Chronic Kidney Disease Part 1 Flashcards
Hallmark of DM nephropathy
persistent albuminuria > 300 mg/24 hours
dm retinopathy + absence of clinical or laboratory evidence of other kidney or renal tract disease
microalbuminuria=urinary albumin excretion of > 30 mg/24 hours and less than 300 mg/24 hours in 2 of 3 samples
DEFINICAO MICROALBUMINURIA= presnca de albuminuria maior q o valor normal mas nao detectavel no dipstick 30-300mg/dia
According to the American Diabetes Association, for patients with type 2 diabetes mellitus, urine albumin should be assessed annually, starting from the point of diagnosis.
Microalbuminuria is associated with kidney dysfunction and atherosclerotic cardiovascular events.
Healthcare workers need to encourage changes in lifestyle and initiate therapy when microalbuminuria is discovered.
If treatment with an ARB or ACE inhibitor does not sufficiently control proteinuria in patients with chronic kidney disease, further control of proteinuria can be done by adding mineralocorticoid receptor antagonists (MRA), such as spironolactone or eplerenone.
However, MRAs are associated with an increased risk of hyperkalemia.
A new agent finerenone which is a nonsteroidal MRA decreased proteinuria while causing lower rates of hyperkalemia.
The current diagnosis of microalbuminuria also includes a urinary albumin/creatinine ratio (UACR) ranging between 2 to 20 mg.
In addition to the individual variability, one should be cautious that some cases have an elevated UACR at baselines, such as males, African Americans, Asians, smokers, people with higher muscle mass, patients with urinary tract infection, and genital leakage.
first pathologic sign in dm nephropathy type 1 dm and proteinuria
glomerular basement membrane thickening
Microalbuminuria develops from a dysfunction of the GBM permitting albumin to enter the urine. inadequate control of blood sugars inhibits this enzyme, reducing the negative charge on GBM and allowing excessive amounts of albumin to leak out. Advanced glycosylation end-products can also neutralize the negative charge of albumin by binding with the proteins of both the GBM and mesangial matrix.[6] Additionally, hyperglycemia initiates the glycation of GBM and podocyte receptors interfering with the charge on GBM.[1][2][6]
The current hypothesis, known as the ‘Steno hypothesis,’ is that systemic vascular endothelial dysfunction initiates the development of microalbuminuria and cardiovascular disease, as there is a strong correlation between these three variables.
Therefore, having comorbidities that cause endothelial damage is considered a risk factor. These include increased age, insulin resistance, dyslipidemia, obesity, hypertension, decreased physical activity, and smoking.[5] Some studies predict a genetic component linking together microalbuminuria, atherosclerosis, and even nephropathy. An increased UAE rate was seen among patients with a deletion-deletion polymorphism of the ACE gene.[6]
Microalbuminuria has been associated with patients who have type 1 or type 2 diabetes. For patients with type 1, the prevalence of microalbuminuria within the first three years after diagnosis is only 6%; however, after five years, it is 41%. In type 2, the prevalence is 20% to 25% for newly diagnosed and long-standing diabetics.[8][9] In patients with uncontrolled hypertension, microalbuminuria was seen in 47.4% of patients; whereas, in patients with controlled blood pressure it was 36.7%.[10]
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Pathophysiology
Microalbuminuria arises when GBM, a complex sieve, leaks an increased amount of albumin. The proposed mechanism is a combination of glomerular size enlargement, GBM thickening, mesangial expansion, and podocyte foot process effacement. Microalbuminuria can also occur via inadequate tubular reabsorption.[2][7]
Dysregulated enzymatic metabolism of the extracellular matrix is the pathogenesis behind developing endothelial damage.[3][8] Thus, at vascular places, other than just the renal system, the albumin can either leak out of or enter the vessel wall. When this happens, albumin can stimulate inflammation, lipid accumulation, and atherosclerosis, which eventually could form fixed albuminuria and decreased kidney function.[7]
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Histopathology
There are structural changes at the level of GBM that lead to microalbuminuria. However, these are heterogeneous and may even be present in patients with normoalbuminuric diabetes. The GBM alterations are typically seen in type 1 diabetes, but not type 2.[8]
Furthermore, researchers found no correlation between increased GBM permeability and any histological changes. Since the majority of the GBM dysfunction is through altered charge selectivity, not size, it would not appear on histology.[2][8]
arteriolar hyalinosis usually seen within
3 to 5 years
exudative lesions in type 1 DM nephropathy pathology
arteriolar hyalinosis, bowmans capsular drops, hyaline caps
45-59 ml/min GFR
stage 3a
GFR 30-44
stage 3b
GFR 15-29
stage 4
GFR less than 15
stage 5
BP target in CKD with proteinuria
less than 120/80
education on RRT and hepatitis B vaccination
Stage 4
AVF creation
stage 5
Goal for Acei or ARB treatment
urine protein level < 0.5 g/day
target for weight loss in obese patients
5%
dietary salt restriction
<5 g (90 meqs sodium per day)
protein requirement for normal adults or those with uncomplicated CKD
0.8 g protein/kg/day
CKD patients with complications
0.6 g protein/kg/day or 0.3 g/kg + ketoacids or a mixture of aminoacid
CKD patients with loss of muscle mass
0.8 g protein/kg/day
CKD with proteinuria
< 0.8 g protein/kg/day + 1 g protein/g proteinuria
at least 3 episodes of itch in a 2 week period that causes difficulty for the patient or as itch that occurs over a 6 month period in a regular pattern
pruritus
associated with hyperparathyroidism or elevated Ca x Phos
calciphylaxis
main regulator of systemic iron hoemostasis
hepcidin
increase in PTH secretion immediate effects
increase in 1a hydroxylase activity,
bone turnover,
ca reabsoprtion
decrease in renal po4 reabsorption
more than 3 rbc/hpf in atleast 2 of 3 freshly voioded midstream clean catch urine
asymptomatic hematuria
imaging to localize and control source of bleeding
cystoscopy
diagnostic when there is any suspicion of upper tract disease
retrograde pyelography
glomerular hematuria + active urine sediment + wbcs/casts
nephritic syndrome
hallmark of nephritic syndrome
glomerular hematuria
definitive finding in nephritic syndrome
rbc casts
principal underlying abnormality in nephrotic syndrome
increased permeability of the glomerular capillaries
most common underlying systemic disease causing nephrotic syndrome
Diabetes Mellitus
1+ urine dipstick protein is equivalent
30-100 mg/dL
most common urine lipid
esterified cholesterol
birefingent birght cross like appearance in polarizing microscope
lipiduria
type of RTA associated in obstructive uropathy
type 4
test of choice to diagnose obstructive uropathy
renal ultrasonography
stage 1 hypertension
140-159/90-99
benzene ring-shaped cysteine crustals
cystinuria
coffin lid crystals
struvite
imaging procedure of choice for stones
noncontrast helical CT scan
radioopaque stones
calcium, cysteine
radiolucent stones
uric acid, indinavir or triamterene stones
size of stones that will pass spontaneously
4 mm
most important vascular complication in patients with CKD
CAD
strongest indicator of possible renal underpefusion
overt hypotension
normal blood glucose in OGTT
less than 140 mg/dL
impaired glucose tolerance or preDM
OGTT 140-199 mg/dL
primary cause of insulin resistance in uremia
impaired tissue sensitivity
independent risk factors for cardiovascular complication in patients with ESKD
insulin resistance and hyperinsulinemia
uremic dyslipidemia
increased triglycerides, ldl and vldl, decreased hdl cholesterol
metformin should be used with caution when eGFR is
less than 60 ml/min
when to discontinue metformin
less than 30 ml/min
insulin sensitizer, causes lactic acidosis in CKD
metformin
T3 levels in CKD
low due to low conversion of T4
strong inhibitors of protein binding of T4
urea, creatinine, indoles, phenols ,heparin
Increase in GH secretion
fasting, insulin induced hypoglycemia, increase of protein
glucose load in growth hormone secretion
decrease GH secretion
reason for reduced linear bone growth in CKD
reduced effectiveness of GF and IGF-1
primary mediator of effects of GH
IGF-1
GH deficiency in GFR and renal plasma flow
decrease GFR and plasma flow
reason for GH resistance
decreased GH receptors and post GH receptor defects, decreased IGF-1 synthesis
stimulates protein synthesis, decreases urea generation and improves nitrogen balance
recombinant human GH
adverse reaction to GH treatment
benign intracranial hypertension, hyperglycemia, fluid retention
most abundant steroid hormone
DHEA
antifibrotic and antiapoptotic effects in kidney
estrogen
responsible for decreased libido, erectile dysfunction, oliospermia and infertility, osteopenia in adults with ESKD
hypogonadism, low testoteron and hyperprolactinemia
development of lipid enriched plaques in the intimal layer of the artery
atherosclerosis
phenomenon of noncalcified nonatheromatous stiffening of smaller muscular arteries
arteriolosclerosis
characterized by medial thickening and heavy calcification without the presence of atheroma
monckerberg’s medial calcific sclerosis
LV remodeling occurs as early as
stage 2
indirect risk factors of CVD/CKD
DM, obesity
partially treated uremia and side effects of dialysis
residual syndrome
most abundant solute excreted by kidney
urea
uremic toxin that impairs platelet function
guanidosuccinic acid
aromatic waste compound normally excreted in the largest quantity
hippurate
uremic solute associated with cardiovascular death in patients undergoing hd
p-cresol sulfate
Fractional excretion of calcium remains unchanged until gfr
<25 ml/min
As GFR decrease Na and Phosphate is maintained by
Decreased reabsorption
absence of cellular (osteoblast and osteoclast) activity, osteoid formation and endosteal fibrosis
low turn over (adynamic bone disease)
bone biopsies that features secondary hpt and mineralization defect, extensive osteoclastic and osteoblastic activity and increased endosteal peritrabecular fibrosis with more osteoid
mixed uremic osteodystrophy
rate of skeletal remodeling: bone resoprtion + formation
turn over
how well bone collagen calcified during the formation phase of skeletal remodeling
mineralization
amount of bone per unit volume of tissue
volume
Dxa to assess fracture risk is recommended/not recommended in
stage 1-3/stage 3b-5
LV remodeling occurs
Stage 2-3 CKD
primary disease of cardiac muscle assoc with ckd causing systolic dysfunction; interstitial myocardial fibrosis
Uremic cardiomyopathy
when is statins recommended in ckd
Stage 3-5 in older than 50 years or less than 50 yo with additional risk factors
screening of anemia starts at stage
G3
tx of aluminum toxicity
deionized water or chelation with desferrioxamine
most effective tx of posttransplantation erythrocytosis
Raas blocker
gold standard in assesing iron stores
Bone marrow iron
if hit is established, what should be considered
Direct thrombin inhibitors or factor Xa
Other tx for uremic bleeding
Ddvap
cryoprecipitate
estrogen
primary prevention of stroke
aspirin
what benefits would initiation of bicarbonate confer
Delay in progression of her CKD
• Improvement in serum potassium
• Improved bone health
• Reduce muscle wasting
As microalbuminuria occurs mostly in the absence of any serious underlying renal disease, more benign and common causes of microalbuminuria should be considered first. The following questions should be asked:
Is this transient - This may be because of physical exertion and fever
Is this orthostatic - Typically seen in tall, thin adolescents or people younger than 30 years; there is an association with severe lordosis; normal renal function and albuminuria is frequently less than 1 g/24 hours[13]
Is nonrenal disease causing it, such as severe cardiac failure, sleep apnea - Normal renal function and albumin loss is less than 1 g/24 hours
Are there any symptoms suggestive of nephrotic syndrome or significant glomerular pathology
Are there any changes in the appearance of urine, such as red/smoky, frothy; is there any correlation of this to a respiratory tract infection
Is there ankle, periorbital, labial, or scrotal edema
Has the patient ever been diagnosed with high blood pressure
Is there a history of high cholesterol levels in the patient’s blood
Has the patient ever had a diagnosis of a multisystem disease or another glomerulopathy
Is there a past or family history of any renal disease
If the patient has diabetes mellitus, for how long; are there any complications, such as retinopathy
Is a family history of diabetic nephropathy present
Are there any multisystem inflammatory diseases present, such as systemic lupus erythematosus (SLE) or rheumatoid arthritis
Are there symptoms like joint discomfort, skin rash, bone pain, fever, weight loss, night sweats, or Raynaud syndrome
Is the patient on any medication, including herbal remedies
Are there any past medical illnesses, such as jaundice, malaria, tuberculosis, syphilis, or endocarditis
Is the patient at risk of HIV infection or hepatitis
complicacoes da proteinuria
With progressive disease, patients can develop macroalbuminuria, diabetic kidney disease, and proteinuria.[1] The level of serum albumin is unable to predict the nutritional status of a patient. However, during states of extreme starvation, serum albumin is low, and urine albumin is high.
Other complications of proteinuria are:
Pulmonary edema which is attributable to fluid overload
Acute kidney injury secondary to intravascular depletion and progression of kidney disease
Increased risk of cardiovascular diseases
Increased risk of vascular thrombosis, such as renal vein thrombosis
Increased risk of bacterial infections
albuminuria prognostico
The main reason to test the UAE level is to evaluate the patient for possible future complications. However, providers should not merely view microalbuminuria as a kidney damage marker, but as a predictor of kidney dysfunction progression rate and reflect the effect of systemic disorders on the kidney.[1]
It is well known that the glomerular filtration rate (GFR) is useful in staging chronic kidney disease. In comparison to microalbuminuria, GFR is a pure kidney damage marker. Several studies have demonstrated that there is a continuous correlation between microalbuminuria and developing end-stage renal disease. Therefore, when presented with a patient with a reduced GFR classified under stage 3 or 4, the patient with microalbuminuria should be considered very high risk, instead of high risk as per the GFR. This classification ensures that prompt action is taken to prevent further complications, such as macroalbuminuria, diabetic kidney disease, proteinuria, and chronic kidney disease.[5]
Microalbuminuria has links with a high rate of atherosclerotic cardiovascular events (such as coronary artery disease, stroke, and peripheral vascular disease) and subsequently increased morbidity and mortality. The evidence reveals in adults; it is a four to six-fold increase, whereas, in patients with diabetes, it is only two-fold.[3][5][6][9] The risk of cardiovascular events is even higher for patients with macroalbuminuria versus microalbuminuria. Thus, screening and compliance with the treatment of microalbuminuria could prevent macroalbuminuria and even death.[3][6] The UACR range for microalbuminuria starts at 2 mg/day, but data shows that the risk between increased UAE and cardiovascular disease can begin even at 1 mg/day.[3]
Among patients with essential hypertension, microalbuminuria can predict kidney function decline, coronary artery stenosis, and hypertensive retinopathy. Importantly, the latter two are reversible with adequate treatment
albuminuria tto
If microalbuminuria is present, aggressive measures should ensue with the ultimate goal of decreasing the risk of cardio-metabolic complications. The first-line treatment is lifestyle modifications to control diabetes and hypertension. Although it seems trivial, this can save retinal function, prevent further kidney damage, decrease the risk of cerebrovascular accidents, and reduce microvascular complications.[5] For patients with type 2 diabetes with microalbuminuria, reports indicate that a normal protein diet of (0.8 g x kg)/(bodyweight x day) was optimal, not a low protein diet.[19] Interestingly, eating chicken, instead of red meat, saw a reduction in urinary albumin excretion of 46% along with decreasing total cholesterol and apolipoprotein B in type 2 diabetic patients with microalbuminuria.[11]
Maintaining an A1c of less than 7% has been shown to decrease the risk of developing not only microalbuminuria but also macroalbuminuria. The evidence shows that rosiglitazone and insulin have the best outcomes and the least side effects.[11] Angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), or vasodilatory beta-blockers can reduce blood pressure. Although many providers commonly believe that ACE inhibitors and ARBs are interchangeable in the treatment method, some data does not support the effectiveness of ARBs.[5] These classes of drugs have an effect on reducing proteinuria separate from their antihypertensive effect.[20] In patients younger than 50 years, the blood pressure goal should be 120/70-75 mmHg, whereas it is slightly higher at 125-130/80-85 mmHg in those older than 50. Moreover, ACE inhibitors are useful in patients with diabetes, even without hypertension. They have a reno-protective effect of decreasing mesangial expansion and preventing the onset of glomerulosclerosis.[6][11][21] The other anti-hypertensives help manage hypertension but have minimal effect in delaying the progression of kidney disease.[3][22] Normalization of blood pressure in hypertensive patients results in a decrease in intraglomerular pressure and albuminuria.[23]
If treatment with an ARB or ACE inhibitor does not sufficiently control proteinuria in patients with chronic kidney disease, further control of proteinuria can be done by adding mineralocorticoid receptor antagonists (MRA), such as spironolactone or eplerenone. However, MRAs are associated with an increased risk of hyperkalemia. A new agent finerenone which is a nonsteroidal MRA decreased proteinuria while causing lower rates of hyperkalemia.[24]
Immunosuppressants, such as cyclophosphamide and azathioprine should be used in patients who have progressive renal insufficiency or who have vasculitic changes on renal biopsy.[25]
Several experimental drugs show promising evidence but require further studies to evaluate if they decrease the long-term cardiovascular disease associated with microalbuminuria. For one of the groups, the mechanism is by decreasing protein glycation. These medications are thiamine, ALT-711 (a cross-link breaker of advanced glycation), and pimagedine (a second-generation inhibitor of advanced glycation). Additionally, ruboxistaurin, a protein kinase C-beta inhibitor, has been implicated in decreasing UAE.[11] Increased vascular endothelial growth factor (VEGF), which regulates vascular permeability and angiogenesis, has been linked with microalbuminuria in patients with type 2 diabetes. Thus, VEGF inhibitors could be helpful in patients with microalbuminuria.[8] Glycosaminoglycans, such as sulodexide, can also decrease albuminuria.[3] Statins, on the other hand, have a well-documented effect in reducing the risk of cardiovascular disease, but their role in decreasing urinary albumin excretion is still controversial. Due to its cardioprotection, it merits inclusion in the treatment regimen.[3]
When considering the associated comorbidities with microalbuminuria, the treatment recommendations should also include weight loss, aspirin, and maintaining low-density lipoprotein cholesterol of less than 100.[11] Finally, the level of microalbuminuria can serve as an indicator of treatment response, especially in patients with hyperinsulinemia, insulin resistance, and hypertension.[1][3]
In terms of specific treatments, sodium-glucose co-transporter 2 (SGLT2) inhibitors, such as canagliflozin and empagliflozin have gained popularity not only in the management of diabetes mellitus but also in reducing the development or further worsening of albuminuria.[26] A meta-analysis observed that the combination therapy with SGLT2 inhibitors and other hypoglycemic agents helps reduce albuminuria.[27]
Non-dihydropyridine calcium channel blockers (NDCCBs), such as diltiazem and verapamil, decrease proteinuria more than dihydropyridine calcium channel blockers (DCCBs) because NDCCBs affect both the afferent and efferent arteriole.[28][29]
Endothelin activation has an association with renal inflammation and fibrosis. Endothelin A (ETA) receptor blockade leads to the dilation of the glomerular capillaries, reducing albumin permeability. Endothelin B (ETB) reduces arterial pressure by decreasing salt and water reabsorption from the kidneys. Experimental ETA-selective antagonists, such as avosentan and atrasentan, have been shown to decrease proteinuria.[30][31]
e Brito-Ashurst et al. (6) reported that oral
sodium bicarbonate supplements at a dos-
age of approximately 22 mEq/d (and stan-
dard therapy) slowed the decline in mea-
sured CrCl from 5.9 to 1.9 ml/min per 1.73
m
2
. Fewer patients developed end-stage
kidney disease (6.5 versus 33.0%). Nutri-
tional parameters, including dietary intake,
normalized protein nitrogen appearance,
serum albumin, and mid-arm muscle cir-
cumference, improved in the bicarbonate-
supplemented group
