Causes,pathogenesis and diagnosis and treatment

Pathogenesis and diagnosis and treatment

1. Diabetic nephropathy
●PROFESSOR/MOHAMMED BAMASHMOS

2. Definition
►Globally, approximately 20% of the 400 million individuals with diabetes mellitus
have diabetic kidney disease (DKD). DKD is associated with higher cardiovascular
and all-cause morbidity and mortality, so timely diagnosis and treatment are
critical. Screening for early DKD is best done with annual spot urine
albumin/creatinine ratio testing, and diagnosis is confirmed by repeated elevation
in urinary albumin excretion. Treatment includes management of hyperglycemia,
hypertension, hyperlipidemia, and cessation of tobacco use. Multiple
antihyperglycemic medications, including sodium-glucose cotransporter-2
inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl-peptidase-4
inhibitors, may help prevent DKD by lowering blood glucose levels and through
intrinsic renal protection. 

3. ►Multiple antihyperglycemic medications, including sodium-glucose
cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, and
dipeptidyl-peptidase-4 inhibitors, may help prevent DKD by lowering blood glucose
levels and through intrinsic renal protection. Blood pressure should be monitored
at every clinical visit and maintained at less than 140/90 mm Hg to prevent
microvascular changes. Angiotensin-converting enzyme inhibitors and
angiotensin receptor blockers prevent progression of DKD and may decrease
albuminuria. Statin therapy should be considered for all patients with DKD, and
tobacco cessation reduces the risk of DKD. Given the complexity of the disease
and the risk of poor outcomes, patients who progress to stage 3 DKD or beyond
may benefit from referral to nephrology subspecialists.

4. ►Risk factors

6. Pathogenesis

10. Stages

11. Diagnosis
►Microalbuminuria is the earliest detectable marker of DKD and is defined as
elevated levels of albumin in the urine
9
  (Table 2 
7,9–11
). The American Diabetes
Association recommends annual screening of urinary albumin (spot urine
albumin/creatinine ratio) and estimated glomerular filtration rate (eGFR) in
patients who have had type 1 diabetes for at least five years, in all patients with
type 2 diabetes beginning at the time of diagnosis, and in all patients who have
comorbid hypertension.
9

16. Prevention and treatment
►preferably in the morning (51,52). The eGFR is calculated from the serum
creatinine concentration. Although the Chronic Kidney Disease-Epidemiologic
Prognosis Initiative equation is more accurate, particularly at eGFR levels in the
normal or near-normal range, the Modification of Diet in Renal Disease equation
is typically reported by clinical laboratories (52). Confirmation of albuminuria or
low eGFR requires two abnormal measurements at least 3 months apart. If
features atypical of DKD are present, then other causes of kidney disease should
be considered. Atypical features include sudden onset of low eGFR or rapidly
decreasing eGFR, abrupt increase in albuminuria or development of nephrotic or
nephritic syndrome, refractory hypertension, signs or symptoms of another
systemic disease, and >30% eGFR decline within 2–3 months of initiation of a
renin-angiotensin system inhibitor (53).

18. Glycemic control
►Prevention of diabetic complications, particularly DKD, by long-term intensive
glycemic control from early in the course of diabetes is well established for DM1
and DM2 (19,22). However, intensive glucose control after onset of complications
or in longstanding diabetes has not been shown to reduce risk of DKD
progression or improve overall clinical outcomes. Targeting low HbA1C
(6%–6.9%) compared with standard therapy in this population did not reduce risk
of cardiovascular (CV) or microvascular complications but increased the risk of
severe hypoglycemia (54–56). Furthermore, an analysis of patients with DM2 and
early-stage CKD showed 30% and 40% higher risks for all-cause mortality and
CV mortality, respectively, with intensive glycemic control compared with
standard therapy (57

19. ►The finding that intensive glycemic control incurs great risk of hypoglycemia and
does not benefit the risk of CVD or all-cause mortality has been sustained over
the long term (8–10 years). A small benefit of intensive glycemic control on the
risk of ESRD was observed, but the absolute number of patients was minute (58).
A stratified analysis showed that the greatest benefit of intensive glycemic control
for preventing ESRD was seen in participants without kidney disease at study
entry, further supporting the concept that intensive glycemic control initiated
during early diabetes can prevent DKD (59

20. ►The finding that intensive glycemic control incurs great risk of hypoglycemia and
does not benefit the risk of CVD or all-cause mortality has been sustained over
the long term (8–10 years). A small benefit of intensive glycemic control on the
risk of ESRD was observed, but the absolute number of patients was minute (58).
A stratified analysis showed that the greatest benefit of intensive glycemic control
for preventing ESRD was seen in participants without kidney disease at study
entry, further supporting the concept that intensive glycemic control initiated
during early diabetes can prevent DKD (59

21. Glycemic target
►The American Diabetes Association recommends that targets for glycemia
should be tailored to age, comorbidities, and life expectancy of individual
patients. More stringent goals, such as HbA1C<6.5%, may be reasonable for
patients with shorter duration of diabetes, younger age, absence of
complications, and a longer life expectancy. To the contrary, less stringent goals
of HbA1C<8% are recommended for patients with longstanding diabetes, older
age, micro- and macrovascular complications, and limited life expectancy (51).
Similarly, the National Kidney Foundation–Kidney Disease Outcomes Quality
Initiative and the Kidney Disease Improving Global Outcomes (KDIGO) guidelines
recommend a target HbA1c of about 7.0% to prevent or delay progression of the
microvascular complications of diabetes. However, patients at risk for
hypoglycemia, such as those with diabetes and CKD, should not be treated to an
HbA1c target of <7.0% (53).

24. Blood pressure control
►management of hypertension, the Eighth Joint National Committee (JNC-8)
recommended initiation of pharmacologic treatment at a systolic BP ≥140 mmHg
or diastolic BP ≥90 mmHg, with treatment goals less than these levels. In the
general hypertensive population, including those with diabetes, initial
antihypertensive treatment may include a thiazide-type diuretic, a calcium
channel blocker, an angiotensin-converting enzyme (ACE) inhibitor, or an
angiotensin receptor blocker (ARB). In black patients with diabetes, the JNC-8
recommends initial treatment with a thiazide diuretic or calcium channel blocker.
The same BP targets are recommended for those with CKD irrespective of
diabetes status. In patients who are diabetic with high levels of albuminuria, the
medication regimen should include an ACE inhibitor or an ARB alone or in
combination with medication from another drug class (60)

25. ►The KDIGO guidelines recommend use of an ACE or an ARB and a BP goal
<130/80 mmHg in all patients with CKD and albuminuria irrespective of diabetes
status (52). There is unambiguous evidence that renin-angiotensin system
blockade with either an ACE inhibitor or an ARB reduces the progression of DKD
in patients with macroalbuminuria (61). However, combination therapy (an ACE
inhibitor and an ARB administered together) increases the risk of serious side
effects, primarily hyperkalemia and AKI, and offers no clinical benefits (62,63).

30. ►DIRECT RENlN INHIBITOR
►Aliskiren, Remikiren, Enalkiren
►The latest class of RAS inhibitory drugs
►available for the treatment of cardiovascular and renal diseases in which ACE inhibitors and ARBs are
currently used
►nonpeptide which binds selectively to the catalytic site of renin and competitively blocks the access or
angiotensinogen to this site.
►As a result, Ang 1 is not produced and the effector chain of RAS is interrupted.
►While the concentration of renin in plasma is increased by feedback, the plasma renin activity (PRA) is
decreased.
►Ang I and Ang II levels fall in a dose-dependent manner.
►Aliskiren causes dose-related fall in BP which is more marked in the depleted subject with high basal PRA.

31. ►LIPID MANAGEMENT
►DKD alters lipid metabolism, leading to increased low-density
lipoprotein–cholesterol complex and increasing risk of poor outcomes
attributable to atherosclerotic cardiovascular disease. Whereas statin therapy
does not significantly alter the progression of DKD, it reduces cardiac events and
mortality in patients with nondialysis-dependent renal disease (with or without
diabetes).
5
 Many statins are metabolized by the kidneys; therefore, doses should
be reduced if a patient has significantly decreased eGFR. Atorvastatin (Lipitor)
doses do not need to be adjusted.

32. ►DIETARY MODIFICATION
►Dietary modification has the potential for preventing progression of DKD; however,
the evidence for specific interventions is mixed. The American Diabetes
Association recommends a protein-restricted diet (0.8 g per kg per day) in
patients with DKD, based on studies that show that this can slow the decline of
GFR and progression to ESRD.
48,49
 A Mediterranean diet and the dietary
approaches to stop hypertension (DASH) diet can have beneficial outcomes.
These diets include whole-grain carbohydrates, fiber, fresh fruits and vegetables,
omega-3 and omega-9 fats, and less than 2,300 mg per day of sodium. Foods that
are high in sugar, saturated fats, and processed carbohydrates should be
avoided.
49
 In patients who have DKD, routine monitoring for alterations in
phosphorus, potassium, and vitamin D may guide additional dietary modification.

33. ►CONSIDERATIONS IN CHILDREN AND ADOLESCENTS
►The evaluation and treatment of DKD in children and adolescents with types 1 and 2
diabetes are guided by limited evidence. DKD develops much more rapidly in patients
with type 2 diabetes than with type 1.
50
 For this reason, screening should begin within
five years of diagnosis of type 1 diabetes (or at age 10 or onset of puberty, whichever
comes first) and at the time of diagnosis for patients with type 2 diabetes.
50

►ACE inhibitor or ARB treatment should be considered for adolescents with elevations in
albumin/creatinine ratio and hypertension only after appropriate reproductive counseling
for young women about potentially teratogenic effects; ACE inhibitor or ARB treatment
should be avoided in women considering pregnancy.
51
 Because tobacco use increases
progression of DKD, adolescents should be counseled to avoid smoking (cigarettes,
e-cigarettes).
51

34. ►PREGNANCY CONSIDERATIONS
►Reproductive education and preconception counseling are critical for all women
of childbearing age who have diabetes, but limited data guide management of
DKD specifically. Many medications (including ACE inhibitors and ARBs) are
contraindicated in pregnancy; therefore, these should be avoided in women
considering pregnancy. For women who have diabetes and conceive,
recommended glycemic targets (A1C target less than 6% if possible and less than
7% if hypoglycemia occurs
52
) are different from those for nonpregnant women to
support healthy pregnancy and fetal development.