renal disease in diabetes from prediabetes to late vasculopathy complications prof basset essawy...

Prof Basset El EssawyM.B.B.CH, Msc, MD PhD FASN

Maitre es Science Medical (Nephrology, France)DIU Organ Transplantation ( France)

DIU Pediatric Nephrology ( France)AFSA Clinical Nephrology and Hypetension ( France)C1 & C2 Immunology and Immunopathology ( France)

Diplome Des Etude Approfonde (DEA) Immunology of Organ transplantation ( France)

Prof. of Internal Medicine and Nephrology AlAzhar University

Renal Disease in Diabetes: From Prediabetes to Late Vasculopathy Complications 30/6/2016

Mansoura International Hospital 10 / 08 / 2016 Nephrology Fellowship Program

• Epidemiological data & Trends in the Prevalence of Diabetic Kidney Disease in USA.

• Summary of less than expected benefits from the large DM Treatment trials.

• Insuline Resistance, measurment & Defnition of prediabetes.

• Prediabetes and Nephropathy.

• Case presentations.

• Insulin resistance and vascular calcification

Definition of Diabetic Kidney Disease

• DKD was defined as DM with the presence of:- Albuminuria (ratio of urine albumin to creatinine

≥ 30 mg/g).- Impaired GFR- Both.

KDOQI. KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Am J Kidney Dis. 2007;49(2):(suppl 2) S12-S154.

American Diabetes Association. Standards of medical care in diabetes—2010. Diabetes Care. 2010;33:(suppl 1) S11-S61.

DyslipidemiaInsuline Resistance

Obesity, DM & HTN

http://www.niddk.nih.gov/health-information/health-statistics/Pages/kidney-disease-statistics-united-states.aspx#4Accessed August 9 2016

- The incidence of CKD is increasing most rapidly in people ages 65 and older.- The incidence of recognized CKD in people ages ≥ 65 > doubled between 2000 and 2008.- The incidence of recognized CKD among 20- to 64-year-olds is less than 0.5 %.

CKD Prevalence-The prevalence of CKD is growing most rapidly in people ages 60 and older.

-Between the 1988–1994 National Health and Nutrition Examination Survey (NHANES) study and the 2003–2006 NHANES study, the prevalence of CKD in people ages ≥ 60 jumped from 18.8 to 24.5 %.

- During that same period, the prevalence of CKD in people between the ages of 20 and 39 stayed consistently < 0.5 %. http://www.niddk.nih.gov/health-information/health-statistics/Pages/kidney-disease-statistics-united-states.aspx#4

Accessed August 9 2016

Quantification of Kidney Function and the Prevalence of

Renal Impairment. Bob L. Lobo Pharmacy. 2007;64(19):2017-2026 . The GFR is currently accepted as the best measure of overall kidney function.

The overall frequency of CKD in U.S. adults has been estimated at 11% (19.2 million people).

3.3% of adults in the US have stage 1 CKD.3.0% have stage 2 CKD.4.3% have stage 3 CKD.0.4% have stage 4 or 5 CKD.

The decreases in GFR often occur without markers of kidney damage.

Approximately 11% of all adults ≥ 65 ys without

HTN or DM have stage 3-5 CKD.

Ratio stage 1-3 : stage 4-5 26.5 1

http://www.niddk.nih.gov/health-information/health-topics/kidney-disease/kidney-disease-of-diabetes/Pages/facts.aspx

Accessed August 9 2016

- United States Renal Data System. USRDS 2007 Annual Data Report. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, U.S. Department of Health and Human Services; 2007.

- National Institute of Diabetes and Digestive and Kidney Diseases. National Diabetes Statistics, 2007. Bethesda, MD: National Institutes of Health, U.S. Department of Health and Human Services, 2008.

Design, Setting, and Participants:

- Cross-sectional analyses of the 3rd National Health and Nutrition Examination Survey (NHANES III) from 1988-1994 (N = 15 073)/ (n of Participants = 1431)

-NHANES 1999-2004 (N = 13 045) (n of Participants = 1443)

-- NHANES 2005-2008 (N = 9588) (n of Participants = 1280)

- Participants with DM were defined by levels of A1c of ≥ 6.5%, use of glucose-lowering medications, or both.

- DKD was defined by albuminuria, Decrease in GFR, or both.

Prevalent cases are estimated numbers of persons in the US population and were calculated using National Health and Nutrition Examination Survey sample weighting. Error bars indicate 95% confidence intervals. GFR indicates glomerular filtration rate.

Temporal Trends in the P

revalence of Diabetic K

idney Disease in the U

nited States

A. 2011;305(24):2532-2539

Temporal Trends in the Prevalence of Diabetic Kidney Disease in the United States JAMA. 2011;305(24):2532-2539

• Conclusions

- Prevalence of DKD in the USA increased from 1988 to 2008 in proportion to the prevalence of DM.

- Among persons with DM, prevalence of DKD was stable despite increased use of glucose-lowering medications and renin-angiotensin-aldosterone system inhibitors.

• Epidemiological data & Trends in the Prevalence of Diabetic Kidney Disease in USA

• Insulin resistance and vascular calcification.

1- How much we are successful in acheving our target of intensive control of DM ( A1c = 6.5 % ) ?

• Macrovascular (Cardiovascular) complications– MI– Stroke– Mortality

• Microvascular complications– Neuropathy– Retinopathy– Nephropathy– Dementia

Summary of the Recent Outcome Studies

ACCORD ↑ Death (All & CVD)HbA1c – 7.5 v 6.4% ↓ non fatal MI

↓ incident microvascular Cx

ADVANCE ↓ microvascular disease

HbA1c – 7.3 v 6.5% [renal complications]

VADT ↓ microvascular diseaseHbA1c – 8.4 v 6.9% [incident albuminuria]

How much we are successful?

Outcome of Intensive Glycaemia Control

Example Advance study- A strategy of intensive glucose control that lowered A1c to 6.5% yielded a

1- < 7 % reduction in the major macrovascular complication

2- 21% relative reduction in nephropathy.3- 10% relative reduction in the combined outcome of

major macrovascular and microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy.

The ADVANCE Collaborative Group. Intensive Blood Glucose Control and VascularOutcomes in Patients with Type 2 Diabetes. N Engl J Med 358;24 june 12, 2008

- Gaede P et al. N Engl J Med. 2008 Feb 7;358(6):580-91.

Multifactorial Intervention in type II DM160 patients from Steno2

7.8 ys TTT & 5.5 FU

1ry end point death2ndry end point ESRD

Intensive:A1cACEI/ARABsStatinsASAExercise

Posttrial follow-up of the ADVANCE-Observational Study

(ADVANCE-ON).N Engl J Med 2014

Ticking Clock Hypothesis in Type II DM1996 & 1999 Requestioned!!!

• The clock of the micro-Vascular complication start ticking with hyperglycemia

• The Clock of Macro-Vascular Complication start ticking with the insulin resistance before the manifest apperance of Type II DM (during the period of Prediabetes)

- Haffner SM, et al: Cardiovascularrisk factors in confirmed prediabetic individuals:does the clock for coronary heart disease start ticking before the onset ofclinical diabetes? JAMA 263:2893–2898,1990.

Why?• - The prevelance of DKD among Diabetics did not

change despite the substantial huge progress in DM care and management.

• The outcome of the large Diabetes intensive control trials is less than expected in term of both micro and macrovascular complications.

Conclusion

The diabetic complications process both micro and macrovascular start very early 1-2 decades before the Diagnosis of DM

In Prediabetes stage

Intervening early in the course of CKD

020406080

100120140

0 10 20 30 40 50 60 70Years

Early intervention

Late intervention

The question is when and in which stage the definition of early interventions ?

• Insuline Resistance, Measurment & Defnition of prediabetes.

• Prediabetes and Nephropathy

• Case presentations

Steps in the Development of Diabetes

Defect in mitochondrial fat oxidation Excess energy intake

Increase fat content in fat, muscle and liver cell

Insulin Resistance

Release of FFA and inflammatory cytokins from fat cell

Death of islet cell

Diabetes Mellitus

1-2 decades before DM

Prevalence of IR in Selected Metabolic Disorders

Bonora E, et al. Diabetes. 1998;47:1643-1649.Haffner SM, et al. Am J Med. 1997;103:152-162.

IRHypertension: 58%

Hyperuricemia: 63%Hypertriglyceridemia: 84%

T2DM: 92%

Low HDL cholesterol: 88%

Those who have multiple disorders (DM, HTN, Dyslipidemia, and Hyperuricemia): 95%

When these conditions are clustered together, there is even an increased probability that the individual has IR and is at an increased risk for CVD.

Measurement of Insuline Resistance (IR)There is no one test that can directly detect IR. 1- A Clinical picture may suspect IR if the person has

glucose levels, TG levels & LDL cholesterol, and HDL cholesterol Levels .

2- One of the most common ways of detecting IR is

by using the homeostatic model assessment (HOMA). It involves measuring glucose and insulin levels and then using a calculation to estimate function of the insulin producing β cells & insulin sensitivity.

Interrelation Between Atherosclerosis and IR

HypertensionHypertensionObesityObesityHyperinsulinemiaHyperinsulinemiaDiabetesDiabetesDyslipidemiaDyslipidemiaSmall, dense LDLSmall, dense LDLInflammationInflammationHypercoagulabilityHypercoagulability

InsulinInsulinResistanceResistance AtherosclerosisAtherosclerosis

CVD & CKD

Any patient with IR has numerous reasons to be at very high risk for atherosclerosis.

Definition of Prediabetes?

A Change in Definition Results in an Increased Number of Adults With Prediabetes in the United States.Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Follow- up report on the diagnosis of diabetes mellitus. Diabetes Care. 2003; 26:3160-3167.

68 % of primary care docs can’t identify the valuesSigworth, S., et al. (2007). Journal of General Internal Medicine 22(S1): 106.

Diagnostic Method CriteriaImpaired fasting glucose (IFG) 100-125 mg/dl

IFG WHO/European 110-125 mg/dl

Impaired glucose tolerance, 2h post (IGT) 140-199 mg/dl

HbA1c 5.7 – 6.4%

Hemodynamic &Morphological

Glomerular Lesions

The 1990’s Model of Nephropathy in DM focused on urinary albumin abnormalities

Normo-albuminuria

Micro-albuminuria

Proteinuria

• Insuline Resistance and Nephropathy as measured by Albuminuria

• The insulin Resistance Atherscelrosis Study

• 982 nondiabetic subjects • Age 40-69 years.• Cross-sectional study• The relationship of insulin sensitivity estimated by a

frequently sampled IV glucose tolerance test and the minimal model and fasting plasma insulin concentration, to microalbuminuria (albumin-to-creatinine ratio > or = 2 mg/mmol)

• Results : • 15% Microalbuminuria• 32% HTN - Diabetes. 1998 May;47(5):793-800.

• Subjects with microalbuminuria had a lower degree of insulin sensitivity & Higher fasting insulin

concentrations (P = 0.05) compared with subjects without microalbuminuria.

• Conclusion: Authors suggest a relationship between insulin resistance and microalbuminuria in non-DM subjects that is partially dependent on BL Pr, glucose levels & obesity.

Drawback: Indirect Measurement of Insulin SensitivityDiabetes. 1998 May;47(5):793-800.

Diabetes 55: 1456–1462, 2006

In T2DM patients, more severe insulin resistance is independently associated with microalbuminuria.

• 50 patients with T2DM with Normoalbuminuria Vs 50 patients with T2DM with microalbumiurua

• 29 patients with T2DM with Macroalbuminuria Vs 29 patients with T2DM with microalbumiurua

• All matched vs 20 healthy control with No Familly history of DM and HTN

Clinical and laboratory characteristics of patients withmicroalbuminuria (case subjects) and normoalbuminuria (controlsubjects) included in the main study

Data are frequency or means SD. ACEi, ACE inhibitor; CCB,calcium channel blocker; dBP, diastolic blood pressure; MAP, mean arterial pressure; sBP, systolic blood pressure. *P 0.05 vs. patients with normoalbuminuria. †Fisher’s exact test: diet, P 0.006; ACEi,P 0.044; diuretics, P 0.006; CCB, P 0.01.

Main characteristics of T2DM patients with macroalbuminuria(case subjects) and microalbuminuria (control subjects)with serum creatinine 1.5 mg/dl included in the substudy

Data are frequency or means SD. ACEi, ACE inhibitor; CCB,calcium channel blocker; dBP, diastolic blood pressure; MAP, meanarterial pressure; sBP, systolic blood pressure. *P 0.05 vs. patientswith microalbuminuria. †Fisher’s exact test: diuretics, P 0.0029.

FIG. 1. GDR in 100 patients with T2DM considered according to the presence of micro- or normoalbuminuria regardless of arterial blood pressure (A) or considered according to the presence of arterial hypertension or normal blood pressure regardless of the urinary albumin excretion (B). Diabetes 55: 1456–1462, 2006

GDR in 35 normo- and 35 microalbuminuric patients with T2DM and HTN and in 15 normo- and 15 microalbuminuric patients with T2DM and normal Bl Pr. GDR is significantly higher in normo- than in microalbuminuric patients but is comparable between patients with normal or high blood pressure, regardless of normo or microalbuminuria.Diabetes 55: 1456–1462, 2006

Nonlinear inverse relationship between GDR and probability of microalbuminuria in the 100 patients with T2DM included in the main study (Pmodel 0.001); x-axis, GDR; y-axis, probability of microalbuminuria (where 0 normoalbuminuria; 1 microalbuminuria). Diabetes 55: 1456–1462, 2006

Conclusion• In T2DM , more severe insulin resistance is

independently associated with microalbuminuria.

• Regardless of the degree of albuminuria and renal function, all study patients were insulin resistant, (P 0.0001) than that of non-DM healthy subjects without family history of DM and HTN evaluated under the same experimental conditions.

Hemodynamic &Morphological

Glomerular Lesions

The 2010’s Model of Nephropathy in DM focused on GFR abnormalities ± Albuminuria

Normo-albuminuria

Micro-albuminuria

Proteinuria

eGFR changes

30% of US adults are at high risk for developing DM and are considered to have pre-DM.

Relatively little is known about CKD prevalence in Pre-DM.

The combined data from the 1999 through 2000, 2001 through 2002, 2003 through 2004, and 2005 through 2006 continuous National Health and Nutrition Examination Survey ( NHANES) were examined.

- N = 8188- Age ≥ 20 ys.- eGFR was calculated according to MDRD & CKD-EPI equations for calibrated creatinine .- Presence of albuminuria at a single measurement .

Unadjusted population prevalence (%) and age-, gender-, and of stages 1 through 4CKD, with estimation of GFR by the MDRD Study equation, by diabetes status, NHANES 1999 through 2006. -Diagnosed diabetes is defined as self-report of provider diagnosis; -Undiagnosed diabetes is defined as FPG 126 mg/ml, without a report of provider diagnosis; -Prediabetes is defined as FPG 100 and 126 mg/dl; - No diabetes is defined as FPG 100 mg/ml. -CKD is defined by MDRD Study equation–calculated eGFR stage and a single determination of albuminuria (stages 1 and 2). Values in parentheses (A) and bars (B) represent 95% CI.

Adjusted ) population prevalence (%) and age-, gender-, and race/ethnicity of stages 1 through 4 CKD, with estimation of GFR by the MDRD Study equation, by DM status, NHANES 1999 through 2006.- Diagnosed DM is defined as self-report of provider diagnosis.- Undiagnosed DM is defined as FPG 126 mg/ml, without a report of provider diagnosis. -Prediabetes is defined as FPG 100 and 126 mg/dl.-No diabetes is defined as FPG 100 mg/ml. -CKD is defined by MDRD Study equation–calculated eGFR stage and a single determination of albuminuria (stages 1 & 2). -Values in bars (B) represent 95% confidence intervals

Unadjusted population prevalence of reduced kidney function and albuminuria by diabetes status, NHANES 1999 through 2006

P 0.001 across diabetes categories for all definitions listed. ACR, albumin-creatinine ratio; CI, confidence interval.- Gender-specific cutoffs were as follows: Microalbuminuria, ACR 17 mg/g and 25 mg/g, and macroalbuminuria, ACR 250 and 355 mg/g, for men and women, respectively.

CKD defined by MDRD Study equation–calculated eGFR 60 ml/min per 1.73 m2 or single micro/macroalbuminuria measurement; prediabetes, FPG 100 and 126 mg/dl and no self-report of diabetes; no diabetes, FPG 100 mg/dl and no self-report of diabetes. BMI, body mass index; CI, confidence interval.aPrevalence estimates adjusted for age, gender, and race/ethnicity, excluding variables being examined (e.g., age-stratified prevalence adjusted for gender and race/ethnicity only). Models that produced prevalence estimates included individuals in all four categories of diabetes status; models that produced P values included only those with prediabetes or no diabetes.bPrevalence for other race/ethnicity not shown because of small sample sizes, but individuals in category are included inall analyses.

Female

Conclusions

- Individuals with Pre-DM warrant earlier detection and management efforts to prevent development progression, and complications of both DM & CKD.

- Possible interventions, perhaps first targeting obese individuals, who are most at risk for Pre-DM, to prevent CKD and its progression in this population should be explored in further studies.

-A high burden of CKD exists among individuals with pre-DM.

- Male Patient 44 ys old- KC of DM > 15 ys, HTN > 6 ys , Dyslipidemia and ESRD initiated

haemodilaysis on 15/07/2014 through Right Permicath inserted on 14/07/2014.

• He has got left A-V fistula created on 4/8/2014 • Become non functioning and complicated by steal phenomena associated

with fingre dryness + gangrene

He was admitted to the hospital with fever and feet lesions.

Left hand after creation of the Arterio -Venous Fistula

Right Hand

Rt Foot

He was admitted to the hospital with fever and feet lesions.

Lt Foot

Healthy Control Matched for Age

• S Ca S Ph S Mg+• 15/2/2015 06:00 AST L 1.96• 4/2/2015 14:03 AST L 1.92 1.20 L 0.68• 28/1/2015 14:06 AST L 2.01 H 1.60 0.77• 10/1/2015 17:39 AST L 1.96 H 2.50 0.83• 7/1/2015 14:07 AST L 1.95 H 2.30 0.79• 10/12/2014 18:54 AST L 2.07 H 2.90 0.79• 5/11/2014 18:34 AST L 1.83 H 3.30 0.77• 28/10/2014 10:50 AST L 2.07 H 2.30 L 0.72• 3/9/2014 19:32 AST L 1.84 H 2.00 L 0.69• 12/4/2014 07:30 AST L 1.83 H 1.80 L 0.64• 8/4/2014 09:35 AST L 1.95 H 2.10 L 0.69• 6/4/2014 18:49 AST L 1.73 H 2.00 L 0.62

PTH Hormones

29/1/2015 07:41 AST H 8.3

10/12/2014 18:57 AST H 15.6

3/9/2014 19:24 AST H 17.7

15/7/2014 12:54 AST H 22.0

- Khamys Mushyt . KSA. Case 1- 2010: A 60-Year-Old Woman with

Non-Diabetic Renal Disease and Non-healing Skin Ulcers. 2010.

- Female 60 ys old a known case of ESRD on regular haemodialysis through left A-V fistula since 10 ys.

- She is presented with bilateral area of painful black dry necrotic skin in both feet and left index fingre and wrist.

Bazari et al., Case 7-2007: A 59-Year-Old Woman with Diabetic Renal Disease and Non-healingSkin Ulcers. N Engl J Med 2007;356:1049-57.

Her original kidney disease was classified as chronic glomerulonephritis as she presented the 1st times 10 ys earlier:

- With bilateral small sized kidney:- Rt 8.6 and lt 8.9 cm

- History of 10 ys poorly controlled HTN.- Patient is not diabetic.- - She is also a known case of HCV +ve

- On admission her PTH level was 2499 and ALP 2356 which was improved to 1372 and 1027 respecively after two weeks of 60 mg of cinacalcet.

Lab Results: Hgb 12.1 platelet 267 WBCs 6.1 Cr Ca 2.87, phosphate 2.36, Na 136, K

4, S cr 494 and blood urea 17.6S Albumin 31, Uric acid 0.37, Cholestrol 8.07 and TG 4.80

Immunological tests

cANCA and pANCA was -ve Cryoglobulin was -veanticardiolipin Ab-IgG and IgM –veAnti-phospholipid -veANA -veAnt- ds-DNA –veHbsAg – ve - Anti-HBs-Ab 55.73

HCV genotype G1 - HCV PCR copy Nu 4,286000HIV –veCMV IgG +ve & IgM -veSyphalis antibodies -ve

After Ultrasound and CT neck;

Subtotal para thyroidectomy and total thyroidectomy was done and histopathology revealed both parathyroid adenoma and multiple nodular goiture

Lt ankle

RT hand

Female 60 ys old History of 10 ys poorly controlled HTN- Patient is not diabetic.

ESRD on regular haemodialysis through left A-V fistula since 10 ys.

.- She is also a known case of HCV +ve-PTH level was 2499 and ALP 2356

which was improved to 1372 and 1027 respecively after two weeks of 60 mg of cinacalcet.

Cr Ca 2.87, phosphate 2.36 mmol/l

Cholestrol 8.07 mmol/l and TG 4.80

Male Patient 44 ys oldKC of DM > 15 ys, HTN > 6 ys ,

Dyslipidemia

ESRD initiated haemodilaysis on 15/07/2014 ( 6 Months when he was admitted) through Right Permicath inserted on 14/07/2014

He has got left A-V fistula created on 4/8/2014 and non functioning and complicated by steal phenomena and he has fingre dryness + gangrene

- PTH 8.3 and ALP 149S Ca 2.01 mmol/l Ph 1.60 Mg+

0.77( Serum albumin < 30 g/dl all the time)Lipid profile was controlled

SMOKING

Insuline resistance induced by high fructose feeding in ratscould evoke Osteogenic transdifferentiation of VSMCs and promote vascular calcifications

Atherosclerotic calcification, especially in the coronary arteries, is related to insulin resistance.

- 1632 nondiabetic from the Multi-Ethnic Study of Atherosclerosis with valid data on homeostasis model assessment index (HOMA-IR), AAC, CAC,and TAC. Adipocytokines, SFA, and VFA were also determined.

Association of calcium score with HOMA-IR. (A) Prevalence of AAC, CAC, and TAC according to quartiles of HOMA-IR. P values were estimated by chi-square test. (B) Median calcium score among participants with the indicated calcium score or the sum score >0 according to quartiles of HOMA-IR. Error bar indicates the interquartile range. P values were estimated by one-way ANOVA using log-transformed dataThere are a modest association of insulin resistance with the presence but not extent of calcified atherosclerosis, especially in the coronary aortic beds. As the association was independent of adipocytokines, inflammation biomarkers and abdominal fat composition, it is possible that vascular calcification may not be the main mechanism for insulin resistance to promote atherosclerosis. For TAC, the association tended to be stronger in participants with abdominal obesity

NICE Guidline for Chest pain

George Youssef, Matthew J. Budoff . Coronary artery calcium scoring, what is answered and what questions remain.Cardiovasc Diagn Ther 2012;2(2):94-105

The receiver operating characteristics (ROC) curve of high sensitivity C-reactive protein (hsCRP), Framingham risk score (FRS), coronary artery calcium score (CACS), and FRS combined with CACS for the prediction of coronary atherosclerotic plaque by computed tomography coronary angiogram.

-Jong-Shiuan Yeh,et al. Combined Framingham Risk Score and CoronaryArtery Calcium Score

Predict Subclinial CoronaryPlaque Assessed by Coronary ComputedTomography Angiogram in AsymptomaticTaiwanese Population,-Acta Cardiol Sin 2013;29:429435

Uraemic Vasculopathy 1- Calcific Uraemic Arterilopathy) (Calciphylaxsis) 2- Vascular Calcifications

Levin A, et al. Kidney Int.2007;71:31-38.

Diabetic Vascular Complications &/OR Uraemic Vascular Complications

1- Peripheral Vascular Complications A- Diabetic Foot

B- Peripheral arterial calcification

2- Cardivascular Complications

Summary• DKD is a common and morbid complication of DM & as well pre-

DM and the leading cause of CKD in the developed world.

• Approximately 40% of persons with DM develop DKD, manifested as albuminuria, impaired GFR, or both.

• Even mild degrees of albuminuria and decrease in GFR are associated with markedly increased risks of CVD & death and higher health care costs.

• In addition, DKD accounts for nearly 50% of all incident cases of ESRD in the US.

• 5 ys survival for patients with ESRD < 40%; Medicare spending on the US ESRD program reached $26.8 billion in 2008.

• Therefore, prevention of DKD is important to improve health outcomes of DM Patients and to reduce the social burden of CKD.

SANTHI K. GANESH et al., Association of Elevated Serum PO4, Ca PO4 Product, andParathyroid Hormone with Cardiac Mortality Risk in ChronicHemodialysis PatientsJ Am Soc Nephrol 12: 2131–2138, 2001

SANTHI K. GANESH et al., Association of Elevated Serum PO4, Ca PO4 Product, and Parathyroid Hormone with Cardiac Mortality Risk in Chronic Hemodialysis Patients J Am Soc Nephrol 12: 2131–2138, 2001

• Tight vs Standard Glycemic Control and Later CV Events, Survival• VADT randomized 1791 military veterans who had type 2 diabetes and a mean initial

HbA1c level of 9.5% to standard or intensive glycemic control (N Engl J Med 2009;360:129-139). The participants had a mean age of 60, had had diabetes for an average of 11.5 years, and were generally overweight (mean weight of 214 lb; average body-mass index [BMI] of 31.2 kg/m2).

• Those with a BMI of >27 kg/m2 were started on metformin plus rosiglitazone and those with a BMI of <27 kg/m2 were started on glimepiride plus rosiglitazone (maximal doses in the intensive-therapy group and half-maximal doses in the standard-therapy arm).

• Insulin was added for patients who did not achieve an HbA1c below 6% (intensive-therapy group) or below 9% (standard-therapy group). Investigators could then alter the medications as they saw fit.

• After 5.6 years of treatment (ending in May 2008), the median HbA1c levels were 6.9% for patients in the intensive-therapy group vs 8.4% in the standard-therapy group. There were no significant effects on major cardiovascular events or death with intensive vs standard therapy when the main results were reported in 2009.

• The current analysis included about 5 additional years of observational follow-up, after participants returned to usual care. A total of 1391 participants completed annual follow-up surveys that asked about cardiovascular events. The researchers had complete data for 9.8 years of follow-up and partial data for 11.8 years of follow-up

• The 17% relative reduction in the rate of cardiovascular events with intensive therapy compared with standard therapy

Why Calcifications in uraemics occures in the vascular system including the kidney vesseles and do not happen in the urinary tract and kidney which is

known to have such calcifications in different context ( Hypercalcemia – Hypervitamenosis D etc)

• Why Not Respiratory tract and Gastrointestinal tract in uraemics

• Coronary Calcifications happen in non CKD Patients

Bone remodeling

Acute phase reactants

Uremic milieu

Muscle catabolism

Endothelial dysfunction Monocyte adhesion Smooth muscle cell proliferation LDL oxidation Vascular calcification

Appetite REE

Adipocytokine production

Insulin resistance

Fetuin-A

Pro-inflammatory cytokines

Stenvinkel KI 2005 67:1216-23

Insuline Resistance

- Sharon M. Moe and Neal X. ChenJ Am Soc Nephrol 19: 213–216, 2008.

Mechanism of Vascular calcification in CKD

Arterial Calcification* and All-Cause Mortality Risk in CKD Patients on Dialysis N=110 3mo HD/ no prior CVD 6 mo before enroll/. Dopplar US 4 major Bl Ves/ F up 53 mo

l 0 Arteries Calcified

1 Artery Calcified

2 Arteries Calcified

3 Arteries Calcified

4 Arteries CalcifiedN=110

Duration of Follow-Up (months)

0 20 40 60 8073% risk of all-cause

mortality in patients with 4 arterial sites calcified.

-Arterial calcification was determined byD- US. Measurement sites included: common carotid artery, abdominal aorta, iliofemoral axis, and legs. Comparisons between probability of all-cause survival according to calcification score were significant: P<0.0001 (χ2=42.66).Blacher J et al. Hypertension. 2001;38:938-942.

- ESRD bone remodeling outocmes in term of Ca, P and PTH serum level

distrubance have its significant impact on the CV outcome and mortality

SANTHI K. GANESH et al., Association of Elevated Serum PO4, Ca PO4 Product, and Parathyroid Hormone with Cardiac Mortality Risk in Chronic Hemodialysis Patients J Am Soc Nephrol 12: 2131–2138, 2001

Calcification of Coronary Arteries is Highly Prevalent Among CKD Patient Populations

CKD = chronic kidney disease; RIND=Renagel in New Dialysis; TTG=treat-to-goal.1. Russo D et al. Am J Nephrol. 2007;27:152-158.2. Spiegel DM et al. Hemodial Int. 2004;8:265-272.3. Chertow GM et al. Kidney Int. 2002;62:245-252.

Percentage of CKD Patients With Coronary Artery Calcification Across 3 Studies in Different CKD Populations

(Russo1)

(Spiegel, RIND2)

(Chertow, TTG3)

Calcification Is Prevalent and Progressive in the Majority of Patients with CKD Not on Dialysis

• 51% of CKD patients had calcification at baseline

• At 2 years, there was a 57% increase in calcification score, with a mean total calcium score of 602

P<0.01

Patients with calcification and normal renal function (n=6)Patients with calcifications and CKD (n=27)

Rate of Coronary Artery Calcification Progression

CKD = chronic kidney disease.Russo D et al. Am J Nephrol. 2007;27:152-158.

Age Coronary Artery Calcification Scores in Young Dialysis Patients

N=39 (7-30ys) Vs N= 60 control – EBCT – 23 <20 ys &16 between 20-30ys14/16 (CACS 1157) HD vs 3/60 normal(CACS 1-77)

22 patients follow up Scan 18 -24 mo =doubling of CACS

10,000

0 5 10 15 20 25 30 35Age (years)

*Determined by electron beam computed tomography.

Goodman WG et al. N Engl J Med. 2000;342:1478-1483.

Despite the young age, calcification scores nearly doubled in patients with a positive initial scan when rescanned at

20 months (n = 10)

Factors Associated With Coronary Calcification* in Young Dialysis Patients

BMI, serum Ca X Ph-ion product, serum alkaline phosphatase, serum albumin, & cholesterol,Ca = calcium; P = phosphorus.*Determined by electron beam computed tomography (EBCT); †Determined using unpaired t-tests; Data are presented as means ± standard deviations.Goodman WG et al. N Engl J Med. 2000;342:1478-1483.

FactorCoronary Calcification

(N=14)No Calcification

(N=25) P Value†

Dose of oral calcium (mg/day) 6456 ± 4278 3325 ± 1490 0.02

Serum P (mg/dL) 6.9 ± 0.9 6.3 ± 1.2 0.06

Serum Ca (mg/dL) 9.5 ± 1.0 9.1 ± 0.9 0.25

Age (y) 26 ± 3 15 ± 5 <0.001

Duration of dialysis (y) 14 ± 5 4 ± 4 <0.001

Factors Associated With Increased Arterial Calcification

Calcification ScoreCharacteristics 0 1 2 3 4 ANOVAAge (y) 41.4 48.4 53.9 65.7 63.2 0.001Dialysis (mo) 52 81 85 101 107 0.001

Fibrinogen (g/L) 3.98 4.19 4.26 4.98 5.04 0.001Serum calcium (mg/dL) 9.20 9.24 9.24 9.40 9.44 0.07

Serum phosphorus (mg/dL) 6.01 6.10 6.19 5.39 6.10 NS

Ca x P product (mg2/dL2) 54.52 56.26 26.63 51.30 57.50 NS

CaCO3 (g/d elemental) 1.35 1.35 1.50 1.84 2.18 0.001PTH (pg/mL) 360 409 477 221 237 0.047Hypercalcemia (%) 8 10 18 36 42 0.034

Patient Characteristics and Values (Mean) by Calcification Score in 120 Stable Nondiabetic Patients With ESRD Undergoing Dialysis

(n=120)ANOVA = analysis of variance; Ca=calcium; CO=carbonate; ESRD=end-stage renal disease; NS=not significant; P=phosphorusBold type = statistically significant differences between groups.Patients with a mean daily elemental calcium intake from a phosphate binder of 1.5 g/d had a mean calcification score of 2.

Guérin AP et al. Nephrol Dial Transplant. 2000;15:1014-1021.

The Degree of Coronary Artery Calcification (CAC) Has Been Shown to Have Significant Impact on

Mortality in CKD Patients New to Dialysis

- Block GA, Raggi P, Bellasi A, Kooienga L, et al. Kidney Int. 2007;71:438-441.

*Multivariable adjusted (age, race, gender, DM) P- value represents significance across all 3 groups.

The presence and severity of CAC at initiation of hemodialysis is an important predictor of long-term survival

Patients with the most severe calcification had a mortality rate >4 times that of patients without calcification

0 6 12 18 24 30 36 42 48 54 60 660.00

Months

P=0.002

CAC 1-400

CAC >400

(n=127)

Adjusted survival by baseline CAC score*

Framingham CV Risk Paradox

• It has been found that the incidence of CVA is higher in those who have low and intermediate CV risk based on the Framingham Risk stratification score.

- Ferket BS, Genders TSS, Colkesen EB, et al. Systematic review of guidelines on imaging of asymptomatic coronary artery disease. J Am Coll Cardiol 2011;57:1591-600.

Receiver operating characteristic analysis shows additional prognostic value of coronary calcium scanning to the Framingham risk score in women and men

The receiver operating characteristics (ROC) curve of high sensitivity C-reactive protein (hsCRP), Framingham risk score (FRS), coronary artery calcium score (CACS), and FRS combined with CACS for the prediction of coronary atherosclerotic plaque by computed tomography coronary angiogram.

-Jong-Shiuan Yeh,et al. Combined Framingham Risk Score and CoronaryArtery Calcium Score

Predict Subclinial CoronaryPlaque Assessed by Coronary ComputedTomography Angiogram in AsymptomaticTaiwanese Population,-Acta Cardiol Sin 2013;29:429435

NICE Guidline for Chest pain

Addition of CAC score > 400 was found to have additive value of prediction of CV risk.

The screening of asymptomatic intermediate-risk patients for refinement of risk stratification and imaging in stable patients with chest discomfort to exclude obstructive CAD may constitute the best current indications.

A review of imaging guidelines for asymptomatic CAD showed that 11 of 14 guidelines support the use of CAC scoring in intermediate-risk patients.

- Ferket BS, Genders TSS, Colkesen EB, et al. Systematic review of guidelines on imaging of asymptomatic coronary artery disease. J Am Coll Cardiol 2011;57:1591-600.

Summary: Calcification of Coronary & other Arteries in CKD Patients

Coronary artery calcification is significant and progressive in a majority of patients with early CKD

There is an association between arterial calcification and increased risk of all-cause mortality in ESRD patients on dialysis.

Hyperphosphatemia is an independent risk factor of VC

Daily calcium intake is one modifiable risk factor associated with calcification of coronary & other arteries

KDIGO Recommendations for Calcium Use Restrictions and Calcification Detection

In patients with CKD stages 3-5D and hyperphosphatemia, KDIGO suggests restricting the dose of calcium-based phosphate binders and/or the dose of calcitriol or vitamin D in the presence of:

CKD = chronic kidney disease; KDIGO=Kidney Disease: Improving Global Outcomes; MBD=mineral and bone disorder; PTH=parathyroid hormone.Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2009;76(suppl 113):S1-S130.

In patients with CKD stages 3-5D: For the detection of calcification the use of commonly available modalities is suggested:

– Lateral abdominal X-ray to detect the presence/absence of vascular calcification– Echocardiogram to detect the presence/absence of valvular calcification

The presence and severity of cardiovascular calcification strongly predict cardiovascular morbidity and mortality in patients with CKD

It is suggested that patients with known vascular/valvular calcification be considered at highest cardiovascular risk. It is reasonable to use this information to guide the management of CKD-MBD

Persistent/recurrent hypercalcemia Arterial calcification Persistently low PTH Adynamic bone

disease

Reduction of established vascular calcification in WTand sham-operated LDLR/ mice (A) and LDLR/ micewith CKD (B). treated with sevelamer from 22 to 28 wk afterbirth. Data are means SEM; n 6 to 10.

In conclusion, dietary supplementation of l-lysine ameliorated VC by modifying key pathways that exacerbate VC.

Thank you

Management- Injury to the heart, the kidneys, and the vascular tree in patients with DM, HTN, or ESRD appears to be ameliorated by the reduction ofBl Pr to normal or near-normal levels by the use of ACEI (which have

effects other than the Anti-HTN)

- Anti-hyperlipidemic therapy- Smoking cessation- Measures to adjust Ca & Ph and hyperhomocystinemia. - Only early recognition and aggressive targeted treatment of all patients

with CKD are likely to decrease the progression of CKD itself and high mortality from CV causes among patients with “Uraemic vasculopathy."

- For at least some patients on dialysis, more prolonged and frequent nocturnal dialysis.

Pierratos A, et al. Nocturnal hemodialysis: three-year experience. J Am Soc Nephrol 1998;9:859-868.

THANK YOU

• In patients with ESRD cardiac arrest, acute MI, and cardiac arrhythmia account for about 1/3of all deaths.

• Despite considerable differences in background prevalence and mortality in different countries, mortality after MI is 16 to 19 times as high among patients with renal failure as in the general population.

• Herzog CA, Ma JZ, Collins AJ. Poor long-term survival after acute myocardial infarction among patients on long-term dialysis. N Engl J Med 1998;339:799-805. [

• Ritz E, Amann K. Optimal haemoglobin during treatment with recombinant human erythropoietin. Nephrol Dial Transplant 1998;13:Suppl 2:16-22.

• Smoking• Hyperlipidemia (including elevated Lp(a) lipoprotein levels)• Insulin resistance syndrome• Hyperhomocystinemia• Are all factors contributing to both vasculopathy induced by

renal disease and coronary artery disease in the normal population.

• In patients with renal disease, the risk is compounded because of the high prevalence of multiple risk factors.

• - Becker BN, Himmelfarb J, Henrich WL, Hakim RM. Reassessing the cardiac risk profile in chronic hemodialysis patients: a hypothesis on the role of oxidant stress and other non-traditional cardiac risk factors. J Am Soc Nephrol 1997;8:475-486.

So we are repoting here a case of sero negative uraemic vasculitis

ROC analysis comparing the value of Framingham risk function, UKPDS risk engine, and the CAC score for predicting cardiovascular events. AUC denotes area under the curve

Regardless of symptoms, CAD may be present without CAC. This point warrants emphasis even though CAC scoring “had a negative predictive value of 99% for greater than 70% stenosis.” First, acute myocardial infarction often occurs at sites of less than 50% stenosis.3 Second, symptoms are notoriously misleading in acute myocardialinfarction. In a recent observational study involving more than 1 million patients who Were hospitalized with acute myocardial infarction, 42% of women and 31% of men did not have chest pain4; this was most pronounced in younger women, in whom CAC may be absent.

3. Stone GW, Maehara A, Lansky AJ, et al. A prospective naturalhistorystudy of coronary atherosclerosis. N Engl J Med 2011;364:226-35. 4. Canto JG, Rogers WJ, Goldberg RJ, et al. Association of ageand sex with myocardial infarction symptom presentation andin-hospital mortality. JAMA 2012;307:813-22.

Within K/DOQI target recommendations for stage 3-5

Urine and Serum Calcium Levels Throughout the Progression of CKD

*P<0.05 CKD2 vs CKD3; †P<0.05 CKD3 vs CKD4.CKD=chronic kidney disease (number represents K/DOQI stage); K/DOQI=Kidney Disease Outcomes Quality Initiative.Adapted with permission from Craver L et al. Nephrol Dial Transplant. 2007;22:1171-1176.

7.8 5.4

1.5 9.0 13.5

55.085.6

CKD 3 CKD 4 CKD 5

CKD Stages

Above K/DOQI target recommendations for stage 3-5

Below K/DOQI target recommendations for stage 3-5

Urine Calcium Excretion250

14CKD2

74CKD3179

CKD443

CKD Stage

(n=317)

Calcium Adequacy

Calcium Absorption in Dialysis Patients

50100150200250300350400

Placebo Ca Carbonate Ca Acetate

(mg) n = 6

ESRD patients received test meal consisting of 346 mg of PO and 201 mg of Caand placebo, Ca carbonate (1 g elemental Ca), or Ca acetate (1g elemental Ca)

(1 g) (1 g)

355314

Mai M, Emmett M, Sheikh M. et al. Kid Int. 1989;36:690-695.

Comparing Imaging Tests for Measuring Coronary Artery Calcification Score

TestSensitivity

(%)Specificity

(%)Likelihood Ratio

(95% confidence interval)Area Under

Pulse pressure Quartile 2 Quartile 3 Quartile 4

484451

424554

0.82 (0.53, 1.27)0.79 (0.49, 1.28)1.12 (0.66, 1.88)

X-ray* Score: 1-6 Score: 7-24

2.53 (1.49, 4.28)7.50 (2.89, 19.5)

ECHO†

1 calcified valve 2 calcified valves

1.79 (1.09, 2.96)1.88 (1.05, 3.39)

CACS=coronary artery calcification score; EBCT=electron beam computed tomography; ECHO = echocardiogram.*X-ray of abdominal aorta semiquantitatively estimated with an X-ray score of 0 to 24. †ECHOs graded as 0 to 2 for absence or presence of calcification of mitral and aortic valves.Bellasi A et al. Kidney Int. 2006;70:1623-1628.

X-ray and echocardiograms have been shown to accurately measure vascular calcification in patients on dialysis

Pathophysiology of vascular calcifications

Adapted from Giachelli Kidney Int 2009

Pathophysiology of vascular calcifications

Mizobuchi JASN 2009 20: 1453-64

Summary • Coronary artery calcification is significant and progressive in

a majority of patients with early CKD• In healthy adults, the effects of calcium supplementation on

fracture risk have been mixed– However, supplementation did increase the risk of myocardial

infarction and kidney stones

• Patients with CKD often have an excess of calcium• In patients with CKD stages 3 to 5D, restricting the dose of

calcium may be valuable if the patient has persistent/recurrent hypercalcemia or other calcium-related issues

• X-ray and echocardiograms have been shown to accurately measure vascular calcification in patients on dialysis

CKD = chronic kidney disease.

Chertow GM, Burke SK, Raggi P. Treat to Goal Working Group. Kidney Int. 2002;62:245-252.

6 months 12 months

Sevelamer Calcium

*Within treatment P<0.001

Treat to Goal

Qunibi W, Moustafa M, Muenz LR, et al. AJKD. 2008; Advance On Line

n = sev 99 66 62 n = ca 101 75 70

n = sev 100 80 68 n = ca 103 71 58

*Significant within treatment

10%15%20%25%30%35%

6 months 12 monthsM

Sevelamer Calcium Acetate

CARE 2

Summary

• Vascular calcifications are quite common in CKD

• Vascular calcifications are associated with worse outcome

• Vascular calcifications are a modifiable risk factor

• Sevelamer beyond its phosphate binding effect offers additional pleiotropic effects

HAUFFE R J , and WINCHESTER D E Cleveland Clinic Journal of Medicine 2013;80:370-373

Vascular Calcifications• Prevalence

• Pathophysiology

• Clinical consequences

• Assessment

• Prevention / Treatment

Both intimal (AIC) and media calcification (AMC) increase mortality in HD patients

Nephro Dial Transplant 2003;18:1731-1740

Adjusted RR mortality: AMC 15.7; AIC 4.85

Stages of Chronic Renal Disease

130 120 110 100 90 80 70 60 50 40 30 20 15 10 0

Stage IKidney damage with

normal or GFR

Stage IIKidney damage

with mild GFR

Stage IIIModerate

Stage IVSevere GFR

Stage VKidney failure

National Kidney Foundation. Am J Kidney Dis 2002; 39(2 Suppl 1):S1–S266

Glomerular filtration rate (mL/min/1.73m2)

Serum Calcium May Not Reflect Total Body Calcium Load

Ca=calcium.Kidney Disease: Improving Global Outcomes. Kidney Int. 2009;76(suppl 113):S1-S130.

Distribution of Calcium in the Body

Bone Ca99% of total body Ca(990 g)

Intracellular Ca0.9% of total body Ca(9 g)

Interstitial Ca0.075% of total body Ca(0.75 g)

Plasma Ca0.025% of total body Ca(0.25 g)

Total body calcium = 1000 g

Overall Calcium Homeostasis in CKD Patients on Dialysis

Ca=calcium; CKD=Chronic kidney disease; ECF=extracellular fluid.Figure excludes the loss of calcium from sweat. Bushinsky DA. Clin J Am Soc Neprol. 2010:5:S12-S22.

Intestine

Dialyzer

Kidney

Excretion

Change in Extracellular Calcium Levels in Patients on Dialysis

ECF=extracellular fluid; Ca=calcium.

Bushinsky DA. Clin J Am Soc Neprol. 2010:5:S12-S22.

Change of Extracellular Calcium Levels With or Without Vitamin DE

0 25 50 75Calcium Intake (mmol Ca/d)

g Ca/w

Calcium Intake (mg Ca/d)0 1000 2000 3000

With 1,25(OH)2D3

Without 1,25(OH)2D3

1- Peripheral Vascular Complicationsin Patients with DM and CKD

• A- Diabetic Foot

• B- Peripheral arterial calcification

- Diabetic Foot in Patient with Diabetic Nephropathy

- The increased incidence of diabetic foot complications is observed in all stages of Diabetic Nephropathy.

Even as early evidence of nephropathy as microalbuminuria

Microalbuminuria persay is an independent risk factor for foot ulcer (RR=8.2, p < 0.0001).

- Guerrero-Romero F, Rodriguez-Moran M. Relationship of microalbuminuria with the diabetic foot ulcers in type II diabetes. J Diabetes Complications. 1998;12:193–196.

Diabetic foot in Renal Failure Data- Foot complications are > 2 fold frequencyin diabetic patients with ESRD. - This include all foot complications, namely

ulceration, infection, gangrene, and amputation.

- The rate of amputations is 6.5 –10 times higher in comparison to the general diabetic population.

N. Papanas et al. The Diabetic Foot in End Stage Renal Disease. Renal Failure, 29:519–528, 2007.

- Game et al., Temporal association between the incidence of foot ulceration and the start of dialysis in diabetes mellitus. Nephrol Dial Transplant. 2006;21:3207–3210

- Game et al., Temporal association between the incidence of foot ulceration and the start of dialysis in diabetes mellitus.

Nephrol Dial Transplant. 2006;21:3207–3210.

There are increased incidence rate of foot ulceration by 3.35 (95% CI: 1.59–7.04) in the 1st ys after initiation of dialysis, followed by an increased rate by 4.56 (95% CI: 2.19–9.5) in the 2nd–5th year.

-The increased incidence rates of major amputation were 31.98 (95% CI: 2.09–490.3) and 34.01 (95% CI: 1.74– 666.2), respectively.

• Conclusion. These results reveal a close relationship between the onset of RRT in diabetes and the onset of foot ulceration, and confirm the high incidence of amputation in those on dialysis.

• Urgent steps should be taken to coordinate all aspects of diabetes foot care before and after the start of RRT.

• - Game et al., Temporal association between the incidence of foot ulceration and the start of dialysis in diabetes mellitus. Nephrol Dial Transplant. 2006;21:3207–3210.

Pre Dialysis Dialysis Amputation Ratio 1 2.3

- The rate of amputation was 57% among patients on hemodialysis compared with 25% in those with pre-dialysis renal failure (p = 0.006).

- Morbach et al., Increased risk of lower-extremity amputationamong Caucasian diabetic patients on dialysis. DiabetesCare. 2001;24:1689–1690.

- Laurie Barclay, Dialysis treatment is independently associated with foot ulceration in patients with diabetes and stage IV or V chronic kidney disease (CKD), Diabetes

Care. June 1, 2010

Diabetic Neuropathy+Uraemic Neuropathy

+ Diabetic Angiopathy

Uraemic Vasculopathy

N. Papanas et al. Renal Failure, 29:519–528, 2007.

2- Cardivascular Complications

- More than 2/3 of cases of ESRD are caused by DM or primary hypertensive renal disease.

- These two diseases cause diffuse atherosclerosis and arteriolosclerosis.

- At all stages of progressive renal disease, CV problems are the most important cause of death; they account for approximately 50 % of mortality among both patients on dialysis and recipients of renal allografts.

- Jungers P, Massy ZA, Khoa TN, et al. Incidence and risk factors of atherosclerotic cardiovascular accidents in predialysis chronic renal failure patients: a prospective study. Nephrol Dial Transplant 1997;12:2597-2602.

- Kasiske BL, Guijarro C, Massy ZA, Wiederkehr MR, Ma JZ. Cardiovascular disease after renal

transplantation. J Am Soc Nephrol 1996;7:158-165. (Abstract ).

Prof Basset El Essawy MD PhD FASNMaitre es Science Medical (Nephrology;France)

DIU Organ Transplantation ( France)DIU Pediatric Nephrology ( France)

AFSA Clinical Nephrology and Hypertension ( France)C1 & C2 Immunology and Immunopathology ( France)Diplome Des Etude Approfonde (DEA) Immunology of

Organ transplantation ( France)

Diabetic Complications and Uraemic Vasculopathy: Farmingham CV risk Score is it enouph?

50% of Mortality in Chronic Kidney Disease and Renal Transplant patients is due to Cardiovascular Cause

Jungers P, Massy ZA, Khoa TN, et al. Incidence and risk factors of atherosclerotic cardiovascular accidents in predialysis chronic renal failure patients: a prospective study. Nephrol Dial Transplant 1997;12:2597-2602.

- Kasiske BL, Guijarro C, Massy ZA, Wiederkehr MR, Ma JZ. Cardiovascular disease after

renal transplantation. J Am Soc Nephrol 1996;7:158-165. (Abstract ).

• Mechanisms and types of Vascular Calcifications

• Impact of type and site of peripheral arterial calcifications on mortality

• Coronary artery clacifications and Framingham CV risk scores

• Insights into management

• Insuline Resistance and its measurment.

• Defnition of prediabetes.

• Prediabetes and Nephropathy

• International Society of Nephrology Has to take the lead of prospective studies for both detection and follow up with patient who have

PreDaibetic Nephropathy

And Implementing a preventive strategy

- Male Patient 44 ys old- KC of DM > 15 ys, HTN > 6 ys , Dyslipidemia and ESRD initiated

haemodilaysis on 15/07/2014 through Right Permicath inserted on 14/07/2014 in Saqr Hospital

• He has got left A-V fistula created on 4/8/2014 and non functioning and complicated by steal phenomena and he has fingre dryness + gangrene

• He has peripheral arterial disease amanfiested in his both upper limb • and both hand finge• The Ct angio revealed extensive calcifications in the whole vascular tree• The patient was discussed with Prof Martha Pavlakis so far no treatment

options for this vascular calcifications• patient still febrile

• DKD is a common and morbid complication of DM and the leading cause of CKD in the developed world.

• Approximately 40% of persons with DM develop DKD, manifested as albuminuria, impaired GFR, or both.

• Even mild degrees of albuminuria and decrease in GFR are associated with markedly increased risks of CVDcardiovascular disease and death and higher health care costs.5- 7

• In addition, DKD accounts for nearly 50%of all incident cases of ESRD in the US.7

• Five-year survival for patients with ESRD is less than 40%; Medicare spending on the US ESRD program reached $26.8 billion in 2008.7

• Therefore, prevention of DKD is important to improve health outcomes of persons with DM and to reduce the societal burden of CKD.

THANK YOU

A sample frame from a coronary artery calcification score study.

CHAUFFE R J , and WINCHESTER D E Cleveland Clinic Journal of Medicine 2013;80:370-373

Diagnosis

Diagnostic Method CriteriaImpaired fasting glucose (IFG) 100-125 mg/dl

IFG WHO/European 110-125 mg/dl

Impaired glucose tolerance, 2h post (IGT) 140-199 mg/dl

HbA1c 5.7 – 6.4%

ADA (2011). Diabetes Care 34(Supplement 1): S11-S61.

• 982 nondiabetic subjects • Age 40-69 years.• Cross-sectional study• The relationship of insulin sensitivity estimated by a

frequently sampled intravenous glucose tolerance test and the minimal model and fasting plasma insulin concentration, to microalbuminuria (albumin-to-creatinine ratio > or = 2 mg/mmol)

• Results : • 15% Microalbuminuria, • 32% HTN Diabetes. 1998 May;47(5):793-800.

Temporal Trends in the Prevalence of Diabetic Kidney Disease in the United States JAMA. 2011;305(24):2532-2539

The insulin Resistance Atherscelrosis Study

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