Proteinuria induces tubular cell turnover: A potential mechanism for tubular atrophy

Thomas, Mark; Brunskill, Nigel J.; Harris, Kevin; Bailey, E.; Pringle, J. H.; Furness, Peter; Walls, John

doi:10.1046/j.1523-1755.1999.055003890.x

Cited by 125 publications

(96 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Apoptosis in early FSGS was evident in both proximal and distal nephron segments. Although proximal tubule cells have been shown to respond to albumin overload by programmed cell death both in vitro (12) and in animal models (9,11), our surprising findings necessitated confirmation of albumin-induced apoptosis in a cell culture model of the distal tubule.…”

Section: Discussionmentioning

confidence: 84%

“…The rationale for undertaking this study was that (1) there is a well-documented correlation between tubular damage and proteinuria in patients with FSGS (19 -23), and (2) ongoing proteinuria has been associated with tubular cell apoptosis both in vitro (12) and in animal models (9,11). Apoptosis, characterized by cell shrinkage, nuclear condensation, and internucleosomal DNA fragmentation, has recently been documented in an increasing array of renal disorders, and renal tubule cell apoptosis is emerging as a possible common pathway in response to a variety of insults that are applied at an intensity below the threshold for necrotic cell death (30,31).…”

Section: Discussionmentioning

confidence: 99%

“…The rationale for this line of investigation was derived from findings in animal studies that progressive proteinuria is associated with tubule cell apoptosis (9,11). In biopsy samples from patients with idiopathic FSGS, apoptosis was correlated with cell proliferation and expression of proapoptotic molecules.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Induction of Renal Tubular Cell Apoptosis in Focal Segmental Glomerulosclerosis

Erkan¹,

Garcia²,

Patterson³

et al. 2005

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

The hypothesis that apoptosis represents a proximate mechanism by which tubule cells are damaged in FSGS was tested. Thirty kidney biopsy specimens from children with idiopathic early FSGS were studied retrospectively. Unexpected, apoptosis was evident in both proximal and distal tubule cells. There was a significant correlation between the degree of proteinuria and the number of apoptotic cells. Fas protein was detected predominantly in the tubule cells that underwent apoptosis. When compared with patients with other chronic proteinuric states, those with FSGS displayed a proliferation/ apoptosis ratio in favor of proliferation in the glomerulus but dramatically in favor of apoptosis in the tubules. When both proteinuria and apoptosis were included in a stepwise logistic regression procedure, only apoptosis was found to predict independently the development of ESRD. Prolonged incubation of cultured Madin-Darby canine kidney (distal/collecting) cells with albumin also resulted in a dose-and duration-dependent induction of apoptosis and activation of the Fas pathway, lending support to the novel finding of distal tubule cell apoptosis in patients with FSGS. The results indicate that an elevated tubule cell apoptosis rate at the time of initial biopsy represents an independent predictor of progression to ESRD in patients with early FSGS.

show abstract

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Induction of Renal Tubular Cell Apoptosis in Focal Segmental Glomerulosclerosis

Erkan¹,

Garcia²,

Patterson³

et al. 2005

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…Indeed, the majority of the renal biopsies that were done on our patients at the time of ARF showed features that were consistent with acute tubular injury with interstitial inflammation and edema. It is possible that proteinuria itself may contribute to the observed tubular and interstitial damage, because there is increasing evidence to suggest that exposure of proximal tubular cells to albumin overload can lead to endoplasmic reticulum stress (32), induction of apoptosis (33), tubular chemokine and cytokine expression, and activation of the complement cascade resulting in inflammation (34 -36) and interstitial fibrosis (37). Nevertheless, it is unclear why patients with MCD might be more sensitive to these effects compared with those with other forms of the NS or why it occurs more frequently in adults than in children.…”

Section: Discussionmentioning

confidence: 99%

Adult Minimal-Change Disease

Waldman

Crew²,

Valeri³

et al. 2007

Clinical Journal of the American Society of Nephrology

351

439

View full text Add to dashboard Cite

Minimal-change disease (MCD) counts for 10 to 15% of cases of primary nephrotic syndrome in adults. Few series have examined this disease in adults. A retrospective review was performed of 95 adults who had MCD and were seen at a single referral center. Examined were presenting features, response to daily versus alternate-day steroids, response to second-line agents, relapse patterns, complications of the disease and therapy, presence of acute renal failure (ARF), and outcome data. Sixty-five patients received daily and 23 received alternate-day steroids initially. There were no differences in remissions, time to remission, relapse rate, or time to relapse between daily-and alternate-day-treated patients. More than one quarter of patients were steroid resistant. At least one relapse occurred in 73% of patients; 28% were frequently relapsing. A significant proportion of frequently relapsing patients became steroid dependent. Second-line agents were used for steroid dependence, steroid resistance, or frequent relapses. No single agent proved superior. There were more remissions with second-line agents in steroid-dependent patients compared with steroid-resistant patients, and remissions were more likely to be complete in steroid-dependent patients. ARF occurred in 24 patients; they tended to be older and hypertensive with lower serum albumin and more proteinuria than those without ARF. At follow up, patients with an episode of ARF had higher serum creatinine than those without ARF. Four patients progressed to ESRD. These patients were less likely to have responded to steroids and more likely to have FSGS on repeat renal biopsy. In this referral MCD population, response to daily and alternate-day steroids is similar. Second-line agents give greater response in patients who are steroid dependent. ARF occurs in a significant number of adult MCD patients and may leave residual renal dysfunction. Few patients progress to ESRD. M inimal-change disease (MCD) is the most common cause of the nephrotic syndrome (NS) in children. It accounts for 70 to 90% of the NS in children who are younger than 10 yr and 50% in older children. It is also an important cause of primary NS in adults of all ages, accounting for 10 to 15% of cases (1,2). Although there are many data regarding the course, response to treatment, and outcomes in pediatric patients, only a few series have examined these issues in adults (3-8). Relatively less is known about the presentation of MCD in adult patients, response to agents other than steroids, the risk for acute renal failure (ARF), and the long-term outcome. Moreover, most series of adults with MCD have not been in US populations, and it is unknown whether the features and course of the disease are the same in differing parts of the world.We therefore performed a retrospective review of 95 patients who had primary adult-onset MCD and were treated at a single tertiary care center in the past 15 yr. Many of the patients were referred by outside nephrologists for opinions regarding treatment. This review...

show abstract

“…On the basis of our observations, we suggest the following tentative scenario: whether proteinuria causes podocyte damage, or vice versa, or both are true, proteinuria is associated with tubular cell damage (35). For example, increased apoptosis of tubular epithelial cells occurs in proteinuric rats (36) and angiotensinconverting enzyme inhibitor treatment lowers proteinuria and effectively prevents glomerulotubular disconnection, possibly by reducing proteinuria, in Heymann's nephritis in rats (37). We suspect that the cells lining the proximal portion of the proximal tubule may be particularly susceptible to injury associated with proteinuria.…”

Section: Discussionmentioning

confidence: 99%

Atubular Glomeruli and Glomerulotubular Junction Abnormalities in Diabetic Nephropathy

Najafian

Kim

Crosson

et al. 2003

Journal of the American Society of Nephrology

107

View full text Add to dashboard Cite

Abstract. Atubular glomeruli (AG) have been described in several renal disorders. However, little attention has been paid to AG in diabetic nephropathy (DN). Preliminary studies suggested that tip lesions were frequently present in type 1 diabetic (D) patients with proteinuria. The aim of this study was to determine the frequency of AG and their possible relationship with tip lesions in DN. Renal biopsies from eight proteinuric type 1 D patients with normal to moderately reduced GFR (76 Ϯ 26 ml/min per 1.73 m 2 ) and eight normal subjects were studied by light (LM) and electron microscopy (EM). Glomerular volume, volume of the glomerular corpuscle, which is tuft, and the fractional volumes of proximal, distal, and atrophic tubules per cortex were estimated using appropriate stereologic methods. Glomerulotubular junctions were examined on serial sections and classified into glomeruli attached to: normal tubules (NT); short atrophic tubules (SAT); long atrophic tubules (LAT); atrophic tubules with no observable glomerular opening (ATNO); and atubular glomeruli (AG). EM studies showed typical diabetic changes in biopsies, including increased GBM width (P Ͻ 0.00001) and mesangial fractional volume (P Ͻ 0.0001) and decreased filtration surface density (P Ͻ 0.01) compared with normal subjects. Seventeen percent of glomeruli in the D patients were atubular, and 51% were attached to atrophic tubules. Tip lesions were present in all SAT, 64% of LAT, 82% of ATNO, and only 9% of NT and were never observed in normal subjects. The relative volume of AG was smaller than glomeruli in other categories (P Ͻ 0.05). Fractional volume of proximal (P Ͻ 0.01) and distal (P Ͻ0.01) tubules per cortex were decreased, while fractional volume of cortical interstitium (P Ͻ0.00001) and atrophic tubules (P Ͻ0.01) were increased in D patients. Fractional volume of atrophic tubules, %AG, and percent of glomeruli with tip lesion explained 94% of the GFR variability in diabetic patients (P Ͻ0.05). Thus, AG and glomerulotubular junction abnormalities may be important in the development and progression of DN.Atubular glomeruli (AG) have been described in several renal disorders (1,2). AG, by definition, have open circulation but no observable tubular attachment and are thus presumably nonfunctioning (3). This phenomenon, first described by Oliver (4) as a finding in chronic Bright disease in humans, had been confirmed in experimental chronic pyelonephritis (5,6). Marcussen et al. (7-13) studied atubular glomeruli in cisplatin-and lithium-induced nephropathies in rats and chronic pyelonephritis and renal artery stenosis in humans. More recently, this phenomenon was documented in Adriamycin-induced nephrosis and the remnant kidney model in rats (14,15). An important contribution of AG to renal function impairment has been hypothesized (2,15). However, despite that 44% of all new cases of end-stage renal disease in the United States are due to diabetes, little attention has been paid to the possible role of this entity in diabetic nephropathy (1,2). ...

show abstract

Proteinuria induces tubular cell turnover: A potential mechanism for tubular atrophy

Abstract: Protein-overload proteinuria in rats induces tubular cell apoptosis. This effect is only partially balanced by proliferation and potentially provides a direct mechanism whereby heavy proteinuria can induce tubular atrophy and progressive renal failure.

Cited by 125 publications

References 17 publications

Induction of Renal Tubular Cell Apoptosis in Focal Segmental Glomerulosclerosis

Induction of Renal Tubular Cell Apoptosis in Focal Segmental Glomerulosclerosis

Adult Minimal-Change Disease

Atubular Glomeruli and Glomerulotubular Junction Abnormalities in Diabetic Nephropathy

Contact Info

Product

Resources

About