EARLY DIAGNOSIS OF DIABETIC

NEPHROPATHY

Dr. Nabieh Al-HilaliConsultant Physician and Nephrologist

Member of ERA-EDTA and ISNMedicare Middle East

OBJECTIVES To discuss the risk of development of

Diabetic nephropathy

To discuss pros and cons of Microalbuminuria

Is there any Novel biomarkers for early detection of diabetic nephropathy?

DIABETIC N BACKGROUND

BACKGROUND More than 387 million people are currently

suffering from diabetes. The International Diabetes Federation

estimated that this would rise to 592 million within a generation.

Egypt is one of the 20 countries of the IDF.

There were over 7.5 million cases of diabetes in Egypt in 2014.

MENA More than 37

million people in the MENA

By 2035 this will rise to 68 million.

PREVALENCE OF DIABETES IN EGYPT 2014

DIABETIC NEPHROPATHY

DIABETIC NEPHROPATHY Diabetic nephropathy is a clinical syndrome characterized by the following: Persistent albuminuria (>300 mg/d or

>200 μg/min) that is confirmed on at least 2 occasions 3-6 months apart

Progressive decline in the GFR Elevated arterial blood pressure In the 1930s, Kimmelstiel and Wilson

described the classic lesions of nodular glomerulosclerosis in diabetes associated with proteinuria and hypertension.

NATURAL HISTORY OF DIABETIC NEPHROPATHYDiabetic Nephropathy progresses through

five predictable stages which are as follows:-

Stage 1 (very early diabetes ) Above-normal GFR.(>90ml/min ) with

enlarged kidneysHyperglycemia leads to hyperfiltration

due to osmotic load and to toxic effects of high sugar on kidney cells

NATURAL HISTORY OF DIABETIC NEPHROPATHY(CONTD.) Stage 2 (developing) Silent phase with *Continued hyperfiltration and hypertrophy *The GFR remains elevated or has returned

to normal ( GFR 60-89ml/min )

*Glomerular damage has progressed to significant microalbuminuria

NATURAL HISTORY OF DIABETIC NEPHROPATHY (CONTD.)Stage 3 (overt, or dipstick-positive)

Glomerular damage has progressed to clinical albuminuria more than 300 mg /day

GFR 30-59ml/min .

Basement membrane thickening

Hypertension typically develops during stage 3.

NATURAL HISTORY OF DIABETIC NEPHROPATHY (CONTD.)Stage 4 (late-stage) Glomerular damage continues, with increasing

amounts of protein albumin in the urine. The kidneys’ filtering ability has begun to decline

steadily, and blood urea nitrogen (BUN) and creatinine (Cr) has begun to increase.

The glomerular filtration rate (GFR) decreases further more with ( GFR 15-29ml/min ).

Almost all patients have hypertension at stage 4.

NATURAL HISTORY OF DIABETIC NEPHROPATHY (CONTD.)Stage 5 (ESRD) GFR has fallen to <15 ml/min and renal

replacement therapy (i.e., haemodialysis, peritoneal dialysis, kidney transplantation) is needed.

DIABETIC NEPHROPATHY

Currently, DN is the leading cause of chronic kidney disease in the United States and other Western societies.

Diabetes is responsible for 30-40% of all ESRD) cases in the United States

Studies among Arabs showed that about half of the ESRD in different dialysis modalities are diabetic.

Alhilali N. et al in 2003 and 2007

RISK FACTORS OF DIABETIC NEPHROPATHY Genetic Factors Inadequate Glucose Control High blood pressure Hyperlipidemia Smoking Long Standing Diabetes Pregnancy Poor nutrition during pregnancy Overweight Unhealthy diet Physical inactivity Ethnicity

DIABETIC N PREVENTIONDETECTION

PREVENTION OF DIABETIC NEPHROPATHY Good evidence suggests that early

treatment delays or prevents the onset of diabetic nephropathy .

Regular outpatient follow-up is key in managing diabetic nephropathy successfully.

EARLY DETECTION OF DIABETIC NEPHROPATHY Recently, attention has been called to

atypical presentations of diabetic nephropathy with dissociation of proteinuria from reduced kidney function.

Also noted is that microalbuminuria is not always predictive of diabetic nephropathy.

DIABETIC N BIOMARKERS

WHAT IS BIOMARKER ? Biomarker: A biologic element that can be

used to measure the presence of disease progress of disease the effects of treatment.

Inflammation Renal injury

Diabetic Nephropathy Progression

Warning albuminureaDecline in GFR

BiomarkersSoluble TNF receptors 1 and 2

FGF23FABPs

PEDF

FGF21

FABPs = Fatty acid binding proteins; FGF =Fibroblast growth factor; GFR = glomerular filtration rate;PEDF = Pigment epithelium-derived factor; TNF = Tumor necrosis factor;

MICROALBUMINURIA In the past, persistent microalbuminuria was the

most studied biomarker in diabetic nephropathy. Both the presence and the incremental changes

in microalbuminuria had been shown to correlate with the development and progression of chronic kidney disease in diabetic patients.

Furthermore, microalbuminuria was also shown to be a risk factor for the development of macrovascular complications in diabetic patients.

CHALLENGED OF MICROALBUMINURIA- 1/2 high variability,

low sensitivity and specificity in predicting kidney disease progression in diabetic nephropathy.

spontaneous remission of MA could occur in more than half of diabetic patients.

Furthermore, 20% of type 2 diabetic patients had their GFR decline to ≤60 mL/ min/1.73 m2 before or even without passing the stage of microalbuminuria.

Progression diabetic nephropathy is not necessarily parallel with progression of urinary albumin excretion.

CHALLENGED OF MICROALBUMINURIA- 2/2 Only a minority of patients with MA progress to

proteinuria

one third of patients with MA, progressive renal function decline starts already at the onset of MA, not proteinuria.

.As a prognostic biomarker for progression of diabetic nephropathy, microalbuminuria fails in terms of sensitivity and specificity

Therefore these doubts about microalbminuria has promoted vigorous search for new markers

NOVEL BIOMARKERS This has led to active research on new prognostic

biomarkers for progressive diabetic nephropathy in recent years.

Of the emerging candidate biomarkers, 1.Serum cystatin C 2.Markers of inflammation 3.Fatty acid binding proteins(FABP) 4.Pigment epithelium-derived factor (PEDF) 5. Fibroplast Growth Factor 21(FGF21) 6.Peptidome

have provided the most promising data.

SERUM CYSTATIN C Serum cystatin C is produced by all nucleated cells,

freely filtered by the glomeruli

completely metabolized by the proximal renal tubules.

An observational study by Krolewski et al. showed that the measurement of serum cystatin C

improved the risk prediction of DN progression to ESRD in diabetic patients.

Subjects given a higher baseline CKD stage by cystatin C-based eGFR than by creatinine-based eGFR

MARKERS OF INFLAMMATION

Inflammation is clearly one of the key players in the pathogenesis of diabetic nephropathy

It is also potential candidate for the prediction of progressive kidney disease in diabetes.

FGF23, an endocrine hormone (related to phosphate homeostasis and vitamin D activation),

Circulating TNF receptors (1 and 2), had been shown to predict renal outcome in DN.(Niewczas et al)

another study has shown the predictive effect of FGF23 on the risk of progression in diabetic nephropathy was dependent on the TNF receptor

These suggested the superiority of using serum TNF receptor 1 over conventional biomarkers, such as microalbuminuria

FATTY ACID BINDING PROTEINS Recently, fatty acid binding proteins,(a

group of diverse proteins involved in lipid homeostasis), have also been reported as potential biomarkers for diabetic nephropathy.

Elevated urinary levels of liver-fatty acid binding protein (L-FABP) were detected in diabetic patients even before the onset of microalbuminuria.

PEPTIDOME Composed of low molecular weight protein

and peptide fragment

Its presence correlate with early renal function decline in diabetes.

It reflect changes in both tubular and glomerular protein expression.

Thus, urine peptide expression may provide insight into renal pathophysiologic mechanisms.

Bhensdadia et al Urinary haptoglobin as a potential

prognostic biomarker for progressive diabetic nephropathy was identfied.

Although as a single marker urinary haptoglobin adds little to albuminuria, together the two appear to provide better diagnostic accuracy than albuminuria alone.

CONCLUSIONS

CONCLUSIONSTo conclude, As a prognostic biomarker for progression of diabetic

nephropathy, microalbuminuria fails in terms of sensitivity and specificity

There is clearly a need for novel biomarkers with high sensitivity and specificity for predicting the progression of diabetic nephropathy.

good biomarkers could also bring new insights into the pathogenesis of diabetic nephropathy, and open up new therapeutic options for preventing nephropathy progression.

it is anticipated that more biomarkers will continue to be discovered.