The document discusses the management of diabetic nephropathy through a holistic approach, emphasizing lifestyle interventions such as individualized nutrition, protein intake, salt restriction, and smoking cessation. It highlights the importance of glycemic control, weight management, and appropriate medication use, including SGLT-2 inhibitors and GLP-1 receptor agonists, while addressing blood pressure and lipid management. Additionally, it reviews the role of antithrombotic therapy in reducing cardiovascular risks in patients with diabetes and chronic kidney disease.

1. MANAGEMENT OF
DIABETIC NEPHROPATHY
DR ELSATHOMAS

2. HOLISTIC APPROACH FOR IMPROVING
OUTCOMES IN PATIENTS WITH DIABETES
AND CHRONIC KIDNEY DISEASE

3. LIFESTYLE INTERVENTIONS IN
PATIENTS WITH DIABETES AND CKD
• Nutrition intake
• Patients with diabetes and CKD should consume an
individualized diet high in vegetables, fruits, whole grains,
fiber, legumes, plant-based proteins, unsaturated fats, and
nuts; and lower in processed meats, refined carbohydrates,
and sweetened beverages.

4. PROTEIN INTAKE
 Guidelines suggest
maintaining a protein
intake of 0.8 g of protein/kg
(weight)/d for those with
diabetes and CKD not
treated with dialysis (2C).
 Patients treated with
hemodialysis, and particularly
peritoneal dialysis should
consume between 1.0 and 1.2 g
protein/kg (weight)/d

5. SALT INTAKE
o Sodium intake be <2 g of
sodium per day or <5 g of
sodium chloride per day in
patients with diabetes and
CKD (2C).
KDIGO - <2000 mg/day,
ADA - 1500 to <2300 mg/day

6. SMOKING
• Smoking Appears to promote onset and progression of diabetic kidney disease
• Several studies have reported a higher prevalence of microalbuminuria and
macroalbuminuria and reduced GFR (<60 mL/min/1.73 m 2 ) among patients
with type 2 diabetes who smoked compared with their nonsmoking
counterparts
• Precise mechanism not clear - One hypothesis is activation of multiple
cellular pathways in smokers with diabetes results in accumulation of reactive
oxygen species and a loss of kidney redox homeostasis

7. WEIGHT LOSS
• Weight Loss Goal should be individualized to the patient and should be both
achievable and maintainable; NKF recommends a target BMI of 18.5-24.9 (ie, within
the normal range) for patients with diabetes and CKD

8. GLYCEMIC CONTROL

9. GLYCEMIC CONTROL
Guidelines recommend hemoglobin A1c
(HbA1c)/TIR or GMI to monitor glycemic
control in patients with diabetes and
CKD, at least twice per year is reasonable for
patients with diabetes meeting treatment goals.
HbA1c may be measured as often as 4 times
per year if the glycemic target is not met or
after a change in glucose-lowering therapy.
Accuracy and precision of HbA1c
measurement declines with advanced
CKD (G4-G5), particularly among patients
treated by dialysis

10. • Hba1c reflects average
glycemia over 3 months,
but does not provide a
measure of glycemic
variability or
hypoglycemia
• A 14-day CGM
assessment of TIR and
GMI can serve as a
surrogate for A1C for
use in clinical
management
• 70%TIR=HBA1C OF 7

11. • The ADA recommends a starting HbA1c target of <7% to reduce microvascular complications
in most non-pregnant adult patients with T1D and T2D without hypoglycemia risk.
• Although higher goals (i.e., <8%) are acceptable for patients with limited life expectancy and
in whom the harms of treatment may outweigh the benefits
KDIGO Guidelines recommend an individualized HbA1c target
ranging from <6.5% to <8.0% in patients with diabetes and CKD not
treated with dialysis (1C).

12. HBA1C=7
TIR-70%
TBR-4%
TBR<54-
1%

13. • RCT, tested the “glucose hypothesis”
• Over its mean 6.5 years of therapy, the DCCT demonstrated that intensive
treatment, i.e., HbA1c -7.2% reduced the risks of development and
progression of early stages of retinopathy, nephropathy, and neuropathy by
34%–76%, compared with conventional treatment (HbA1c 9%)

14. EPIDEMIOLOGY OF DIABETES
INTERVENTIONS AND
COMPLICATIONS(EDIC)
• The DCCT was
followed by the EDIC
observational study of
the DCCT cohort
(1994 to date) .
• The beneficial effects of
prior DCCT intensive
versus conventional
treatment on diabetes
complications persisted
- “metabolic memory”

15. UNITED KINGDOM PROSPECTIVE DIABETES STUDY
(UKPDS)
• Reducing the HbA1c level by approximately 0.9% in patients with type 2 diabetes reduced the risk for
microvascular complications,
• The differences in HbA1c were lost within 1 year, but a 24% lower risk of microvascular disease and myocardial
infarction ( 15%) persisted.All-cause mortality was also reduced ( 13%).-
− − “legacy effect.”

17. ANTIDIABETC
MEDICATIONS

21. METFORMIN
metformin suppresses gluconeogenesis by inhibiting a specific mitochondrial isoform
of glycerophosphate dehydrogenase (mGPD), an enzyme responsible for converting
glycerophosphate to dihydroxyacetone phosphate, thereby preventing glycerol from
contributing to the gluconeogenic pathway,

22. The dose should be reduced to 1000 mg daily in patients with eGFR 30–44 ml/min/1.73 m2
and in some patients with eGFR 45–59 ml/min/1.73 m2 who are at high risk of lactic
acidosis

23. METFORMIN IS CONTRAINDICATED IN PATIENTS WITH
FACTORS PREDISPOSING TO LACTIC ACIDOSIS.
Impaired kidney function (estimated glomerular filtration rate [eGFR]
Concurrent active or progressive severe liver disease
Active alcohol abuse
Unstable or acute heart failure at risk of hypoperfusion
Past history of lactic acidosis during metformin therapy
Decreased tissue perfusion or hemodynamic instability due to infection or other causes

27. SGLT-2 INHIBITORS

30. Recommendation
Treat patients with type 2 diabetes (T2D), CKD, and eGFR
≥20 ml/min per 1.73 m2
with an SGLT2i (1A).

31. • Sick day protocol (For illness
or excessive exercise or
alcohol intake):
• Temporarily withhold SGLT2i,
• check blood glucose and blood
ketone levels more often, and
seek medical help early.
• Peri-procedural/perioperative care:-
1. Inform patients about risk of diabetic
ketoacidosis;
2. withhold SGLT2i the day of day-stay
procedures and limit fasting to minimum
required;
3. withhold SGLT2i at least 2 days in
advance and the day of
procedures/surgery requiring 1 or more
days in hospital and/or bowel preparation,
4. measure both blood glucose and blood
ketone levels on hospital admission
(proceed with procedure/surgery if the
patient is clinically well and ketones
are <1.0 mmol/l), and
5. restart SGLT2i after procedure/surgery o

32.  A reversible decrease in the eGFR with commencement of SGLT2i treatment may
occur and is generally not an indication to discontinue therapy.
 Once an SGLT2i is initiated, it is reasonable to continue an SGLT2i even if eGFR
falls below 20 ml/min per 1.73 m2
, unless it is not tolerated or kidney replacement
therapy is initiated.
 SGLT2i have not been adequately studied in kidney transplant recipients, who may
benefit from SGLT2i treatment, but are immunosuppressed and potentially at
increased risk for infections; therefore, the recommendation to use SGLT2i
treatment does not apply to kidney transplant recipients.

37. INCRETIN DRUGS
GLP1 is a peptide hormone produced by enteroendocrine L cells within the terminal ileum
and colon

38. MOA

39. INCRETIN SIGNALLING
PATHWAY IN KIDNEY

41. • GLP1R agonists belong to two main structural categories — exendin 4-based
compounds and analogues based on human GLP1 .
• Human GLP1-based agents have greater sequence homology to native GLP1
• . Exenatide and lixisenatide are based on the structure of exendin 4, a salivary
protein isolated from the Gila monster lizard (Heloderma suspectum)
• These agents have relatively short half-lives (~3 hours), which leads to fluxes in
plasma drug levels throughout the day and to activation of GLP1R for ~6 hours
after injection.The pulsatile stimulation of GLP1R results in less robust effects
on hyperglycaemia over the course of a day compared with drugs based on
human GLP1 that have longer half-lives

47. SULFONYLUREAS
• Class of insulin secretagogues that stimulate pancreatic insulin secretion by
closing K-ATP channels on β-cell plasma membranes.
• First-generation sulfonylureas are long-acting and almost exclusively
excreted by the kidneys.
• Second-generation agents are short-acting and primarily metabolized by the
liver, with most metabolites undergoing renal clearance. Their use carries the
risk for hypoglycemia as GFR declines and insulin clearance decreases.
• Sulfonylureas are highly protein-bound but can be displaced into circulation
by other drugs used in patients with DM (e.g., salicylates, β-blockers), further
contributing to hypoglycemia.
• The metabolites of gliclazide and glipizide are inert or weakly active and may
be used in patients with ESRD on dialysis.

48. THIAZOLIDINEDIONES
• Peroxisome proliferator-activated receptor (PPAR)modulators, which
work to increase insulin sensitivity.
• Their use is limited by causing weight gain and fluid retention
through transcriptional upregulation of tubular amiloride-sensitive
sodium channels.
• Rosiglitazone was withdrawn from the market because of the
increased risk for myocardial infarction reported with its use,
although pioglitazone remains in use.
• Higher rates of bone fractures also have been reported

49. Α-GLUCOSIDASE INHIBITORS
• α-Glucosidase hydrolyses complex starches to
oligosaccharides in the lumen of the small
intestine, releasing glucose.
• Inhibition of this enzyme maintains less glucose
absorption, and thus should be taken at the start
of meals.

50. BP MANAGEMENT
• Hypertension is defined as a systolic blood pressure >130 mmHg or a diastolic
blood pressure >80 mmHg based on an average of 2 measurements obtained on 2
occasions. Individuals with blood pressure >180/110 mmHg and cardiovascular
disease could be diagnosed with hypertension at a single visit
• The recommendation to support a blood pressure goal of <130/80 is consistent
with guidelines from the ACR ,AHA, ISH AND ESC

53. ACEI AND ARB

54. KDIGO RECOMMENDS TREATMENT WITH AN ACEI OR
ARB FOR PATIENTS WITH DIABETES, HYPERTENSION,
AND ALBUMINURIA, AND TO TITRATE TO THE HIGHEST
APPROVED DOSE THAT IS TOLERATED

55. • For patients with diabetes, albuminuria, and normal blood pressure,
treatment with an ACEi or ARB may be considered.
• A small percentage (3.5%) of patients in the RENAAL trial, and
30.9% (163 of 527) of randomized patients in the INNOVATION
study were normotensive, suggesting that use of RAS blockade
may be beneficial in patients without hypertension
• Available data suggest that ACEi and ARB treatments are not
beneficial for patients with neither albuminuria nor elevated blood
pressure

65. CCB
• Three randomized trials in CKD have shown that those assigned to
dihydropyridine calcium channel blocker (DHP-CCB) therapy experienced
less kidney protection than those not assigned to DHP-CCB, perhaps
because of DHP-CCB–induced arteriolar vasodilation resulting in
glomerular hypertension.
• However, in the Avoiding Cardiovascular Events Through Combination
Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial,
ACE inhibitor plus amlodipine therapy protected kidney function better
than ACE inhibitor plus diuretic therapy, especially in non-Blacks.

66. • Both groups had similar BP control
• But the group initially randomized to an ACE inhibitor with a calcium
antagonist had a 20% CV risk reduction compared with the ACE
inhibitor plus diuretic group
• Possibly, the benefit of amlodipine in the ACCOMPLISH study was seen
because the CKD patients had low-level proteinuria.
• In addition, there is evidence that chronic thiazide therapy is nephrotoxic.
• Thus, if a CCB is needed for BP control, the first choice should be a
nondihydropyridine CCB (NDHP-CCB).

67. PATHWAY 2 TRIAL
• Addition of Spironolactone to A+C+D in resistant HTN is
better than a Beta or a Alpha Blocker.

68. LIPID MANAGEMENT
• Diabetic dyslipidemia is characterized by elevated triglyceride levels, low high-density lipoprotein
cholesterol (HDL-C) levels, and an excess of highly atherogenic, small, dense low- density
lipoprotein cholesterol (LDL-C)
• Statin therapy is a cornerstone of therapy for the primary and secondary prevention of ASCVD
among people with diabetes and CKD.
• The 2013 KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease
recommended statin initiation for most adults with diabetes and CKD who are not treated with
dialysis.
(i) adults >50 years old with CKD and eGFR < 60 ml/min/1.73 m2 (grade 1B recommendation) and
(ii) adults aged 18–49 years with CKD with diabetes, known coronary heart disease, prior ischemic
stroke, or estimated 10-year incidence of coronary heart disease death or nonfatal MI >10% (grade
2A recommendation).

69. • In nondialysis CKD patients, a beneficial effect on lowering cholesterol was
confirmed in the Study of Heart and Renal Protection (SHARP), which included
more than 9000 patients with a wide range of CKD and no history of CVD,
randomized to simvastatin and ezetimibe or placebo.A 17% reduction in adverse
CV outcomes was seen for every 33 mg/dl reduction in LDL-C, whether the CKD
subject was diabetic or nondiabetic, with no impact on mortality.
• However, in DM dialysis patients the AURORA, SHARP, and 4D trials did not show
significant reductions in CV events or mortality despite LDL-C falling by up to 42%.
• Ezetimibe is an appropriate alternative first-line agent for patients who cannot
tolerate statins, and fibrates should be used as primary therapy in patients whose
triglyceride levels exceed 400 mg/dL
• Statin/fibrate combinations should be used with caution because of an increased risk
of rhabdomyolysis. This risk appears to be greater among patients with kidney
impairment and appears to be lower with fenofibrate than with gemfibrozil

70. ANTITHROMBOTIC THERAPY
• Hyperglycemia has a procoagulant effect on platelet aggregation independent of insulin levels, and
hyperinsulinemia itself carries an inhibitory effect on fibrinolysis and thus significantly increases the risk
for thrombosis. Platelet reactivity is known to increase with advancing CKD
• AntithromboticTherapy Review of trials suggests that aspirin may offer a modest benefit in reducing
cardiovascular risk in patients with diabetes, although the evidence is equivocal
• Current ADA diabetes management guidelines, endorsed by AHA and ACR, recommend low-dose aspirin
(75-162 mg/d) for primary prevention in patients at increased cardiovascular risk (ie, a 10-year risk of
>10%) and for those with diabetes and existing cardiovascular disease
• Antithrombotic Therapy Clopidogrel at 75 mg/d is a useful alternative for patients unable to tolerate
aspirin, and dual antiplatelet therapy for 1 year with aspirin plus clopidogrel should be considered for
patients experiencing an acute coronary syndrome

71. • THANKYOU