Nephrology

Guide to Intravenous Fluids
Solution	Na+	K+	Cl-	Lactate	mOsm/L	Dextrose
D5W					278	50
D10W					556	100
D50W					2780	500
NS	154		154		286
½NS	77		77		143
3%NS	513		513		1026
D5NS	154		154		564	50
D5½NS	77		77		421	50
LR	130	4	109	28	272	50
D5LR	130	4	109	28	524	50
1 amp NaHCO3 = 50 ml = 44 mEq 1 amp 7.5% KCl = 20 ml = 20 mEq 1 amp 14.9% KCl = 20 ml = 40 mEq 1 amp 46% KPO4 = 15 ml = 66 mEq K, 45 mM PO4 1 amp 10% CaCl2 = 10 ml = 14 mEq 1 amp 10% Ca gluconate = 10 ml = 4.7 mEq

Urinalysis Interpretation
Urine Dipstick

Specific gravity: Estimate of U_Osm. Typical range = 1.005-1.030
Each 0.001 inc in specific gravity above 1.0 implies a 30 mOsm/kg inc in U_Osm such that SG 1.010 ~ U_Osm 300

pH: Varies between 4.5-8.0 with a number of metabolic conditions
May be useful in differential diagnosis of RTA

Protein: Typically negative. Positive test implies significant albuminuria
Positive test implies > 300-500 mg/day, but should always prompt quantitative assessment (24 hour urine or urine total protein/Cr ratio)
False positives with contrast and concentrated or alkaline urine
Less sensitive for immunoglobulins or light chains (can be detected with sulfosalicylic acid test) and microalbuminuria

Leukocyte esterase: Typically negative. Positive test implies WBCs present
False positives with vaginal secretion contamination
False negatives associated with proteinuria, glucosuria, inc SG

Nitrites: Typically negative. Positive test suggests presence of Gm- bacteria
Enterobacteriaceae frequently convert nitrates to nitrites

Blood: Reflects presence of heme, presumably as intact RBCs
False positives with myoglobinuria or free hemoglobin (hemoglobinuria)
False negatives with Vitamin C
Gross hematuria with negative blood on dipstick suggests medication (deferoxamine, rifampin, phenazopyridine, etc), food dye (beets, blackberries, etc), bile pigments, or porphyria

Ketones:
Better detects acetoacetate and acetone than b-hydroxybutyrate (i.e. detection of DKA better than ETOH ketoacidosis)

Bilirubin: Usually conjugated
Often suggestive of liver disease

Glucose: Proximal tubule transport maximum (T_max) of glucose = 180-200 mg/dl
Glucosuria suggests serum glucose level greater than T_max or proximal tubule dysfunction (Fanconi's syndrome)
Urine Microscopy (Urine Sediment)
Cells:

RBCs: GN suggested by small, dysmorphic RBCs caused by osmotic injury while passing through tubules

WBCs:
PMNs suggest UTI
Eosinophils suggest AIN, atheroembolic disease, prostatitis, or RPGN
Sterile pyuria suggests tuberculosis

Renal tubular epithelial cells: Often seen with renal tubular damage (i.e. ATN)

Oval fat bodies: Sloughed tubular cells containing fat droplets (seen with nephrotic syndrome)
Casts:

Hyaline: Consists of protein alone. Not specific for disease, and can be seen with concentrated urine and a number of pathologic conditions

RBC: Indicative of GN due to intraparenchymal bleeding

WBC: Indicative of pyelonephritis, GN, AIN

Granular: Consists of sloughed tubular casts seen with tubular injury (coarse granular = classic ATN)
Crystals:

Rhomboid: uric acid.

Bipyramidal: calcium oxalate.

Dumbell-shaped: calcium oxalate.

Hexagonal plates: cystine.
Lipids: suggests nephrotic syndrome, oval fat bodies, maltese cross.

Proteinuria
Definition: Urinary protein excretion > 150-300 mg/day
Causes:

Glomerular: Often associated with nephrotic syndrome
Pathophysiology: inc filtration of macromolecules (i.e. albumin) due to disruption of filtration barrier (i.e. DM, GN, etc)

Tubular: Usually less than 2 grams in 24 hours
Pathophysiology: incexcretion due to dec proximal tubule reabsorption of LMW filtered proteins (i.e. ATN, tubulointerstitial disease, etc)

Overflow: May have proteinuria as high as those with glomerular disease
Pathophysiology: inc excretion of LMW proteins due to marked overproduction (i.e. MM, MGUS, etc)
Finding of disparity between weakly positive urine dipstick for protein and highly positive protein quantitation is highly suggestive of overflow proteinuria

Tissue: Usually less than 500 milligrams in 24 hours
Pathophysiology: Tissue inflammation leads to protein leaking into urine (i.e. UTI, malignancy)
Proteinuria quantitation:

24 hr urine collection: Measure concurrent Cr to assess adequacy (15-20 mg/kg/day in females and 20-25 mg/kg/day in males)

Urine total protein/Cr ratio: Spot estimate of 24 hr output per 1.73m² (i.e. total protein/Cr ratio of 3.5 ~ 3.5 grams in 24 hr collection)
Assumes patient excretes on the order of 1 gm of Cr at steady state. So less accurate at extremes of body habitus and in ARF
DDx massive proteinuria (>10g/24hr): only 4 things…
Minimal change, membranous nephropathy, diabetes, amyloidosis.

Nephrotic Syndrome
Definition:
Heavy proteinuria (24 hour urine collection >3.5 gm or urine total protein/Cr ratio > 3.0-3.5 mg/mg)
Hypoalbuminemia (serum albumin <3 g/dl)
Peripheral edema
Dyslipidemia
Differential Diagnosis: Common primary renal diseases

Minimal change disease:
Causes: Idiopathic (most common), genetic, allergic (some associate with atopic disease), post-URI, malignancy (Hodgkin's disease in particular), NSAIDs, heavy metals (lead, mercury, lithium)
Pathology: Normal LM and IF. Fusion of epithelial foot processes on EM
Most common cause of nephrotic syndrome in children

Focal segmental glomerulosclerosis:
Causes: Idiopathic (most common), genetic, heroin, HIV-associated nephropathy/parvovirus B19 (collapsing variant), obesity, healed prior injury/reduced nephron mass (reflux nephropathy, renal agenesis, renal dysplasia)
Pathology: Focal segmental sclerosis on light microscopy. No immune deposits except non-specific IgM and C3 in lesions on IF. Fusion of epithelial foot processes on EM
More common in African American. Important to distinguish between primary and secondary (associated with adaptation to hyperfiltration)

Membranous nephropathy:
Causes: Idiopathic (most common), autoimmune disease (SLE, RA, etc), malignancy (solid tumor, non-Hodgkin's lymphoma in particular), Hep B, syphilis, malaria, penicillamine, gold, NSAIDs
Pathology: "Spike and dome" pattern with thick GBM on LM. IF and EM show immune complex deposits in subepithelial space
Most common GN in adults in U.S

Membranoproliferative glomerulonephritis:
Causes: Idiopathic, Hep C (most common), subacute bacterial endocarditis, cryoglobulinemia, SLE
Pathology: Thickened GBM with "splitting" appearance of capillary wall and cell proliferation on LM. IF and EM show immune complex deposits in subendothelial space
Frequently has features of nephritic syndrome as well
Differential Diagnosis: Common systemic causes

Amyloidosis:
Causes: Idiopathic, MM/MGUS, chronic inflammatory diseases.
Pathology: Glomeruli filled with amorphous material positive for congo red stain and green birefringence with polarized light. Immunohistology can identify protein subtype

Diabetic nephropathy:
Causes: Type 1 or 2 DM
Pathology: Classic = nodular glomerulosclerosis (Kimmelstiel-Wilson nodules)
Work-up:
Standard H&P (assess for systemic disease and review medications)

Labs: CBC, chemistry panel, albumin, ANA, RF, ESR, CRP, HIV, Hep B/C serologies, RPR, ASO, Ca, SPEP/UPEP, cryoglobulin, Hba1c
Fasting lipid panel
Proteinuria quantitation: 24 hr urine or spot urine total protein/Cr ratio
Renal ultrasound: Large kidneys suggest DM, HIV, infiltrative disease (amyloid, lymphoma)
Renal consultation for possible renal Bx, particularly if new or rapid onset
Treatment of complications:

Proteinuria: Uncontrolled proteinuria independently associated with progressive loss of renal function
ACE-I/ARB: dec intraglomerular pressure--> dec protein excretion
Spironolactone: Evidence growing in literature of ability to dec protein excretion, particularly in DM
1Dietary protein intake should replace urinary protein loss. Beware malnutrition in CKD patients placed on restricted protein diet

Edema: Due to renal Na retention
Dietary salt restriction (2-3g NaCl/day)
Diuretic therapy: Loop diuretics usually required and at higher dose due to dec albumin

Dyslipidemia:
Aggressive treatment with lipid lowering agents (statin first line)

Hypercoagulable state: inc risk (10-40%) of thromboemboli due to urinary loss of ATIII, protein C and S
Incidence of DVT disproportionately high in membranous GN
Consider WITHU of renal vein thrombosis in setting if ARF
Anticoagulation if evidence of thrombosis and some propose prophylaxis for membranous with severe hypoalbuminemia

Infections: Low level of IgG may play role. Pneumococcal infection especially common. SBP may develop in some patients with ascites

ARF: May be associated with development of renal vein thrombosis (dull back pain may be sole symptom). Also, crescentic GN may rarely occur in membranous GN

Low C3/Low C4	Low C3 (normal C4)
MPGN type 1	MPGN type 2
Lupus	Post-infectious GN
Cryoglobulinemia

Oliguria: Urine output < 500 ml/day; Anuria < 200 ml/day
Assess volume status:
History: Check if NPO, N/V/D, dehydrated. Check I/Os over past few days to see if patient persistently positive or negative
PE: Check for orthostatics, tachycardia, JVP, crackles on pulmonary exam, abdominal exam (palpable bladder), and edema
Labs: Consider chemistry panel to rule out ARF. BUN/Cr ratio > 20 suggests pre-renal cause
Radiology: Consider CXR for evidence of CHF
If thought to be volume depleted, attempt fluid challenge (250-500 ml NS)
If thought to be volume overloaded or in CHF, try diuresis with furosemide. Start at 20 mg IV if furosemide naive; may need higher doses (up to 200mg IV) if the patient has significant renal impairment. If patient already on furosemide, try doubling usual dose
If patient has a Foley and is anuric (<100 ml/day), ask RN to flush Foley to make sure that it is not clogged
If post-renal obstruction is suspected, check a post-void residual. If volume is > 150-200 ml, then leave the Foley in place
If unable to place Foley, try larger size catheter and/or Coude tip catheter with Uro-jet (Lidocaine jelly in syringe); if this fails, call Urology

GFR Estimation
Cr-based GFR estimations are most accurate in steady-state, therefore estimations will underestimate true GFR in ARF with rising Cr. Normal values for GFR are 120 ml/min for men and 100 ml/min for women, though GFR will vary depending on size, age, and physiologic state.
For example, true GFR in a cachectic female with a Cr of 1.0 mg/dl is much lower than a muscular male with the same Cr
MDRD equation: Logarithmic 4 variable equation used by UCLA lab system to estimate GFR in ml/min/1.73m². A 6 variable equation (age, sex, race, Cr, BUN, albumin) is also available.
Cockroft-Gault equation:
24 hr urine collection:
Factors other than decreased GFR that may cause elevation of creatinine:
Decreased secretion: Trimethoprim, cimetidine
Interference with assay: Ketoacidosis (acetone, acetoacetate), cefoxitin, flucytosine, ascorbic acid, nitromethane
Enhanced production: Large meat meals, rhabdomyolysis (conversion of creatine to creatinine)

Acute Renal Failure (ARF)/Acute Kidney Injury (AKI)
Definition: No formal definition though some have considered the use of the proposed RIFLE classification scheme

RIFLE Classification for Acute Renal Failure
Classification	GFR Criteria	UOP Criteria
Risk	inc Baseline Cr x 1.5 OR GFR dec > 25%	UO < 0.5 ml/kg/h x 6 hours
Injury	inc Baseline Cr x 2 OR GFR dec > 50%	UO < 0.5 ml/kg/h x 12 hours
Failure	inc Baseline Cr x 3 OR GFR dec > 75% OR SCr > 4 mg/dl with inc in Cr by 0.5 mg/dl	UO < 0.3 ml/kg/h x 24 hours OR anuria x 12 hours
Loss	Persistent ARF = complete loss of kidney function > 4 weeks
ESKD	End stage kidney disease > 3 months

Causes:

Prerenal: Associated with dec renal perfusion (40-70% of cases of ARF)
Intravascular volume:
Hemorrhage (i.e. GIB, retroperitoneal hematoma, trauma)
Urinary loss (i.e. excess diuresis)
Third spacing
GI losses (i.e. vomiting, diarrhea)
SVR:
Sepsis
Anaphylaxis
Cirrhosis/HRS
Effective circulating volume:
CHF
Intraglomerular pressure (small vessel):
ACEI/ARB, NSAIDs, cyclosporine, tacrolimus
Vascular (large vessel):
Dissection, embolism, thrombosis, renal artery stenosis with ACE-I, vasculitis

Intrinsic renal failure: Associated with renal parenchymal injury (30-50% of cases of ARF)
Acute tubular necrosis (ATN):
Exogenous nephrotoxins: Aminoglycosides, amphotericin, acyclovir, contrast
Endogenous nephrotoxins: Myoglobinuria, hemoglobinuria, uric acid, paraproteinemia
Renal ischemia: Hypotension, severe dehydration, shock, sepsis, hypoxia
Acute interstitial nephritis (AIN):
Drugs: Antibiotics (B-lactams most common, though most classes of antibiotics have known associations), phenytoin, allopurinol, NSAIDs, diuretics, PPI
Infections: Legionella, leptospirosis, CMV, histoplasmosis, Rickettsia
Immunologic: SLE, Sjögren's, sarcoidosis, cryoglobulinemia, TINU syndrome
Glomerulonephritis (GN):
Anti-GBM: Goodpasture's and primary anti-GBM glomerulonephritis
Immune complex: SLE, IgA, post-infectious, membranous, MPGN, cryoglobulins
Pauciimmune (ANCA-associated): Wegner's granulomatosis, microscopic polyangiitis, Churg-Strauss
Vascular:
Malignant HTN, scleroderma renal crisis, DIC, preeclampsia, TTP/HUS, cholesterol emboli

Post-renal failure: Associated with urinary obstruction (2-5% of cases of ARF)
Urethral/bladder dysfunction/obstruction (i.e. BPH, urethral stricture)
Bilateral ureter or pelvic obstruction (i.e. stones, malignancy, retroperitoneal fibrosis)
Work-up:
Strongly consider Foley if not present. If post void residual is > 150-200ml, keep catheter in place
Calculate the fractional excretion of Na (FENa; see below)

Urinalysis: Assess for active sediment or casts
ATN: Coarse granular casts
AIN: WBC casts, urine eosinophils
GN: RBC casts and dysmorphic red cells
Renal ultrasound: Assess for stones, masses, hydronephrosis, size, and echogenicity
Consider acute GN work-up based on history and urinalysis (i.e. active sediment with dysmorphic RBCs and RBC casts): Blood cultures, ASO, C3, C4, CH50, ESR, CRP, ANA, RF, DSDNA, ANCA, anti-GBM, Hep B/C serologies, cryoglobulins
Treatment:

Basic goals:
Treat underlying cause
Minimize fluid/electrolyte imbalance
Avoid nephrotoxins and renal dose medications
Ensure adequate nutrition

Dialysis: ARF severe enough to cause dialysis dependence is associated with upwards of 50% in-hospital mortality
Indications: No definitive guidelines but most would agree with starting for following indications

Acidosis, particularly if pH < 7.1

Electrolyte imbalance: incK, incPO₄ (especially in tumor lysis), severe incCa or incMg

Intoxication: Lithium, toxic alcohols, theophylline, salicylates

Overload (volume): After failing diuretic management

Uremic complications: Encephalopathy, seizures, pericarditis, platelet dysfunction
Dialysis dose:
Controversial though most would advocate for steady state BUN below 80-100 mg/dl
May be done every other day or daily if indicated. Some evidence that daily dialysis associated with improved outcomes
Types of dialysis:

Hemodialysis (HD):
Physiology: Intermittent solute removal via diffusion (dialysis) + fluid removal via transmembrane pressure (ultrafiltration)
Advantages: Rapid solute removal and acid-base correction. May use any vascular access (catheter or AV shunt)
Complications: Hypotension, arrhythmia, dialysis disequilibrium syndrome (nausea, vomiting, seizures), bleeding, membrane reaction, access malfunction

Continuous renal replacement therapy (CRRT):
Physiology: Continuous solute removal via diffusion (dialysis) + fluid removal via transmembrane pressure with additional dilutional component from replacement fluid (hemofiltration)

Continuous dialysis + hemofiltration (CVVHDF):
Advantages: More hemodynamically stable than HD. Excellent for removal of large fluid volumes over 24 hours versus intermittent HD.
Complications: Similar to HD but less cardiovascular and neurological side effects (slower rates of removal). AV fistulas/grafts should not be used as access for CRRT.

Peritoneal Dialysis (PD):
Physiology: Peritoneum is used as dialysis membrane with solute removal via diffusion + fluid removal dependent on dialysate glucose/icodextrin concentration
Advantages: Ambulatory. Can be done during day or evening at home (home HD not as available at present). More hemodynamically tolerable than HD
Complications: Peritonitis, hyperglycemia with glucose based solutions, access malfunction. Generally not used for ARF as it takes 4 weeks for inserted PD catheter site to heal prior to use
Evaluation of urinary composition in ARF Fractional Excretion of Sodium (FENa):
More accurate than urinary Na at assessing prerenal state
More specific in oliguric than non-oliguric renal failure
Intrinsic renal diseases that occasionally have low FENa include acute GN, pigment nephropathy, AIN, contrast nephropathy
FENa may be inaccurate in setting of diuretic use given false elevations in urinary Na. However, low FENa in setting of diuretics suggests severe prerenal state
Fractional Excretion of Urea (FEUrea):
May be used in patients on diuretics (can also use FE uric acid)
Differentiating prerenal azotemia from intrinsic renal failure

Evaluation of Urinary Composition in Acute Renal Failure
Test	Prerenal Azotemia	Intrinsic Renal Failure (ATN)
FENa	<1%	>2%
FEUrea	<35%	>50%
Urinary Na (mmol/L)	<20	>40
Urinary Sediment	Normal or occasional granular casts	Brown granular casts, cellular debris

Note the parameters listed above may not be true in someone with underlying CKD because of defects in urinary concentration and Na reabsorption. In such patients a cautious trial of fluids may be indicated despite contrary urinary studies

Definition: ARF in the setting of cirrhosis or fulminant hepatic failure in the absence of other renal diseases

Pathophysiology: Splanchnic arterial vasodilation due to accumulation of local vasodilators (i.e. nitric oxide, etc) from portal HTN --> dec SVR --> Activation of compensatory mechanisms (i.e. sympathetic nervous system, renin-angiotensin-aldosterone system, endothelin, etc) --> Avid sodium and H₂O retention and renal vasoconstriction --> prerenal ARF

Clinical presentation: Often exacerbated by infection (SBP most common), acute hepatic injury superimposed on cirrhosis, GIB, or overdiuresis
Type I HRS: Rapidly progressive ARF with doubling of Cr to > 2.5 mg/dl or fall in GFR to 20 ml/min in less than 2 weeks
Associated with poor prognosis and 50-80% mortality upon onset due to progressive circulatory, hepatic, and renal failure
Type II HRS: Slowly progressive increase in Cr to > 1.5 mg/dl or fall in GFR to 40 ml/min

Work-up: Diagnosis of exclusion though the following have been proposed as diagnostic criteria
Chronic or acute advanced liver failure and portal HTN
Cr > 1.5 mg/dl or GFR < 40 ml/min
Absence of shock, ongoing bacterial infection, fluid loss, or current/recent treatment with nephrotoxins
No sustained improvement in renal function after withdrawal of diuretics and volume challenge with 1.5 L of NS
Proteinuria < 500 mg/day
Absence of obstructive uropathy or parenchymal disease on U/S
Other helpful criteria include: Urine volume < 500 ml/day, urine Na < 20 mmol/L, U_Osm > serum Osm, urine RBC count < 50/hpf, serum Na < 130 mmol/L

Treatment:
Definitive treatment is liver transplant with all other therapies serving as bridges to transplant
Diet: Na restriction to prevent edema and refractory ascites
Diuretics: Spironolactone as first line therapy. Furosemide to be added for refractory edema or ascites. However, need cautious use to avoid overdiuresis and exacerbation of HRS
Arterial vasoconstrictors:
Terlipressin (V1 receptor agonist): IV infusion along with albumin may have beneficial effects. However, limited availability in U.S. and may be associated with ischemic adverse events
Midodrine (alpha-agonist; 5-15 mg PO tid) and octreotide (somatostatin analogue; 100-200 mg SQ tid): Octreotide alone not shown to be effective. Limited data regarding beneficial effects of dual treatment or midodrine alone in addition to albumin.
Transjugular intrahepatic portosystemic shunt (TIPS): Decompresses portal HTN and may be associated with suppression of renin-angiotensin-aldosterone system and improved renal perfusion. Major side effect includes hepatic encephalopathy and shunt dysfunction
Dialysis as needed until liver transplantation: if dialysis has been prolonged > 1 month, patient may qualify for a dual liver-kidney transplantation

Definition per National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI):
Evidence of structural or functional kidney abnormalities (abnormal urinalysis, imaging, histology, etc) for > 3 months OR
GFR < 60 ml/min/1.73 m² for > 3 months

NKF-KDOQI Stages:
Stage I: GFR > 90 ml/min/1.73m² + persistent albuminuria
Stage II: GFR 60-89 ml/min/1.73m² + persistent albuminuria
Stage III: GFR 30-59 ml/min/1.73m²
Stage IV: GFR 15-29 ml/min/1.73m²
Stage V: GFR < 15 ml/min/1.73m² or dialysis dependence

Symptoms: Azotemia = inc BUN, Cr, and other waste products. Uremia = symptomatic azotemia
General: Anorexia, malaise, pruritus
GI: Nausea, vomiting
CV: Pericarditis, HTN, accelerated atherosclerosis, inc lipids, edema
Heme: Anemia, platelet dysfunction
Neuro: Peripheral neuropathy, encephalopathy, seizures
Metabolic: inc K, inc PO4, dec Ca, acidosis, inc PTH, osteodystrophy

General treatment:
Treat reversible causes of renal dysfunction including causes of dec renal perfusion (i.e. hypovolemia, hypotension, infection, drugs)
Avoid nephrotoxins
Consider restricting dietary protein intake to 0.8-1.0 g/kg of high biologic value protein for predialysis patients (some possible retardation of CKD progression). Must weigh risks of such strict limitations and potential for malnutrition. Renal dietician should be involved
Nephro-Vite 1 tab PO daily (high in Vitamin B, low in Vitamin A and C)
BP control < 130/80 per K/DOQI guidelines with ACEI/ARB preferred particularly in DM
ACE-I/ARBs for proteinuria (goal: dec protein excretion to < 500-1000 mg/day) and BP control (< 130/80)

Treatment of complications:
Edema: Dietary Na and diuretic therapy, typically a loop diuretic
Metabolic acidosis: Risks of bone disease given H+ buffering along with inc skeletal muscle breakdown and dec albumin synthesis. Sodium bicarbonate tabs (0.5-1.0 mEq/kg/day) to goal TCO2 > 22 mEq/L. Sodium citrate may be considered by patients as more tolerable
incK: Low K diet (no OJ, dairy, bananas, melons, potatoes) +/- loop diuretic +/- Kayexalate. Avoidance of drugs that inc serum K such as NSAIDS. Cautious use of ACEI/ARB and Aldactone
incPO4: Dietary PO4 restriction of 800mg/day. Oral PO4 binders (Ca carbonate, Ca acetate, sevelamer, or lanthanum) as needed with meals. Goal Ca-PO4 product < 55mg²/dl². Avoid aluminum based binders given risks of aluminum toxicity
Secondary hyperparathyroidism: Associated with dec Ca, inc PO4, and dec Vitamin D 1,25-OH production among other factors in CKD. Goal to control PO4 and consider supplementation with Vitamin D analogues or cinacalcet (Ca sensing receptor agonist)
Anemia: Normocytic and normochromic due to dec erythropoietin production among other factors in CKD. Supplemental erythropoietin for goal hemoglobin 11-12 g/dl after ruling out other causes (i.e. Fe, folate, or Vitamin B12 deficiency, etc). Note that worse outcomes may be associated with Hgb correction > 13 g/dl
Dyslipidemia: CKD equivalent to CAD, so current goal LDL < 100 mg/dl, and some would consider lower target

Renal replacement therapy: Early identification and early referral to nephrologist. Preparation for renal replacement therapy in Stage IV CKD (HD, PD, or renal transplant). Dialysis typically initiated when GFR < 15 ml/min in diabetics, GFR < 10 ml/min in non-diabetics, or when symptoms or other metabolic indications occur.

Requirements for Outpatient Hemodialysis
Prior to being accepted for outpatient hemodialysis, ALL patients need Hep B serologies, Hep C serologies, HIV, CXR and PPD placed and read.
These tests usually take 3-4 days so plan ahead if you think a patient will need outpatient dialysis.

Definition: Na < 135 mmol/L.

Causes: Initial classification based on serum osmolality
Isoosmotic (275-295 mmol/L) = Pseudohyponatremia
Hyperproteinemia
Hyperlipidemia
Hyperosmotic hyponatremia (> 295 mmol/L)
Hyperglycemia: Every 100 mg/dl inc in glucose > 150 dec measured Na by 1.6 mmol/L
Hypertonic infusion (mannitol, sucrose, maltose, glycine)
Hypoosmotic hyponatremia (< 275 mmol/L): Most common form of hyponatremia with further work-up based on volume status of patient

Hypovolemic: Associated with dec effective circulatory volume as stimulus for ADH secretion
Causes: Diuretics, osmotic diuresis, salt wasting nephropathy, diarrhea, vomiting, third spacing, sweat, burns, cerebral salt wasting, NPO
Treatment: IVF hydration

Euvolemic:
Causes: Primary polydipsia, SIADH, adrenal insufficiency, hypothyroidism, reset osmostat, beer potomania
Treatment: Free H2O restriction (<1-1.5 L/day) and treat underlying cause

Hypervolemic: Associated with dec effective circulatory volume as stimulus for ADH secretion
Causes: CHF, cirrhosis, nephrotic syndrome
Treatment: Free H2O restriction and diuresis

Work-up:
Urine Osmolality:
U_Osm < 100 mOsm/kg suggests primary polydipsia, malnutrition (beer potomania), or reset osmostat
U_Osm > 100 mOsm suggests continued ADH secretion despite hyponatremia
Urine Sodium: More informative than FENa, which in setting of normal renal function is reflective of Na balance. For instance, a euvolemic SIADH patient on a normal diet may have a FENa < 1%
U_Na < 20 mmol/L suggests dec effective circulatory volume
U_Na > 40 mmol/L suggests SIADH
Serum uric acid and urea tend to be elevated in prerenal state and low in SIADH

Treatment:
Serial sodiums should initially be followed q2-6 hours depending on rate of correction and severity of hyponatremia
Asymptomatic hyponatremia:
Correct no more than 10-12 mmol/L in 24 hours and 18 mmol/L in 48 hours to avoid osmotic demyelination syndrome. Patients with chronic hyponatremia, elderly, and women are at a high risk.
Symptomatic hyponatremia:
Severe symptoms (seizures, coma): inc Na 3-5 mmol/L at a rate of 1-2 mmol/L/hr but not more than 10-12 mmol in 24 hours
Moderate symptoms (AMS, lethargy): inc Na 3-5 mmol/L at a rate 0.5mmol/L/hr but not more than 10-12 mmol in 24 hours
Androgue-Madias Equation shows effect of 1L of any fluid on serum Na:

TBW = 0.6 x weight (kg) for men and 0.5 x weight (kg) for women
Caution in treatment of hypovolemic state as restoration of euvolemia will abolish ADH stimulus for H₂O conservation resulting in more rapid self-correction of hyponatremia than anticipated by above equation
Available Na solutions:
3% Saline = 513 mmol Na/L
0.9% Saline (NS) = 154 mmol Na/L
0.45%Saline (½NS) = 77 mmol Na/L
.

Definition:
Hypo-osmolality (Serum Osm < 275 mOsm/kg)
Inappropriately high urinary concentration (U_Osm > 100 mOsm/kg) in setting of hypo-osmolality
Clinical euvolemia
Elevated urinary Na (> 40 mmol/L) while on normal salt and H₂O intake
Normal thyroid, adrenal, and kidney function

Causes:
Tumors: Small cell lung carcinoma, mesothelioma, pancreatic carcinoma, duodenal carcinoma
CNS disorders: Tumor, abscess, ischemia, hemorrhage, infection, trauma
Medications: Phenothiazine, TCAs, SSRIs, clozapine, desmopressin, oxytocin, carbamazepine, vincristine, cisplatin, cyclophosphamide, Ecstasy, chlorpropamide, clofibrate
Pulmonary disease: Infection, tumor, mechanical ventilation, COPD exacerbation, ARDS
Other: Pain, nausea, HIV

Treatment:
Free H₂O restriction
Increased solute input (i.e. salt tabs or high salt, high protein diet) leads to urinary excretion of excess solutes in larger body of water and negative H₂O balance
Loop diuretic (i.e. furosemide) interferes with countercurrent concentrating mechanism and leads to excretion of free H₂O in excess of Na
Demeclocycline or lithium to induce nephrogenic DI in refractory patients
Vasopressin receptor (V2) antagonists once available

Causes:
Unreplaced water losses:
Insensible loss (sweating, tachypnea, burns). U_Osm often > 800 mOsm/kg
GI loss (vomiting, diarrhea). U_Osm often > 800 mOsm/kg
Renal losses:
Central or nephrogenic DI. U_Osm often < 250 mOsm/kg
Osmotic diuresis. U_Osm often 300-400 mOsm/kg
Sodium overload: U_Osm often > 800 mOsm/kg
Hypertonic solutions (3% NaCl).
Mineralocorticoid excess (rare)
Water redistribution: rare, transient
Excessive exercise or seizures

Treatment:

Rate of repletion:
As general guide, may give half of free water deficit in first 24 hours and remainder over next 1-2 days
However, need to check frequent serial Na and correct no more than 10-12 mEq/L change in 24 hours to avoid cerebral edema
Remember to take into account insensible losses (approx. 30 ml/hr) and ongoing urinary/stool losses when calculating the amount of free H₂O to give

Definition: > 3L urine output per 24 hours without exogenous diuretic use

Causes:
Central DI: Deficient ADH secretion. Spot U_Osm often < 250 mOsm/kg
Causes: Familial, neurosurgery, tumor, trauma, infection (TB, meningitis), infiltrative disease (sarcoid, Histiocytosis X), Sheehan's
Nephrogenic DI: Renal resistance to ADH. Spot U_Osm often < 250 mOsm/kg
Causes: Familial, hypercalcemia, hypokalemia, demeclocycline, lithium, sickle cell anemia, cystic kidney disease, pregnancy
Primary polydipsia: Excess free H₂O intake. Spot U_Osm often < 250 mOsm/kg
Causes: psychogenic, hypothalamic disease, anticholinergics
Osmotic diuresis: Associated with high solute excretion. Spot U_Osm often > 300 mOsm/kg
Causes: Hyperglycemia, post-obstructive diuresis, high-protein tube feedings, saline load (IVFs, etc), contrast

Work-up:
Check 24 hr urine osmoles:
< 600-900 mosm/24 hours implies water diuresis
> 900 mosm/24 hours implies solute diuresis
Check 24 hr urine for Na and K:

If > 70% implies electrolyte diuresis
If < 70% implies non-electrolyte solute diuresis
Water restriction test:
Check urine volume every hr and U_Osm, serum Osm, and serum Na at baseline and every other hr. Check plasma ADH at baseline
Cease water restriction when 1) U_Osm normal (>600 mOsm/kg; suggests primary polydipsia), 2) U_Osm stable x 3 yet with rising serum Osm, or 3) serum Osm > 295 mOsm/kg
Check plasma ADH level before DDAVP given
Administer DDAVP 10 mg nasally or 4 mg subcutaneous and continue serial urine volume and urine Osm
Interpretation:
Complete central DI: > 50-100% rise in U_Osm (often > 450 mOsm/kg)
Complete nephrogenic DI: < 10-15% rise in U_Osm
Partial central or nephrogenic DI: 15-50% rise in U_Osm
Plasma ADH low or low normal --> likely partial central DI
Plasma ADH normal or high --> likely partial nephrogenic DI

Treatment:
Central DI: Exogenous DDAVP for replacement
Nephrogenic DI: Treatment aimed at reducing symptoms. Low Na diet, thiazide diuretics, NSAIDs, trial of DDAVP

Definition: K < 3.5 mmol/L

Clinical manifestations: Proportionate to degree and duration
Neuromuscular: Weakness, paralysis, rhabdomyolysis (K < 2-2.5)
CV: Arrhythmia (VT, VF), prolonged QT, PVCs, U waves
Renal: Nephrogenic DI, increased ammoniagenesis, metabolic alkalosis

Causes:
decK intake (rare except in extreme malnutrition)
Transcellular shift: Alkalemia, insulin excess, B-adrenergic stimulation (i.e. albuterol), hypokalemic periodic paralysis, high cell proliferation (i.e. AML, RBC production after EPO, WBC production after GM-CSF)
GI losses: Diarrhea, laxatives, villous adenoma, VIPoma.
Loss of K with intestinal secretions largely due to high K in fluid
Renal losses: Diuretics, mineralocorticoid excess, vomiting, NGT suction, DKA, osmotic diuresis, RTA I and II, hypomagnesemia, PCN, amphotericin B, gentamicin, foscarnet, salt-wasting nephropathy
Loss of K with gastric loss (i.e. NGT suction) due to metabolic alkalosis causing inc distal Na delivery (accompanies excreted HCO₃ load) with associated K exchange and inc aldosterone causing inc distal K secretion
Other: Dialysis, plasmapheresis, sweat loss

Work-up:
Assess symptoms, BP, acid-base status, and EKG
Calculate transtubular K gradient:

TTKG > 4 = renal or endocrine defect
TTKG < 2 = extrarenal causes
Other: Check 24 hr urine K
UK > 30 mmol/day suggests renal losses
UK < 25 mmol/day suggests extrarenal losses

Treatment:
General rule for replacement:

If Cr<1, still calculate as if Cr=1.
Preferred method = oral replacements up to 40 mEq/hr (more may result in GI upset/diarrhea/esophagitis)
Err towards under-correction in renal failure and consider using moderate oral doses with rechecking of K frequently
Replete IV for symptomatic and EKG changes
Peripheral line: Max IV rate = 10 mEq/hr
Central line: Max IV rate = 20 mEq/hr (use cardiac monitor and frequent serum K checks). Generally avoided except in severe cases of arrhythmia
Remember you can give IV and PO simultaneously for rapid input
Replete Mg in setting of hypomagnesemia or patient will be refractory to K repletion

Definition: K > 5.5 mmol/L
Pseudohyperkalemia: K may be falsely elevated if intra-tube hemolysis (often mentioned by lab), WBC > 100,000 or platelets > 800,000 (redraw in heparinized tube), tourniquet draw, hereditary spherocytosis

Clinical manifestations:
Neuromuscular: weakness, paralysis
EKG abnormalities: Acute rises are most dangerous and associated with arrhythmia
K = 6-7: peaked T waves
K = 7-8: widened QRS, dec P amplitude
K = 8-9: sine waves
K > 9: AV dissociation, VT, VF

Causes:
incK intake: Salt substitutes, dietary indiscretion (with renal failure), overzealous K replacement
Transcellular shift: Acidemia, insulin deficiency, hyperosmolality (glucose, contrast), inc cell destruction (tumor lysis, rhabdomyolysis, hemolysis, blood transfusion), B-adrenergic blockade, digoxin overdose, vigorous exercise, succinylcholine, hyperkalemic periodic paralysis
decrenal excretion:
Renal failure
Hyporeninemic hypoaldosteronism: DM nephropathy, NSAIDs, cyclosporine
Hypoaldosteronism: Adrenal insufficiency, CAH, ACEI/ARB, heparin, spironolactone
Diminished aldosterone action: Amiloride, triamterene, trimethoprim, pentamidine, tacrolimus, type II pseudohypoaldosteronism, tubulointerstitial disease
Hyperkalemic type I RTA--> deceffective circulatory volume

Work-up:
Assess symptoms, diet (including TPN), med list, BP, acid-base status, and EKG
Calculate transtubular K gradient:
TTKG > 10 = external causes
TTKG < 7 = renal or endocrine defect

Treatment:
K = 5.5-6.5, no EKG changes
D/C any offending drugs and external sources of K. Chang to low K diet
Kayexalate, a cationic exchange resin, 15-45 grams PO q4-6 hours PRN. Kayexalate takes up K and releases Na in the gut. Side effects include volume overload and intestinal necrosis (caution in patients with ileus or bowel surgery). Often given with sorbitol to prevent constipation.
Loop diuretic PRN. Thiazides generally less effective, particularly with renal failure.
K > 6.5 + EKG changes or K > 8
CaCl or Ca gluconate 1 gram IV over 2-5 min PRN with cardiac monitoring q5 min. Ca infusion antagonizes the proarrhythmic effects of hyperkalemia. Effect lasts up to 30 min. DO NOT USE IF DIGOXIN TOXICITY SUSPECTED.
Insulin 10 units regular IV push with 1 amp D50W IV push. D50 prevents hypoglycemia so should avoid if patient already hyperglycemic. May dec K by 1 mmol/L, works in 15-30 min, and lasts hours.
NaHCO₃ 1 amp IV over 5 min q30 min. Less effective if patient not acidotic or has ESRD. May dec K by 0.5-1 mmol/L, works in 30-60 min, and lasts hours. Watch for Na load
Albuterol 10-20 mg hand held nebs (note this is 2-8x the usual dose) or 0.5mg by IV infusion (rarely given). May dec K by 1 mmol/L, works in 60-90 min nebulized or 30 min IV, and lasts about 4 hours. Major side effects include b-stimulation (arrhythmia) and not as effective in ESRD
Kayexalate and diuretics as above
Dialysis: May consider holding insulin/D50, NaHCO3, and albuterol if patient without dangerous EKG findings and plans are to dialyze immediately. Each measure shifts K intracellular and will make removal of K by dialysis less effective
Important to note that of the above measures, only Kayexalate, diuretics, or dialysis will remove total body K rather than redistribute

Calcium relationships:
Total Ca = Protein bound (primarily albumin) + complexed (primarily to anions like PO4) + free (ionized Ca)
Primary determinant of clinical manifestations of Ca disorders is the ionized Ca. Approximately 45-50% of total Ca is ionized
Conversion factors of total Ca (mg/dl) and ionized Ca (mmol/L):
Molecular weight of Ca = 40 grams, so 40 mg/L = 1 mmol/L = 4mg/dL
So if total Ca = 10 mg/dl then it is 2.5 mmol/L. Assuming that 50% of total Ca is ionized then a total Ca of 10 mg/dl is approximately equivalent to 1.25 mmol/L ionized Ca
Total Ca is effected by changes in albumin concentration and the proportion of bound Ca is effected by systemic pH
Every dec 1 g/dL of albumin below 4 --> 0.8 mg/dL dec in total Ca
Every dec 0.1 of pH below 7.4 --> 0.12 mg/dL inc in ionized Ca

Clinical manifestations: Depends on rate of onset and are potentiated by alkalosis, dec Mg, dec K, inc catecholamines
Neuro:
Mild: circumoral numbness, paresthesias, cramps
Severe: seizure, tetany, laryngospasm, carpopedal spasm
Signs: Trousseau's = carpal spasm with cuff inflation. Chvostek's = twitching of facial muscles with facial nerve tapping
Psych: Irritability, anxiety, depression
CV: Arrhythmia, prolonged QT interval on EKG, depressed function
Optho: Papilledema
Chronic: Dry puffy skin, alopecia, cataracts, basal ganglia calcification, extrapyramidal disorders

Causes:
incLoss of Ca from circulation:
Extravascular deposition: inc PO4 (renal failure, rhabdomyolysis, tumor lysis), acute pancreatitis (precipitation of Ca soaps)
Intravascular binding: Ca chelation (citrate or EDTA in massive blood transfusion, lactate, foscarnet), acute respiratory alkalosis (inc albumin binding --> dec ionized fraction)
Osteoblastic metastases
decEntry of Ca into circulation:
Hypoparathyroidism (dec production or dec action): post-surgical, autoimmune, infiltrative disease, cinacalcet, autosomal dominant hypocalcemia (activating mutation of Ca sensing receptor results in low PTH secretion), dec Mg, pseudohypoparathyroidism
Hypovitaminosis D (dec production or dec action): dec dietary intake, malabsorption, dec 25-hydroxylation in liver failure, dec 1-hydroxylation in renal failure, inc metabolism
Bisphosphonates
Critical illness: Appears related to inflammatory cytokines diminishing PTH and vitamin D production and PTH action. Examples include sepsis or burns

Work-up:
Confirm with ionized Ca measurement or corrected total Ca
Other useful tests include: intact PTH, Mg, PO₄, Vitamin D 25-OH, Vitamin D 1,25-OH, and Cr
PTH must be interpreted with concomitant Ca measurement
A normal PTH with a low Ca is inappropriate and suggestive of hypoparathyroidism

Differential Diagnosis of Hypocalcemia Based On Lab Findings
Disorder	PTH	PO4	25-OH-D	1,25-(OH)2-D
Hypoparathyroidism	Low	High	Nl	Low
Pseudohypoparathyroidism	High	High	Nl	Low
Vitamin D 25-OH deficiency: (dietary, malabsorption, cirrhosis)	High	Low	Low	Low, nl, or high
Vitamin D 1,25-OH deficiency: (renal, hereditary)	High	Low	Nl or high	Low
Vitamin D 1,25-OH resistance	High	Low	Nl	Very high
Hypomagnesemia	Low, nl or high	High	Nl	Low or nl
inc bone formation: Healing, mets, hungry bone syndrome	Nl or high	Low nl	Nl	Nl or high
Soft tissue calcification	Nl or high	High	Nl	Nl, high or low

Treatment:
Mild asymptomatic:
Oral replacement with extra 1000 mg elemental Ca daily (500 mg CaCo3 ~ 200 mg elemental Ca)
Consider IV replacement in those unable to take PO
Severe or symptomatic: (iCa < 0.7-0.8 mmol/L or total < 7 mg/dL)
IV Ca: 1-2 grams Ca gluconate or Ca chloride over 20 min. Do not give any faster given possible side effect of inducing cardiac arrhythmia. May follow by infusion of 0.5 mg/kg/hr. Follow serum Ca q4-6 hr and gradually taper infusion
Correct hypomagnesemia
Treat underlying condition
Chronic: Frequent complication of CKD given hyperphosphatemia and dec Vitamin D 1,25-OH production.
Consider addition of calcitriol or other Vitamin D analogues
If patient is on dialysis, dialysate Ca bath may be altered
Watch Ca repletion with hyperphosphatemia. Beware of calciphylaxis if Ca-PO₄ product (Total serum Ca x PO₄) > 70

Renal: ARF (prerenal, vasoconstriction), polyuria (nephrogenic DI), dehydration, nephrolithiasis

GI: Anorexia, nausea, vomiting, constipation

CV: Short QT on EKG, enhanced sensitivity to digitalis, bradyarrhythmia

Neuro: Apathy, depression, coma, hyperreflexia

Musculoskeletal: Chondrocalcinosis, pseudogout, osteitis fibrosa cystica (associated with hyperparathyroidism)

Soft tissue: Ectopic calcification

Calcium supplementation

Hyperparathyroid (primary or tertiary)/Hereditary (Familial hypocalciuric hypercalcemia):
Hyperparathyroidism accounts for 90% of ambulatory cases
Note: Secondary hyperparathyroidism associated with low Ca

Immobility/Infections (TB, histoplasmosis, coccidiomycosis, leprosy)

Milk-alkali/Medications (Thiazides, diuretics, lithium, estrogens, antiestrogens)

Paget's disease, Parenteral nutrition

Addison's disease/Adrenal insufficiency

Neoplasm: accounts for majority (65%) of hospitalized cases
PTH-RP mediated (squamous cell lung carcinoma, renal, breast)
Vitamin D 1,25-OH mediated (lymphoma)
Osteolytic mediated (multiple myeloma, metastases, lymphoma)

Zollinger-Ellison

Endocrine (non-parathyroid): Thyrotoxicosis, pheochromocytoma

Excess Vitamin D 25-OH, Vitamin D 1,25-OH, Vitamin A

Sarcoidosis

Work-up:
Ionized Ca, PO4, Cl, TCO2, Vitamin D 25-OH, Vitamin D 1,25-OH, PTH, PTHrP, TFTs, SPEP/UPEP, alkaline phosphatase
Consider Vitamin A, skeletal survey, nuclear bone scan, and BM Bx depending on level of clinical suspicion

Treatments for Hypercalcemia
Treatment	Mechanism	Onset	Duration	Side effects
NS Hydration: 200-300 ml/hr titrated to UOP 100-150 ml/hr	Na-induced volume expansion reverses dehydration and inhibits proximal tubule Ca reabsorption	Hours	Temporizing while IVF running	Volume overload, rarely effective alone
Loop diuretic (i.e. furosemide)	Na-induced natriuresis and inhibits ascending limb Ca reabsorption (Note: thiazides may worsen hypercalcemia)	Hours	Temporizing while diuretic in effect	Other electrolyte abnormalities (K, Mg), volume depletion (ensure patient volume replete before instituting)
Bisphosphonate: Zoledronic acid (4mg over 15 min) or Pamidronate (90mg IV over 24 hours or 60mg IV over 4 hours)	Inhibits osteoclast-mediated bone resorption	2-4 days	Weeks to months	decMg, decPO4, caution in renal failure given prolonged half-life (use lower dose)
Calcitonin (4-8 IU/kg IM/SQ q6-12 hours)	Inhibits osteoclast-mediated bone resorption	Hours	Tachyphylaxis at 48 hours	Rarely side effects, nausea, flushing, hypersensitivity
Prednisone (20-40mg PO daily)	Inhibits Vitamin D 1,25-OH synthesis by mononuclear cells (effective versus lymphoma or granulomatous disease)	2-4 days	Days	Typical side effects of steroid usage
Gallium nitrate (200 mg/m2/day continuous IV for 5 days)	Inhibits osteoclast-mediated bone resorption	3-5 days	Weeks	Nephrotoxic, requires continuous infusion, rarely used
Oral PO4 (0.5-1 gm PO tid)	Complexes Ca in gut	Days	Temporizing while in use	Calciphylaxis (do not use if Ca-PO4 product > 55)
Dialysis	Removes systemic Ca via diffusion	Immediate	Temporizing while in use	Use for patients with severe hypercalcemia

Other Electrolyte Replacement

Magnesium:

General rule: Every 1.0 gm of MgSO4 given IV will inc serum Mg 0.1 mEq/L (if Cr is <1)
Oral replacement may also be used with Mg Oxide though absorption is 15-50% and may cause diarrhea
Patients with renal failure will require lowering of dose by 50% or more

Phosphate:

Phosphate > 2.0 mg/dl--> Replete orally with Neutra-Phos or KPhos (2 tablets/packets TID)
Phosphate 1.5-2.0 mg/dl--> 0.08 mmol/kg IV NaPhos or KPhos over 6 hours
Phosphate < 1.5 mg/dl--> 0.16 mmol/kg IV NaPhos or KPhos over 6 hours
Be careful with phosphate replacement in patients with hypercalcemia as chance of metastatic calcification
Patients with renal failure will require lowering of dose by 50% or more

Step 1:
Check ABG and chemistry panel. Identify changes in pH, HCO₃, and pCO₂, and see if the perturbation in PCO₂ or HCO₃ explains the trend in pH. VBG may be used to estimate arterial pH (add ~ 0.05) and pCO2 (subtract ~ 5) except in cases of circulatory failure. In most clinical cases, venous chemistry total CO2 can substitute for blood gas HCO₃
If pH is low and pCO₂ is high, patient has a primary respiratory acidosis
If pH is low and HCO₃ is low, patient has a primary metabolic acidosis
If pH is high and pCO₂ is low, patient has a primary respiratory alkalosis
If pH is high and HCO₃ is high, patient has a primary metabolic alkalosis

Step 2:
Check anion gap to look for an anion gap acidosis (even if pH is normal): Anion Gap = Na - (Cl + HCO₃)
Low albumin will cause lower AG (for every dec in albumin by 1, AG dec by 2.5). Other causes of low anion gap include inc unmeasured cations (paraproteinemia, lithium, K, Ca, Mg), bromide intoxication, hyperlipidemia
If high, calculate D anion gap (AG):

DAG = Patient's AG - Normal AG (use patient's baseline AG, or, if unknown, 12 at UCLA)

Step 3:
Add the DAG to patient's HCO₃ (DAG + patient's HCO₃)
If < 24: a non-gap metabolic acidosis AND/OR a respiratory alkalosis is present in addition to gap metabolic acidosis
If > 24: a metabolic alkalosis AND/OR a respiratory acidosis is present in addition to gap metabolic acidosis

Step 4:
Identify any additional respiratory or metabolic process by using the formulas below to calculate expected pCO₂ and serum HCO₃ based on serum HCO₃ and compare to actual pCO₂ and HCO₃
If actual pCO₂ = expected pCO₂--> pure metabolic process
If actual pCO₂ > expected pCO₂--> primary respiratory acidosis also present
If actual pCO₂ < expected pCO₂--> primary respiratory alkalosis also present
If actual HCO₃ = expected HCO₃--> pure respiratory process
If actual HCO₃ > expected HCO₃--> primary metabolic alkalosis also present
If actual HCO₃ < expected HCO₃--> primary metabolic acidosis also present

Metabolic Acidosis
For every dec in HCO₃ by 10, pCO₂ should dec by 10-12 OR
Winter's Formula: Expected pCO₂ = 1.5 x HCO₃ + 8 +/- 2 (Use in simple acidosis)

Metabolic Alkalosis
For every inc in HCO₃ by 10, pCO₂ should inc by 7
The formulas below predict expected serum HCO₃ based on pCO₂ in the following settings:

Acute Respiratory Acidosis
For every inc in pCO₂ by 10, HCO₃ should inc by 1 and pH should dec by 0.08

Chronic Respiratory Acidosis
For every inc in pCO₂ by 10, HCO₃ should inc by 3.5 and pH dec by 0.03

Acute Respiratory Alkalosis
For every dec in pCO₂ by 10, HCO₃ should dec by 1-2

Chronic Respiratory Alkalosis
For every dec in pCO₂ by 10, HCO₃ should dec by 5
Remembering the renal compensation for a respiratory problem is as easy as A-B-C, 1-2-3! Just use THE BOX!!
For every change in pCO2 of 10, the bicarb (HCO3) will change by the number in the box for the given respiratory process. For example, in an acute respiratoy acidosis with a pCO2 of 60 (20 pts above normal), you would expect the HCO3 to rise by 2 points.

	Acid	Base
Acute	inc 1	dec 2
Chronic	inc 3.5	dec 5

Methanol

Uremia (renal failure)

Diabetic ketoacidosis, Dilutional acidosis

Paraldehyde, Pyroglutamic acid (acetaminophen), Phenformin

INH, Iron

Lactic acidosis

Ethylene glycol, ETOH ketoacidosis

Salicylates, Starvation ketoacidosis
Anion gap and osmolal gap metabolic acidosis:
If suspect toxic ingestion calculate osmolal gap:

Calculated serum osmolality = (2 x Na) + (BUN / 2.8) + (glucose / 18)

Osmolal gap = Measured serum osmolality - Calculated serum osmolality
Normal osmolal gap <= 10 mOsm/kg
Conditions include methanol ingestion, ethylene glycol ingestion, ethanol intoxication, renal failure, paraldehyde, ketoacidosis, lactic acidosis
Other substances that cause osmolal gap without anion gap acidosis include isopropanol, mannitol, contrast, severe hyperproteinemia
Non gap metabolic acidosis (HARDPUT):

Hyperalimentation

Acetazolamide

RTA, Renal failure (early)

Diarrhea

Pancreatic fistula

Ureteral diversion (ureterosigmoidostomy, ileal loop, etc)

Toluene ingestion
Urine anion gap may help distinguish GI and renal causes of non-gap metabolic acidosis:

Urine Anion Gap = Urine Na + Urine K - Urine Cl
If negative, GI HCO₃ loss (diarrhea) is likely cause (Negative means "below the belt")
If positive, renal HCO₃ loss (RTA) is likely cause (Positive means "above the belt")

Metabolic Alkalosis:
Check urine chloride to divide into chloride responsive and chloride resistant
Chloride responsive (U_Cl < 20 mmol/L):
NGT suction, vomiting
Diuretics (late)
Posthypercapnea
Cystic fibrosis
Low chloride intake
Laxative-induced diarrhea
Chloride resistant (U_Cl > 40 mmol/L):
Mineralocorticoid excess (frequently hypertensive): May include primary hyperaldosteronism, renin-secreting tumors, Cushing's syndrome, Liddle's syndrome, renovascular disease, apparent mineralocorticoid excess, licorice ingestion
Diuretics (early)
Alkali load, antacids
Bartter's or Gitelman's syndrome
Severe hypokalemia

Respiratory Acidosis:
Respiratory depression
COPD
Neuromuscular weakness/kyphoscoliosis
Pleural effusions
Pneumothorax
Pneumonia
Pulmonary edema
Bronchospasm/laryngospasm

Respiratory Alkalosis:
Sepsis
Respiratory distress (PE, CHF, hypoxemia, restrictive lung disease)
Head trauma
Liver disease
Salicylates
Hyperthyroidism
Pregnancy, progesterone
Central hyperventilation
Anxiety

Proximal (Type II): Failure to reabsorb HCO₃ in the proximal tubule
DDx: Congenital, Fanconi's, myeloma, ifosfamide, heavy metals, hyperparathyroidism, aminoglycosides, cystinosis, glycogen storage disease, acetazolamide, amyloidosis, topiramate
Work-up: Fractional excretion of HCO₃ (FEHCO₃) > 15% (calculate like FENa) after normalization of serum HCO₃

Distal (Type I & IV): Failure to acidify urine in the cortical collecting duct

Type I (classic distal): Failure of H⁺-ATPase to secrete H⁺ into urine
DDx: Collagen vascular disease (Sjögren's, rheumatoid arthritis) congenital, chronic hyperglobulinemia
Amphotericin may cause holes in luminal membrane allowing back-leak of H⁺ ions
Often associated with hypokalemia, hypercalciuria, and nephrolithiasis

Type IV: Lack of aldosterone production or action leads to failure to reabsorb Na and secrete H⁺ and K
DDx associated with hyporeninemic hypoaldosteronism: Diabetic nephropathy, tubulointerstitial diseases, ACEI, NSAIDs, cyclosporine, obstructive uropathy
Primary hypoaldosteronism will give similar clinical picture except inc renin
DDx associated with aldosterone resistance: Spironolactone, epithelial Na channel blockage (amiloride, triamterene, trimethoprim, pentamidine), pseudohypoaldosteronism (type I & II), distal chloride shunt (tacrolimus)
Often associated with hyperkalemia and metabolic acidosis

Work-up:
Urine PCO₂ - Blood PCO₂ < 30
Urine PCO₂ will be lower than normal (70) because urine will not be acidified and subsequently less drive for H⁺ + HCO₃ --> H₂CO₃ --> H₂O + CO₂
Send ABG on urine (have patient urinate in cup with mineral oil to prevent PCO₂ diffusion to air) and check blood gas
Serum HCO₃ must be normal before obtaining the above studies (will likely need to give HCO₃ IV)

Tolerance:
After long term use of loop diuretics, the distal segments hypertrophy
Thiazides (often metolazone 2.5-5 mg PO 30 minutes prior to loop diuretic dose) are then used to block the distal sites

Clinical conditions of diuretic resistance:
Renal insufficiency:
Frequently need higher doses due to inherent diuretic resistance from dysfunctional tubules. Can give up to 160 mg IV Lasix. If no effect, start an IV Lasix drip after a loading dose. Need to watch for ototoxicity with high doses
If still little response, add metolazone
Dialysis if fluid overload state is refractory to high dose diuretics
Nephrotic Syndrome:
Diuretics bound to albumin and transported to renal tubules for secretion into intraluminal space
decintravascular albumin leads to diffusion of diuretics into extravascular space and decreased transport to renal tubules
incbinding of diuretic to filtered urinary albumin and dec free diuretic to interact with appropriate channels
May need to inc dose of diuretic by 2-3x of normal amount
Consider concomitant infusion of albumin with furosemide (controversial if more effective than furosemide alone)
Cirrhosis:
Spironolactone (50-100 mg/day titrated to max 400 mg/day) as first line
Add loop diuretic (furosemide 40-160 mg/day) for refractory edema or ascites
CHF:
Loop diuretics at inc frequency. Diuretic free periods allow rebound Na retention to occur so frequent dosing (i.e. furosemide q6-8 hours) or drip may be appropriate
Add metolazone if lack of response with loop diuretic

Sulfa allergy:
Ethacrynic acid does not contain sulfa
Check K, Mg q6-12 hours depending on the frequency and strength of diuretic administration and replete to keep K > 4.0 and Mg > 2.0

Definition: Necrosis of skeletal muscle with release of intracellular muscle enzymes and pigments into circulation

Causes: Crush injuries, severe exertion, alcoholism, seizure, infection, drugs (statins, cocaine, etc), hypokalemia, hypophosphatemia, malignant hyperthermia/NMS, metabolic myopathies, inflammatory myopathies, mitochondrial disorders

Clinical manifestations:
Asymptomatic with mild rhabdomyolysis to severe cases with myalgias and myoglobinuria
ARF: Possible mechanisms include renal ischemia due to volume depletion, tubular obstruction from the heme pigment casts, and tubular injury from the free iron
DIC: Thromboplastin released from damaged cells

Work-up:
inc CK (skeletal fraction): Typically > 10,000 to cause injury, but can be > 100,000 IU/L. CK peaks within 24 hours and dec ~40%/day, so if delayed presentation, CK on admission may be markedly lower than at time of initial insult
Electrolytes: inc K, inc PO₄, dec Ca, inc uric acid, metabolic acidosis
Urinalysis: Reddish/brown urine with urinalysis noted positive for heme but negative for cells (similar to hemoglobinuria; unlike hemoglobinuria where it is red, plasma color is clear in myoglobinuria). Urine sediment may show reddish-gold pigmented casts
Gross pigmenturia may not be present because myoglobin more rapidly cleared from serum than CK
Other: inc Serum AST/ALT

Treatment: Goal is to treat underlying illness and prevent/manage ARF. Similar management as for hemoglobinuria, the other type of pigment nephropathy
Monitor frequent electrolytes (K, Ca, PO₄)
Hypocalcemia common in early phase, but avoid Ca replacement unless symptomatic or severe as risk of Ca-PO₄ precipitation and development of hypercalcemia during recovery phase.
Fluid resuscitation: Normal saline to enhance renal tubular perfusion and prevent tubular obstruction
Begin NS 0.5-1 L/hr and titrate to urine output of 200-300 ml/hr
Monitor for fluid overload and compartment syndrome which can worsen with vigorous hydration
If diuresis not achieved with volume repletion, add diuretic
Urine alkalinization: Theoretical benefit of decreasing pigment cast formation and release of free iron from myoglobin.
Conflicting reports and no controlled trials. Use only if adequate urine output achieved. Consider 1-2 amps of NaHCO₃ in ½ NS @ 100ml/hr titrated to goal urine pH > 6.5
Side effects include worsening hypocalcemia, Ca-PO₄ precipitation, and hypokalemia
Mannitol: Theoretical benefit of forced diuresis to flush out pigment as well as act as free radical scavenger
Conflicting reports and no controlled trials. Use only if adequate urine output achieved
Side effects include osmotic diuresis with volume depletion and hypernatremia, hyperosmolarity and associated volume overload (Monitor serial plasma osmolality D/C if osmolal gap > 55 mOsm/kg), and ARF
Dialysis: May be needed for hyperkalemia, hyperphosphatemia, or volume overload

Definition: Differs study to study, but often defined by 25% inc or absolute inc of 0.5 mg/dL of serum Cr within 1 week of contrast administration

Epidemiology: Estimates depend on definition and population, though likely 1-2% of all patients, and relatively common cause of hospital-acquired ARF (~12%)

Risk factors: DM, CKD (Cr > 1.5 mg/dl or GFR < 60 ml/min), volume depletion, myeloma, CHF, contrast factors (high osmolality, large volume, ionic)

Prophylaxis: Optimal treatment unclear, but should be done for all patients at risk
IV hydration: Should be considered for all patients
NS 1 ml/kg/hr beginning 6-12 hours prior to contrast and 6-12 hours afterwards
Limited evidence for benefit of NaHCO₃ over NS. May consider NaHCO₃ if limited time for IVF hydration, but need to monitor for alkalemia and hypocalcemia
Consider 3 amps of NaHCO₃ added to 1L sterile H₂O (~150-175 mEq/L NaHCO₃) as bolus of 3 ml/kg 1 hr prior to contrast then 1ml/kg/hr continued for 6 hours afterwards
N-acetylcysteine: Conflicting reports of efficacy, but often given due to minimal side effects
N-acetylcysteine 1200mg PO BID given day before and 24-48 hours after contrast exposure
Some evidence for IV N-acetylcysteine so may consider for patients unable to take PO or for emergency procedures. However, side effects include fair rate of anaphylactoid reactions
Consider 1200 mg N-acetylcysteine IV bolus prior to contrast and then 1200 mg IV BID for 48 hours after contrast exposure
Continuous hemofiltration: Limited evidence with positive results using serum Cr (which is eliminated from serum with hemofiltration) as measure of ARF
Discuss with renal service prior to institution as may be useful in patients already with access. However, use requires presence of vascular access and ICU stay for day of CVVH
Note hemodialysis alone is not effective
Other: Withhold diuretics and NSAIDs if possible 24 hours prior to and after contrast and metformin 48 hours prior to and after contrast. Forced diuresis with mannitol and dopamine has been associated with worse outcomes. Some limited data available regarding possible beneficial effects of theophylline and Vitamin C

Acute, short-term catheter (i.e. Quinton, Mahurkar):
Double lumen, non-cuffed, non-tunneled catheter
May be inserted at bedside into femoral, jugular or subclavian (less preferable because of risk of subclavian stenosis or thrombosis) vein via modified Seldinger technique
Typical longevity of catheter by insertion site:
Internal jugular: 2-4 weeks
Femoral vein (in non-ambulatory patient): ~7 days
Femoral vein (in ambulatory patient): Single use only

Tunneled catheter (i.e. PermCath):
Double lumen, cuffed catheter that is tunneled under the skin
Inserted into jugular, femoral or subclavian (less preferable) vein by interventional radiology or vascular surgery
Typical longevity of catheter is 6 months to one year
Often used as a bridge until maturation of AV fistula or graft

Arteriovenous Access:
AV Fistula:
Placed by vascular surgery under regional anesthesia via a subcutaneous anastomosis of an artery to an adjacent vein
Safest and longest lasting permanent vascular access for hemodialysis
Requires minimum 1 month, and possibly 4-6 months, maturation time prior to use
AV Graft:
Placed by vascular surgeon under regional anesthesia via a synthetic tube graft connecting an artery and vein
Used when patient vasculature inadequate for AV fistula
Allow 2-3 weeks for maturation prior to use
Clotting and infection risk higher with AV graft than AV fistula

Complications associated with hemodialysis access:
Catheter insertion related complications:
Arterial puncture, pneumothorax/hemothorax, pericardial tamponade, air embolism, brachial plexus injury, mediastinal hemorrhage, arrhythmias
Catheter infectious complications:
Prevention:
Aseptic insertion and handling of catheters
Infection of uncuffed catheters:
Localized exit site or tunnel infection:
If erythema present but no purulent discharge, treat with antibiotics for 2 weeks
Remove catheter if systemic signs of infection are present (e.g. fever, leukocytosis, hypotension), if positive blood cultures, if pus can be extruded from the catheter insertion site, or if the erythema does not clear after treatment with antibiotics
Systemic infection:
Signs of local infection may or may not be present Remove catheter if there are signs of systemic infection without another obvious source or if fungemia
On removal, the catheter tip should be cultured using sterile technique and consideration may be made for blood cultures from line and peripherally
Antibiotic therapy should be continued for a minimum of 2 to 3 weeks
Infections in cuffed catheters (PermCath):
Tunnel site infections without bacteremia:
Can be given a brief trial of antibiotics but failure to respond within 36-72 hours requires removal of catheter
Catheter-related bacteremia without tunnel site infection or signs of sepsis:
Initial course of parenteral antibiotics
Given patients may be difficult access, catheter may be left in patients who become asymptomatic on antibiotic therapy and have no evidence of tunnel or exit site infection
Catheter should be removed in all patients who are still symptomatic after 36-72 hours of antibiotic therapy
Catheter related fungemia: Catheter should be removed
Complications of catheter related infections:
Endocarditis
Osteomyelitis
Suppurative thrombophlebitis
Spinal epidural abscess
Sepsis
Catheter dysfunction:
Early catheter dysfunction:
Intracatheter thrombosis:
Treatment with intraluminal administration of tPA
Malposition or catheter tip thrombosis:
Persistent low flow despite intracatheter thrombolytics requires examination under fluoroscopy to diagnose malposition of the catheter tip or tip thrombosis
Late catheter dysfunction (> 5 days):
Fibrin sleeves and mural thrombi:
Fibrin sleeves begin developing 1-3 weeks after insertion of the catheter
May cause intraluminal obstruction and serve as a nidus for infection
Suspected in catheters that infuse but are difficult to aspirate
Diagnosis made by interventional radiology with a catheter venogram
Treatment with either thrombolytics, snare stripping of the fibrin or replacement of the catheter
Complications with AV fistulas or grafts:
Stenosis:
Caused by thrombosis, myointimal hyperplasia, pseudoaneurysm, needle stick injury
Signs and symptoms:
Recurrent clotting
Difficulty with needle placement or hemostasis after needle withdrawal
Persistently swollen arm
High venous pressures during dialysis
Positive recirculation study
Pulse with absent thrill (suggests low flow) or discontinuous water hammer type pulse over the graft
Work-up:
Doppler ultrasound
Angiography
Treatment:
Thrombolysis or surgical thrombectomy if clot
Percutaneous transluminal catheter angioplasty Surgical revision
Infections:
More common in AV grafts than fistulas
Initial antibiotics should cover gram negatives, gram positives (including enterococcus). Total antibiotics for 3 wks with graft and 6 wks with fistula (similar to endocarditis treatment)
Extensive infection or septic embolus warrants surgical excision of graft/fistula
Consider a tagged white cell scan in FUOs
Distal ischemia/"Steal":
More common in DM, PVD, elderly
May require surgical revascularization and ligation of access
Aneurysm (fistula)/Pseudoaneurysm (graft):
Avoid needle insertion
Vascular surgery assessment should be pursued and may require revision, particularly for pseudoaneurysms

Renal Transplant
Differential of Renal Transplant Graft Dysfunction Immediate graft dysfunction (hours post-transplant):
Ischemic renal injury
Calcineurin inhibitor nephrotoxicity
Hyperacute rejection
Urinary leak or urinary tract obstruction
Vascular thrombosis
Volume depletion/prerenal
Recurrence of primary renal disease (particularly primary FSGS)
Early graft dysfunction (days to weeks post-transplant):
Acute rejection (cellular, humoral or both)
Calcineurin inhibitor nephrotoxicity, including TTP/HUS
Urinary leak or urinary tract obstruction/
Volume depletion/prerenal
Infection
Recurrence of primary renal disease (particularly primary FSGS)
Delayed graft function (perioperative ATN)
Late onset graft dysfunction (months to years post-transplant):
Acute rejection (cellular, humoral or both)
Calcineurin inhibitor nephrotoxicity, including TTP/HUS
Chronic allograft nephropathy
Recurrence of primary renal disease or de novo glomerulonephritis
Transplant renal artery stenosis (RAS)
BK virus nephropathy
Post-transplant lymphoproliferative disease (PTLD)
Note: Donor characteristics will affect graft function at all stages (i.e. poor prognostic factors include donor elderly age, history of stroke, donor hypertension, glomerular and interstitial scarring on biopsy, etc)
Work-up of renal allograft dysfunction Physical exam:
Vital signs:
Fever and oliguria are not necessarily present with acute rejection. Given effect of potent immunosuppression, fever likely more suggestive of infection
Monitor for hypertension
Volume status (i.e. JVP, edema, urine output)
Consider transplant RAS in the edematous patient
Palpate renal graft looking for tenderness or enlargement which may represent acute rejection or pyelonephritis
Excruciating graft pain suggestive of urine leak
Auscultate for a new bruit which may represent transplant RAS
Laboratory exam:
Standard chemistry panel
CBC with platelets and differential:
Low platelets in setting of ARF should make one worried nephrotoxicity associated with calcineurin inhibitor-induced thrombotic microangiopathy
Urinalysis and culture:
Pyuria can indicate either acute rejection or infection
Proteinuria may represent recurrence of primary disease (especially FSGS) or chronic allograft nephropathy
Calcineurin inhibitor levels (cyclosporine, tacrolimus):
Most useful drawn as trough levels. Draw cyclosporine and tacrolimus daily.
May help differentiate between calcineurin inhibitor nephrotoxicity and rejection
Sirolimus trough:
Most useful drawn as trough level. Draw intermittently during hospital course rather than daily given long half-life
Doppler renal ultrasound:
Anatomic and surgical problems must be excluded
Renal graft biopsy:
Technique: Core needle (18 gauge spring loaded) biopsy performed with local anesthetic and ultrasound guidance
Post-biopsy monitoring:
Vitals every 15 min and 2 hours post-biopsy then hourly for 6 hours
Patients should remain lying flat, relatively immobile, and can begin ambulating within 6-8 hours of bed rest
Gross hematuria should be noted to renal fellow on call
Complications:
Perinephric or urinary bleeding
Post-biopsy arteriovenous fistula
Ureteral obstruction from blood clots
Immunosuppressive Medications In Renal Transplant Note that decisions about immunosuppressive medications should be made by the renal transplant fellow and attending

Corticosteroids:
Class: Corticosteroids
Mechanism: Inhibits lymphocyte proliferation and cell mediated immune response
Toxic effects: Immunosuppression, glucose intolerance, osteonecrosis, cosmetic changes, impaired wound healing, cataracts, hyperlipidemia, psychosis
Maintenance immunosuppression: Varies according to protocol
Following steroid pulse, prednisone 20 mg daily immediately post-transplant and then usually tapered to 5 mg daily within 3 months
Recently, select patients are being transferred to steroid-sparing regimens immediately post-transplant
Monitoring: Monitor blood sugars for hyperglycemia

Cyclosporine (Neoral, Gengraf, Sandimmune):
Class: Calcineurin inhibitor
Mechanism: Inhibits calcineurin which blocks T-cell function and IL2 secretion
Toxic effects: Nephrotoxicity (acute and chronic), HTN (higher degree than tacrolimus), hyperlipidemia, glucose intolerance, neurotoxicity, hyperuricemia, gout, malignancy, infection, HUS/TTP, hirsutism, and gingival hyperplasia (higher degree than tacrolimus), hyperkalemia, hypomagnesemia, RTA
Drug interactions: Due to interaction with p450 enzyme CYP3A4
deccyclosporine levels: Anti-epileptics (barbiturates, phenytoin, carbamazepine), rifampin
inccyclosporine levels: Calcium channel blockers (verapamil, diltiazem, amlodipine), antifungal agents (-azoles), erythromycin, protease inhibitors, amiodarone
Dosing:
Note: Sandimmune is an older generic form of cyclosporine and is not equivalent to Neoral or Gengraf, which have more consistent bioavailability
If "cyclosporine" and not "Neoral" or "Gengraf" is ordered through pharmacy, the patient may receive the older generic form
Maintenance immunosuppression: varies according to protocol. Some centers and the outpatient clinic have adopted use of 2 hour peak level.
0-1 month: Trough 200-300
1-3 months: Trough 150-250
3-6 months: Trough 125-175
>6 months: Trough 100-175

Tacrolimus or FK 506 (Prograf):
Class: Calcineurin inhibitor
Mechanism: Inhibits calcineurin which blocks T-cell function and IL2 secretion
Toxic effects: Nephrotoxicity (acute and chronic), HTN, hyperlipidemia, glucose intolerance (higher degree than cyclosporine), neurotoxicity (higher degree than cyclosporine), hyperuricemia, gout, malignancy, infection, HUS/TTP, hair loss, hyperkalemia, hypomagnesemia, RTA
Drug interactions: Similar to cyclosporine
Maintenance immunosuppression: Varies according to protocol
1-3 months: Trough 8-12
>3 months: Trough 6-10

Mycophenolate mofetil (CellCept, Myfortic):
Class: Inosine monophosphate dehydrogenase inhibitor
Mechanism: Inhibits B- and T-cell proliferation
Toxic effects: Diarrhea, nausea, vomiting, dyspepsia, leukopenia, anemia, thrombocytopenia, opportunistic infections, lymphoproliferative disorders
Dosing:
Note: Myfortic is enteric-coated and may be associated with less GI side effects.
Equivalent dose of Myfortic 720 mg ~ CellCept 1 gm
Maintenance immunosuppression: No formal protocol for measuring drug levels at present
Typically dosed 1-1.5 gm PO bid
Higher doses frequently given to those who are African American, larger size, or prior history of rejection

Sirolimus (Rapamune):
Class: Macrolide antibiotic compound
Mechanism of action: Inhibits mTOR which blocks T-cell function and IL2 signal transduction
Toxic effects: Hyperlipidemia, thrombocytopenia, leukopenia, anemia, HUS/TTP, skin ulcers, pneumonitis, delayed wound healing, infection (PCP prophylaxis should always be given for 1 year), malignancy, hypokalemia, leg edema
Dosing:
Combination with calcineurin inhibitors may increase risk of calcineurin inhibitor toxicity
Everolimus, a newer mTOR inhibitor, is presently being studied
Drug interactions: Similar to cyclosporine
Maintenance immunosuppression:
1-6 months: Trough 8-15
>6 months: Trough 6-12

Rabbit antithymocyte globulin (Thymoglobulin):
Class: Polyclonal T-cell antibody
Mechanism: Cytotoxic antibodies directed against various T-cell markers leading to depletion of peripheral blood T-cells
Toxic effects: Fever, rigors, arthralgias, anaphylaxis, thrombocytopenia, leukopenia, delayed opportunistic infection (CMV prophylaxis should always be given), lymphoma
Dosing:
Daily dose must be infused into central vein usually for 7-14 days
Premedication generally given with methylprednisolone, Benadryl, and Tylenol
Doses may be given by RN via IVPB with frequent monitoring of vital signs (q15 min for 1 hr then q hr until infusion complete)

Muromonab-CD3 (OKT3):
Class: Anti-CD3 monoclonal antibody
Mechanism: Antibody directed against T-cell receptor function inhibits T-cell function
Toxic effects: Fever, rigors (common first-dose reaction, should still always consider infections), arthralgias, anaphylaxis, non-cardiogenic pulmonary edema, nephrotoxicity, neurological complications (aseptic meningitis), delayed opportunistic infection (CMV prophylaxis should always be given), lymphoma, coagulopathy, thrombocytopenia, TTP/HUS
Dosing:
Daily dose may be given via peripheral line usually for 7-14 days
Premedication generally given with methylprednisolone, Benadryl, and Tylenol
First few doses must be given by MD in the hospital with frequent monitoring of vital signs (q15 min for 2 hours then q30 min for 2 hours). CD3 levels may be followed
Doses of other immunosuppressives may be lowered
If second course of OKT3, should always check for OKT3 antibodies prior to administration

Intravenous gammaglobulin (IVIG):
Class: Polyclonal Ig produced from pooled plasma of multiple donors
Mechanism: Multiple complex mechanisms involving suppression or elimination of anti-HLA T- and B-cells as well as altered cytokine signaling
Toxic effects: Nephrotoxicity (osmotic mediated ATN from sucrose, maltose, and other additives), hemolytic anemia, dilutional and pseudohyponatremia, headache, fever, chills, myalgia, arthralgia, aseptic meningitis
Dosing:
Daily dose may be given via peripheral line usually for 2-4 days
Premedication generally given with methylprednisolone, Benadryl, and Tylenol
Renal Transplant Rejection Decisions about rejection treatment should be made by the renal transplant fellow and attending
Banff Classification System:
(1) Normal
(2) Antibody-mediated (humoral) rejection: Rejection associated with at least 3 of the 4 following criteria: graft dysfunction, histologic evidence of tissue injury, positive staining for C4d, demonstration of donor specific antibody. This may be concurrent with categories 3, 4, and 5. Histologic types include the following:
Type I: An ATN-like histology, with minimal inflammation
Type II: A capillary glomerulitis, with margination and/or thromboses
Type III: Arterial-transmural inflammation/fibrinoid changes
(3) Borderline changes: Characterized by no intimal arteritis, the presence of foci of mild tubulitis (1-4 mononuclear cells/tubular cross section), and at least 10-25% involvement of interstitium. Findings are suspicious, but not diagnostic, for acute rejection
(4) Acute/active cellular rejection: Histologic types include the following:
Type IA: Significant interstitial inflammation (>25% of parenchyma) and moderate tubulitis (>4 mononuclear cells/tubular section)
Type IB: Significant interstitial inflammation (>25% of parenchyma) and severe tubulitis (>10 mononuclear cells/tubular section)
Type IIA: Mild to moderate arteritis found in at least one arterial cross section
Type IIB: Severe arteritis, which is associated with > 25% loss of luminal area
Type III: Transmural arteritis, and/or arterial fibrinoid alterations, and necrosis of medial smooth muscle cells occurring in association with lymphocytic inflammation of the vessel
(5) Chronic allograft nephropathy: Fibrosis is observed, with or without alloimmune injury. This may be concurrent with categories 2, 3, and 4
Treatment: Varies per protocol and center
Acute cellular rejection, tubulointerstitial type (Banff 4, Type IA or IB):
Pulse methylprednisolone, 3-5 mg/kg for 3-5 days, is first line therapy.
Conversion of maintenance cyclosporine to tacrolimus as well as addition of mycophenolate if not already present
Antithymocyte globulin for steroid resistant or recurrent acute cellular rejection.
Consider muromonab as third-line agent but must weigh potential risks
Acute cellular rejection, vascular type (Banff 4, Type IIA, IIB, or III):
Pulse methylprednisolone along with Thymoglobulin is first line therapy.
Conversion of maintenance cyclosporine to tacrolimus as well as addition of mycophenolate if not already present .
Consider muromonab for steroid resistant or recurrent acute vascular rejection but must weigh potential risks
Acute humoral rejection (Banff 2):
Pulse methylprednisolone along with IVIG is first line therapy
Consider additional antithymocyte globulin if severe acute cellular rejection is also present
Some data regarding use of concurrent plasmapheresis