Renal disease in diabetes from prediabetes to late vasculopathy complications Prof Basset Essawy -NMGH

Prof Basset El Essawy
M.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.

Dyslipidemia
Insuline Resistance

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

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-informatio
-
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.
TemporalTrendsinthePrevalenceofDiabeticKidneyDiseaseintheUnitedStates
JAMA.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.
Why?

Kidney Disease in USA
Treatment trials.
• Insuline Resistance, measurment & Defnition of prediabetes.
• Prediabetes and Nephropathy.
• Case presentations.
• 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 disease
HbA1c – 8.4 v 6.9% [incident albuminuria]
19
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 Vascular
Outcomes 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 DM
160 patients from
Steno2
7.8 ys TTT & 5.5 FU
1ry end point death
2ndry end point ESRD
Intensive:
A1c
ACEI/ARABs
Statins
ASA
Exercise

Posttrial follow-up of the ADVANCE-
Observational Study
(ADVANCE-ON).
N Engl J Med 2014

Ticking Clock Hypothesis in Type II DM
1996 & 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
0
20
40
60
80
100
120
140
0 10 20 30 40 50 60 70
Years
GFR(ml/min)
Early intervention
Late intervention
The question is when and in which stage the definition of early
interventions ?

Kidney Disease in USA
Treatment trials.
• 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.
IR
Hypertension: 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
HypertensionHypertension
ObesityObesity
HyperinsulinemiaHyperinsulinemia
DiabetesDiabetes
DyslipidemiaDyslipidemia
Small, dense LDLSmall, dense LDL
InflammationInflammation
HypercoagulabilityHypercoagulability
InsulinInsulin
ResistanceResistance
InsulinInsulin
ResistanceResistance
AtherosclerosisAtherosclerosisAtherosclerosisAtherosclerosis
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 values
Sigworth, S., et al. (2007). Journal of General Internal Medicine 22(S1): 106.
Diagnostic Method Criteria
Impaired 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
ESRD
• 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 Sensitivity
Diabetes. 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 with
microalbuminuria (case
subjects) and
normoalbuminuria (control
subjects) 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, mean
arterial pressure; sBP, systolic blood
pressure. *P 0.05 vs. patients
with 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
ESRD
eGFR changes
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 4
CKD, 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).

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.
Age
Female
BMI
HTN
Race

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 associate
with fingre dryness + gangrene
He was admitted to the hospital with fever and feet lesions.

Left hand after
creation
of the Arterio
-Venous
Fistula

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

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 17.6
S Albumin 31, Uric acid 0.37, Cholestrol 8.07 and TG 4.80

Immunological tests
cANCA and pANCA was -ve
Cryoglobulin was -ve
anticardiolipin Ab-IgG and IgM –ve
Anti-phospholipid -ve
ANA -ve
Ant- ds-DNA –ve
HbsAg – ve - Anti-HBs-Ab 55.73
HCV genotype G1 - HCV PCR copy Nu 4,286000
HIV –ve
CMV IgG +ve & IgM -ve
Syphalis 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

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 old
KC 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 149
S Ca 2.01 mmol/l Ph 1.60 Mg+ 0.77
( Serum albumin < 30 g/dl all the time)
Lipid profile was controlled

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

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 data
There 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
Coronary
Plaque
Assessed by
Coronary
ComputedTomograp
hy Angiogram in
AsymptomaticTaiwan
ese Population,
-Acta Cardiol Sin
2013;29:429435

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

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, and
Parathyroid Hormone with Cardiac Mortality
Risk in Chronic
Hemodialysis Patients
J 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 HbA1cbelow 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

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

- Sharon M. Moe and Neal X. Chen
J Am Soc Nephrol 19: 213–216, 2008.
Mechanism of Vascular calcification in CKD

106
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
ProbabilityofSurvival
0 Arteries Calcified
1 Artery Calcified
N=110
1.00
Duration of Follow-Up (months)
0
0.25
0.50
0.75
0 20 40 60 80
73% 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).

- 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

111
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
51
64
83
0
20
40
60
80
100
CKD Patients Not on
Dialysis
Incident Dialysis Prevalent Dialysis
Patients(%)
(Russo1
)
(Spiegel,
RIND2
)
(Chertow,
TTG3
)

112
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
73 80
41
276
602
384
0
100
200
300
400
500
600
700
800
Baseline Follow-up Annualized
Progression
TotalCalciumScore(Agaststonunits)
P=NS
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.

113
Age Coronary Artery Calcification Scores in Young Dialysis Patients
N=39 (7-30ys) Vs N= 60 control – EBCT – 23 <20 ys &16 between 20-30ys
14/16 (CACS 1157) HD vs 3/60 normal(CACS 1-77)
22 patients follow up
Scan 18 -24 mo =doubling of CACS
CalcificationScore*
0.1
1
10
100
1000
10,000
0 5 10 15 20 25 30 35
Age (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)

114
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.
Factor
Coronary 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

115
Factors Associated With Increased Arterial
Calcification
Calcification Score
Characteristics 0 1 2 3 4 ANOVA
Age (y) 41.4 48.4 53.9 65.7 63.2 0.001
Dialysis (mo) 52 81 85 101 107 0.001
Fibrinogen (g/L) 3.98 4.19 4.26 4.98 5.04 0.001
Serum 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 0.001
PTH (pg/mL) 360 409 477 221 237 0.047
Hypercalcemia (%) 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=phosphorus
Bold 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
lock 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 66
0.00
0.25
0.50
0.75
1.00
Months
Survivaldistributionfunction
P=0.002
CAC=0
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

Receiver operating characteristic analysis shows additional prognostic value of coronary
calcium scanning to the Framingham risk score in women and men
George Youssef, Matthew J. Budoff . Coronary artery calcium scoring, what is
answered and what questions remain.Cardiovasc Diagn Ther 2012;2(2):94-105

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/ mice
with CKD (B).
treated with
sevelamer from
22 to 28 wk after
birth. Data are
means SEM; n
6 to 10.

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

Management
- Injury to the heart,the kidneys, and the vascular tree in patients with
DM,HTN, or ESRD appears to be amelioratedby the reduction of
Bl Pr to normal or near-normallevels 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 recognitionand 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.

• In patientswith ESRD cardiac arrest, acute MI, and cardiac
arrhythmia account for about 1/3of all deaths.
• Despite considerable differences in background prevalence
andmortality in different countries, mortality after MI is 16
to 19 times as high among patients with renalfailure 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 resistancesyndrome
• Hyperhomocystinemia
• Are all factors contributingto both vasculopathy induced by
renal disease and coronary arterydisease in the normal
population.
• In patients with renal disease,the risk is compounded
because of the high prevalence of multiplerisk factors.
• -
Becker BN, Himmelfarb J, Henrich WL, Hakim RM. Reassessing the cardiac risk profile in chronic

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

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 myocardial
infarction. 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 naturalhistory
study of coronary atherosclerosis. N Engl J Med 2011;364:
226-35.
4. Canto JG, Rogers WJ, Goldberg RJ, et al. Association of age
and sex with myocardial infarction symptom presentation and
in-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
31.5
1.5 9.0 13.5
55.0
85.6
90.7
0
20
40
60
80
100
CKD 3 CKD 4 CKD 5
CKD Stages
Patients(%)
Above K/DOQI target recommendations for stage 3-5
Below K/DOQI target recommendations for stage 3-5
Urine Calcium Excretion
250
200
150
100
50
0
CKD1
14
CKD2
74
CKD3
179
CKD4
43
CKD5
7
CKD Stage
n=
UrineCalcium(mg/24hours)
(n=317)
*
†
Calcium Adequacy

Calcium Absorption in Dialysis Patients
-50
0
50
100
150
200
250
300
350
400
Placebo Ca Carbonate Ca Acetate
CaAbsorption(mg)
n = 6
ESRD patients received test meal consisting of 346 mg of PO and 201 mg of Ca
and placebo, Ca carbonate (1 g elemental Ca), or Ca acetate (1g elemental Ca)
(1 g) (1 g)
-28
355
314
Mai M, Emmett M, Sheikh M. et al. Kid Int. 1989;36:690-695.

Comparing Imaging Tests for Measuring
Coronary Artery Calcification Score
Test
Sensitivity
(%)
Specificity
(%)
Likelihood Ratio
(95% confidence interval)
Area Under
Curve
Pulse pressure
Quartile 2
Quartile 3
Quartile 4
48
44
51
42
45
54
0.82 (0.53, 1.27)
0.79 (0.49, 1.28)
1.12 (0.66, 1.88)
0.51
X-ray*
Score: 1-6
Score: 7-24
61
67
76
91
2.53 (1.49, 4.28)
7.50 (2.89, 19.5)
0.78
ECHO†
1 calcified valve
2 calcified valves
53
47
70
75
1.79 (1.09, 2.96)
1.88 (1.05, 3.39)
0.62
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.
0%
6%
14%
25%
0%
5%
10%
15%
20%
25%
30%
6 months 12 months
Median%ChangeinCAC
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
14%
30%
20%
29%
0%
5%
10%
15%
20%
25%
30%
35%
6 months 12 monthsMedian%ChangeinCAC
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 I
Kidney damage with
normal or  GFR
Stage II
Kidney damage
with
mild GFR
Stage III
Moderate
GFR
Stage IV
Severe
GFR
Stage V
Kidney
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 Ca
99% of total body Ca
(990 g)
Intracellular Ca
0.9% of total body Ca
(9 g)
Interstitial Ca
(0.75 g)
Plasma Ca
(0.25 g)
Total body calcium = 1000 g

153
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.
ECFCa
Intestine
Dialyzer
Kidney
Excretion
Bone

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 D∆ECFCa(mmolCa/wk)
0 25 50 75
Calcium Intake (mmol Ca/d)
80
60
40
20
0
-20
∆ECFCa(mgCa/wk)
3200
2400
1600
800
0
-800
Calcium Intake (mg Ca/d)
0 1000 2000 3000
With 1,25(OH)2D3
Without 1,25(OH)2D3

1- Peripheral Vascular Complications
in 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 frequency
in 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 FASN
Maitre es Science Medical (Nephrology;France)
AFSA Clinical Nephrology and Hypertension ( France)
Diplome Des Etude Approfonde (DEA) Immunology of
Organ transplantation ( France)
Prof Basset El Essawy MD PhD FASN
Maitre es Science Medical (Nephrology;France)
AFSA Clinical Nephrology and Hypertension ( France)
Diplome Des Etude Approfonde (DEA) Immunology of
Organ transplantation ( France)
Diabetic Complications and Uraemic Vasculopathy:
Farmingham CV risk Score is it enouph?
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 ).

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

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

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
©2013 by Cleveland Clinic

Diagnosis
Diagnostic Method Criteria
Impaired 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.

The insulin Resistance Atherscelrosis Study

Renal disease in diabetes from prediabetes to late vasculopathy complications Prof Basset Essawy -NMGH

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