Nephro Exam 1 Material

Roles of the Kidney

1. Excretory Function includes filtration, secretion, and reabsorption
2. Metabolic function includes metabolizing vitamin D to the active form
3. Endocrine function includes producing erythropoietin

Glomerular filtration

A passive process by which water and small molecular weight ions and molecules diffuse across the glomerular-capillary membrane into the Bowman’s capsule and then enters the proximal tubule. Most proteins are too big and remain in circulation.

Secretion

An active process that takes place in the proximal tubule and facilitates the elimination of compounds from the renal circulation into the tubular lumen

Reabsorption

Mostly unionized compounds and is affected by urine pH; occurs ini the distal tubules and collecting duct

What is seen on an urinalysis (UA)?

1. pH
2. Glucose
3. Ketones
4. Nitrite
5. Leukocyte esterase
6. Heme
7. Protein/Albumin
8. Specific gravity
9. Microscopic analysis (cells, casts, crystals)

GFR Defintion

Indicates functional mass in the kidney; only glomerular function

Pros of Creatinine

1. Freely filtered
2. Not secreted (much)
3. Not reabsorbed
4. Rises in kidney dysfunction
5. Endogenous
6. Cheap assay
7. Reliable (IDMS)

Cons/Limitations of Creatinine

1. Input- muscle mass and diet
2. Output- tubular secretion and drugs affecting tubular secretion (probenecid, cimetidine, TMP)
3. Assay
4. Delay/Lag

Cockroft-Gault Equation

ClCr= (140-age)TBW / Scr x 72 \[x0.85\]

When would you use LBW to determine CrCl?

IF TBW is >30% above IBW

When would you round SCr to 1?

If a patient has low muscle mass and SCr < 1. Risks of this include underestimating kidney function and underestimating drug dosing.

MDRD Equation Limitation

1. Normal kidney function (CKD-EPI better here)
2. Adjustment for BSA
3. Need estimation tool
4. Drug dosing?
5. Special populations might be not be accurate

C-G v MDRD

1. MDRD for staging
2. C-G for drug dosing

CKD definition

CKD is defined as abnormalities of kidney structure or function, present for >3 months, with implications for health and CKD is classified based on cause, GFR category, and albuminuria category (CGA)

GFR >90

Category- G1

Definition- normal or increased GFR

GFR 60-89

Category- G2

Definition- Mildly decreased

GFR 45-59

Category- G3a

Definition- Mild to moderately decreased

GFR 30-44

Category- G3b

Definition- Moderately to severely decreased

GFR 15-29

Category- G4

Definition- Severe decrease GFR

GFR

Category- G5/G5D

Definition- Kidney failure

ACR/AER

Protein Reagent Strip- Negative to Trace

Category- A1

Definition- Normal to mildly increased

ACR/AER 30-300

Protein Reagent Strip- Trace to +

Category- A2

Definition- Moderately increased “microalbuminuria”

ACR/AER >300

Protein Reagent Strip- + or greater

Category- A3

Definition- Severely increased “albuminuria”

ACR Equation

Ualbumin (mg/dL) / UCr (g/dL)

Susceptibility factors

1. Increased age
2. Low birth weight
3. Small kidneys
4. Racial minority
5. FH
6. Low income
7. Low education
8. Systemic inflammation
9. Dyslipidemia

Initiation Factors

1. DM
2. HTN
3. Glomerulonephritis
4. Polycystic kidney disease
5. Others

Diabetic Kidney Disease (DKD)

1. Vascular changes in the kidney leading to impaired TGF (feedback mechanism to regular GFR) and hyper filtration
2. Frequently see proteinuria and declining GFR in diabetes
3. Patients may also have DM + another cause of CKD (if the patients DM, at higher risk for progression of CKD)
4. Screen annually in patients with DM (eGFR and albuminuria)- Wait 5 years for T1DM and at diagnosis for T2DM

Nephritic signs/symptoms

\-itis = inflammation


1. Hematuria


1. Proteinuria (\~1-3g/day)

Nephrotic signs/symptoms

1. Proteinuria (>3.5 g/day)
2. Edema
3. Hyperlipidemia
4. Hypercoagulable state

Glomerulonephritis therapeutic options

1. Corticosteroids
2. Cyclophosphamide- infection, gonadal fibrosis/sterility, hemorrhagic cystitis, alopecia, and malignancy
3. Cyclosporine
4. Mycophenolate
5. Rituximab

Progression Factors

1. HTN
2. Hyperglycemia
3. Proteinuria
4. Smoking
5. Obesity

Consequences of CKD

Associated with high prevalence of CVD, HTN, and increased mortality risk

“Progression” of CKD

Change in GFR Category

“Certain drop”

A drop in GFR category AND >25% eGFR decline

“Rapid progression”

Sustained decrease in eGFR > 5 ml/min/1.73 m2 per year

KDIGO BP Target

Pharmacologic recommendations for controlling BP

1. ACE or ARBs preferred (additional benefit)
2. Most patients will require a diuretic


1. Any combo of ACEi/ARB/DRI is not recommended

Contributing Factors to HTN in CKD

1. Sodium and volume
2. Increased vasoconstrictor activity
3. Decreased vasodilator activity
4. EPO use
5. PTH & Ca
6. Structure changes in arteries
7. Primary HTN
8. Renovascular Dz

Medication-Induced HTN

1. NSAIDs
2. Corticosteroids
3. Calcineurin inhibitors
4. Sympathomimetics
5. ESAs
6. Oral contraceptives
7. Illicit drugs (esp. cocaine and amphetamines)


1. Certain herbal/supplements

Diuretic use in CKD (non-anuric patients)

1. Thiazides


1. Offer CV protection
2. Used in GFR > 30 ml/min/1.73m2
3. May be used to enhance fluid removal with Loop Diuretics
2. Loops


1. Primarily used for fluid management
2. High doses usually used in later stages of CKD
3. Adjuvant tx- fluid management and hyperkalemia

How to treat Proteinuria

1. If AER > 30 mg/day, use ACEi or ARB (start low, increase monthly)
2. Alt tx include non-DHP CCB, aldosterone antagonist, direct renin inhibitor

Monitoring after ACEi/ARB initiation

1. Rise in SCr and potassium (continue unless SCr increases by > 30% within 4 weeks); expected to rise
2. Consider reducing the dose or discontinuation if the patient experiences symptomatic hypotension, hyperkalemia, reduce uremia symptoms in ESRD

HbA1c target in patients with diabetes and CKD not treated with dialysis

Metformin GFR adjustments

1. eGFR < 45 = reduce dose
2. eGFR < 30 and dialysis = discontinue

SGLT2 inhibitor GFR adjustments

1. eGFR < 30 = do not initiate
2. Dialysis = discontinue

Common side effect of ACEi/ARB

Angioedemia is slow to progress in ACEi but much more common in ARB; no connection of having a cough

Anemia definition

1. Number of RBCs/hemoglobin is reduced below the normal physiologic requirement necessary for adequate tissue oxygenation
2. Men: Hb < 13 g/dL
3. Women: Hb

Hemoglobin units

g/dL

Hematocrit

1. In %
2. Volume of RBCs in 100 mL of blood
3. Affected by fluid status- fluid overload (lower), IV fluid, Dehydration (higher)

Acute anemia onset symptoms

1. Tachycardia
2. Lightheaded
3. SOB
4. Angina
5. Hypotension

Chronic Onset

1. Tired
2. Malaise
3. Faint
4. Weak
5. Cold
6. Heart Failure Sx
7. Pallor

Erythrocytes

Mature RBCs

RBC Destruction

1. Spleen and Bone marrow
2. Globin broken down to AA
3. Iron goes back to storage

Mean Corpuscular Volume (MCV)

1. Normal range: 80-98 fL
2. High = macrocytic
3. Low = microcytic
4. Normal MCV = normocytic

Red blood cell Distribution Width (RDW)

1. Normal Range: 11.5-14.5
2. Variance in cell widths


1. Increased RDW may indicate a deficiency (B12, Folate, Iron)

Mean Corpuscular Hb (MCH)

1. Normal Range: 26-34 pg
2. % Volume of Hb in each RBC
3. Elevated in Macrocytosis (B12 or folate deficiency)
4. Decreased in… microcytosis, hypochromia, both (e.g. IDA)

Mean Corpuscular Hemoglobin Concentration (MCHC)

1. Normal range: 32%-36%
2. Cell size independent- differentiates between microcytosis and hypochromia


1. Low MCHC = hypochromic

Causes of Anemia

1. RBC loss- bleed
2. RBC destruction (too much)- hemolysis
3. RBC Production (too little)- Deficiency (Iron, B12, Folate, EPO)

Macrocytic Anemias

1. Megaloblastic anemias- Impaired DNA synthesis (improper cell growth); E.g. B12 or Folate Deficiency
2. Non-Megaloblastic anemia- Hemolysis (increased reticulocyte count)

Vitamin B12, Cyanocobalamin

1. Water soluble vitamin
2. Sources: Protein-bound B12 includes fish, meat, poultry, eggs, dairy and free B12 includes fortified cereals, dietary supplements
3. Normal absorption: Protein-bound B12 cleaved from protein by gastric acid; Intrinsic Factor combines with free B12 (IF is a carrier protein from gastric parietal cells); Free B12-intrinsic factor complex (absorbed in distal ileum); alternative pathway in the terminal ileum (non-IF dependent)

B12 Deficiency

Megaloblastic Anemia

Caused by inadequate diet and absorption


1. Pernicious anemia (Schilling test), Atrophic gastritis (decreased stomach acid), GI surgery (e.g. gastric bypass, short bowel syndrome), GI disorders (e.g. Crohn’s, celiac)

Drug induced B12 Deficiency

1. PPI
2. H2RA


1. Metformin (up to \~10% incidence); check B12 levels every 2-3 years

B12 Deficiency Symptoms

1. Weakness, fatigue, etc (sx of anemia)
2. Sore mouth or tongue
3. Neurological effects (Specific to B12 deficiency)- paresthesias in hands/feet, ataxia, loss of proprioception, depression, confusion, dementia, psychosis, memory loss
4. Neuro changes may occur without anemia; High dose FA- corrects anemia, will NOT fix neuro changes

Detecting B12 Deficiency

1. Blood smear- macrocytic, megaloblastic cells
2. MCV- elevated; may be normal (mixed anemia)
3. Serum \[B12\]- low, may be normal (intracellular levels not well detected)
4. Homocysteine- elevated, non-specific test (folate or B6 deficiency also increases Hcy)
5. Methylmalonic acid (MMA)- elevated, specific test for B12 deficiency, increases before serum \[B12\] decreases

Treatment of B12 Deficiency

1. Cyanocobalamin- IM (1 mg daily for 1 week, weekly for 1 month, then monthly), Oral (1-2 mg daily), and Intranasal (1 spray weekly; maintenance only)
2. Hydroxocobalamin- not used for B12 deficiency due to antibody formation (used for cyanide toxicity)
3. Time to recover- 1 week, bone marrow changes within 3 days, neuro symptoms may diminish if treated early
4. Recheck CBC, \[B12\] in 1-2 mo and MMA in 2-3 mo

Cobalamin ADRs'

1. Adverse Drug Reactions: rare
2. Increased RBC production may lead to hypokalemia and intravascular volume expansion/fluid expansion
3. Other- anaphylaxis (parenteral), thrombosis, angioedema, antibody formation to hydroxocobalamin

Folate Deficiency

1. Water soluble B vitamin
2. Sources (destroyed by cooking)- Folate (green leafy veggies, citrus fruits, beans and peas, mushrooms, dairy, liver) and folic acid (synthetic folate: fortified cereals, dietary supplement; FDA requires approx. 100 mcg/day)


1. Normal absorption in the small intestine

Folate deficiency Causes

Megaloblastic anemia; takes months to develop


1. Intake, absorption, or overuse (increased cell division)

Drug-Induced Folate Deficiency

1. Direct DNA Synthesis Inhibitors- Azathioprine, 6-MP, 5-FU, Hydroxyurea, AZT
2. Folate Antagonist- MTX\*, TMP, Triameterene, phenytoin, phenobarbital, primidone

Folic Acid and MTX

1. Moa- Folic acid antagonist; interferes with DNA, RNA, protein synthesis
2. Tx- RA, Cancer, etc.
3. ADR- Bone marrow suppression, megaloblastic anemia in 3-9% of patients
4. FA/Leucovorin rescue- Reduces toxicity (and maybe efficacy of MTX)

Detecting Folate Deficiency

1. Blood Smear- Macrocytic, Megaloblastic cells
2. MCV- elevated, may be normal (mixed anemia)
3. Serum- \[folate\]
4. Homocysteine- elevated, non-specific test

*Also check for B12 deficiency*

Tx of Folate Deficiency

1. Folic Acid- Oral (1 mg daily; pregnancy = 600 mcg) and SC/IM/IV (1 mg daily)
2. Leucovorin/Folinic Acid (active form of FA)- 1 mg IV/IM Daily
3. Duration- approx 4 months (RBC life span); long term (1 mg daily perpetually)
4. ADR- none at replacement doses; excess FA excreted in urine

DI Megaloblastic Anemia Tx

1. Chemotherapy- may not be correct
2. Cotrimoxazole- Leucovorin 5-10 mg daily
3. Phenytoin or phenobarbital- FA 1 mg/day; may use less and may. decreased effectiveness of phenytoin

Iron Consumption

1. Total body store: 3-4 g (2000 mg as Hb, 1000 mg storage, 3 mg transferrin-bound)
2. Intake- \~15 mg/day ferric iron
3. Loss- 1 mg/day; menstruation increases

Normal Iron Absorption

1. Ferric (Fe3+) must be converted to Ferrous (Fe2+) in gut
2. Occurs in Duodenum (and Jejunum)
3. Tightly regulated by Hepcidin (protein produced in liver; decreased in anemia and increased during iron load); absorb only what you need
4. Heme (animal) vs non-heme (plant sources; gastric acid and ascorbic acid enhances absorption) iron- 3x’s > absorption than non-heme

Transferrin

1. Iron transport protein
2. Transfers iron around body
3. To bone marrow- for incorporation into Hb
4. To liver, bone marrow, and spleen- for storage

Ferritin

1. Storage iron


1. Liver, bone marrow, and spleen

Iron Indices

1. Ferritin- measure of storage iron
2. Serum iron
3. Total iron binding capacity- seats on a bus (only so many iron can bind)
4. Transferrin saturation- serum iron x 100/TIBC
5. Reticulocyte hemoglobin content- in circulation 24-48 hours/newer test (not routinely ordered)

Microcytic Anemia: IDA causes

1. Intake/absorption- diet
2. Demand- hematopoiesis and pregnancy
3. Loss- bleeding
4. At risk- children < 2yo, adolescent females, pregnant/lactating, elderly

Development of IDA

1. Body dips into iron stores if more Fe is needed (ferritin will decrease and blood cell size does not change initially)
2. Hb starts to decline- may still be WNL
3. Hb is low- anemia is present

Detecting IDA

1. Blood smear- normal initiall, then microcytic, hypochromic cells
2. MCV- initially WNL, then decreased
3. RDW- increased (nonspecific finding)
4. Serum iron- decreased
5. TIBC- increased
6. TSAT- decreased
7. Ferritin- decreased (usually); may be elevated during inflammation or infection
8. CHr- decreased

Ferrous sulfate 325 mg

65 mg

Ferrous gluconate 325 mg

36 mg

Polysaccharide iron 50 mg

50 mg

Heme iron polypeptide 12 mg

12 mg

Ferrous fumarate 300 mg

99 mg

Factors determining selection of oral iron product

1. Absorption- ferrous > ferric; acid and vitamin C enhance absorption; food decreases absorption; copper, cobalt, molybdenum do not aid absorption, $$$
2. Specific formations- mucopolysaccharides chelator protects iron solubility that may be reduced in the small intestine; ER/SR/EC: Dissolution happens in the small intestine- not absorbed well; docusate added to some products for constipation

Oral Iron

1. Dosing- 200 mg elemental iron daily divided in 2-3 doses; start low and gradually titrate up
2. ADR- GI (dark stool, constipation, nausea, vomiting)
3. Overdoses are lethal; symptoms include pain, vomiting, diarrhea, electrolyte imbalance, shock, CV collapse

Parenteral Iron

1. Indications- intolerance to P, poor absorption, non adherence
2. Pros- effective by overcoming absorption issues and patient daily adherence is not a factor (IV admin in clinic)
3. Cons- time, cost, vascular access, side effects, may worsen infections\*\*\*

IV Iron: Structure

1. Structure- Colloid, iron-carbohydrate; carbohydrate shell\*, iron core (size differs by agents)
2. Molecular weight- Dexferrum > INFeD >> Iron sucrose > ferric gluconate
3. Core size- Dexferrum > INFeD >> iron sucrose > ferric gluconate

IV Labile Iron Release

1. Free, iron first release from IV iron agent
2. Acute ADES’s- N/V, cramps, chest pain, hypotension; 100% of patients given parenteral free iron have ADRs
3. Max dose of iron with no

Characteristics of carbohydrate shell

* Stabilizes molecule
* Prevents rapid release of iron
* Maintains colloidal suspension
* Differs by agent
* The larger the shell, the higher risk for anaphylactic shock; BBW!

Benefits of Blood Transfusions

* Treats Anemia
* Rapid correction of Hb
* Works when ESAs don’t (due to ESA resistance, bone marrow failure, PRCA)
* Use when ESA risks are too high (cancer and stroke)

Risks of Blood Transfusions

* Iron overload
* Volume overload
* Hyperkalemia
* Coagulopathies
* Immune reactions (fever or allergy, hemolytic reaction, lung injury, anaphylaxis, graft v host)
* Infections
* Errors
* Transplant candidates

Iron agents used to treat anemia in CKD

* Oral (not preferred in dialysis patients)
* IV- Iron dextran, sodium ferric gluconate, iron sucrose, ferumoxytol, ferric carboxymaltose
* Dialysate- Ferric pyrophosphate

ESAs used to treat anemia

* IV or SQ'
* Epoetin alfa
* Darbepoetin alfa
* Methoxy polyethylene glycol-epoetin

Initiation of Iron agents in CKD

* Treatment naive (no iron/ESA) or patients on ESA
* Use if increase in Hb Is needed, to avoid/minimize ESA use, if TSAT

Route of Administration considerations of Iron agents in CKD

* Dialysis v non-dialysis (dialysis usually gets IV)
* Severity of iron deficiency
* Venous access
* Prior iron use (side effects?)
* Adherence
* Cost

IV Iron- General Dosing

* Initial/Repletion Dosing- 1000 mg usually divided over several treatments; measure TSAT and ferritin >1 week after last iron dose (e.g. regimen 100 mg TIW x10 doses)
* Maintenance Dosing- hemodialysis - ave blood loss = 1-2 g/year; small periodic doses given to replace losses; varies by patient (e.g. 100 mg every other week)

IV Iron- Monitoring

* What to check- TSAT and Ferritin
* When to check- On ESA therapy (stable) check every 3 months; unstable (changing ESA dose, blood loss, gave iron dose) more frequent