New insight into early detection of diabetic nephropathy

1. Dr. Nabieh Al-Hilali
Consultant Physician and Nephrologist
Member of ERA-EDTA and ISN
Medicare Middle East

2.  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?

4.  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.

5. MENA
 More than 37
million people in
the MENA
By 2035 this will rise
to 68 million.

7. PREVALENCE OF DIABETES IN EGYPT 2014

9. 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.

10. Diabetic Nephropathy progresses through five
predictable stages which are as follows:-
 Stage 1 (very early diabetes )
Above-normal GFR.(>90ml/min ) with
enlarged kidneys
Hyperglycemia leads to hyperfiltration due to
osmotic load and to toxic effects of high
sugar on kidney cells

11.  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

12. 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.

13. 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.

14. Stage 5 (ESRD)
 GFR has fallen to <15 ml/min and renal
replacement therapy (i.e., haemodialysis,
peritoneal dialysis, kidney transplantation)
is needed.

15.  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

16.  Genetic Factors
 Inadequate Glucose Control
 High blood pressure
 Hyperlipidemia
 Smoking
 Long Standing Diabetes
 Pregnancy
 Poor nutrition during pregnancy
 Overweight
 Unhealthy diet
 Physical inactivity
Ethnicity

18.  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.

19.  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.

21.  Biomarker: A biologic element that can be used
to measure
 the presence of disease
 progress of disease
 the effects of treatment.

23. Inflammation Renal injury
Diabetic Nephropathy Progression
Warning
albuminureaDecline in GFR
Biomarkers
Soluble TNF receptors 1 and 2
FGF23
FABPs
PEDF
FGF21
FABPs = Fatty acid binding proteins; FGF =Fibroblast growth factor; GFR =
glomerular filtration rate;
PEDF = Pigment epithelium-derived factor; TNF = Tumor necrosis factor;

24.  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.

25.  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.

26.  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

27.  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.

28. 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

29.  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

30.  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.

31.  Composed of lowmolecular 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.

32. 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.

35. To 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.