Is glomerulosclerosis a consequence of altered glomerular permeability to macromolecules?

Remuzzi, Giuseppe; Bertani, Tullio

doi:10.1038/ki.1990.217

Cited by 371 publications

(180 citation statements)

References 79 publications

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“…The potential mechanisms by which proteinuria may itself promote damage to mesangial, epithelial and tubular cell function has been critically reviewed [34]. Our finding of a correlation between albuminuria and rate of progression in kidney function is compatible with the concept that albuminuria per se may be harmful to the kidney.…”

Section: Discussionsupporting

confidence: 70%

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Reduction in albuminuria predicts a beneficial effect on diminishing the progression of human diabetic nephropathy during antihypertensive treatment

et al. 1994

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Summmr/ Diabetic nephropathy is the main cause of increased mortality and morbidity in IDDM patients. The effect of antihypertensive treatment on the progression of the nephropathy is highly variable. The aim of this study was to evaluate putative predictors of the progression in diabetic nephropathy during long-term antihypertensive treatment. Eighteen hypertensive IDDM patients with diabetic nephropathy, who had not been treated previously, were followed during 3 years of treatment with captopril and frusemide or bendrofluazide. Glomerular filtration rate, arterial blood pressure, albuminuria and adjusted albuminuria were used as putative predictors of rate of decline in glomerular filtration. Fall rate in glomerular filtration rate was 4.6 (4.0) ml. min-1 .year 1 (mean (SD)) during treatment. Relative change in albuminuria (ratio of first year of treatment/baseline) and albuminuria during first year of treatment were significantly correlated to fall rate in glomerular filtration rate during 3 years of treatment (r --0.73, p < 0.001) and (r = 0.60, p < 0.01), respectively. Arterial blood pressure and glomerular filtration rate measured at baseline, during first year of treatment or relative changes in these variables did not correlate with fall rate in glomerular filtration rate during 3 years of treatment. Haemoglobin AI:, serum-cholesterol, protein intake and sodium excretion remained unchanged during treatment, and were not correlated with loss of kidney function. Reduction in albuminuria during captopril treatment predicts an attenuated rate of decline in glomerular filtration rate in early diabetic nephropathy (glomerular filtration rate > 70 ml. rain -1-1.73 m-Z). The finding suggests a clinical application in monitoring the efficacy of antihypertensive treatment in early diabetic nephropathy. [Diabetologia (1994) 37: 511-516] Key words Diabetic nephropathy, albuminuria, antihypertensive treatment, glomerular filtration rate.Diabetic nephropathy develops in 30-40 % of IDDM patients [1,2], and nephropathy is the main cause of increased morbidity and mortality in these patients [1]. Diabetic nephropathy is a clinical syndrome characterized by persistent albuminuria, a relentless decline in glomerular filtration rate, and raised arterial blood pressure [3]. Human and animal studies have demonstrated a correlation between elevation in arterial Received: 21 September 1993 and in revised form: 3 December 1993Corresponding author: Dr. R Rossing~ Steno Diabetes Center, Niels Steensens Vej 2, DK-2820 Gentofte, DenmarkAbbreviations: IDDM, Insulin-dependent diabetes mellitus blood pressure and development and progression of diabetic glomerulopathy [4][5][6][7][8][9][10]. Several studies [11][12][13][14][15][16][17] have demonstrated that the rate of decline in glomerular filtration rate can be reduced by antihypertensive treatment. However the beneficial effect of antihypertensive treatment on the progression of the diabetic nephropathy is highly variable. From a clinical point of view, identification of predic...

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Section: Discussionsupporting

confidence: 70%

“…Remuzzi et al [34] has suggested that proteinuria is not simply a marker of the extent of glomerular damage, but that proteinuria per se may contribute to the kidney lesions. The potential mechanisms by which proteinuria may itself promote damage to mesangial, epithelial and tubular cell function has been critically reviewed [34].…”

Section: Discussionmentioning

confidence: 99%

Reduction in albuminuria predicts a beneficial effect on diminishing the progression of human diabetic nephropathy during antihypertensive treatment

et al. 1994

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“…36 Taken together, these results support the concept that proteinuria represents not only a marker of progression but also a cause for glomerulosclerosis; they also explain why reducing proteinuria through proteinuria-lowering drugs delays progression of CKD. 37 More important, the results of this study provide a biologic rationale for the clinical use of pharmacologic modulators to promote regression of glomerular disease.…”

Section: Discussionmentioning

confidence: 99%

Proteinuria Impairs Podocyte Regeneration by Sequestering Retinoic Acid

Peired¹,

Angelotti²,

Ronconi³

et al. 2013

Journal of the American Society of Nephrology

121

110

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In CKD, the risk of kidney failure and death depends on the severity of proteinuria, which correlates with the extent of podocyte loss and glomerular scarring. We investigated whether proteinuria contributes directly to progressive glomerulosclerosis through the suppression of podocyte regeneration and found that individual components of proteinuria exert distinct effects on renal progenitor survival and differentiation toward a podocyte lineage. In particular, albumin prevented podocyte differentiation from human renal progenitors in vitro by sequestering retinoic acid, thus impairing retinoic acid response element (RARE)-mediated transcription of podocyte-specific genes. In mice with Adriamycin nephropathy, a model of human FSGS, blocking endogenous retinoic acid synthesis increased proteinuria and exacerbated glomerulosclerosis. This effect was related to a reduction in podocyte number, as validated through genetic podocyte labeling in NPHS2.Cre;mT/mG transgenic mice. In RARE-lacZ transgenic mice, albuminuria reduced retinoic acid bioavailability and impaired RARE activation in renal progenitors, inhibiting their differentiation into podocytes. Treatment with retinoic acid restored RARE activity and induced the expression of podocyte markers in renal progenitors, decreasing proteinuria and increasing podocyte number, as demonstrated in serial biopsy specimens. These results suggest that albumin loss through the damaged filtration barrier impairs podocyte regeneration by sequestering retinoic acid and promotes the generation of FSGS lesions. Our findings may explain why reducing proteinuria delays CKD progression and provide a biologic rationale for the clinical use of pharmacologic modulators to induce regression of glomerular diseases.

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“…16 Thus, impaired glomerular sieving appears to initiate and perpetuate parenchymal damage, and ultimately renal scarring and insufficiency, through a common pathway that, independent of capillary pressure, results in increased protein content of the glomerular filtrate with protein overload to glomerular and tubular epithelial cells (Figure 1). 17,18 Indeed, podocytes exposed to excessive protein load release TGF-b, ultimately inducing differentiation of mesangial cells into myofibroblasts. [19][20][21] Protein overload in the tubules induces tubular cells to release cytokines, chemokines, growth factors, and vasoactive molecules, which leads to abnormal interstitial accumulation of inflammatory cells, extracellular matrix collagen, fibronectin, and other components that are responsible for interstitial fibrosis.…”

Section: A Concept Coming From Far Awaymentioning

confidence: 99%

Mechanisms and Treatment of CKD

Ruggenenti

Cravedi

Remuzzi

2012

Journal of the American Society of Nephrology

Self Cite

242

183

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As CKD continues to increase worldwide, along with the demand for related lifesaving therapies, the financial burden of CKD will place an increasing drain on health care systems. Experimental studies showed that glomerular capillary hypertension and impaired sieving function with consequent protein overload play a pathogenic role in the progression of CKD. Consistently, human studies show that proteinuria is an independent predictor of progression and that its reduction is renoprotective. At comparable BP control, inhibitors of the renin-angiotensin system (RAS), including angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), more effectively than non-RAS inhibitor therapy reduce proteinuria, slow progression to ESRD, and even improve the kidney function achieving disease regression in some cases. In participants with diabetes, RAS inhibitors delay the onset of microalbuminuria and its progression to macroalbuminuria, and ACE inhibitors may reduce the excess cardiovascular mortality associated with diabetic renal disease. In addition to RAS inhibitors, however, multimodal approaches including lifestyle modifications and multidrug therapy will be required in most cases to optimize control of the several risk factors for CKD and related cardiovascular morbidity. Whether novel medications may help further improve the cost-effectiveness of renoprotective interventions is a matter of investigation.

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Is glomerulosclerosis a consequence of altered glomerular permeability to macromolecules?

Cited by 371 publications

References 79 publications

Reduction in albuminuria predicts a beneficial effect on diminishing the progression of human diabetic nephropathy during antihypertensive treatment

Reduction in albuminuria predicts a beneficial effect on diminishing the progression of human diabetic nephropathy during antihypertensive treatment

Proteinuria Impairs Podocyte Regeneration by Sequestering Retinoic Acid

Mechanisms and Treatment of CKD

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