Dr alaa saleh diabetic nephropathy

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Diabetic NephropathyDiabetic NephropathyDiabetic NephropathyDiabetic Nephropathy
Dr. Alaa Ibrahim Saleh ,MDDr. Alaa Ibrahim Saleh ,MD
Senior Consultant Nephrologist,Senior Consultant Nephrologist,
King Abdul-Aziz SepecialistKing Abdul-Aziz Sepecialist
Hospital-TaifHospital-Taif
Dr. Alaa Ibrahim Saleh ,MDDr. Alaa Ibrahim Saleh ,MD
Senior Consultant Nephrologist,Senior Consultant Nephrologist,
King Abdul-Aziz SepecialistKing Abdul-Aziz Sepecialist
Hospital-TaifHospital-Taif

3
IntroductionIntroduction
Diabetic Nephropathy (Nephropatica Diabetica),
also known as kimmelstiel.wilson syndrome
and intercapillary glomerulonephritis is a
progressive kidney disease caused by
angiopathy of capillaries in the kidney
glomeruli.
It is characterized by nephrotic syndrome and
nodular glomerulosclerosis.
Muller. J et al., Pathology. Research and practice. Vol.198 (5): 375, 2017

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Diabetic Nephropathy
 is the single most common cause of
end stage renal disease (ESRD) in
Europe and USA (25 % to 45 %) of
patient enrolled in ESRD programs.
 Nephropathy is a major cause of
illness and death in diabetes and is
associated with high rates of
cardiovascular disease.
Kelly K.J. et al., Am.J. Physiol, 2016
IntroductionIntroduction

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The syndrome was discovered by
British Clifford Wilson (1906-
1997) and Germany-Born
American physician paul
kimmelstiel (1900-1970) and was
published for the first time in
1936.
HistoryHistory

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The earliest detectable change in the course of diabetic
nephropathy is a thickening in the glomerulus. At
this stage, the kidney may start allowing more serum
albumin (plasma protein) than the normal in the
urine (albuminuria) and this can be detected by
sensitive medical test for albumin. This stage is called
Microalbuminuria.
Donelly R. et al., J. Hypertes. 21(suppl 1): 7 , 2015
Etiopathology

7
A rise in urinary albumin loss to between 30 to
300 mg/day. Microalbuminuria is a strong
predictor of total and cardiovascular
mortality and cardiovascular morbidity in
diabetic patients. Microalbuminuria has been
proposed as a marker of widespread
endothelial dysfunction that might predispose
individuals to enhanced penetrations in the
arterial wall of atherogenic lipoprotein.
Ochodnicky P. et al., J. Cardiovasc Pharmacol.47: 151 , 2016
Microalbuminuria

Risk factor for development of Diabetic
Nephropathy ( risk factors )
 Hyperglycemia
 Increased blood pressure
 Urinary albumin excretion
 Increase age
 Duration of diabetes
 Presence of retinopathy
 Smoking
 Genetic factors
 Increase cholesterol and triglyceride
 Male sex
 Serum homocysteine levels
American Diabetes association, Diabetes care.27:79 , 2014
8

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Clinical presentations andClinical presentations and
pathophysiologypathophysiology
pathophysiologypathophysiologyStage I:Stage I:
 Hyperfiltration- hypertrophyHyperfiltration- hypertrophy
stage (stage (↑GFR)↑GFR)
 Glucosuria with polyuria andGlucosuria with polyuria and
microalbuminuriamicroalbuminuria
 tight blood glucose control → ↓tight blood glucose control → ↓
hypertrophy → ↓ microalbuminuriahypertrophy → ↓ microalbuminuria
Thrailkil et al. Diabetes care 30 (9): 2321, 2017Thrailkil et al. Diabetes care 30 (9): 2321, 2017
Stage I:Stage I:
 Hyperfiltration- hypertrophyHyperfiltration- hypertrophy
stage (stage (↑GFR)↑GFR)
 Glucosuria with polyuria andGlucosuria with polyuria and
 tight blood glucose control → ↓tight blood glucose control → ↓
hypertrophy → ↓ microalbuminuriahypertrophy → ↓ microalbuminuria
Thrailkil et al. Diabetes care 30 (9): 2321, 2017Thrailkil et al. Diabetes care 30 (9): 2321, 2017

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Stage II (silent stage):Stage II (silent stage):
 Microalbuminuria is normal or nearMicroalbuminuria is normal or near
normal (normal (< 20< 20 μμg/min)g/min)
 GFR (Normal)GFR (Normal)
 Membrane thickening and mesangialMembrane thickening and mesangial
expansionexpansion
 Early HTNEarly HTN
Liu et al. J.Am.Soc.Nephrol.18 (7): 2094,2017Liu et al. J.Am.Soc.Nephrol.18 (7): 2094,2017
Stage II (silent stage):Stage II (silent stage):
 Microalbuminuria is normal or nearMicroalbuminuria is normal or near
normal (normal (< 20< 20 μμg/min)g/min)
 GFR (Normal)GFR (Normal)
 Membrane thickening and mesangialMembrane thickening and mesangial
expansionexpansion
 Early HTNEarly HTN
Liu et al. J.Am.Soc.Nephrol.18 (7): 2094,2017Liu et al. J.Am.Soc.Nephrol.18 (7): 2094,2017

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Stage III: (incipient Nephropathy)
 Occur after 5-15 years of diabetes
 Further thickening basment membrane
 GFR start to ↓
 Microalbuminuria (30-300 mg/24 hr) ((poor
prognosis)
 HTN develop early in this stage
Catania et al. Am.J.Renal Physiol 292 (3):902, 2017
Stage III: (incipient Nephropathy)
 Occur after 5-15 years of diabetes
 Further thickening basment membrane
 GFR start to ↓
 Microalbuminuria (30-300 mg/24 hr) ((poor
prognosis)
 HTN develop early in this stage
Catania et al. Am.J.Renal Physiol 292 (3):902, 2017

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Stage IV:
 Dipstick-positive proteinuria
 Proteinuria ( > 0.5 gm/24 hrs)
 HTN (invariable present)
 GFR gradually ↓
 Histology → diffuse or nodular intercapillary
glomerulosclerosis
Shimazaki et al. Kidney Ini 70, 1769-1776 , 2016
Stage IV:
 Dipstick-positive proteinuria
 Proteinuria ( > 0.5 gm/24 hrs)
 HTN (invariable present)
 GFR gradually ↓
 Histology → diffuse or nodular intercapillary
glomerulosclerosis
Shimazaki et al. Kidney Ini 70, 1769-1776 , 2016

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Stage V:
 On average occur 20 years from the time of
diabetes onset
 Histology → glomerular sclerosis &
atrophy
 Other complication : retinopathy,
neuropathy, cardiac disease
Tsukad et al. Mol.Endocrinol. 20, 11402-1111 , 2016
Stage V:
 On average occur 20 years from the time of
diabetes onset
 Histology → glomerular sclerosis &
atrophy
 Other complication : retinopathy,
neuropathy, cardiac disease
Tsukad et al. Mol.Endocrinol. 20, 11402-1111 , 2016

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Feature suggestive of nondiabeticFeature suggestive of nondiabetic
renal disease in diabetic patientsrenal disease in diabetic patients
Feature suggestive of nondiabeticFeature suggestive of nondiabetic
renal disease in diabetic patientsrenal disease in diabetic patients
 Absence of diabetic retinopathy
 Overt nephropathy with diabetes of
less than 5 years
 Renal failure without significant
proteinuria
 Presence of red blood cells casts
 Hypocomplementemia
Kawamura et al. Mol.Endocrinol, 20, 844-856 , 2016
 Absence of diabetic retinopathy
 Overt nephropathy with diabetes of
less than 5 years
 Renal failure without significant
proteinuria
 Presence of red blood cells casts
 Hypocomplementemia
Kawamura et al. Mol.Endocrinol, 20, 844-856 , 2016

PathologyPathologyPathologyPathology
 Histopathologic changes observed in
diabetic nephropathy typically affect the
glomeruli, vasculature and tubular
interstitial compartment
 Nodular intercapillary glomerulosclerosis
(characteristic)
Mazzuco et al. Am.J. Kidney Dis.39 (4):713, 2015Mazzuco et al. Am.J. Kidney Dis.39 (4):713, 2015
 Histopathologic changes observed in
diabetic nephropathy typically affect the
glomeruli, vasculature and tubular
interstitial compartment
 Nodular intercapillary glomerulosclerosis
(characteristic)
Mazzuco et al. Am.J. Kidney Dis.39 (4):713, 2015Mazzuco et al. Am.J. Kidney Dis.39 (4):713, 2015

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HistopathologyHistopathologyHistopathologyHistopathology
 Glomerular lesions:
Diffuse intercapillary glomerulosclerosis
Nodular intercapillary glomerulosclerosis
 Vascular lesions:
Subintimal hyaline arteriosclerosis
Benign arteriosclerosis
 Tubular and interstitial lesions
Hyaline and glycogen deposits
Savoldi et al. Type 2 diabetes and overt nephropathy. ASN, 2015Savoldi et al. Type 2 diabetes and overt nephropathy. ASN, 2015
 Glomerular lesions:
Diffuse intercapillary glomerulosclerosis
Nodular intercapillary glomerulosclerosis
 Vascular lesions:
Subintimal hyaline arteriosclerosis
Benign arteriosclerosis
 Tubular and interstitial lesions
Hyaline and glycogen deposits
Savoldi et al. Type 2 diabetes and overt nephropathy. ASN, 2015Savoldi et al. Type 2 diabetes and overt nephropathy. ASN, 2015

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PathogenesisPathogenesisPathogenesisPathogenesis
A. Hemodynamic Alteration:
- Systemic and renal hemodynamics critically affectedSystemic and renal hemodynamics critically affected
- HTN usually occur before ↓ GFR.HTN usually occur before ↓ GFR.
B. Abnormal metabolic and glycemicB. Abnormal metabolic and glycemic
control:control:
-- Improved control of hyperglycemia and ↓ intraglomerular andImproved control of hyperglycemia and ↓ intraglomerular and
systemic HTN → ↓ progression nephropathysystemic HTN → ↓ progression nephropathy
- Pancreatic transplantation reverse NephropathyPancreatic transplantation reverse Nephropathy
- Abnormal glycosylation of proteins that form the glomerularAbnormal glycosylation of proteins that form the glomerular
basement membranebasement membrane
Kanetsuna et al. Am.J. Renal.physiol, 291 (6): 1315 , 2016Kanetsuna et al. Am.J. Renal.physiol, 291 (6): 1315 , 2016
A. Hemodynamic Alteration:
- Systemic and renal hemodynamics critically affectedSystemic and renal hemodynamics critically affected
- HTN usually occur before ↓ GFR.HTN usually occur before ↓ GFR.
B. Abnormal metabolic and glycemicB. Abnormal metabolic and glycemic
control:control:
-- Improved control of hyperglycemia and ↓ intraglomerular andImproved control of hyperglycemia and ↓ intraglomerular and
systemic HTN → ↓ progression nephropathysystemic HTN → ↓ progression nephropathy
- Pancreatic transplantation reverse NephropathyPancreatic transplantation reverse Nephropathy
- Abnormal glycosylation of proteins that form the glomerularAbnormal glycosylation of proteins that form the glomerular
basement membranebasement membrane
Kanetsuna et al. Am.J. Renal.physiol, 291 (6): 1315 , 2016Kanetsuna et al. Am.J. Renal.physiol, 291 (6): 1315 , 2016

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c. Genetic predisposition:
-- Genetic susceptibility is supported by theGenetic susceptibility is supported by the
association of a family history of HTNassociation of a family history of HTN
and an ↑ incidence of Nephropathy.and an ↑ incidence of Nephropathy.
- Studies involving the renin-angiotensin- Studies involving the renin-angiotensin
system evidence for a genetic basis ofsystem evidence for a genetic basis of
diabetic nephropathydiabetic nephropathy
- Recent genome-wide linkage scansRecent genome-wide linkage scans
have identified several chromosomalhave identified several chromosomal
regions that likely contain diabeticregions that likely contain diabetic
nephropathy susceptibility genesnephropathy susceptibility genes
c. Genetic predisposition:
-- Genetic susceptibility is supported by theGenetic susceptibility is supported by the
association of a family history of HTNassociation of a family history of HTN
and an ↑ incidence of Nephropathy.and an ↑ incidence of Nephropathy.
- Studies involving the renin-angiotensin- Studies involving the renin-angiotensin
system evidence for a genetic basis ofsystem evidence for a genetic basis of
diabetic nephropathydiabetic nephropathy
- Recent genome-wide linkage scansRecent genome-wide linkage scans
have identified several chromosomalhave identified several chromosomal
regions that likely contain diabeticregions that likely contain diabetic
nephropathy susceptibility genesnephropathy susceptibility genes

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D. Race:
-- The incidence of diabetic Nephropathy isThe incidence of diabetic Nephropathy is
two to threefold higher in Africantwo to threefold higher in African
Americans and sex times higher inAmericans and sex times higher in
native Americans compared to whites.native Americans compared to whites.
D. Race:
-- The incidence of diabetic Nephropathy isThe incidence of diabetic Nephropathy is
two to threefold higher in Africantwo to threefold higher in African
Americans and sex times higher inAmericans and sex times higher in
native Americans compared to whites.native Americans compared to whites.

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E. Connective tissue growth factor (CTGF)
- (CTGF) ↑ in kidney disease(CTGF) ↑ in kidney disease
- Level ↑ with progression of kidney disease (inLevel ↑ with progression of kidney disease (in
Diabetics)Diabetics)
- Level ↑ with ↑ ProteinuriaLevel ↑ with ↑ Proteinuria
- Role in early and late stage of Diabetic NephropathyRole in early and late stage of Diabetic Nephropathy
- Upregulated by factors increase in hyperglycemiaUpregulated by factors increase in hyperglycemia
and HTNand HTN
i.i. Advanced glycation end productAdvanced glycation end product
ii.ii. Vascular endothelial growth factorVascular endothelial growth factor
iii.iii. Angiotensin IIAngiotensin II
iv.iv. Insulin like growth factor-1Insulin like growth factor-1
Diabetic Nephropathy: Fibrogen , 2016Diabetic Nephropathy: Fibrogen , 2016
E. Connective tissue growth factor (CTGF)
- (CTGF) ↑ in kidney disease(CTGF) ↑ in kidney disease
- Level ↑ with progression of kidney disease (inLevel ↑ with progression of kidney disease (in
Diabetics)Diabetics)
- Level ↑ with ↑ ProteinuriaLevel ↑ with ↑ Proteinuria
- Role in early and late stage of Diabetic NephropathyRole in early and late stage of Diabetic Nephropathy
- Upregulated by factors increase in hyperglycemiaUpregulated by factors increase in hyperglycemia
and HTNand HTN
i.i. Advanced glycation end productAdvanced glycation end product
ii.ii. Vascular endothelial growth factorVascular endothelial growth factor
iii.iii. Angiotensin IIAngiotensin II
iv.iv. Insulin like growth factor-1Insulin like growth factor-1
Diabetic Nephropathy: Fibrogen , 2016Diabetic Nephropathy: Fibrogen , 2016

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F. Activation of protein kinase- C-mitogen
↑ synthesis of diacylglycerol from glycolytic
intermediates regulator of all aspects
of the development and progression of
Aiello et al. Surv Opthalmol.47 suppl, 2: 263 , 2014
F. Activation of protein kinase- C-mitogen
↑ synthesis of diacylglycerol from glycolytic
intermediates regulator of all aspects
of the development and progression of
Aiello et al. Surv Opthalmol.47 suppl, 2: 263 , 2014

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Clinical featuresClinical featuresClinical featuresClinical features
 Edema: swelling : usually around eye, legsEdema: swelling : usually around eye, legs
 Foamy or excessive frothing of the urineFoamy or excessive frothing of the urine
 Wight gain (fluid accumulation)Wight gain (fluid accumulation)
 AnorexiaAnorexia
 Nausea and vomitingNausea and vomiting
 MalaiseMalaise
 FatigueFatigue
 HeadacheHeadache
 HiccupsHiccups
 Generalized itchingGeneralized itching
Diabetologia, 2017- pub MedDiabetologia, 2017- pub Med
 Edema: swelling : usually around eye, legsEdema: swelling : usually around eye, legs
 Foamy or excessive frothing of the urineFoamy or excessive frothing of the urine
 Wight gain (fluid accumulation)Wight gain (fluid accumulation)
 AnorexiaAnorexia
 Nausea and vomitingNausea and vomiting
 MalaiseMalaise
 FatigueFatigue
 HeadacheHeadache
 HiccupsHiccups
 Generalized itchingGeneralized itching
Diabetologia, 2017- pub MedDiabetologia, 2017- pub Med

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TreatmentTreatmentTreatmentTreatment
Preventing disease progressionPreventing disease progression
 Adequate treatment of HTNAdequate treatment of HTN
 Prevent use of radiocontrast andPrevent use of radiocontrast and
Nephrotoxic drugs.Nephrotoxic drugs.
 Prevent overuse of diureticsPrevent overuse of diuretics
 Treat UTITreat UTI
 Glycemic ControlGlycemic Control
Giuseppe et al. Nature Clinical Practice Nephrology.2, 132 , 2016Giuseppe et al. Nature Clinical Practice Nephrology.2, 132 , 2016
Preventing disease progressionPreventing disease progression
 Adequate treatment of HTNAdequate treatment of HTN
 Prevent use of radiocontrast andPrevent use of radiocontrast and
Nephrotoxic drugs.Nephrotoxic drugs.
 Prevent overuse of diureticsPrevent overuse of diuretics
 Treat UTITreat UTI
 Glycemic ControlGlycemic Control
Giuseppe et al. Nature Clinical Practice Nephrology.2, 132 , 2016Giuseppe et al. Nature Clinical Practice Nephrology.2, 132 , 2016

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Treatment ofTreatment of
Treatment ofTreatment of
 ACE inhibitors (maximum dose) → ↓ACE inhibitors (maximum dose) → ↓
albuminuriaalbuminuria
 Tight glycemic controlTight glycemic control
 Protein restrictionProtein restriction
 Development of overtDevelopment of overt
macroalbuminuria and diabeticmacroalbuminuria and diabetic
nephropathy can be avoided.nephropathy can be avoided.
Pharmabiz. Com , 2016Pharmabiz. Com , 2016
 ACE inhibitors (maximum dose) → ↓ACE inhibitors (maximum dose) → ↓
albuminuriaalbuminuria
 Tight glycemic controlTight glycemic control
 Protein restrictionProtein restriction
 Development of overtDevelopment of overt
macroalbuminuria and diabeticmacroalbuminuria and diabetic
nephropathy can be avoided.nephropathy can be avoided.
Pharmabiz. Com , 2016Pharmabiz. Com , 2016

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Management afterManagement after
macroalbuminuriamacroalbuminuria
Management afterManagement after
macroalbuminuriamacroalbuminuria
 Once macroalbuminuria develops, the course cannotOnce macroalbuminuria develops, the course cannot
be reversedbe reversed
 Control blood pressureControl blood pressure
-- Regard pressure > 135/85 mmHg as abnormalRegard pressure > 135/85 mmHg as abnormal
- Attempt to lower systolic level to 100-110 mmHg- Attempt to lower systolic level to 100-110 mmHg
- Include ACE inhibitor in regimen- Include ACE inhibitor in regimen
- Consider including nondihydropyridine calcium- Consider including nondihydropyridine calcium
channel Blocker to decrease production ofchannel Blocker to decrease production of
lymphokineslymphokines
 Smoking CessationSmoking Cessation
Josep M., Nature Clinical Practice Nephrology.2, 192 , 2016Josep M., Nature Clinical Practice Nephrology.2, 192 , 2016
 Once macroalbuminuria develops, the course cannotOnce macroalbuminuria develops, the course cannot
be reversedbe reversed
 Control blood pressureControl blood pressure
-- Regard pressure > 135/85 mmHg as abnormalRegard pressure > 135/85 mmHg as abnormal
- Attempt to lower systolic level to 100-110 mmHg- Attempt to lower systolic level to 100-110 mmHg
- Include ACE inhibitor in regimen- Include ACE inhibitor in regimen
- Consider including nondihydropyridine calcium- Consider including nondihydropyridine calcium
channel Blocker to decrease production ofchannel Blocker to decrease production of
lymphokineslymphokines
 Smoking CessationSmoking Cessation
Josep M., Nature Clinical Practice Nephrology.2, 192 , 2016Josep M., Nature Clinical Practice Nephrology.2, 192 , 2016

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ManagementManagementManagementManagement
 Prevent radiocontrast induced renal shutPrevent radiocontrast induced renal shut
downdown
 Avoid using high volume of iodinatedAvoid using high volume of iodinated
radiocontrast (coronary angio)radiocontrast (coronary angio)
 Avoid risk factors:Avoid risk factors:
-- sepsissepsis
- Hypoxia- Hypoxia
- Dehydration- Dehydration
- Use of nephrotoxic antibiotics- Use of nephrotoxic antibiotics
- Use of antifungal agents- Use of antifungal agents
- Use of NSAID- Use of NSAID
Tsikouris, J.Cli Pharmacol 44:327 , 2016Tsikouris, J.Cli Pharmacol 44:327 , 2016
 Prevent radiocontrast induced renal shutPrevent radiocontrast induced renal shut
downdown
 Avoid using high volume of iodinatedAvoid using high volume of iodinated
radiocontrast (coronary angio)radiocontrast (coronary angio)
 Avoid risk factors:Avoid risk factors:
-- sepsissepsis
- Hypoxia- Hypoxia
- Dehydration- Dehydration
- Use of nephrotoxic antibiotics- Use of nephrotoxic antibiotics
- Use of antifungal agents- Use of antifungal agents
- Use of NSAID- Use of NSAID
Tsikouris, J.Cli Pharmacol 44:327 , 2016Tsikouris, J.Cli Pharmacol 44:327 , 2016

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 Restrict the dietary protein (0.6 - 0.8 gm/kg ofRestrict the dietary protein (0.6 - 0.8 gm/kg of
body wt)body wt)
 Maintain hydrationMaintain hydration
 Lower diuretic doseLower diuretic dose
 Avoid renal damage from infection and drugAvoid renal damage from infection and drug
useuse
 Control vascular disease and dyslipidemiaControl vascular disease and dyslipidemia
Mauro Verrelli, Chronic Renal failure, Medicine , 2015Mauro Verrelli, Chronic Renal failure, Medicine , 2015
 Restrict the dietary protein (0.6 - 0.8 gm/kg ofRestrict the dietary protein (0.6 - 0.8 gm/kg of
body wt)body wt)
 Maintain hydrationMaintain hydration
 Lower diuretic doseLower diuretic dose
 Avoid renal damage from infection and drugAvoid renal damage from infection and drug
useuse
 Control vascular disease and dyslipidemiaControl vascular disease and dyslipidemia
Mauro Verrelli, Chronic Renal failure, Medicine , 2015Mauro Verrelli, Chronic Renal failure, Medicine , 2015

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BradykininBradykinin
 Bradykinin system plays a critical role inBradykinin system plays a critical role in
protecting the kidney from damage causedprotecting the kidney from damage caused
by diabetes mellitusby diabetes mellitus
 Enhancing the action of kinins as means ofEnhancing the action of kinins as means of
minimizing this diabetic complication is veryminimizing this diabetic complication is very
importantimportant
Tan et al., Am.J.Renal Physiol.293 (4):1035 , 2017Tan et al., Am.J.Renal Physiol.293 (4):1035 , 2017
BradykininBradykinin
 Bradykinin system plays a critical role inBradykinin system plays a critical role in
protecting the kidney from damage causedprotecting the kidney from damage caused
by diabetes mellitusby diabetes mellitus
 Enhancing the action of kinins as means ofEnhancing the action of kinins as means of
minimizing this diabetic complication is veryminimizing this diabetic complication is very
importantimportant
Tan et al., Am.J.Renal Physiol.293 (4):1035 , 2017Tan et al., Am.J.Renal Physiol.293 (4):1035 , 2017

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PLoS One. 2017 Jul 10;12(7):e0180964. doi: 10.1371/journal.pone.0180964.
eCollection 2017.
Plasma bradykinin and early diabetic nephropathy
lesions in type 1 diabetes mellitus.
Wheelock KM1
, Cai J2
, Looker HC1
, Merchant ML2
, Nelson RG1
, Fufaa
GD1
, Weil EJ1
, Feldman HI3
, Vasan RS4
, Kimmel PL5
, Rovin BH6
, Mauer
M7
, Klein JB2
; CKD Biomarkers Consortium.
CONCLUSIONS:
Higher plasma bradykinin and related peptide concentrations measured
before clinical onset of diabetic nephropathy in persons with T1D were
associated with preservation of glomerular structures, suggesting that
elevations of these kinin concentrations may reflect adaptive responses to
early renal structural changes in diabetic nephropathy.

40
ThiamineThiamine
 Thiamine has been shown to reduce DiabeticThiamine has been shown to reduce Diabetic
Nephropathy and retinopathy in experimental animalsNephropathy and retinopathy in experimental animals
 Last study used benfotiamine which ameliorate theLast study used benfotiamine which ameliorate the
effects of both albuminuria/ proteinuria andeffects of both albuminuria/ proteinuria and
hyperglycemia on oxidative stress and advancedhyperglycemia on oxidative stress and advanced
glycation end products accumulation in renal tissueglycation end products accumulation in renal tissue
 Benfotiamine 300 mg TID ↓ inflammtory responsesBenfotiamine 300 mg TID ↓ inflammtory responses
and fibrotic responses → ↓ progression to CRFand fibrotic responses → ↓ progression to CRF
Clinical trials. gov , 2016Clinical trials. gov , 2016
ThiamineThiamine
 Thiamine has been shown to reduce DiabeticThiamine has been shown to reduce Diabetic
Nephropathy and retinopathy in experimental animalsNephropathy and retinopathy in experimental animals
 Last study used benfotiamine which ameliorate theLast study used benfotiamine which ameliorate the
effects of both albuminuria/ proteinuria andeffects of both albuminuria/ proteinuria and
hyperglycemia on oxidative stress and advancedhyperglycemia on oxidative stress and advanced
glycation end products accumulation in renal tissueglycation end products accumulation in renal tissue
 Benfotiamine 300 mg TID ↓ inflammtory responsesBenfotiamine 300 mg TID ↓ inflammtory responses
and fibrotic responses → ↓ progression to CRFand fibrotic responses → ↓ progression to CRF
Clinical trials. gov , 2016Clinical trials. gov , 2016

42
GlutathioneGlutathione
 Glutathione treatment can be beneficialGlutathione treatment can be beneficial
affect diabetic rats and preserve renal andaffect diabetic rats and preserve renal and
neural function.neural function.
 This suggests a potential usefulness ofThis suggests a potential usefulness of
dietary glutathione treatment to reducedietary glutathione treatment to reduce
diabetic complications.diabetic complications.
Osawa et al. Ann.N.Y.Acad.Sci, 1043(1):440 , 2016Osawa et al. Ann.N.Y.Acad.Sci, 1043(1):440 , 2016
GlutathioneGlutathione
 Glutathione treatment can be beneficialGlutathione treatment can be beneficial
affect diabetic rats and preserve renal andaffect diabetic rats and preserve renal and
neural function.neural function.
 This suggests a potential usefulness ofThis suggests a potential usefulness of
dietary glutathione treatment to reducedietary glutathione treatment to reduce
diabetic complications.diabetic complications.
Osawa et al. Ann.N.Y.Acad.Sci, 1043(1):440 , 2016Osawa et al. Ann.N.Y.Acad.Sci, 1043(1):440 , 2016

44
ThiazolidinedionesThiazolidinediones
 Thiazolidinediones (Pioglitazone andThiazolidinediones (Pioglitazone and
rosiglitazone)are synthetic agonists ofrosiglitazone)are synthetic agonists of
peroxisome proliferator-activatedperoxisome proliferator-activated
receptors that have shown promise inreceptors that have shown promise in
vitro and animal models ofvitro and animal models of
nephropathynephropathy
Usha et al., Nature clinical practice nephropathy.1,33-43 , 2015Usha et al., Nature clinical practice nephropathy.1,33-43 , 2015
ThiazolidinedionesThiazolidinediones
 Thiazolidinediones (Pioglitazone andThiazolidinediones (Pioglitazone and
rosiglitazone)are synthetic agonists ofrosiglitazone)are synthetic agonists of
peroxisome proliferator-activatedperoxisome proliferator-activated
receptors that have shown promise inreceptors that have shown promise in
vitro and animal models ofvitro and animal models of
Usha et al., Nature clinical practice nephropathy.1,33-43 , 2015Usha et al., Nature clinical practice nephropathy.1,33-43 , 2015

45
C-peptideC-peptide
 C-peptide, a by product of insulinC-peptide, a by product of insulin
production, may provide new hope forproduction, may provide new hope for
patients suffering from diabeticpatients suffering from diabetic
Diabetologia , 2016- PubMedDiabetologia , 2016- PubMed
C-peptideC-peptide
 C-peptide, a by product of insulinC-peptide, a by product of insulin
production, may provide new hope forproduction, may provide new hope for
patients suffering from diabeticpatients suffering from diabetic
Diabetologia , 2016- PubMedDiabetologia , 2016- PubMed

46
Protein Kinase-C inhibitorsProtein Kinase-C inhibitors
 Protein Kinase-C inhibitorsProtein Kinase-C inhibitors
- Vitamin E- Vitamin E
- Thiazolidinediones- Thiazolidinediones
- Protein Kinase C specific inhibitor- Protein Kinase C specific inhibitor
 Prevent diabetes induced glomerular hyperfiltration,Prevent diabetes induced glomerular hyperfiltration,
albuminuria and glomerular over expression of TGF-Balbuminuria and glomerular over expression of TGF-B
Koya et al., FASEB J.14: 1439 , 2015Koya et al., FASEB J.14: 1439 , 2015
Protein Kinase-C inhibitorsProtein Kinase-C inhibitors
 Protein Kinase-C inhibitorsProtein Kinase-C inhibitors
- Vitamin E- Vitamin E
- Thiazolidinediones- Thiazolidinediones
- Protein Kinase C specific inhibitor- Protein Kinase C specific inhibitor
 Prevent diabetes induced glomerular hyperfiltration,Prevent diabetes induced glomerular hyperfiltration,
albuminuria and glomerular over expression of TGF-Balbuminuria and glomerular over expression of TGF-B
Koya et al., FASEB J.14: 1439 , 2015Koya et al., FASEB J.14: 1439 , 2015

49
Anti-Connective tissue growth factorAnti-Connective tissue growth factor
 Anti-Connective tissue growth factor (anti-CTGF)Anti-Connective tissue growth factor (anti-CTGF)
 Anti-CTGF therapy during the early stages of diabeticAnti-CTGF therapy during the early stages of diabetic
nephropathy help delay the onset and reduce thenephropathy help delay the onset and reduce the
severity of cardiovascular diseases and retinopathyseverity of cardiovascular diseases and retinopathy
which frequently accompany progression to renalwhich frequently accompany progression to renal
failurefailure
Diabetic Nephropathy:Fibrogen , 2016Diabetic Nephropathy:Fibrogen , 2016
Anti-Connective tissue growth factorAnti-Connective tissue growth factor
 Anti-Connective tissue growth factor (anti-CTGF)Anti-Connective tissue growth factor (anti-CTGF)
 Anti-CTGF therapy during the early stages of diabeticAnti-CTGF therapy during the early stages of diabetic
nephropathy help delay the onset and reduce thenephropathy help delay the onset and reduce the
severity of cardiovascular diseases and retinopathyseverity of cardiovascular diseases and retinopathy
which frequently accompany progression to renalwhich frequently accompany progression to renal
failurefailure
Diabetic Nephropathy:Fibrogen , 2016Diabetic Nephropathy:Fibrogen , 2016

51
CarnosineCarnosine
 Carnosine is a dipeptide of the amino acid betaCarnosine is a dipeptide of the amino acid beta
alanine and histidine, highly concentrate in musclealanine and histidine, highly concentrate in muscle
and brain tissues.and brain tissues.
 inhibit the fibronectin and collagen type VI ininhibit the fibronectin and collagen type VI in
podocytes.podocytes.
 protects against the adverse effects of renal cellsprotects against the adverse effects of renal cells
 Antioxidant inhibit diabetic nephropathy by protectingAntioxidant inhibit diabetic nephropathy by protecting
podocytes and mesangial cells.podocytes and mesangial cells.
Janssen et al., Daibetes 54 (8): 2320 , 2017Janssen et al., Daibetes 54 (8): 2320 , 2017
CarnosineCarnosine
 Carnosine is a dipeptide of the amino acid betaCarnosine is a dipeptide of the amino acid beta
alanine and histidine, highly concentrate in musclealanine and histidine, highly concentrate in muscle
and brain tissues.and brain tissues.
 inhibit the fibronectin and collagen type VI ininhibit the fibronectin and collagen type VI in
podocytes.podocytes.
 protects against the adverse effects of renal cellsprotects against the adverse effects of renal cells
 Antioxidant inhibit diabetic nephropathy by protectingAntioxidant inhibit diabetic nephropathy by protecting
podocytes and mesangial cells.podocytes and mesangial cells.
Janssen et al., Daibetes 54 (8): 2320 , 2017Janssen et al., Daibetes 54 (8): 2320 , 2017

53
Pyridoxal PhosphatePyridoxal Phosphate
 Promising active form of vitamin B6Promising active form of vitamin B6
 Prevent progression of nephropathy inPrevent progression of nephropathy in
streptozotocin –induced diabetic rats bystreptozotocin –induced diabetic rats by
inhibiting formation of advanced glycationinhibiting formation of advanced glycation
end productsend products
Sakurako et al., Nephrology Dialysis Transplantaion.22 (8): 2165 , 2015Sakurako et al., Nephrology Dialysis Transplantaion.22 (8): 2165 , 2015
Pyridoxal PhosphatePyridoxal Phosphate
 Promising active form of vitamin B6Promising active form of vitamin B6
 Prevent progression of nephropathy inPrevent progression of nephropathy in
streptozotocin –induced diabetic rats bystreptozotocin –induced diabetic rats by
inhibiting formation of advanced glycationinhibiting formation of advanced glycation
end productsend products
Sakurako et al., Nephrology Dialysis Transplantaion.22 (8): 2165 , 2015Sakurako et al., Nephrology Dialysis Transplantaion.22 (8): 2165 , 2015

55
Sulonex (Sulodexide)Sulonex (Sulodexide)
Last reports revealed that results still notLast reports revealed that results still not
satisfactorysatisfactory
Medical News Today , 2016Medical News Today , 2016
Sulonex (Sulodexide)Sulonex (Sulodexide)
Last reports revealed that results still notLast reports revealed that results still not
satisfactorysatisfactory
Medical News Today , 2016Medical News Today , 2016

56
Meprine inhibitor (actinonin)Meprine inhibitor (actinonin)
 Meprine brush border enzyme (renalMeprine brush border enzyme (renal
proximal tubules) play a role in ischemiaproximal tubules) play a role in ischemia
 Meprine is cytotoxic renal tubular epithelialMeprine is cytotoxic renal tubular epithelial
cellscells
Bylander et al., Am. J. Renal Physiol.294 (3):480 , 2016Bylander et al., Am. J. Renal Physiol.294 (3):480 , 2016
Meprine inhibitor (actinonin)Meprine inhibitor (actinonin)
 Meprine brush border enzyme (renalMeprine brush border enzyme (renal
proximal tubules) play a role in ischemiaproximal tubules) play a role in ischemia
 Meprine is cytotoxic renal tubular epithelialMeprine is cytotoxic renal tubular epithelial
cellscells
Bylander et al., Am. J. Renal Physiol.294 (3):480 , 2016Bylander et al., Am. J. Renal Physiol.294 (3):480 , 2016

57
RuboxistaurinRuboxistaurin
 Protein kinase C beta inhibitorProtein kinase C beta inhibitor
 Showed favourable effects on kidneyShowed favourable effects on kidney
damage and function in patients with type IIdamage and function in patients with type II
diabetes and nephropathydiabetes and nephropathy
William M et al,Adv chronic Kidney Dis 12 ( 2) 212 , 2016William M et al,Adv chronic Kidney Dis 12 ( 2) 212 , 2016
RuboxistaurinRuboxistaurin
 Protein kinase C beta inhibitorProtein kinase C beta inhibitor
 Showed favourable effects on kidneyShowed favourable effects on kidney
damage and function in patients with type IIdamage and function in patients with type II
diabetes and nephropathydiabetes and nephropathy
William M et al,Adv chronic Kidney Dis 12 ( 2) 212 , 2016William M et al,Adv chronic Kidney Dis 12 ( 2) 212 , 2016

58
Red Cabbage (Brassica Oleracea)Red Cabbage (Brassica Oleracea)
 Ameliorates diabetic nephropathy in ratsAmeliorates diabetic nephropathy in rats
 Antioxidant and antihyperglycemicAntioxidant and antihyperglycemic
 Extract of red cabbage offer a potentialExtract of red cabbage offer a potential
therapeutic for treatment of diabetestherapeutic for treatment of diabetes
Kataya and Hamza. Evidence-based complementary and alternative medicineKataya and Hamza. Evidence-based complementary and alternative medicine
, 2017, 2017
Red Cabbage (Brassica Oleracea)Red Cabbage (Brassica Oleracea)
 Ameliorates diabetic nephropathy in ratsAmeliorates diabetic nephropathy in rats
 Antioxidant and antihyperglycemicAntioxidant and antihyperglycemic
 Extract of red cabbage offer a potentialExtract of red cabbage offer a potential
therapeutic for treatment of diabetestherapeutic for treatment of diabetes
Kataya and Hamza. Evidence-based complementary and alternative medicineKataya and Hamza. Evidence-based complementary and alternative medicine
, 2017, 2017

59
Search: keywords, title, authors, DOI
Search
Amelioration of streptozotocin-induced diabetic
nephropathy by melatonin, quercetin, and resveratrol in
rats
Show all authors
H Elbe, N Vardi, M Esrefoglu, ...
First Published May 8, 2014 Research Article

Dr alaa saleh diabetic nephropathy

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