Collapsing glomerulopathy superimposed on diabetic nephropathy: insights into etiology of an under-recognized, severe pattern of glomerular injury

Salvatore, Steven; Reddi, Alluru S.; Chandran, Chandra; Chevalier, James M.; Okechukwu, Chike Nathan; Seshan, Surya V.

doi:10.1093/ndt/gft408

Cited by 43 publications

(34 citation statements)

References 28 publications

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“…We did not observe an association between mesangiolysis or hyalinosis with EXHC (data not shown). Salvatore et al 20 described a series (n=26) of HIV-negative patients with diabetes and collapsing glomerulopathy with epithelial proliferation in Bowman's space (pseudocrescents), virtually identical to the EXHC observed in our study. They propose that severe arteriolosclerosis leads to hypoxic injury to podocytes and resultant collapse of the glomerular tuft.…”

Section: Discussionsupporting

confidence: 83%

“…18 Additional features not included in the RPS scoring are segmental sclerosis (SS) and extracapillary hypercellularity (EXHC), which have been noted in patients with diabetes and may have prognostic importance. [19][20][21] We postulated that the RPS Diabetic Nephropathy Classification does not include several glomerular parameters that could be useful for phenotyping and prognosticating the clinical course for DKD. The objectives of these analyses were to: (1) provide a detailed characterization of light microscopic pathologic lesions in clinical biopsy specimens with diabetic glomerulosclerosis; and (2) quantify the risk for diabetic ESRD according to individual nephropathologic lesions and determine which are independently associated with the risk for ESRD.…”

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confidence: 99%

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Segmental Sclerosis and Extracapillary Hypercellularity Predict Diabetic ESRD

Mottl

Gasim

Schober

et al. 2017

JASN

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Pathogenetic markers of diabetic kidney disease (DKD) progression to ESRD are lacking. We characterized the prognostic value of histologic findings in DKD for time to ESRD in native kidney specimens from biopsies performed from 1995 to 2011 with diabetic glomerulosclerosis as the only glomerular disease diagnosis (=109). Biopsy specimens were analyzed according to standard methods, including determination of diabetic nephropathy class, as defined by the Renal Pathology Society. Clinical data were extracted from electronic medical records. We used competing risk models, with death as the competing risk, to estimate subdistribution hazard ratios (HRs) for ESRD. All multivariable models included age, sex, black race, baseline eGFR, and baseline proteinuria. Pathologic characteristics achieving <0.1 were added into successively complex models. ESRD occurred in 56% of patients, and 26% of patients died before reaching ESRD. In univariate analyses, diabetic nephropathy class was not statistically significant in predicting time to ESRD. The final multivariable model (=106) showed a borderline association between mild mesangial expansion and decreased risk for ESRD (subdistribution HR, 0.64; 95% confidence interval, 0.40 to 1.00). Poor prognostic factors in the final model included segmental sclerosis and extracapillary hypercellularity (subdistribution HR, 2.04; 95% confidence interval, 1.36 to 3.05; and subdistribution HR, 2.21; 95% confidence interval, 1.19 to 4.11, respectively). In conclusion, we identified segmental sclerosis and extracapillary hypercellularity as novel, poor prognostic indicators of time from DKD to ESRD. Whether these indicators represent a distinct pathogenetic phenotype of DKD will require a large study with a broad spectrum of disease severity.

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Section: Discussionsupporting

confidence: 83%

mentioning

confidence: 99%

Segmental Sclerosis and Extracapillary Hypercellularity Predict Diabetic ESRD

Mottl

Gasim

Schober

et al. 2017

JASN

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“…Furthermore, in the presence of hyperglycemia, mesangial cells express renin and angiotensinogen (52) that stimulates increased production of TGF-β and VEGF-A in podocytes, resulting in augmented thickening of the extracellular matrix and higher rates of podocyte apoptosis (53–55). Clinical cases of DN carry the risk of collapsing glomerulopathy, which is characterized by expansion of the glomerular basement membrane, capillary wall deformation, and epithelial cell proliferation, all of which are associated with an overexpression of glomerular VEGF-A (56–58). Collectively, the progressive changes of DN include increased proteinuria, the fusion of podocyte foot processes, and alterations in glomerular endothelial cell proliferation and maintenance that have all been identified both in humans and multiple animal models (59).…”

Section: Role Of Vegf In Diabetic Nephropathymentioning

confidence: 99%

Therapeutic angiogenesis by vascular endothelial growth factor supplementation for treatment of renal disease

Logue

McGowan²,

George³

et al. 2016

Current Opinion in Nephrology and Hypertension

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Purpose of Review Vascular endothelial growth factors (VEGFs) influence renal function through angiogenesis, with VEGF-A being the most potent inducer of vascular formation. In the normal glomerulus, tight homeostatic balance is maintained between the levels of VEGF-A isoforms produced by podocyte cells, and the VEGF receptors (VEGFRs) expressed by glomerular endothelial, mesangial, and podocyte cells. Renal disease occurs when this homeostatic balance is lost, manifesting in the abnormal autocrine and paracrine VEGF-A/VEGFR signaling, ultrastructural glomerular and tubular damage, and impaired filtration. Recent Findings Preclinical disease models of ischemic renal injury, including acute ischemia/reperfusion, thrombotic microangiopathy, and chronic renovascular disease, treated with exogenous VEGF supplementation demonstrated therapeutic efficacy. These results suggest a therapeutic VEGF-A paracrine effect on endothelial cells in the context of acute or chronic obstructive ischemia. Conversely, renal dysfunction in diabetic nephropathy appears to occur through an upregulated VEGF autocrine effect on podocyte cells, which is exacerbated by hyperglycemia. Therefore, VEGF supplementation therapy may be contraindicated for treatment of diabetic nephropathy, but specific results will depend on dose and on the specific site of VEGF delivery. A drug delivery system that demonstrates cell specificity for glomerular or peritubular capillaries could be employed to restore balance to VEGF-A/VEGFR2 signaling, and by doing so prevent the progression to end stage renal disease (ESRD). Summary This review discusses the preclinical data available for VEGF supplementation therapy in models of renal disease.

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“…Also, glomerular epithelial hyperplasia can become particularly florid, appearing as crescentic glomerulonephritis. This particular difficulty is often encountered on a background of membranous glomerulopathy, diabetic glomerulopathy, or membranous lupus nephritis or TMA, further complicating interpretation [30, 31, 47]. As no data exist detailing any specific test to differentiate crescents from CGP this formidable question is often relegated to experience and opinion.…”

Section: The Difficult Diagnosis; Entities Mimicking Cgpmentioning

confidence: 99%

“…In the case of underlying diabetic glomerulopathy, Salvatore et al . have recently addressed the question of collapsing lesions superimposed on diabetic glomerulopathy (Figure 1T) and their study suggested that these lesions might be attributable to ischemia [47]. Similarly, CGP in TMA is thought to be due to ischemia.…”

Section: The Difficult Diagnosis; Entities Mimicking Cgpmentioning

confidence: 99%

Collapsing glomerulopathy: a 30-year perspective and single, large center experience

Cossey

Larsen

Liapis

2017

Clinical Kidney Journal

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Collapsing glomerulopathy (CGP) is a pattern of kidney injury seen on renal biopsy with multiple associations and etiologies. It is most commonly described in African-Americans and others with recent African ancestry. The disease is rapidly progressive and often presents with abrupt onset of renal failure and nephrotic-range proteinuria. Since its description 30 years ago, this entity has transformed from a morphologic diagnosis typically seen in the setting of HIV infection to a complicated diagnosis with numerous etiologies, many of which are associated with underlying apolipoprotein L1 (APOL1)-risk variants or other genetic disorders. We review the evolution of CGP, and its history and proposed pathomechanisms. We also present the disease spectrum from our experience with emphasis on recognizing the lesion, distinguishing from mimics and linking the histopathological pattern to a specific cause. Our understanding continues to evolve as clinicians and scientists work toward a more complete understanding of the molecular pathways of injury in this disease and how these might be disrupted for therapeutic purposes. Much still remains to be discovered in CGP as the molecular underpinnings leading to disease are still not completely understood and no effective treatment exists despite the high morbidity. Based on this rapid evolution, CGP is a modern template of how we diagnose and think about kidney disease. The story of CGP represents the current shift in nephrology and nephropathology from morphology-alone-based diagnosis to a comprehensive approach including molecular diagnostics. We believe this new, holistic approach will lead to pathogenesis-centered diagnoses that will help to individualize risk stratification and treatment protocols.

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Collapsing glomerulopathy superimposed on diabetic nephropathy: insights into etiology of an under-recognized, severe pattern of glomerular injury

Abstract: CG contributes to an increased level or new onset of proteinuria in DN which may be intractable. CG in DN with advanced vascular hyalinosis is presumably due to ischemic podocyte injury and is of prognostic significance.

Cited by 43 publications

References 28 publications

Segmental Sclerosis and Extracapillary Hypercellularity Predict Diabetic ESRD

Segmental Sclerosis and Extracapillary Hypercellularity Predict Diabetic ESRD

Therapeutic angiogenesis by vascular endothelial growth factor supplementation for treatment of renal disease

Collapsing glomerulopathy: a 30-year perspective and single, large center experience

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