A presentation about nephrology aspects of diabetes mellitus

1. Dr.Tanvir Mahmud
Resident(Phase-B),Nephrology

2. Introduction
 Diabetic kidney disease is a major cause of morbidity and
mortality in diabetes.
 Indeed, the excess mortality of diabetes occurs mainly in
proteinuric diabetic patients and results not only from end-
stage renal disease (ESRD) but also from cardiovascular
disease.
 Clinically diabetic kidney disease is characterized by
progressive kidney damage reflected by increasing
albuminuria, impairment in renal function(decline in
glomerular filtration rate (GFR)), elevated blood pressure
Diabetic nephropathy,Joris j.roelofs,2019

3. Epidemiology
 According to WHO report 2016,8% of total population
of Bangladesh was affected by DM,whereas 3% of total
deaths of all-ages occurred due to Diabetes.
 Approximately 3% of newly diagnosed patients with T2
DM have overt nephropathy.
 About 25-40% of people with diabetes will eventually
develop kidney disease.
 DKD is the most common primary diagnosis for
patient who start dialysis(~50%) (Board review 2021)

7. Risks for development of DKD &
progression
 Unmodifiable risks:
1.Genetic susceptibility:Family H/O predisposition to abnormal
sodium handling & HTN;ACE,angiotensin 2 type 2
receptor,aldose reductase genotypes
2.Ethnicity:African descents,Hispanics,pima indians with type 2
DM
3.Gender: Caucasian males and females of african descent
4.Age:probably early onset
5.Duration of DM
 Modifiable:HTN,early glomerular hyperfiltration,prolonged
uncontrolled hyperglycemia,obesity,tobacco smoking.use of
OCP,high protein diets

8. Pathogenesis

9. Different pathways and networks involved
in the initiation and progression of DKD

10. Pathogenesis
a. Genetic and environment factor
b. Alterted intra renal hemodynamics
c. Hyperglycemia and activation of pathway of glucose
metabolism
d. Growth factors and cytokines
e. Renin angiotensin system and oxidative stress

12. Stages of Diabetic nephropathy
Stage GFR Albuminuri
a
BP Time
course
Stage-1
Hyperfiltration &
nephromegaly
Elevated Absent Normal At diagnosis
Stage-2
Clinical latency
High
normal
Absent Normal <5 yrs
Stage-3
Microalbuminuria(incipient
nephropathy)
Normal; 30-300
mg/day
Raising(with
in or above
normal)
5-15 yrs
Stage-4
Macroalbuminuria or
persistent albuminuria(overt
nephropathy)
Decreasing >300 mg/day increased 10-15 yrs
Stage-5
Chronic kidney
disease(CKD)
Diminished Decreasing increased 15-30 yrs

13. Clinical manifestation of diabetic kidney of Non-glomerular origin.
1. Tubular protenuria
2. Fluid / electrolytes disorder
- Glycosuric osmotic diuresis
Hypoaldosteronism
- RTA type IV
- Hypercalciuria
3. Obstructive Nephrology, Neurogenic bladder
4. CIN
5. Papillary Necrosis
6. Pyelonephritis-
Bacterial,Fungal,Emphysematus,Xanthogranulomatous.

14. Investigation
 The main evaluation in the patient with suspected
DKD:
1.Measurement of urinary albumin or protein
2.Measurement of serum creatinine and eGFR
3.Measurement of BP
4.Ophthalmologic examination

15.  Further investigation and assessment:
1.Urinalysis (?haematuria);quantify proteinuria
2.S.electrolyte,serum albumin.HBA1C,lipid profile
3.Consider serum & urine electrophoresis in older patients
4.Consider USG,esp. if microscopic haematuria(kidneys
are often normal sized in DN despite decreased GFR)
5.Assess for peripheral neuropathy
6.Examine for other evidence of CVD (bruits,pulses,etc.&
ECG/ECHO)

16. Kidney Biopsy

17.  Kidney biopsy is usually performed when suspicion of
Nondiabetic kidney disease (NDKD),reported
prevalence 10% to 85%
 Indications for kidney biopsy in DM:
1.Nephrotic range proteinuria or kidney failure in the
absence of diabetic retinopathy or neuropathy.
2.Nephrotic range proteinuria or kidney failure with
diabetes duration less than 5 years(esp Type 1)
3.Unexplained microscopic hematuria or AKI.

18. 4.Rapidly worsening kidney function or proteinuria in
patients with previously stable kidney function.
5.Presence of extra renal manifestations and/or positive
serology suggestive of another glomerular
disease:positive ANCA/ANA,hypocomplementemia,
dsDNA,Cardiolipin ab,HIV,M-spike in Serum/Urine,
Cryoglobulin,HBsAg,AntiHCV

19. Structural changes:Histopathology
of DN
 Glomerular enlargement & basement membrane
thickening(upto 3 times normal)-is the earliest change
 Mesangial expansion:
-Mild to severe diffuse mesangial expansion without nodules
-Nodular glomerular intracapillary lesion(kimmelstiel-wilson
lesion):nodular glomerulosclerosis with mesangiolysis
aand capillary microaneurysm
-Advanced diabetic sclerosis
 Vascular lesions including hyalinization of afferent &
efferent arterioles,pathognomonic of DN and arterial
intimal fibrosis.

21. Hematuria and DKD
a. Presence of hematuria, indicate NDKD but it may be
present in DKD also.
b. In study it shows DKD patients with hematuria had
significantly lower GFR
c. Prevalence of NS and Retinopathy was significantly
higher in hematuric patient.
d. MN, FSGS,AIN,PSGN,IgAN is frequently associated
with T2DM in which NDRD is suspected.

22.  Patients with diabetes and chronic kidney disease
(CKD) should be treated with a comprehensive
strategy to reduce risks of kidney disease progression
and cardiovascular disease.

23. Management and Monitor
Glycemic Monitoring and target
in DM/CKD
KDIGO recommend using Hb AIC to Monitor glycemic
control in Patient with Diabetes and Kidney.

26. New proposal:
1. Glycated Albumin and Fructosamiae
2-4 weeks time Frame.
2. Recommendation –HbA1C target ranging from <6.5 %
to <8% in Patient with DM and CKD not treated with
HD.
<6.5% for prevention of complication
<8% Multiple Comorbidities / increases burden of
hypoglycemia

27. Lifestyle interventions in patients with
diabetes and CKD
 Nutrition:
- 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
- Protein intake of 0.8 g protein/kg (weight)/d for those
with diabetes and CKD not treated with
dialysis.(KDIGO,2020)

28.  Patients treated with hemodialysis,and particularly
peritoneal dialysis, should consume between 1.0 and
1.2 g protein/kg (weight)/d.
 Sodium intake should be <2 g of sodium per day (or
<90 mmol of sodium per day, or <5 g of sodium
chloride per day) in patients with diabetes and CKD.

29.  Patients with diabetes and CKD are advised to
undertake moderate-intensity physical activity for a
cumulative duration of at least 150 minutes per week,
or to a level compatible with their cardiovascular and
physical tolerance.

30.  Patients with obesity, diabetes, and CKD should be
encouraged/advised to lose weight, particularly patients
with eGFR more than 30 ml/min per 1.73 m2.
 With an eGFR <30 ml/min per 1.73 m2, and kidney failure
treated with dialysis, patients may spontaneously reduce
dietary intake, and malnutrition and muscle-wasting are
potential concerns. whether intentional weight loss offers
health benefits is unclear in this population.
 Therefore, depending on individual context,
recommending intentional weight loss may not be
appropriate for some patients with advanced CKD.

31. Hypertension in DKD
 Hypertension occurs in ~40% of Type 1 DM and 70% of
type 2.
 Higher BP is associated with both development and
progression of DKD.
 If hypertension develop in T1DM patient it is almost
always diabetic renal parenchymal diseases.
 T2DM patient hypertension often precedes the onset
of DM, as a feature of metabolic syndrome and
multifactorial.

34. BLOOD PRESSURE MANAGEMENT IN PATIENTS WITH CKD,
WITH OR WITHOUT DIABETES, NOT RECEIVING DIALYSIS
 Adults with high BP and CKD be treated with a target systolic
blood pressure (SBP) of <120 mm Hg.
 Less intensive BP-lowering therapy in patients with very
limited life expectancy or symptomatic postural
hypotension.
 RASi (ACEi or ARB) for people with high BP, CKD, and
moderately-to-severely increased albuminuria with
diabetes.

35.  RASi (ACEi or ARB) should be administered using the
highest approved dose that is tolerated.
 Changes in BP, serum creatinine, and serum potassium
should be checked within 2-4 weeks of initiation or
increase in the dose of a RASi, depending on the current
GFR and serum potassium.
 Hyperkalemia associated with use of RASi can often be
managed by measures to reduce the serum potassium
levels rather than decreasing the dose or stopping RASi.

36.  ACEi or ARB therapy is to be continued unless serum
creatinine rises by more than 30% within 4 weeks following
initiation of treatment or an increase in dose.
 Reducing the dose or discontinuing ACEi or ARB is to be
considered in either symptomatic hypotension or uncontrolled
hyperkalemia despite medical treatment, or to reduce uremic
symptoms while treating kidney failure (estimated glomerular
filtration rate [eGFR] <15 ml/min per 1.73 m2).
 Mineralocorticoid receptor antagonists are effective for
management of refractory hypertension but may cause
hyperkalemia or a reversible decline in kidney function

37. Anti hyperglycemic therapies in
patients with type 2 DM and CKD

39. Metformin
 Metformin is recommended for treating patients with
T2D, CKD, and an eGFR ≥30 ml/min per 1.73 m2.
 Monitor eGFR in patients treated with metformin.
Increase the frequency of monitoring when the eGFR
is <60 ml/min per 1.73 m2
 patients who experienced significant gastrointestinal
side effects from the immediate-release formulation
could be considered for a switch to extended release
metformin and monitored for improvement of
symptoms.

41. Sodium–glucose cotransporter-2 inhibitors
(SGLT2i)
 SGLT2i is recommended for treating patients with
T2D, CKD, and an eGFR ≥30 ml/min per 1.73 m2
 For patient who initiate SGLT2I of an GFR>30
ml/min and subsequently decline to an eGFR<30
ml/min. The SGLT2i can be continuted until of
RRT.

43. Benefit –
1. CV outcome benefit
2. Kidney outcome benefit
Harms-
1. DKA
2. Fracture risk- canagliflozin
3. Genital mycotic infection
4. Foot care including amputation

44.  Reasonable to withhold SGLT2I during time of
prolonged fasting, surgery and critical medical illness.
 If patient is at risk of hypovolumia ,consider
decreasing thiazide or loop diuretics dosages,before
start SGLT2I
 A reversible decrease in eGFR with commencement of
SGLT2I
 Kidney transplant patient –not recommended

45. GLP-1 RA
RECOMMENDATION-
- In patient with T2DM and CKD who have not achived
individualized glycemic targets despite use of metformin
and SGLT2I,or who are unable to use those medications,a
long acting GLP-1 is recommended.
- To minimize GI side effect start low dose and gradualy
titrate up slowly.
- Should not be used in combination with DPP-4 inhibitor.
- Risk of hypoglycemia in low in GLP-1 alone, but increase
with other medication sulbonylureas or insulin.

47. Insulin in CKD & Dialysis
 Insulin requirement may be reduced as kidney function
decline due to reduced insulin clearance,reduction of
gluconeogenesis in kidney ,uremia induced anorexia & weight
loss
 There is no evidence based guideline or recommendation
about which type of insulin to be used or avoided depending
on severity of CKD
 Insulin requirement may be 25% lower the day after dialysis
compared with the day before.
 Mean blood glucose is lower on dialysis days as HD improves
insulin sensitivity & inadequate GIT absorption due to
gastroparesis in DKD
 Meta analysis of insulin in T2 DM do not show a kidney benefit

48. Diabetic dyslipidemia
 Altered profile of plasma lipoprotein in patients with
DM involving increased triglycerides & small dense
low density lipoprotein(LDL) and decreased high
density lipoprotein(HDL) cholesterol is called diabetic
dyslipidemia.
 LDL-C is the primary target in diabetic dyslipidemia.
 Statin is the first option to reach LDL-C goal.
 Ezetemibe or PCSK9 inhibitors can be added to statin
to achieve LDL goal

49.  Studies on Statin in DM on MHD show no significant
benefit in CV outcome,rather 5 fold increase in
haemorrhagic stroke.
 KDIGO did not recommend routinely initiating statin
therapy in patients undergoing
haemodialysis,although the guideline suggests
continuing statins in those who were receiving from
predialysis.

50. Dialysis modalities for Diabetics
Modality Advantages Disadvantages
Haemodialysis Very effective
Frequent medical follow
up(in center)
No protein loss in
dialysate
May be poorly tolerated in
patients with advanced cardiac
disease
Multiple AV access surgeries often
required,risk of severe hand
ischemia
Relatively high incidence of
hypotension during HD
Pre dialysis hyperkalemia
Prone to hypoglycemia

51. Modality Advantages Disadvantages
CAPD Good cardiovascular
tolerance
No need for AV access
Good control of serum
potassium
Lower risk of
hypoglycemia
Peritonitis,exit site
infection & tunnel
infection (however,risks
similar to those in
nondiabetic dialysis
patients)
Protein loss to dialysate
Increased intraabdominal
pressure effects
(hernias,fluid leaks,etc)
Often needs helper

52. Transplantation
I. Long time patient survival in DKD after
Transplantation is superior to any modalities of
dialysis
II. Patients with ESRD due to DKD who received a
transplant will have a projected lifespan of 19 yrs
compared to 8 yrs for those who remain on dialysis.
III. Living related donor, provide the best long term
result
IV. Living unrelated donor also provide excellent result
V. Patient and allograft survival are superior in living
donor to cadaveric.

53. Post transplant period care-
1. Difficulty in controling blood sugar due to steroid
2. Anti hypertensive treatment required due to steroid /
CNI
3. Dyslipidemia due to CNI.
4. UTI
Recurrence:
Histological recurrence occurs eventually in 100%
recipients ( usually within 5 yrs).A reported cause of graft
loss in <2%,has important implication of CV disease and
patient survival.

54. Thank You