glomerulosclerosis from Minimal Change Disease

In rodents, parietal epithelial cells (PECs) migrating onto the glomerular tuft participate in the formation of focal segmental glomerulosclerosis (FSGS) lesions. We investigated whether immunohistologic detection of PEC markers in the initial biopsies of human patients with first manifestation of idiopathic nephrotic syndrome with no immune complexes can improve the sensitivity to detect sclerotic lesions compared with standard methods. Ninety-five renal biopsies were stained for claudin-1 (PEC marker), CD44 (activated PECs), and LKIV69 (PEC matrix); 38 had been diagnosed as early primary FSGS and 57 as minimal change disease. PEC markers were detected on the tuft in 87% of the biopsies of patients diagnosed as primary FSGS. PEC markers were detected in FSGS lesions from the earliest stages of disease. In minimal change disease, no PEC activation was observed by immunohistology. However, in 25% of biopsies originally diagnosed as minimal change disease the presence of small lesions indicative of a sclerosing process were detected, which were undetectable on standard periodic acid-Schiff staining, even though only a single histologic section for each PEC marker was evaluated. Staining for LKIV69 detected lesions with the highest sensitivity. Two novel PEC markers A-kinase anchor protein 12 and annexin A3 exhibited similar sensitivity. In summary, detection of PECs on the glomerular tuft by immunostaining improves the differentiation between minimal change disease and primary FSGS and may serve to guide clinical decision making.

Focal and segmental glomerulosclerosis: clinical and kidney biopsy correlations.

BackgroundPrimary focal segmental glomerulosclerosis (FSGS) is a common glomerular disease in adults and ranks among the top causes of a primary glomerular disease causing end-stage renal disease (ESRD). Primary FSGS is, however, a diagnosis of exclusion and distinction between primary versus secondary FSGS is not always obvious, resulting in a number of patients with secondary FSGS undergoing unnecessary immunosuppressive therapy.MethodsWe reviewed the Mayo Clinic Renal Pathology Database for patients with a diagnosis of FSGS on native renal biopsy and divided the patients into nephrotic syndrome-associated (NS-associated) and non-nephrotic syndrome-associated (NNS-associated) FSGS as a first approximation followed by dividing the lesion according to the degree of foot process effacement (FPE) on electron microscopy (EM) examination.ResultsA total of 41 patients with FSGS with complete evaluation were identified. Of these, 18 were classified as having NS and 23 were classified as having NNS. Baseline characteristics (age, gender, body mass index, serum creatinine and hematuria) were not different between the groups. All of the patients with NS showed diffuse FPE ranging from 80 to 100% (mean 96%). On the other hand, of the 23 patients in the NNS group, 22 had segmental FPE and showed patchy effacement, with all cases showing 20–60% FPE (mean of 48%).ConclusionAdult patients presenting with NS, an FSGS lesion on LM, extensive FPE (≥80%) on EM examination and no risk factors associated with secondary FSGS are likely to have primary FSGS. Conversely, the absence of NS in a patient with segmental FPE on EM strongly suggests a secondary FSGS. Dividing FSGS into the presence or absence of NS together with the degree of FPE on EM examination is more helpful as it provides a more practical way to separate patients into cases of primary versus secondary FSGS.