Diabetic Nephropathy 31170bae72594217b86d0042e300e5cb

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Diabetic Nephropathy 1
📒
Diabetic Nephropathy
Dates
Type 📒 Lesson
Nombre Montoya Corral José Luis
Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) in adults. 
Most of these have type 2 diabetes 
Mortality among patients with diabetic nephropathy is high, with cardiovascular diseases 
predominating
Normoalbuminuria: urinary albumin excretion rate (UAER) less than 20 µg/min or 
urinary albumin to creatinine ratio (UACR) less than 30 mg/g (or 30 mg/day)
Microalbuminuria: UAER between 20 and 200 µg/min or UACR between 30 and 300 
mg/g (30 to 300 mg/day)
Macroalbuminuria: UAER greater than 200 µg/min or UACR greater than 
300 mg/g (>300 mg/day).
UAER = Urinary Albumin Excretion Rate 
💡 “moderately increased albuminuria” rather than microalbuminuria and 
“severely increased albuminuria” instead of macroalbuminuria.
PATHOPHYSIOLOGY
complex and remains incompletely understood
Long-term deleterious impacts of hyperglycemia and insulin resistance are central to the 
development and progression of diabetic nephropathy 
Type 1 and type 2 diabetes have shown that improved glycemic control can reduce the 
risk of developing diabetic nephropathy
@April 19, 2021
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Established diabetic glomerular lesions in the native kidneys of patients with type 1 
diabetes regress with prolonged normalization of glycemic levels after successful 
pancreas transplantation
Hyperglycemia is necessary for the development and maintenance of diabetic 
nephropathy because correction of hyperglycemia allows expression of reparative 
mechanisms that facilitate healing of the original diabetic glomerular injury
Hemodynamic mechanisms 
likely play a significant role in the pathogenesis of diabetic nephropathy through 
neurohormonal (e.g., renin-angiotensin–aldosterone system activation) and tubular 
(e.g., tubuloglomerular feedback) pathways
💡 unlikely that all patients with diabetes and hyperfiltration develop diabetic 
kidney disease.
Presence of reduced GFR in normo albuminuric patients with type 1 diabetes is 
associated with more severe glomerular lesions, and these patients may be at 
increased risk of further progression
Systemic blood pressure levels and a lack of normal nocturnal blood pressure dipping 
may both be implicated in the progression and genesis of diabetic nephropathy
A genetic predisposition to diabetic nephropathy is suggested 
in multiple cross-sectional studies in type 1 and type 2 diabetic 
siblings concordant for diabetes
💡 HS6ST1 and near RAB38/CTSC
Diabetic nephropathy is characterized not only by glomerular disease but also by 
tubulointerstitial injury
Glomerular changes have received more attention than tubulointerstitial changes in 
diabetic kidney disease research, tubular injury may be more closely associated with 
kidney function than glomerular injury
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Tubular damage may occur earlier than glomerular injury in the course of diabetic 
nephropathy
Tubular changes associated with diabetic nephropathy include basement membrane 
thickening, tubular hypertrophy, epithelial–mesenchymal transition, glycogen 
accumulation, and interstitial inflammation
Basement membrane thickening and tubular hypertrophy are mainly related to 
extracellular matrix (ECM) accumulation, which reflects an imbalance between ECM 
synthesis and degradation, is the principal cause of mesangial expansion, and 
contributes to expansion of the interstitium late in the disease
These include increased levels of tumor growth factor (TGF)-ß; activation of protein 
kinase C, which stimulates ECM production through the cyclic adenosine 
monophosphate (cAMP), pathway; increased advanced glycation end products; and 
increased activity of aldose reductase, leading to accumulation of sorbitol
Oxidative stress is increased in diabetes and is also related to diabetic nephropathy, 
mediated through altered nitric oxide production and action, and endothelial dysfunction
Angiotensin II increases intraglomerular pressure and hyperfiltration and also increases 
the production of injurious mediators such as protein kinase C
Glycocalyx dysfunction has recently attracted attention as a potential mediator of both 
diabetic glomerulopathy and tubulopathy
Under exposure to hyperglycemic conditions, the glycocalyx is modified, leading to 
exposure of heparan sulfate domains that allow chemokine binding
Albuminuria is likely to at least in part occur as a consequence disruption of the 
glycocalyx
PATHOLOGY
Type 1 diabetes 
Glomerular lesions can appear within a few years after diabetes onset
The changes in kidney structure caused by diabetes are specific, creating a pattern 
not seen in any other disease, and the severity of these diabetic lesions is related to 
the functional disturbances of the clinical kidney disease, as well as to diabetes 
duration, glycemic control, and genetic factors.
Light Microscopy 
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Kidney hypertrophy is the earliest structural change in type 1 diabetes but is 
not reflected in any specific light microscopic changes
Glomerular structure remains normal or near normal even after decades of 
diabetes, whereas others develop progressive diffuse mesangial expansion
40% to 50% of patients developing proteinuria, there are areas of extreme 
mesangial expansion called Kimmelstiel-Wilson nodules (nodular mesangial 
expansion)
Nodules are thought to result from earlier glomerular capillary 
microaneurysm formation
Although Kimmelstiel-Wilson nodules are diagnostic of diabetic 
nephropathy, they are not necessary for severe kidney disease to develop.
Early changes often include arteriolar hyalinosis lesions involving 
replacement of the smooth muscle cells of afferent and efferent arterioles 
with PAS-positive waxy, homogeneous material
severity of these lesions is directly related to the frequency of global 
glomerulosclerosis, perhaps as the result of glomerular ischemia
Glomerular basement membrane (GBM) and tubular basement membrane 
(TBM) thickening may be seen with light microscopy, although they are 
more easily seen with electron microscopy
Tubular glomeruli and glomerulotubular junction abnormali 
ties are present in proteinuric patients with type 1 diabetes and may be 
important in the progressive loss of GFR in diabetic nephropathy.
💡 Tubular atrophy and interstitial fibrosis occur
Immunofluorescence
Diabetes is characterized by increased linear staining of the GBM, TBM, 
and Bowman capsule, especially for immunoglobulin G (mainly IgG4) and 
albumin
Electron Microscopy
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The first measurable change observed in diabetic nephropathy is thickening 
of the GBM, which can be detected as early as 1.5 to 2.5 years after onset 
of type 1 diabetes
A measurable increase in the relative area of the mesangium begins by 4 to 
5 years
20% (normal) to about 40% when proteinuria begins, and to 60% to 80% in 
patients with stage 3 chronic kidney disease (CKD)
Qualitative and quantitative changes in the renal interstitium are observed 
in patients with various kidney diseases
Interstitial fibrosis is characterized by an increase in ECM proteins and 
cellularity
Pathogenesis of interstitial changes in diabetic nephropathy is different from 
the changes that occur in the mesangial matrix, GBM, and TBM. Whereas 
for all but the later stages of diabetic nephropathy, GBM, TBM, and 
mesangial matrix changes represent the accumulation of basement 
membrane ECM material, early interstitial expansion is largely a result of 
cellular alterations, and only later, when GFR is already compromised, is 
interstitial expansion associated with increased interstitial fibrillar collagen 
and peritubular capillary loss
Type 2 diabetes 
Glomerular and tubular structures in type 2 diabetes are less well studied but 
overall seem more heterogeneous than those observed in type 1 diabetes
Between 30% and 50% of patients with type 2 diabetes who have clinical 
features of diabetic nephropathyhave typical changes of diabetic nephropathy, 
including diffuse and nodular mesangial expansion and arteriolar hyalinosis
Despite the presence of albuminuria, have absent or only mild diabetic 
glomerulopathy, whereas others have disproportionately severe tubular and 
interstitial abnormalities and/or vascular lesions and/or an increased number of 
globally sclerosed glomeruli
Microalbuminuria more frequently have morphometric glomerular structural 
measures in the normal range on electron microscopy and less severe lesions 
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compared with patients with type 1 diabetes and microalbuminuria or overt 
proteinuria
It is unclear why some studies show more structural heterogeneity in type 2 
than in type 1 diabetes, whereas others do not
When biopsies are performed for research purposes, the incidence of other 
definable kidney diseases is very low (<5%).
A significant proportion of patients with type 2 diabetes exhibit an accelerated 
GFR decline in the absence of albuminuria. This may reflect a predominance of 
microvascular disease rather than glomerular disease, thereby attenuating 
albuminuria risk.
STRUCTURAL-FUNCTIONAL RELATIONSHIPS 
IN DIABETIC NEPHROPATHY
Kidney disease progression rates vary greatly among individuals with diabetes
considerable overlap in glomerular structural changes between long-standing 
normoalbuminuric and microalbuminuric patients, as some normoalbuminuric patients 
with long standing type 1 diabetes can have quite advanced kidney lesions, whereas 
many patients with longstanding diabetes and normoalbuminuria have structural 
measurements within the normal range
Ultimately expansion of the mesangium, mainly resulting from ECM accumulation, 
reduces or even obliterates the glomerular capillary luminal space, decreasing the 
glomerular filtration surface and therefore decreasing the GFR
Fraction of the glomerulus occupied by mesangium correlates with both GFR and 
albuminuria in patients with type 1 diabetes
inverse relationship between mesangial expansion and total peripheral GBM filtration 
surface per glomerulus. GBM thickness is also directly related to the albumin excretion 
rate.
Extent of global glomerulosclerosis and interstitial expansion are correlated with the 
clinical manifestations of diabetic nephropathy (proteinuria, hypertension, and declining 
GFR)
Type 1 diabetes, glomerular, tubular, interstitial, and vascular lesions tend to progress 
more or less in parallel, whereas in patients with type 2 diabetes, this often is not the 
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case
Type 2 diabetes patients with microalbuminuria, those patients with typical diabetic 
glomerulopathy have a higher risk of progressive GFR loss than those with lesser 
degrees of glomerular changes
Most of these abnormalities are associated with tuft adhesions to Bowman capsule at or 
near the glomerular tubular junction (tip lesions).
The data on structural-functional relationships in type 2 diabetes are less abundant
although there seems to be a subset of patientswho have normal glomerular structure 
despite persistent albuminuria
relationships between kidney function and glomerular structure are less precise in 
patients with type 2 diabetes
Rate of GFR decline significantly correlates with the severity of diabetic 
glomerulopathy lesions
These lesions include changes in the structure of renal tubules, interstitium, arterioles, 
and podocytes
Changes in podocyte structure and density occur early in diabetic nephropathy and 
might contribute to increasing albuminuria in these patients
REVERSAL OF DIABETIC NEPHROPATHY LESIONS
The lesions of diabetic nephropathy have long been considered irreversible
In pancreas transplant recipients, the lesions of diabetic nephropathy were unaffected 
after 5 years of normoglycemia but reversed in all patients by 10 years post transplant, 
with a remarkable amelioration of glomerular structure abnormalities evident by light 
microscopy
💡 total disappearance of Kimmelstiel-Wilson nodular lesions
The long time necessary for these diabetic lesions to disappear 
is consistent with their slow rate of development
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💡 No usar Crockroft Gault, ya no sirve