Equations for estimating GFR with serum creatinine overestimate measured GFR in Blacks. The authors report new equations, without race as an inflation factor, using cystatin C and creatinine that ...reduced errors in estimation between Black participants and non-Black participants.
Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD) in the Western world. Better control of glycemia and blood pressure, including renin-angiotensin system blockade ...(RASB), appear to have slowed DKD progression rate but have been unable to substantially decrease the annual incidence of new cases of DKD related ESKD. Thus, new treatment targets are needed. Higher levels of serum uric acid (SUA) have been associated with increased risk and progression of DKD in persons with types 1 (T1D) and 2 (T2D) diabetes and of chronic kidney disease (CKD) in general. This review presents the epidemiological, clinical, and clinical trial evidence regarding the hypothesis that SUA reduction could slow progression of DKD and/or CKD in general.
This study aimed to determine whether early administration of drugs that block the renin–angiotensin system slows the progression of change in glomerular mesangial fractional volume and retinopathy ...progression of two steps or more, according to the retinopathy severity scale. Early blockade of the renin–angiotensin system did not modify nephropathy progression in patients with type 1 diabetes but had important effects in slowing retinopathy.
Early blockade of the renin–angiotensin system did not modify nephropathy progression in patients with type 1 diabetes but had important effects in slowing retinopathy.
Diabetic nephropathy, responsible for more than 45% of cases of end-stage renal disease in the United States,
1
may be structurally advanced once albuminuria becomes detectable.
2
,
3
Blockers of the renin–angiotensin system are more effective than other antihypertensive agents in slowing nephropathy progression in patients who have proteinuria, diabetes mellitus, and a reduced glomerular filtration rate (GFR),
4
–
6
and such blockers can also decrease proteinuria in patients with diabetes.
7
Although the reduction of proteinuria in patients with diabetes has been associated with a reduction in the rate of decline in GFR in small studies,
8
this association has not been systematically tested; . . .
The clinical manifestations of diabetic nephropathy, proteinuria, increased blood pressure, and decreased glomerular filtration rate, are similar in type 1 and type 2 diabetes; however, the renal ...lesions underlying renal dysfunction in the 2 conditions may differ. Indeed, although tubular, interstitial, and arteriolar lesions are ultimately present in type 1 diabetes, as the disease progresses, the most important structural changes involve the glomerulus. In contrast, a substantial subset of type 2 diabetic patients, despite the presence of microalbuminuria or proteinuria, have normal glomerular structure with or without tubulointerstitial and/or arteriolar abnormalities. The clinical manifestations of diabetic nephropathy are strongly related with the structural changes, especially with the degree of mesangial expansion in both type 1 and type 2 diabetes. However, several other important structural changes are involved. Previous studies, using light and electron microscopic morphometric analysis, have described the renal structural changes and the structural-functional relationships of diabetic nephropathy. This review focuses on these topics, emphasizing the contribution of research kidney biopsy studies to the understanding of the pathogenesis of diabetic nephropathy and the identification of patients with a higher risk of progression to end-stage renal disease. Finally, evidence is presented that the reversal of established lesions of diabetic nephropathy is possible.
Despite the high costs of treatment of people with kidney disease and associated comorbid conditions, the amount of reliable information available to guide the care of such patients is very limited. ...Some treatments have been assessed in randomized trials, but most such trials have been too small to detect treatment effects of a magnitude that would be realistic to achieve with a single intervention. Therefore, KDIGO convened an international, multidisciplinary controversies conference titled “Challenges in the Conduct of Clinical Trials in Nephrology” to identify the key barriers to conducting trials in patients with kidney disease. The conference began with plenary talks focusing on the key areas of discussion that included appropriate trial design (covering identification and evaluation of kidney and nonkidney disease outcomes) and sensible trial execution (with particular emphasis on streamlining both design and conduct). Break out group discussions followed in which the key areas of agreement and remaining controversy were identified. Here we summarize the main findings from the conference and set out a range of potential solutions. If followed, these solutions could ensure future trials among people with kidney disease are sufficiently robust to provide reliable answers and are not constrained by inappropriate complexities in design or conduct.
Podocyte Detachment and Reduced Glomerular Capillary Endothelial Fenestration in Human Type 1 Diabetic Nephropathy
Masao Toyoda 1 ,
Behzad Najafian 2 3 ,
Youngki Kim 2 ,
M. Luiza Caramori 4 and
...Michael Mauer 2 4
1 Division of Nephrology and Metabolism, Department of Internal Medicine; Tokai University School of Medicine, Kanagawa, Japan
2 Division of Pediatric Nephrology, Department of Pediatrics; University of Minnesota, Minneapolis, Minnesota
3 Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota
4 Department of Medicine, University of Minnesota, Minneapolis, Minnesota
Address correspondence and reprint requests to Michael Mauer, MD, Professor of Pediatrics and Medicine, University of Minnesota,
420 Delaware St. SE, MMC 491, Minneapolis, MN 55455. E-mail: mauer002{at}umn.edu
Abstract
The aim of this study was to investigate the structural characteristics of podocytes and endothelial cells in diabetic nephropathy.
We studied 18 patients with type 1 diabetes (seven normoalbuminuric, six microalbuminuric, and five proteinuric), and six
normal control subjects. Groups were not different for age. Type 1 diabetic groups were not different for diabetes duration
or age at diabetes onset. Podocyte foot process width (FPW), fraction of glomerular basement membrane (GBM) surface with intact
nondetached foot processes (IFP), fraction of glomerular capillary luminal surface covered by fenestrated endothelium S S (Fenestrated/cap) and classic diabetic glomerulopathy lesions were morphometrically measured. Albumin excretion (AER) and
glomerular filtration (GFR) rates were also measured. GFR correlated inversely and AER directly with GBM and mesangial measurements
in diabetic patients. FPW correlated inversely with GFR ( r = −0.71, P = 0.001) and directly with AER ( r = 0.66, P = 0.003), GBM, and mesangial parameters. The GBM fraction covered by IFP was decreased in proteinuric versus control subjects
( P = 0.001), normoalbuminuric patients ( P = 0.0002) and microalbuminuric patients ( P = 0.04) and correlated with renal structural and functional parameters, including AER ( r = −0.52, P = 0.03). Only 78% of GBM was covered by IFP in proteinuric patients. S S (Fenestrated/cap) was reduced in normoalbuminuric ( P = 0.03), microalbuminuric ( P = 0.03), and proteinuric ( P = 0.002) patients versus control subjects. S S (Fenestrated/cap) correlated with mesangial fractional volume per glomerulus ( r = −0.57, P = 0.01), IFP ( r = 0.61, P = 0.007), and FPW ( r = −0.58, P = 0.01). These novel studies document that podocyte detachment and diminished endothelial cell fenestration are related to
classical diabetic nephropathy lesions and renal function in type 1 diabetic patients and support a need for further studies
of podocyte/GBM adherence and podocyte/endothelial cell functional interactions in diabetic nephropathy.
AER, albumin excretion rate
FPW, foot process width
FSGS, focal and segmental glomerulosclerosis
GBM, glomerular basement membrane
GFR, glomerular filtration rate
LS(Slit/PGBM), slit diaphragm length density per PGBM
LS(Slit/MGBM), slit diaphragm length density per MGBM
MGBM mesangial GBM
PGBM, peripheral GBM
SS(IFP/PGBM), fraction of PGBM covered by intact foot processes
SS(IFP/MGBM), fraction of MGBM covered by intact foot processes
SS(Fenestrated/cap), surface density of fenestrated endothelium per glomerular capillary lumen
SV(PGBM/glom), surface density of PGBM per glomerulus
TBCA, tuft to Bowman's capsule adhesions
VV(MC/glom), mesangial cell fractional volume per glomerulus
VV(Mes/glom), mesangial fractional volume per glomerulus
VV(MM/glom), mesangial matrix fractional volume per glomerulus
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 29 May 2007. DOI: 10.2337/db07-0019.
This manuscript and its contents are solely the responsibility of the authors and do not necessarily represent the official
views of NCRR or NIH.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted May 12, 2007.
Received January 8, 2007.
DIABETES
Fabry nephropathy is associated with progressive accumulation of globotriaosylceramide (GL3) in podocytes. Reducing this GL3 burden may reduce podocyte injury. Sensitive methods to quantify podocyte ...GL3 content may determine whether a given strategy can benefit podocytes in Fabry disease. We developed an unbiased electron microscopic stereological method to estimate the average volume of podocytes and their GL3 inclusions in 6 paired pre- and post-enzyme replacement therapy (ERT) biopsies from 5 men with Fabry disease. Podocyte GL3 content was regularly reduced (average 73%) after 11-12 months of ERT. This was not detectable using a semi-quantitative approach. Parallel to GL3 reduction, podocytes became remarkably smaller (average 63%). These reductions in podocyte GL3 content or size were not significantly correlated with changes in foot process width (FPW). However, FPW after ERT was significantly correlated with the magnitude of the decrease in podocyte GL3 content from baseline to 11-12 months of ERT. Also podocytes exocytosed GL3 inclusions, a phenomenon correlated with their reduction in their GL3 content. Demonstrable after11-12 months, reduction in podocyte GL3 content allows for early assessment of treatment efficacy and shorter clinical trials in Fabry disease.
Interstitial expansion is associated with glomerular filtration rate (GFR) loss in many renal diseases, including diabetic nephropathy. The Renin–Angiotensin System Study (RASS) tested whether a ...5-year renin–angiotensin system (RAS) blockade with enalapril or losartan versus placebo slowed progression of early diabetic nephropathy lesions in 285 normoalbuminuric, normotensive, normal/high GFR patients with type 1 diabetes. RASS found no benefit to the RAS blockade on diabetic glomerular lesions but observed an unexpected 50% increase in the fractional volume of the renal cortex which is the interstitium. The effects of the RAS blockade on individual interstitial components––striated collagen, interstitial cells, and peritubular capillaries––were not assessed. We evaluated by electron microscopy changes in fractional volume of each component in seven patients from each group between baseline and five years. At baseline, 49% of the interstitium was collagen, 12% cells, 26% peritubular capillaries, 7% space, and 2% artifact. There was no overall change in the interstitial composition during the RASS. There were no statistically significant effects of treatment group on any interstitial components. Renal volume remained stable in all groups. The RAS blockade affected neither the approximately 50% increase in interstitium fractional volume per cortex nor the parallel increase in all interstitial components that occurred over the five years of the RASS.
Chronic kidney disease is a major complication of Fabry disease. Podocytes accumulate globotriaosylceramide inclusions more than other kidney cell types in Fabry patients. Podocyte injury occurs ...early in age, and is progressive. Since injured podocytes detach into the urine (podocyturia), we hypothesized that podocyturia would increase in Fabry patients and correlate with clinical severity of Fabry nephropathy. Urine specimens from 39 Fabry patients and 24 healthy subjects were evaluated for podocyturia. Most of the Fabry patients and many healthy subjects had podocyturia. The number of podocytes per gram of urine creatinine (UPodo/g Cr) was 3.6 fold greater in Fabry patients (3,741 ± 2796; p = 0.001) than healthy subjects (1,040 ± 972). Fabry patients with normoalbuminuria and normoproteinuria had over 2-fold greater UPodo/g Cr than healthy subjects (p = 0.048). UPodo/gCr was inversely related to eGFR in male patients (r = -0.69, p = 0.003). UPodo/gCr was directly related to urine protein creatinine ratio (r = 0.33; p = 0.04) in all Fabry patients. These studies confirm increased podocyturia in Fabry disease, even when proteinuria and albuminuria are absent. Podocyturia correlates with clinical severity of Fabry nephropathy, and potentially may be of prognostic value.
Current therapies for Fabry disease are based on reversing intracellular accumulation of globotriaosylceramide (Gb3) by enzyme replacement therapy (ERT) or chaperone-mediated stabilization of the ...defective enzyme, thereby alleviating lysosomal dysfunction. However, their effect in the reversal of end-organ damage, like kidney injury and chronic kidney disease, remains unclear. In this study, ultrastructural analysis of serial human kidney biopsies showed that long-term use of ERT reduced Gb3 accumulation in podocytes but did not reverse podocyte injury. Then, a CRISPR/Cas9-mediated α-galactosidase knockout podocyte cell line confirmed ERT-mediated reversal of Gb3 accumulation without resolution of lysosomal dysfunction. Transcriptome-based connectivity mapping and SILAC-based quantitative proteomics identified α-synuclein (SNCA) accumulation as a key event mediating podocyte injury. Genetic and pharmacological inhibition of SNCA improved lysosomal structure and function in Fabry podocytes, exceeding the benefits of ERT. Together, this work reconceptualizes Fabry-associated cell injury beyond Gb3 accumulation, and introduces SNCA modulation as a potential intervention, especially for patients with Fabry nephropathy.
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