Impotante for student

1. DIABETIC NEPHROPATHY
Dr. M Yaqoob BAHAR, MD
Feb 19, 2023

2. DEFINITION
• Diabetic nephropathy is defined as:
• albuminuria (albumin excretion rate>300 mg/24 hours, which
equates to 24-hour urinary protein >0.5 g)
• declining renal function in a patient with known diabetes who
does not have a urinary tract infection, heart failure, or any other
renal disease
• Presence of diabetic retinopathy

3. • is the leading cause of chronic kidney disease (CKD) and ESRD requiring
renal replacement therapy.
• CKD in individuals with DM is associated with an increased risk of
cardiovascular disease, and the prognosis of individuals with diabetes on
dialysis is poor.
• Individuals with diabetic nephropathy commonly have diabetic retinopathy.
• The presence of CKD in individuals with DM and no retinopathy should
prompt investigation for alternative causes of kidney disease
• Microvascular Complication

4. PATHOGENESIS
• pathogenesis of diabetic nephropathy is related to chronic hyperglycemia
• Due to effects of soluble factors (growth factors, angiotensin II, endothelin, AGEs),
hemodynamic alterations in the renal microcirculation (glomerular hyperfiltration or
hyperperfusion, increased glomerular capillary pressure), and structural changes in
the glomerulus (increased extracellular matrix, basement membrane thickening,
mesangial expansion, fibrosis).
• Some of these effects may be mediated through angiotensin II and
mineralocorticoid receptors.
• Smoking accelerates the decline in renal function.
• Because only 20–40% of patients with diabetes develop diabetic nephropathy,
additional genetic or environmental susceptibility factors likely contribute

5. PATHOLOGY
• ALWAYS PRESENT
• Glomerular basement membrane thickening.
• Tubular basement membrane thickening.
• Mesangial expansion with predominance of increased mesangial matrix.
• Interstitial expansion with predominance of increased extracellular matrix material.
• OFTEN OR USUALLY PRESENT
• Kimmel stiel-Wilson nodules (nodular glomerulosclerosis)
• Global glomerulosclerosis
• Focal segmental glomerulosclerosis
• Atubular glomeruli
• Foci of tubular atrophy
• Afferent and efferent arteriolar hyalinosis

6. PATHOLOGY
• SOMETIMES PRESENT
• Hyaline caps or fibrin caps (Highly characteristic of diabetic
nephropathy)
• Capsular drops (Highly characteristic of diabetic nephropathy)
• Atherosclerosis.
• Glomerular micro-aneurysms

7. FACTORS PROMOTING THE DEVELOPMENT
AND PROGRESSION OF NEPHROPATHY
• Blood pressure
• Poor glycaemic control
• Dyslipidaemia
• Smoking
• High protein intake
• Small kidneys
• Genetic factors

8. NATURAL HISTORY
1. Hyperfiltration
2. Silent stage
3. Microalnuminuria (Moderatly increased)
4. Macroalbuminuria (severely increased)
5. Uremia

9. NATURAL HISTORY

10. 1. HYPERFILTRATION
• Increased Glomerular Filtration Rate (GFR >90ml min),
• Adjust with age, 20% from baseline
• Concomitant renal hypertrophy (glomerular and tubular)
• Various factors contributing are:
• Intra renal hemodynamic abnormalities
• TGF-B
• Increased salt absorption
• Osmotic load and toxic effect of high sugar levels on kidney
cells

11. 2. SILENT STAGE
• The GFR has returned to normal with no evidence of albuminuria
• Glomerular damage occurs in the form of basement membrane
thickening and mesangial expansion.
• Ambulatory BP monitoring studies have shown modest rise in BP
and absence of nocturnal dip

12. 3. INCIPENT NEPHROPATHY/
MICROALBUMINURIA
• Now called moderately increased albuminuria
• Urine AER has increased to 30 to 300 mg/24 hrs
• Renal functions could be normal or reduced
• 30-50% of patients may show reversal of microalbuminuria
• Persistent microalbuminuria, if untreated, will progress to end-
stage renal disease (ESRD).
• Therefore, all diabetes patients should be screened for
microalbuminuria on a routine basis.

13. 4. MACROALBUMINURIA/ OVERT
NEPHROPATHY
• Severely increased albuminuria
• The urine AER is more than 300 mg of albumin in a 24-hour
period.
• Over two thirds of patient in this stage have Hypertension.
• If untreated a vicious cycle of progressive renal impairment
develops leading to ESRD.

14. 5. UREMIA
• GFR has fallen to <15 ml/min and renal replacement
therapy (i.e., haemodialysis, peritoneal dialysis, kidney
transplantation) is needed
• Sign and symptoms of uremia

15. SIGNS & SYMPTOMS
• General
• Fatigue & malaise
• Edema
• Ophthalmologic
• AV nicking
• Cardiac
• HTN
• Heart failure
• Pericarditis
• CAD
• GI
• Anorexia
• Nausea/vomiting
• Dysgeusia
• Skin
• Pruritis
• Pallor
• Neurological
• MS changes
• Seizures

18. CLINICAL MANIFESTATIONS
• Stages 1–4 CKD are asymptomatic.
• Symptoms develop slowly with the progressive decline in
GFR, are nonspecific, and do not manifest until kidney
disease is far advanced (GFR less than 5–10 mL/min/1.73
m2).
• Uremic syndrome.
• Fatigue
• anorexia, nausea
• a metallic taste in the mouth.

19. • Neurologic symptoms such as irritability, memory impairment, insomnia,
restless legs, paresthesias, and twitching may be due to uremia.
• Generalized pruritus (without rash)
• decreased libido and menstrual irregularities
• Pericarditis
• Pleuritic chest pain

20. COMMON PHYSICAL FINDINGS
• Hypertension
• volume overload.
• Uremic signs:
• seen with a profound decrease in GFR (less than 5–10
mL/min/1.73 m2)
• generally sallow and ill appearance
• halitosis (uremic fetor)
• the uremic encepholopathic signs of decreased mental
status, asterixis, myoclonus, and possibly seizures

21. ASTERIXIS, FLAPPING TREMOR

22. SCREENING AND DIAGNOSIS OF
DIABETIC NEPHROPATHY
• Diabetes should be screened annually with serum creatinine and eGFR and
urine Alb:Creatinine (ACR)
• Starting 5 yrs after diagnosis of type 1
• Starting at the diagnosis of type lI
• Elevated urine ACR confirmed ≥ 2 times and not in setting of UTI ,acute
febrile illness, vigorous exercise, uncontrolled hypertension, and heart failure
• Microalbuminuria: ACR 30-300 mg/mmol
• Macroalbuminuria: ACR >300 mg/mmol

23. • Screening should be done when the person is free from acute
illness and with stable glucose levels
• Early morning urine sample is preferred
• Serum creatinine level should also be measured annually
• Recently serum Cystatin C - A naturally circulating protein, freely
filtered by glomerulus has been suggested as an alternative to
creatinine measurement.

24. CALCULATIONS: EGFR
• Cockcroft-Gault
• Men: CrCl (mL/min) = (140 - age) x wt (kg)
• SCr x 0.81
• Women: multiply by 0.85
• MDRD
• GFR (mL/min per 1.73 m2) = 186 x (SCr x 0.0113)-1.154 x (age)-0.203 x (0.742
if female) x (1.12 if African-American)

25. TREATMENT
• Major therapeutic interventions include –
• Control of blood glucose to near normal level
• Antihypertensive treatment
• Lipid lowering therapy
• Restriction of dietary proteins
• Cessation of smoking

26. • Primary prevention:
• Diabetic Control and Complications Trial showed that intensive glycemic control
reduces the occurrence of microalbuminuria
• ADVANCE study and VETERAN trial recently confirmed similar findings.
• Secondary prevention :
• UKPDS proves that tight glycemic control reduces progression from
microalbuminuria to overt nephropathy
• A recent trial also confirms that ESRD development was retarded by
multifactorial interventions
• Nephropathy:
• Once overt nephropathy develops, results are disappointing regarding
metabolic control in preventing further progression of disease

27. KDIGO GUIDELINES FOR MANAGEMENT
OF HYPERGLYCEMIA AND GENERAL
DIABETES CARE IN CKD
• Target Hemoglobin A1c(HbA1c) of 7.0% to prevent or delay progression of
the microvascular complications of diabetes, including DKD.
• No treatment if HbA1c target is <7.0% in patients at risk of hypoglycemia.
• Target HbA1c can be extended to > 7.0% in individuals with co-morbidities
or limited life expectancy

28. METFORMIN
• Metformin to be continued in people with
• GFR ≥ 45 ml/min/1.73 m(GFR categories G1-Ga)
• Its use should be reviewed in those with GFR 30-44 ml/min/1.73 m(GFR category G3b)
• Discontinued in people with GFR<30 ml/min/1.73 m(GFR categories G4-G5) and risk of
hypoglycemia.

29. DIPEPTIDYL PEPTIDASE INHIBITORS
• Sitagliptin, saxagliptin, linagliptin, alogliptin
• Linagliptan: No adjustment needed
• Sitagliptin :
• (eGFR) of 30 or greater to less than 50 mL/min/1.73 m2: 50 mg once daily,
• eGFR less than 30 mL/min/1.73 m2, a dose of 25 mg once daily is advised.
• Saxagliptin:
• 2.5-5 mg daily in patients with an eGFR greater than 50 mL/min,
• eGFR of 50 mL/min/1.73 m2 or less to 2.5 mg daily.
• Alogliptin also requires a dose reduction:
• from 25 mg daily to 12.5 mg daily in patients with an eGFR of less than 60 mL/min/1.73
m2
• and to 6.25 mg daily if the eGFR is less than 30 mL/min/1.73 m2

30. ALPHA-GLUCOSIDASE INHIBITORS
• Acarbose
• Miglitol
• eGFR<25: avoid

31. SGLT2
• Canagliflozin, Dapagliflozin, Empagliflozin
• increased excretion of glucose in the urine, which may help subjects lose up to 5 kg of
weight over a year.
• decreased glucose reabsorption is also accompanied by increased urinary excretion of
sodium, which, in turn, may help with further blood pressure lowering
• it is not recommended in patients with an eGFR < 45 mL/min/1.73 m2.
• Increased glucosuria is believed to increase the risk of urinary tract infections, especially
candidal infections, and more frequently in women
• SGLT-2 inhibitors can reduce albuminuria and, after an initial decline (~3 mL/min per 1.73
m2) in GFR, may slow further decline in kidney function in individuals with and without
T2DM and CKD

32. GLP-1 ANALOGUES
• Liraglutide: is not metabolized by the kidney, and no dose adjustment is necessary
in patients with a decreased GFR

33. BLOOD PRESSURE CONTROL
• ACE-I or ARB's are not recommended for the primary prevention of diabetic
nephropathy in normotensive normo-albuminuric patients with diabetes
• ACE inhibitors and ARB's are effective in slowing the progression of kidney
disease characterized by microalbuminuria in hypertensive patients with type
1 or type 2 diabetes.
• ACE inhibitors, ARBs, and nondihydropyridine calcium channel blockers have
a greater anti-protein-uric effect than other antihypertensive classes in
hypertensive patients with diabetic nephropathy.

34. HTN
• Dihydropyridine calcium channel blockers, when used alone in the
absence of ACE inhibitors or ARB's are less effective than other
agents in slowing progression of diabetic nephropathy.
• ADA states " In patients with type 2 diabetes, hypertension,
macroalbuminuria and renal insufficiency ARBs have shown to
delay progression“

35. KDIGO GUIDELINES FOR MANAGEMENT OF
HYPERTENSION IN DIABETIC NEPHROPATHY
AND PROTIENURIA
• Both diabetic and non-diabetic adults with CKD and urine albumin excretion
<30 mg/24 hours whose office BP is consistently >140/90 mm Hg, be treated
with BP-lowering drugs to maintain a BP that is consistently ≤ 140/90 mm
Hg.
• Both diabetic and non-diabetic adults with CKD and with urine albumin
excretion of >30 mg/24 hours whose office BP is consistently > 130/80 mm
Hg, be treated with BP-lowering drugs to maintain a BP that is consistently <
130/80 mm Hg.
• There is insufficient evidence to recommend the combination of an ACE-|
with an ARB to prevent progression of CKD

36. PRECAUTIONS TAKEN WHILE STARTING
AN ACE-I OR AN ARB
• Monitoring of blood pressure, potassium, and serum creatinine level is
important.
• Potassium level up to 5.5 mEg/Land an increase in serum creatinine up to
30% from baseline within the first three months with close monitoring is
tolerable
• Medication needs to be reduced or discontinued if potassium levels remain
elevated at > 5.5mEq/L or if the serum creatinine continues to rise or does
not improve.
• Avoid in people with suspected functional renal artery stenosis

37. ACE-I AND ARBS
• Start at lower dose in people with GFR <45 ml/min/1.73 m
• Assess GFR and measure serum potassium within 1 week of starting or
following any dose escalation
• Temporarily suspend during intercurrent illness, planned IV radiocontrast
administration, bowel preparation prior to colonoscopy, or prior to major
surgery
• Do not routinely discontinue in people with GFR <30 ml/min/1.73 m as they
remain nephroprotective
• Ramipril: decrease cardiovascular risk

38. TREATMENT GOAL FOR LIPIDS IN
DIABETIC NEPHROPATHY
• Mechanism
• Low-density lipoprotein <2.6 mmol/L (100 mg/dL)
• High-density lipoprotein >1 mmol/L (40 mg/dL) in men, >1.3
mmol/L (50 mg/dL) in women
• Triglycerides <1.7 mmol/L (150 mg/dL)
• Dyslipidemia is common in people with diabetes and CKD.
Cardiovascular events are a frequent cause of morbidity and
mortality in this population.

39. KDIGO GUIDELINES FOR MANAGEMENT OF
DYSLIPIDEMIA IN DIABETES AND CKD
• Lowering low-density lipoprotein cholesterol (LDL-C) with statin-based therapies
reduces risk of major atherosclerotic events in patients with CKD including those
with diabetes.
• LDL-C lowering medicines, such as statins or statin+ezetimibe combination reduces
risk of major atherosclerotic events in patients with diabetes and CKD, including
those who have undergone kidney transplant.
• Not recommended to initiate statin therapy in patients with diabetes who are
treated by dialysis
• Atorvastatin is better

40. MANAGEMENT OF ANEMIA IN
DIABETIC NEPHROPATHY
• Iron deficiency, AOCD
• Measure ferritin level
• Anemia Screening: measure Hb levels
• When clinically indicated in patients with GFR >60 ml/min/1.73 m (GFR
categories G1-G2)
• Annually in patients with GFR 30-59 ml/min/1.73 m (GFR categories G3a-
Gb)
• Twice a year in patients with GFR<30 ml/min/1.73 m (GFR categories G4-
G5)
• EPO and darbopoetin, HIF inhibitors

41. DIETARY PROTEIN RESTRICTION
• A low protein diet reduces urinary albumin excretion and hyper-filtration
independent of changes in glucose control and blood pressure.
• KDIGO GUIDELINE FOR PROTIEN INTAKE
• Lowering protein intake to 0.8 g/kg/day in adults ‡ diabetes and GFR<30
ml/min/ 1.73 m2(GFR categories G4-G5) with appropriate education.
• Avoiding high protein intake (>1.3 g/kg/day) in adults with CKD at risk of
progression

42. TREATMENT OF ESRD
• Transplantation(kidney only, simultaneous pancreas with kidney,
pancreas after kidney)
• Hemodialysis
• Continuous ambulatory peritoneal dialysis

43. HEMODIALYSIS
• Renal replacement therapy should be started earlier than in non diabetic patients
• Intradialytic hypotension is common in diabetic patient on dialysis because of
autonomic neuropathy and disturbed left ventricular compliance
• Following approach is used to avoid intradialytic hypotension - Long dialytic
session, omission of antihypertensive drugs before dialytic session, controlled
ultrafiltration, correction of anemia by EPO therapy, alternative modalities such as
CAPD
• High prevalence of cardiovascular complications in diabetic patients entering
dialysis programme
• Dialysis partially reverses the insulin resistance and requirement compared prior to
dialysis

44. PERITONEAL DIALYSIS
• According to heaf and co worker, during the first 2 years, survival is better for
diabetic patient treated with CAPD compared to HD
• Survival advantage no longer demonstrated beyond 2 years as by then
residual renal function has already decayed
• CAPD provides slow and sustained ultra filtration without rapid fluctuation of
fluid volume and electrolyte concentration, a feature that is advantageous for
BP control and prevention of heart failure

45. KIDNEY TRANSPLANT
• Survival of diabetic patients with kidney graft is worse compared to non diabetic patients.
• And survival of diabetic nephropathy patients on dialysis is poorer when compared to
patients with kidney graft.
• Simultaneous kidney with pancreas transplantation(SP) should be the preferred treatment
for type1 DM who meet the selection criteria: Age <55 years and GFR<40.
• Exclusion criteria for SPK: Active smoking, morbid obesity and uncorrected CVD
• Pancreas after kidney transplantation - An alternative strategy, must be considered in a
diabetic patient who has a living kidney donor.
• Firstly the living kidney is transplanted and subsequently once stable renal function is
achieved (GFR>50 ml/min), cadaveric pancreas is transplanted
• Results of Islet cell transplantation are inferior to whole pancreas transplantation

46. • Nephrology consultation should be considered when:
• estimated GFR is <30 mL/min per 1.743 m2
• or with atypical features such as:
• Hematuria
• rapidly declining renal function
• proteinuria > 3 g/day.
• Referral for transplant evaluation should be made when
the GFR approaches 20 mL/min per 1.73 m2

47. • INHALED INSULIN approved by FDA in 2014 - AFREZZA
• Rapid acting insulin taken before each meal or soon after starting the
meal
• Doesn't replace the need of injectable long-acting insulin, hence not
suitable for diabetic emergencies such as DKA
• Common side effects - Low blood sugar, cough, scratchy/sore throat
• Should not be used in smokers and individuals with lung disease