Diabetic Nephropathy Review

Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016 1

JAFAR AL-SAID. M.B.CHB. MD. FASN. FACP.CHAIR OF INTERNAL MEDICINE.NEPHROLOGY AND INTERNAL MEDICINE CONSULTANT.BAHRAIN SPECIALIST HOSPITAL.

Diabetic Nephropathy




• Introduction.• Epidemiology.• Pathogenesis. • Progression. • Diagnosis. • Management.

Scheme


Historical Points• 18th Century Proteinuria was recognized in DM.

• 1930 Kimmelstiel and Wilson described the typical nodular glomerular lesion in Dm with Proteinuria.

• 1950 Kidney disease was recognized as DM complication.

• Current Leading cause of ESRD in USA and western societies.

BatumanVecihi, Khardori Romesh, et. Al. Diabetic Nephropathy: Background, Pathophysiology, Etiology Medscape. Updated: Jul 31, 2015


20-40% of DM patient will develop Nephropathy.

In the presence of Minimal Albuminuria > 300mg/dl It will develop in:

• 80% of DM I.

• 20-40% of DM II.

Introduction

Suma Dronavalli, Irena Duka, George L. Bakris. The Pathogenesis of Diabetic Nephropathy Posted: 08/01/2008; Nat Clin Pract Endocrinol Metab CME © 2008. http://www.medscape.org/viewarticle/577156


Definition

A syndrome characterized in diabetics by 2 of the following:

• Persistent albuminuria > 300mg/day. On at least to occasions 3 -6m apart. • Progressive decline in GFR.• Elevated BP.


Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016 8Hypertension Dyslipidemia Kidney Disease Blindness0%

10%

20%

30%

40%

50%

60%

70%

80% 71% 65%

44%

28%

Comorbid conditions

Distribution of NHANES participants with diabetes, self-reported cardiovascular disease, & single-sample markers of CKD, 2007-2012

Data Source: National Health and Nutrition Examination Survey (NHANES), 1988–1994, 1999-2004 & 2007–2012 participants aged 20 & older. Cardiovascular disease designation is based on self-report of any CVD. CKD is defined as eGFR <60 or ACR ≥30.

Prevalence of Diabetic with CKD. NHANES. Adults 2012.

USRDS 2015

9Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016

Prevalence of CKD by age & risk factor among NHANES participants, 1998-2012

National Health and Nutrition Examination Survey (NHANES), 1988–1994, 1999-2004 & 2007–2012 participants aged 20 & older.

Diabetes defined as either HbA1c >7%, self-reported, or currently taking glucose-lowering medications.

Hypertension defined as BP ≥130/≥80 for those with diabetes or CKD, otherwise BP ≥140/≥90, or taking medication for hypertension.


Distribution of markers of CKD in

NHANES participants with

diabetes, hypertension, self-

reported cardiovascular disease,

& obesity, 2007–2012

National Health and Nutrition Examination Survey (NHANES), 2007–2012 participants aged 20 & older. Single-sample estimates of eGFR & ACR; eGFR calculated using the CKD-EPI equation.



Trends in annual number of ESRD incident cases (in thousands), by primary cause of ESRD, in the U.S. population, 1996-2013

ESRD Incidence by cause


ESRD prevalence by cause

Trends in annual number of prevalent ESRD cases (in thousands), by primary cause of ESRD, in the U.S. population, 1996-2013


Trends in adjusted* prevalence (per million) of ESRD,by primary cause of ESRD, in the U.S. population, 1996-2013

ESRD Prevalence per populationBy cause


Functional

Structural ESRD

Progression

Hemodynamic changes

Thickening of GBM. Mesangial expiation.Glom. hypertrophy

Irreversible Scarring

Hypertension. Decreased eGFR.

Proteinuria.


Microalbuminuria

Macroalbuminuria?

Steinke JM et al. (2005) The early natural history of nephropathy in type 1 diabetes: III. Predictors of 5-year urinary albumin excretion rate patterns in initially normoalbuminuric patients. Diabetes54:2164-2171

Progression


<30mgNormal

30-300mg

Moderate

>300mg

Sever

Albuminuria as continuum value

Microalbuminuria

KDIGO Reference 22


• Is a continuum.

• Varies according to:• Time.• Physical Activity.• Fever.• Blood pressure.• Labs variation. • Dietary Prot. intake.

•

Albuminuria

Tuttle K, Bakris G. et. al. Diabetic Kidney Disease: A Report From an ADA Consensus Conference. Diabetes Care 2014;37:2864–2883 | DOI: 10.2337/dc14-129


Hemodynamic

GeneticMetabolic

Factors Contributing to development of Diabetic Nephropathy

Nephropathy

Ziyadeh FN (2004) Mediators of diabetic renal disease: the case for TGF-â as the major mediator. J Am Soc Nephrol 15 (Suppl 1): S55-S57


Decreased ResistanceAfferent > Efferent

Increased intraglomerular pressure

.Mechanical strain.

.Albumin leak. Mesangial expansion..GBM thickness.Podocytes injury

Hemodynamic Pathway

• Prostanoid.• NO2.• VEGF.• RAAS.• Endothilin.• TGF-B1.


Glycosylation End

Products

PKC

Hyperglycemia Injury

Mesangial Matrix expansion.Cell apoptosis.Increased Podocyte Permeability

VEGFTGFB1

Over expression GLUT 1,4

Friedman EA (1999) Advanced glycation endproducts in diabetic nephropathy. Nephrol Dial Transplant 14 (Suppl 3): S1-S9.Porte D Jr and Schwartz (1996) MW Diabetes complications: why is glucose potentially toxic? Science 272: 699-700.Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414: 813-820.


Glycosylation End Products

Glucose

+Amino A.Proteins.

Advanced glycosylation end products

Microvascular Complications

Makita Z et al. (1991) Advanced glycosylation end products in patients with diabetic nephropathy.N Engl J Med 325: 836-842Singh AK et al. (1998) Effect of glycated proteins on the matrix of glomerular epithelial cells. J Am Soc Nephrol 9: 802-810


Protein Kinase C

Oxidative stressDiacyglycerol

Hyperglycemia

Activation

PKC TGF B1

Mesangial ExpansionGBM thickening

Yamagishi S et al. (2007) Molecular mechanisms of diabetic nephropathy and its therapeutic intervention. Curr Drug Targets 8: 952-959


TGF-B1

Hyperglycemia

Increase expression of TGF-

B1

Cellular Hypertrophy.Collagen Synthesis

Sharma K et al. (1999) Captopril-induced reduction of serum levels of transforming growth factor-â1 correlates with long-term renoprotection in insulindependent diabetic patients. Am J Kidney Dis. 34:818-823Sharma K and Ziyadeh FN (1995) Hyperglycemia and diabetic kidney disease. The case for transforming growth factor-beta as a key mediator. Diabetes 44: 1139-1146


Pathogenesis of Diabetic Nephropathy


MetabolicHemodynamic


• Diabetic Nephropathy is more common within first degree relatives.

Among Pima Indian developed Overt Proteinuria:• 14 % neither parents had Proteinuria. • 23% one parent had proteinuria.• 46% both parents had proteinuria.

Genetic susceptibility

Trevisan R and Viberti G (1995) Genetic factors in the development of diabetic nephropathy. J Lab Clin Med 126: 342-349.Pettitt DJ et al. (1990) Familial predisposition to renal disease in two generations of Pima Indians with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 33: 438-443.


Susceptibility loci for Microvascular complication on Chromosomes: 3, 7, 9, 20.

Diabetic Nephropathy susceptible gene areas on chromosomes:• 7q21.3• 10p15.3• 14q23.1• 18q22.3

Genetic susceptibility

Imperatore G et al. (1998) Sib-pair linkage analysis for susceptibility genes for microvascular complications among Pima Indians with type 2 diabetes. Pima Diabetes Genes Group. Diabetes 47: 821-830.

Vardarli I et al. (2002) Gene for susceptibility to diabetic nephropathy in type 2 diabetes maps to 18q223-23. Kidney Int 62: 2176-2183.

Iyengar SK et al. (2007) Genome-wide scans for diabetic nephropathy and albuminuria in multiethnic populations: the family investigation of nephropathy and diabetes (FIND). Diabetes 56: 1577-1585


Pathology

• ECM expansion.• Mesangial expansion.• Kimmelstiel-Wilson nodule.• Arteriolar Hyalinosis.• Glomerular sclerosis. • Thickening of GBM.• Thickening of TBM.


DMCVD

CKD

Which one started first ??

High CV risk patient


DM + CKDCoronary

Art. disease

CVD risk Assessment

=Tonelli M, Muntner P, Lloyd A, et al.; Alberta Kidney Disease Network. Risk of coronary events in people with chronic kidney diseasecompared with those with diabetes: a population level cohort study. Lancet 2012;380:807–814

AtherosclerosisAMI.Cardiac fibrosis.Art. Calcification.


• Absence of retinopathy.• Rapid decrease eGFR.• Rapidly increasing Proteinuria.• Refractory HTN.• Active urinary sediments.• > 30% reduction of GFR with RAAS. • Clinical picture for other systemic disease.

Increased possibility of causes other than DM leading to the kidney disease:

National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendationsfor Diabetes and Chronic Kidney Disease. Am J Kidney Dis 2007;49(Suppl. 2) S12–S154



Management of Diabetic Nephropathy


Multidisciplinary Approach

Internist

Nephrologist

Patient

Endocrinologist

Dietician

Social worker

Cardiologist

Nurse

Pharmacist


• Lifestyle.•BP. •DM. • Lipids. •Depression.•Compliance.

Managing Diabetic Nephropathy


Certain points to be considered:• Fluid intake. • Salt intake. 5 gm daily. (Na 2.3 gm).• Protein. Recommended 0.8gm/kg daily. • Hyperkalemia. • Acid/Base. • Malnutrition. • Anemia.• PTH, Vit. D, Ca & PO4.

Dietary Remarks in Diabetic Kidney Disease

Tuttle K., Bakris G. Diabetic Kidney Disease: A report from an ADA Consensus. Diabetes Care. Vol. 37, Oct 2014


Target BP in Diabetic patient


Target BP < 140/90mmHg in diabetic CKD. < 130/80mmHg with Alb./Creat. > 30mg/day

Diastolic < 60mmHg was associated with higher ESRD.

Diastolic < 65mmHg was associated with poor CV outcome.

Hypertension in Diabetic patients

• Wheeler DC, Becker GJ. Summary of KDIGO guideline. What do we really know about management of blood pressure in patients with chronic kidney disease? Kidney Int 2013;83: 377–383

• James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014;311: 507–520

Peralta CA, Norris KC, Li S, et al.; KEEP Investigators. Blood pressure components and end-stage renal disease in persons with chronic kidney disease: the Kidney Early Evaluation Program (KEEP). Arch Intern Med 2012;172:41–47

Kovesdy CP, Bleyer AJ, Molnar MZ, et al. Blood pressure and mortality in U.S. veterans with chronic kidney disease: a cohort study. Ann Intern Med 2013;159:233–24


• ACE inh. & ARB reduce the progression of kidney disease.

• This is specifically true in CKD III or higher with significant proteinuria.

• CONTRAINDICATED TO USE COMBINATION ACE inh. and ARB.

RAAS in CKD with DM

Fried LF, Emanuele N, Zhang JH, et al.; VA NEPHRON-D Investigators. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013;369:1892–1903

Parving H-H, Brenner BM, McMurray JJV, et al.; ALTITUDE Investigators. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012;367:2204–2213


Department of Public Health and Clinical Medicine, Medicine, Umeå University, SE-901 87Umeå, Sweden Correspondence to: M Brunström [email protected] Additional material is published online only. To view please visit the journal online. Cite this as: BMJ 2016;352:i717http://dx.doi.org/10.1136/bmj.i717. Accepted: 12 January 2016

mailto:[email protected]

http://dx.doi.org/10.1136/bmj.i717


Aim: Assess the CV mortality and morbidity in DM with different BP targets.

Design: Meta-analysis. (Central, Medline, Ebase, Biosis.)

Eligibility:• RCT > 100 with DM. • Treated for > 12 months.• Comparing two agents.• Two target BP.• One versus two drugs.

Effect of antihypertensive treatment at different blood pressure levels in patients with diabetes mellitus: systematic review and meta-analyses

BMJ 2016;352:i717 | doi: 10.1136/bmj.i717


Results:49 Trials.N = 73 738 participant.

Effect of antihypertensive treatment at different blood pressure levels in patients with diabetes mellitus: systematic

review and meta-analyses

Base Line BP mmHg

all cause mortality RR (95%CI)

CV mortalityRR (95%CI)

MIRR (95%CI)

StrokeRR (95%CI)

ESRDRR (95%CI)

>150 0.89 (0.8-0.99) 0.75 (0.36-0.87)

0.74 (0.63-0.87)

0.77 (0.65-0.91)

0.82 (0.71-0.94)

140-150

0.87 (0.78-0.98) 0.84 (0.76- 0.93)

<140 1.05 (0.95-1.16) 1.15 (1- 1.32)BMJ 2016;352:i717 | doi: 10.1136/bmj.i717


Effect of antihypertensive treatment at different blood pressure levels in patients with diabetes mellitus: systematic review and meta-analyses

Results from meta-analyses stratified according tobaseline systolic blood pressure (SB P), reported for eachoutcome separately

BMJ 2016;352:i717 | doi: 10.1136/bmj.i717


Aim: Control of BP among CKD and DM and Medication.

Hypertension Management and Cardiovascular risk Factors Among Chronic Kidney Disease Patients with Diabetes

Jafar Al-Said, M.B. CHb. MD. FASN, FACP. Soni Murdeshwar. Bahrain Specialist Hospital ESH Annual meeting 2014




Matching:

CV risk profile:




BP changes over follow up:


Number of AnitHTN. Medications:







Control of Sugar in Diabetic Nephropathy


Increased incidence with eGFR < 60ml/min

Causes:• Prolonged action of Insulin.• Prolonged action of oral hypoglycemic agents. • Chronic Malnutrition.• Acute Calorie deprivation.• Alcohol intake.• Deficient Gluconeogenic precursor.

Hypoglycemic incidence in CKD

Tuttle K, Bakris G. et. al. Diabetic Kidney Disease: A Report From an ADA Consensus Conference. Diabetes Care 2014;37:2864–2883 | DOI: 10.2337/dc14-1296


Decreased precision in CKD due to:• Shorter RBC life span.• Acid/Base.• Anemia. • Using Erythrocyte stimulating factors.

HbA1C in CKD

Vos FE, Schollum JB, Coulter CV, Doyle TCA, Duffull SB, Walker RJ. Red blood cell survival in long-term dialysis patients. Am J Kidney Dis 2011;58:591–598.

Nakao T, Matsumoto H, Okada T, et al. Influence of erythropoietin treatment on hemoglobin A1c levels in patients with chronic renal failure on hemodialysis. Intern Med 1998;37:826–830


Optimal survival with HbA1C for ESRD 7-8%.

U curve of HbA1C.

Shurraw S, Hemmelgarn B, Lin M, et al.; Alberta Kidney Disease Network. Association between glycemic control and adverse outcomes in people with diabetes mellitus and chronic kidney disease: a population-based cohort study. Arch Intern Med 2011;171:1920–1927

Kalantar-Zadeh K. A critical evaluation of glycated protein parameters in advanced nephropathy:a matter of life or death: A1C remains the gold standard outcome predictor indiabetic dialysis patients. Diabetes Care 2012;35:1625–1628.

Ramirez SPB, McCullough KP, Thumma JR, et al. Hemoglobin A(1c) levels and mortality in the diabetic hemodialysis population: findings from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Diabetes Care 2012;35: 2527–2532


• HbA1C.• Fructosamine. • 1,5 anhydroglucitol.• Glycated Albumin.

Glycemic markers

Kim WJ, Park C-Y, Lee K-B, et al. Serum 1,5-anhydroglucitol concentrations are a reliable index of glycemic control in type 2 diabetes with mild or moderate renal dysfunction. Diabetes Care 2012;35:281–286.

Inaba M, Okuno S, Kumeda Y, et al.; Osaka CKD Expert Research Group. Glycated albumin is a better glycemic indicator than glycated hemoglobin values in hemodialysis patients with diabetes: effect of anemia and erythropoietininjection. J Am Soc Nephrol 2007;18:896–903


Metformin Dose adjustment according to eGFR

Tuttle K., Bakris G. et.al Diabetic Kidney Disease: A report from an ADA Consensus. Diabetes Care. 2014;37:2864–2883 | DOI: 10.2337/dc14-1296


Dose adjustment for Oral Hypoglycemic agents

Tuttle K, Bakris G. et. al. Diabetic Kidney Disease: A Report From an ADA Consensus Conference. Diabetes Care 2014;37:2864–2883 DOI: 10.2337/dc14-1296


• CKD I – IV SAME AS GENERAL POPULATION. <100mg/dl for LDL / 30-40% reduction from baseline.• ESRD. benefit is not confirmed with lipid

lowering.

• Statins recommended for all diabetic CKD not on dialysis.

Hyperlipidemia in CKD

Palmer SC, Craig JC, Navaneethan SD, Tonelli M, Pellegrini F, Strippoli GFM. Benefits and harms of statin therapy for persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med 2012;157:263–275.

Haynes R, Lewis D, Emberson J, et al. Effects of lowering LDL cholesterol on progression of kidney disease. J Am Soc Nephrol. 8 May 2014

Wanner C, Tonelli M, Cass A, et al. KDIGOclinical practice guideline for lipid management in CKD: summary of recommendation statementsand clinical approach to the patient. Kidney Int2014;85:130321309Reference 34


Incidence 15-25%.Causes:• Steroid.• Calcineurin inh. (Tacrolimus).• Increased Appetite. • Wt. Gain.

Outcome:Increased CV risk.Reduce graft survival.

New Onset Post Transplant Diabetes

Sarno G, Mehta RJ, Guardado-Mendoza R,Jimenez-Ceja LM, De Rosa P, Muscogiuri G. New-onset diabetes mellitus: predictive factors and impact on the outcome of patients undergoing liver transplantation. Curr Diabetes Rev 2013;9:78–85.

Chakkera HA, Mandarino LJ. Calcineurin inhibition and new-onset diabetes mellitus aftertransplantation. Transplantation 2013;95:647–652.


Management outcome of Chronic Kidney Disease in our Nephrology

OPD

JAFAR AL-SAID, TEERATH KUMAR, SONI MERDASHWAR BAHRAIN SPECIALIST HOSPITAL

• HTN and CV highlight Dec. 2012• ESH annual Meeting 2013


Aim of the Study

• What are the CV risk factors in CKD patients followed in our clinic?

• What is the rate of progression of their kidney function?

• What are the factors related to the final kidney function?


Methodology

Retrospective Observational. CKD patient followed in Nephrology OPD over 8.5 years (102month) from Oct. 2003 till April 2012.

Exclusion:1. Patient with only one visit. 2. No lab workup.3. Primary Glomerulonephritis. 4. Transplant.5. Pregnant.

Inclusion:1. Adult > 14 years.2. Had CKD.3. Followed in OPD.


Results• N = 245 patients.

• Mean follow up: 23.6 month (SE 1.6).

• Mean Age: 58.7 years (SE 0.9).

• Mean BMI: 30.9kg/m2 (SE 0.7)(SD10.5)

• Males: 60.8%


Cardiovascular risk factorsTotal CKD population, n = 245

HTN Hyperlipi. DM Hyperuric. IHD PVD Stroke0%

10%20%30%40%50%60%70%80%90%

100%91%

72%

60%

43%

20%9%

6%

Type of CV disease


Demographics of into DM and Non DM

DM Non DM P N 147 98

Age 61.8(0.9) 54(1.8) <0.0001Male

gender55% 69% 0.047

BMI 31.6(0.6) 30(1.4) 0.2


Dividing the total population into DM and Non DM

DM Non DM p

Mean of first eGFR (SE)

42.8 (1.8) 49.4(2.1) 0.02

Mean of Last eGFR (SE)

41(2.1) 51.2(3) 0.005

p 0.58 0.22

Difference in eGFR -0.9(1.7) -2.4(2) 0.5


Variables Correlation Coefficient

p

Systolic1 -0.2 0.012Hb1 0.36 0.001Alb1 0.25 0.03Follow up duration

0.23 0.008

Systolic2 -0.19 0.03Hb2 0.4 0.001Alb2 0.27 0.025PO4 2 -0.4 0.004Beta blocker -0.19 0.025Ca-block -0.22 0.012Vasodilator -0.23 0.007NTG -0.26 0.002

Correlation of the last eGFR with demographic factors, CV risk factors and the medications used in DM


S.Cr and eGFR changes over follow up in HTN and DM subgroups

Non HTN & Non DM (SE)

Non HTN & DM (SE)

HTN & Non DM (SE)

HTN & DM (SE)

P

First Cr 1.4 (0.1) 1.8 (0.34)

1.8 (0.1) 1.9 (0.08) <0.001

Last Cr 1.3 (0.09)

1.8 (0.5) 1.9 (0.14) 2.3 (0.16) 0.5

p 0.07 0.75 0.35 0.05First

eGFR 58.7 (4.2) 52.8 (10.7) 47.8 (2.7) 42.2 (1.8) 0.3

Last eGFR

59.2 (4.6) 61.7 (13.5) 49.9 (3.7) 39.6 (2.1) 0.1

P 0.18 0.13 0.3 0.8

Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016 67HTN DM0%

10%20%30%40%50%60%70%80%90%

100% 87%

55%

ESRD with HD at Bahrain specialist Hospital N = 118 patients


• Diabetic Nephropathy occur in 20-40% of patients with Dm.• Its manifestation require Genetic, Hemodynamic and Metabolic factors.• Growth factors and cytokines play major role in its development. • Proteinuria, decreased GFR and HTN are its main clinical features. • ESRD could develop in 40-80%.• Management require tight control of BP, sugar and lipids.

Conclusion

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Diabetic Nephropathy Review