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 Sepecialist King Abdul-Aziz Sepecialist

Hospital-TaifHospital-Taif

Dr. Alaa Ibrahim Saleh ,MDDr. Alaa Ibrahim Saleh ,MD

Senior Consultant Nephrologist, Senior Consultant Nephrologist, King Abdul-Aziz Sepecialist King Abdul-Aziz Sepecialist

Hospital-TaifHospital-Taif

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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

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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 , 20148

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Clinical presentations and Clinical presentations and pathophysiologypathophysiology

Clinical presentations and Clinical presentations and pathophysiologypathophysiologyStage I:Stage I:

Hyperfiltration- hypertrophy Hyperfiltration- hypertrophy stage (stage (↑GFR)↑GFR)

Glucosuria with polyuria and Glucosuria with polyuria and microalbuminuria microalbuminuria

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- hypertrophy Hyperfiltration- hypertrophy

stage (stage (↑GFR)↑GFR) Glucosuria with polyuria and Glucosuria with polyuria and

microalbuminuria microalbuminuria 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 near Microalbuminuria is normal or near

normal (normal (< 20 < 20 μμg/min)g/min)

GFR (Normal)GFR (Normal)

Membrane thickening and mesangial Membrane 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 near Microalbuminuria is normal or near

normal (normal (< 20 < 20 μμg/min)g/min)

GFR (Normal)GFR (Normal)

Membrane thickening and mesangial Membrane 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 nondiabetic Feature suggestive of nondiabetic renal disease in diabetic patientsrenal disease in diabetic patients

Feature suggestive of nondiabetic Feature 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 glycemic B. Abnormal metabolic and glycemic control: control:

- - Improved control of hyperglycemia and ↓ intraglomerular and Improved 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 glomerular Abnormal 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 glycemic B. Abnormal metabolic and glycemic control: control:

- - Improved control of hyperglycemia and ↓ intraglomerular and Improved 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 glomerular Abnormal 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 the Genetic susceptibility is supported by the

association of a family history of HTN association 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 of system evidence for a genetic basis of diabetic nephropathydiabetic nephropathy

- Recent genome-wide linkage scans Recent genome-wide linkage scans have identified several chromosomal have identified several chromosomal regions that likely contain diabetic regions that likely contain diabetic nephropathy susceptibility genesnephropathy susceptibility genes

c. Genetic predisposition: - - Genetic susceptibility is supported by the Genetic susceptibility is supported by the

association of a family history of HTN association 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 of system evidence for a genetic basis of diabetic nephropathydiabetic nephropathy

- Recent genome-wide linkage scans Recent genome-wide linkage scans have identified several chromosomal have identified several chromosomal regions that likely contain diabetic regions that likely contain diabetic nephropathy susceptibility genesnephropathy susceptibility genes

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D. Race:

- - The incidence of diabetic Nephropathy is The incidence of diabetic Nephropathy is two to threefold higher in African two to threefold higher in African Americans and sex times higher in Americans and sex times higher in native Americans compared to whites.native Americans compared to whites.

D. Race:

- - The incidence of diabetic Nephropathy is The incidence of diabetic Nephropathy is two to threefold higher in African two to threefold higher in African Americans and sex times higher in Americans and sex times higher in native Americans compared to whites.native Americans compared to whites.

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PathogenesisPathogenesisPathogenesisPathogenesisE. Connective tissue growth factor (CTGF)

- (CTGF) ↑ in kidney disease(CTGF) ↑ in kidney disease- Level ↑ with progression of kidney disease (in Level ↑ 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 hyperglycemia Upregulated by factors increase in hyperglycemia

and HTNand HTNi.i. Advanced glycation end productAdvanced glycation end productii.ii. Vascular endothelial growth factorVascular endothelial growth factoriii.iii. Angiotensin IIAngiotensin IIiv.iv. Insulin like growth factor-1 Insulin 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 (in Level ↑ 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 hyperglycemia Upregulated by factors increase in hyperglycemia

and HTNand HTNi.i. Advanced glycation end productAdvanced glycation end productii.ii. Vascular endothelial growth factorVascular endothelial growth factoriii.iii. Angiotensin IIAngiotensin IIiv.iv. Insulin like growth factor-1 Insulin 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 Diabetic Nephropathy

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 Diabetic Nephropathy

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 and Prevent use of radiocontrast and

Nephrotoxic drugs.Nephrotoxic drugs. Prevent overuse of diureticsPrevent overuse of diuretics Treat UTITreat UTI Glycemic Control Glycemic 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 and Prevent use of radiocontrast and

Nephrotoxic drugs.Nephrotoxic drugs. Prevent overuse of diureticsPrevent overuse of diuretics Treat UTITreat UTI Glycemic Control Glycemic 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 of Treatment of microalbuminuriamicroalbuminuria

Treatment of Treatment of microalbuminuriamicroalbuminuria

ACE inhibitors (maximum dose) → ↓ ACE inhibitors (maximum dose) → ↓ albuminuriaalbuminuria

Tight glycemic controlTight glycemic control Protein restrictionProtein restriction Development of overt Development of overt

macroalbuminuria and diabetic macroalbuminuria 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 overt Development of overt

macroalbuminuria and diabetic macroalbuminuria and diabetic nephropathy can be avoided.nephropathy can be avoided.

Pharmabiz. Com , 2016Pharmabiz. Com , 2016

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Management after Management after macroalbuminuriamacroalbuminuriaManagement after Management after macroalbuminuriamacroalbuminuria

Once macroalbuminuria develops, the course cannot Once 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 of channel Blocker to decrease production of lymphokines lymphokines

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 cannot Once 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 of channel Blocker to decrease production of lymphokines lymphokines

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 shut Prevent radiocontrast induced renal shut downdown

Avoid using high volume of iodinated Avoid using high volume of iodinated radiocontrast (coronary angio)radiocontrast (coronary angio)

Avoid risk factors: Avoid risk factors: -- sepsis sepsis - 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 shut Prevent radiocontrast induced renal shut downdown

Avoid using high volume of iodinated Avoid using high volume of iodinated radiocontrast (coronary angio)radiocontrast (coronary angio)

Avoid risk factors: Avoid risk factors: -- sepsis sepsis - 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 of Restrict 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 drug Avoid 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 of Restrict 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 drug Avoid 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 in Bradykinin system plays a critical role in

protecting the kidney from damage caused protecting the kidney from damage caused by diabetes mellitusby diabetes mellitus

Enhancing the action of kinins as means of Enhancing the action of kinins as means of minimizing this diabetic complication is very minimizing 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 in Bradykinin system plays a critical role in

protecting the kidney from damage caused protecting the kidney from damage caused by diabetes mellitusby diabetes mellitus

Enhancing the action of kinins as means of Enhancing the action of kinins as means of minimizing this diabetic complication is very minimizing 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.

https://www.ncbi.nlm.nih.gov/pubmed/28700653

https://www.ncbi.nlm.nih.gov/pubmed/?term=Wheelock%20KM%5BAuthor%5D&cauthor=true&cauthor_uid=28700653

https://www.ncbi.nlm.nih.gov/pubmed/?term=Wheelock%20KM%5BAuthor%5D&cauthor=true&cauthor_uid=28700653

https://www.ncbi.nlm.nih.gov/pubmed/?term=Cai%20J%5BAuthor%5D&cauthor=true&cauthor_uid=28700653

https://www.ncbi.nlm.nih.gov/pubmed/?term=Looker%20HC%5BAuthor%5D&cauthor=true&cauthor_uid=28700653

https://www.ncbi.nlm.nih.gov/pubmed/?term=Merchant%20ML%5BAuthor%5D&cauthor=true&cauthor_uid=28700653

https://www.ncbi.nlm.nih.gov/pubmed/?term=Nelson%20RG%5BAuthor%5D&cauthor=true&cauthor_uid=28700653

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ThiamineThiamine Thiamine has been shown to reduce Diabetic Thiamine has been shown to reduce Diabetic

Nephropathy and retinopathy in experimental animals Nephropathy and retinopathy in experimental animals Last study used benfotiamine which ameliorate the Last study used benfotiamine which ameliorate the

effects of both albuminuria/ proteinuria and effects of both albuminuria/ proteinuria and hyperglycemia on oxidative stress and advanced hyperglycemia on oxidative stress and advanced glycation end products accumulation in renal tissueglycation end products accumulation in renal tissue

Benfotiamine 300 mg TID ↓ inflammtory responses Benfotiamine 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 Diabetic Thiamine has been shown to reduce Diabetic

Nephropathy and retinopathy in experimental animals Nephropathy and retinopathy in experimental animals Last study used benfotiamine which ameliorate the Last study used benfotiamine which ameliorate the

effects of both albuminuria/ proteinuria and effects of both albuminuria/ proteinuria and hyperglycemia on oxidative stress and advanced hyperglycemia on oxidative stress and advanced glycation end products accumulation in renal tissueglycation end products accumulation in renal tissue

Benfotiamine 300 mg TID ↓ inflammtory responses Benfotiamine 300 mg TID ↓ inflammtory responses and fibrotic responses → ↓ progression to CRFand fibrotic responses → ↓ progression to CRF

Clinical trials. gov , 2016Clinical trials. gov , 2016

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GlutathioneGlutathione Glutathione treatment can be beneficial Glutathione treatment can be beneficial

affect diabetic rats and preserve renal and affect diabetic rats and preserve renal and neural function. neural function.

This suggests a potential usefulness of This suggests a potential usefulness of dietary glutathione treatment to reduce dietary 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 beneficial Glutathione treatment can be beneficial

affect diabetic rats and preserve renal and affect diabetic rats and preserve renal and neural function. neural function.

This suggests a potential usefulness of This suggests a potential usefulness of dietary glutathione treatment to reduce dietary 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

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ThiazolidinedionesThiazolidinediones Thiazolidinediones (Pioglitazone and Thiazolidinediones (Pioglitazone and

rosiglitazone)are synthetic agonists of rosiglitazone)are synthetic agonists of peroxisome proliferator-activated peroxisome proliferator-activated receptors that have shown promise in receptors that have shown promise in vitro and animal models of vitro and animal models of nephropathy nephropathy

Usha et al., Nature clinical practice nephropathy.1,33-43 , 2015Usha et al., Nature clinical practice nephropathy.1,33-43 , 2015

ThiazolidinedionesThiazolidinediones Thiazolidinediones (Pioglitazone and Thiazolidinediones (Pioglitazone and

rosiglitazone)are synthetic agonists of rosiglitazone)are synthetic agonists of peroxisome proliferator-activated peroxisome proliferator-activated receptors that have shown promise in receptors that have shown promise in vitro and animal models of vitro and animal models of nephropathy nephropathy

Usha et al., Nature clinical practice nephropathy.1,33-43 , 2015Usha et al., Nature clinical practice nephropathy.1,33-43 , 2015

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C-peptideC-peptide C-peptide, a by product of insulin C-peptide, a by product of insulin

production, may provide new hope for production, may provide new hope for patients suffering from diabetic patients suffering from diabetic nephropathy nephropathy

Diabetologia , 2016- PubMedDiabetologia , 2016- PubMed

C-peptideC-peptide C-peptide, a by product of insulin C-peptide, a by product of insulin

production, may provide new hope for production, may provide new hope for patients suffering from diabetic patients suffering from diabetic nephropathy nephropathy

Diabetologia , 2016- PubMedDiabetologia , 2016- PubMed

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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-B albuminuria 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-B albuminuria and glomerular over expression of TGF-B

Koya et al., FASEB J.14: 1439 , 2015Koya et al., FASEB J.14: 1439 , 2015

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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 diabetic Anti-CTGF therapy during the early stages of diabetic

nephropathy help delay the onset and reduce the nephropathy help delay the onset and reduce the severity of cardiovascular diseases and retinopathy severity of cardiovascular diseases and retinopathy which frequently accompany progression to renal which frequently accompany progression to renal failure failure

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 diabetic Anti-CTGF therapy during the early stages of diabetic

nephropathy help delay the onset and reduce the nephropathy help delay the onset and reduce the severity of cardiovascular diseases and retinopathy severity of cardiovascular diseases and retinopathy which frequently accompany progression to renal which frequently accompany progression to renal failure failure

Diabetic Nephropathy:Fibrogen , 2016Diabetic Nephropathy:Fibrogen , 2016

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CarnosineCarnosine Carnosine is a dipeptide of the amino acid beta Carnosine is a dipeptide of the amino acid beta

alanine and histidine, highly concentrate in muscle alanine and histidine, highly concentrate in muscle and brain tissues.and brain tissues.

inhibit the fibronectin and collagen type VI in inhibit 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 protecting Antioxidant 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 beta Carnosine is a dipeptide of the amino acid beta

alanine and histidine, highly concentrate in muscle alanine and histidine, highly concentrate in muscle and brain tissues.and brain tissues.

inhibit the fibronectin and collagen type VI in inhibit 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 protecting Antioxidant 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

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Pyridoxal PhosphatePyridoxal Phosphate Promising active form of vitamin B6 Promising active form of vitamin B6 Prevent progression of nephropathy in Prevent progression of nephropathy in

streptozotocin –induced diabetic rats by streptozotocin –induced diabetic rats by inhibiting formation of advanced glycation inhibiting 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 B6 Promising active form of vitamin B6 Prevent progression of nephropathy in Prevent progression of nephropathy in

streptozotocin –induced diabetic rats by streptozotocin –induced diabetic rats by inhibiting formation of advanced glycation inhibiting 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

54

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Sulonex (Sulodexide)Sulonex (Sulodexide)Last reports revealed that results still not Last reports revealed that results still not

satisfactorysatisfactory

Medical News Today , 2016Medical News Today , 2016

Sulonex (Sulodexide)Sulonex (Sulodexide)Last reports revealed that results still not Last 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 (renal Meprine brush border enzyme (renal

proximal tubules) play a role in ischemiaproximal tubules) play a role in ischemia Meprine is cytotoxic renal tubular epithelial Meprine 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 (renal Meprine brush border enzyme (renal

proximal tubules) play a role in ischemiaproximal tubules) play a role in ischemia Meprine is cytotoxic renal tubular epithelial Meprine 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 kidney Showed favourable effects on kidney

damage and function in patients with type II damage 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 kidney Showed favourable effects on kidney

damage and function in patients with type II damage 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

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ManagementManagementManagementManagementRed 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 potential Extract of red cabbage offer a potential

therapeutic for treatment of diabetes therapeutic for treatment of diabetes

Kataya and Hamza. Evidence-based complementary and alternative medicine Kataya 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 potential Extract of red cabbage offer a potential

therapeutic for treatment of diabetes therapeutic for treatment of diabetes

Kataya and Hamza. Evidence-based complementary and alternative medicine Kataya and Hamza. Evidence-based complementary and alternative medicine

, 2017, 2017

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

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Dr alaa saleh diabetic nephropathy

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