NEPHROLOGY

Editors: Madison Bandler, Rachel Brown
Reviewed by: Ed Gould, MD and JP Arroyo, MD, PhD

Acute Kidney Injury (AKI)

Authors: Piera Sosa, Rachel Brown

Background:

  • Definition based on 2012 KDIGO Guidelines:
  • Rise in serum creatinine (sCr) ≥ 0.3 mg/dL within 48 hrs or increase ≥ 1.5x baseline in 7d
  • Urine volume <0.5 mL/Kg/H for 6 hours

Stages of AKI:

Based on 2012 KDIGO Guidelines:

Stage Serum Creatinine Urine Output
Stage 1 Increase of ≥ 0.3 mg/dl (≥26.5 μmol/L) or 1.5 - 1.9x baseline < 0.5 ml/kg/h for > 6 hours
Stage 2 2.0 - 2.9x baseline < 0.5 ml/kg/h for > 12 hours
Stage 3 > 3.0x baseline, or increase in serum creatinine to >4.0 mg/dl, or initiation of RRT < 0.3 ml/kg/h for 24 hours or anuria for 12 hours
  • Patients should be staged based on criteria that gives them highest stage (sCr v UOP)
  • Note, risk of need for RRT and risk of death increases with increased stage

Framework for AKI:

Pre-renal/hemodynamic AKI:

  • Volume depletion: GI loss, hemorrhage, burns, critical illness → increased insensible losses
  • Decreased effective circulating volume: cardiorenal, hepatorenal, hemodynamic effects of ACEi/ARB
  • Afferent arteriole constriction: NSAIDs, iodinated contrast
  • Renal vein thrombus
  • Note, when prerenal AKI is prolonged it can lead to intrinsic ATN

Intra-renal: glomerular, tubular, or interstitial diseases

  • ATN = Most common form of intrinsic AKI. Can be ischemic or toxic
  • Toxins: endogenous (e.g. rhabdo) and exogenous (e.g. drugs)
  • Acute interstitial nephritis (AIN): usually drug induced (i.e. NSAIDs, PPIs, beta lactam abx), though can also be secondary to autoimmune disorders (i.e. SLE, Sjögren's)
  • Infection associated – e.g., staphylococcal infections (especially in diabetics), streptococcal infections, legionella)
  • Glomerulonephritis
  • Other causes:
  • Crystalline nephropathy: IV acyclovir, tumor lysis, ethylene glycol
  • Small vessel disease: MAHA, TTP, HUS
  • Large vessel disease: Aortic dissection (leading to renal infarction), renal artery aneurysm or other renal artery abnormality. Note, these would suggest bilateral renal involvement or patient with only one functioning kidney

Post-renal: can occur at any level of the GU system

  • Ureteral: stones, external compression (malignancy, LAD, abscess)
  • Bladder: neurogenic bladder, malignancy, obstructing blood clot
  • Urethra: BPH, prostate cancer, prostatitis
  • In rare instances, retroperitoneal fibrosis
  • Note, when postrenal AKI is prolonged/untreated it can lead to irreversible intrinsic kidney disease

Pre-renal azotemia and acute tubular necrosis comprise the majority of inpatient AKI

Evaluation

  • History (carefully evaluate all medications taken + contrast exposure) and volume assessment (physical exam, CXR, TTE)
  • Labs: CMP, urinalysis, urine protein/Cr ratio
  • 500cc-1L IV fluid challenge: If sCr improves to baseline in <48H then the insult was likely pre-renal. If not, then look for other etiologies
  • Evaluate for obstruction: I/O cath, foley, post void residual >250 cc
  • Renal ultrasound: usually to evaluate for post renal or renal vascular etiologies and not warranted unless any of the following
  • No obvious cause of AKI is identified
  • Abrupt oliguria or anuria (think renal vein thrombus or obstruction)
  • High suspicion for bladder outlet obstruction (PVRs might give you same data)

  • Note, add doppler to evaluate for renal artery stenosis (or if working up resistant hypertension)

  • Urine electrolytes

  • FENa <1% or FEUrea <35% (if on diuretics) suggest pre-renal physiology
    • Not needed in the initial work-up of all patients with AKI. If high suspicion for pre-renal etiology, trial fluid challenge and assess response first
    • Less specific in patients with CKD
  • Urine sodium can be used to assess Na avidity: UNa > 40 suggests ATN and UNa < 20 suggests pre-renal.
  • Urine osmolality can be used as a surrogate marker for Na/volume avidity. If UOsm>SOsm = water retention. Role in AKI in clinical trials still unclear.

Management

All causes

  • Minimize fluctuations in blood pressure
  • Consider holding anti-hypertensive medications, especially ACEi/ARB (remember to determine plan to resume at/after discharge). Note that this hold reflects the uncertainty of hypovolemia as a contributor to AKI, NOT nephrotoxicity.
  • Avoid unnecessary nephrotoxins
  • Dose-adjust medications for changing renal function

Pre-renal

  • True volume depletion: IV volume expansion
  • Cardiorenal syndrome: decongestion/diuresis
  • Hepatorenal syndrome: see Hepatology section for more information

Post-renal

  • Relieve obstruction based on etiology: I/O cath vs foley. Consider involving urology/IR if procedureal intervention is warranted (i.e. urostomy, percutaneous nephrostomy)
  • Monitor for post-obstructive diuresis (see below)

Intra-renal

  • ATN: Supportive care (for rhabdo, see below). Monitor for post-ATN diuresis. If delayed recovery, may need outpatient dialysis
  • Glomerulonephritis: consult AKI service for assistance with biopsy and selecting immunosuppressive agents if needed
  • AIN: review meds, consult nephrology for possible biopsy and recommendations for steroids
  • Infection associated: treat the infection

Monitor for renal recovery

  • Suspect concomitant ATN if sCr decreases with volume expansion, diuresis, or relief of obstruction but remains a few points above baseline

When to consult Nephrology

  • Urgent indication for dialysis (see "Renal Replacement Therapy")
  • Abrupt anuria
  • Cr worsening or urine output inadequate without clear cause
  • Need for kidney biopsy (i.e nephrotic syndrome, RPGN)

Additional information

Rhabdomyolysis: UA positive for blood but no RBCs on microscopy

  • Toxic damage due to myoglobin
  • Serologic markers of muscle injury: elevated CK, AST>ALT with normal ALK Phos
  • Fluids adjusted to urine output goal of 200-300 mL/hr until CK declines (monitor for volume overload while on fluids)
  • Consider isotonic bicarb for initial 1-2L of IVF→ urine alkalinization reduces precipitation
  • Avoid calcium repletion for hypocalcemia unless symptomatic

Post-obstructive diuresis

  • Necessary process to clear accumulated uremic toxins
  • Replace ~50% of urine output to prevent pre-renal azotemia
  • Monitor calcium, phosphorus, and magnesium in severe post-obstructive diuresis

Contrast Induced AKI (CI-AKI)

Authors: Madison Bandler, Alexa Serino

KDIGO Criteria for CI-AKI:

  • sCr increase by 0.5mg/dl or 25% increase in sCr from baseline 48 hours after radiologic procedure where intravenous contrast was administered

Background

  • Mechanism of injury: Direct toxic effect leading to tubular necrosis and indirect effects on renal blood flow leading to medullary ischemia

  • 2024 KDIGO guidelines updated the term from contrast induced nephropathy to contrast associated nephropathy, as the association exists but AKI can be precipitated by various factors including hypotension, atheroemboli, and medications that can coincide with contrast administration

  • When someone develops an AKI do your due diligence and evaluate for the usual causes of AKI, regardless of when they were given contrast

Who is at risk for CI-AKI?

  • Normal kidney function: incidence of CI-AKI is 1-3%

  • Studies show no increase in contrast associated AKI of patient with GFR > 45 ml/min

  • Pre-existing CKD: Incidence of CA-AKI may be as high as 20% in patients with CKD 4-5 (GFR<30 ml/min)

  • GFR <45 ml/min with comorbidities are at intermediate risk

  • Diabetes
  • Reduced intravascular volume (CHF, decompensated cirrhosis, dehydration)
  • Taking nephrotoxic medications

  • Older age

  • Arterial contrast carries a higher risk of CA-AKI than venous contrast

  • High volumes of contrast media and repeated contrast administration within a short period are risk factors

  • No real sCr or eGFR threshold below which iodinated contrast is contraindicated, especially in patients for whom imaging will alter management (e.g. acute stroke, PE, STEMI)

Risk reduction strategies

  • IV fluid repletion: KDIGO guidelines give no clear recommendation for rate or duration for optimal protection, but do recommend IV isotonic crystalloid over oral hydration. No differences in major adverse kidney events with normal saline vs. isotonic sodium bicarb
  • American College of Radiology guidelines recommend the use of intravenous isotonic saline at an infusion rate of 100 ml per hour for 6 to 12 hours before and 4 to 12 hours after angiography.
  • The European Society of Cardiology guidelines suggest a rate of 1 to 1.5 ml per kilogram per hour for 12 hours before and up to 24 hours after the procedure
  • Rate and duration can be decreased based on the risk for hypervolemia
    • POSEIDON trial investigated the efficacy of hemodynamic-guided fluid administration to prevent CA-AKI in patients undergoing cardiac catheterization. This randomized, parallel-group, single-blind trial compared a standard fluid administration protocol with a protocol guided by left ventricular end-diastolic pressure (LVEDP)
    • Both groups received 0.9% isotonic saline at 3 mL/kg for 1 hour before the procedure. The control group continued with isotonic saline at 1.5 mL/kg/hr during and for 4 hours after the procedure. The LVEDP-guided group received isotonic saline at rates adjusted based on LVEDP: 5 mL/kg/hr for LVEDP <13 mm Hg, 3 mL/kg/hr for LVEDP 13-18 mm Hg, and 1.5 mL/kg/hr for LVEDP >18 mm Hg.
    • Incidence of CA-AKI was significantly lower in the LVEDP guided group
  • Typically recommend holding diuretics prior to contrast administration, but if patient is volume up, consider administer diuretic and fluid at a rate that matches urine output

Management

  • Medication management: Consider holding nephrotoxic medications such as NSAIDs, RAAS inhibitors, diuretics, zoledronate, methotrexate etc. in people with AKI or eGFR <30 for 24 hours before and 48 hours after contrast administration

  • Pharmacologic intervention: High-dose statins, with or without N-acetylcysteine (NAC), have shown potential benefits in reducing the incidence of contrast-induced AKI

  • Use low-osmolality or iso-osmolality contrast whenever possible and minimize contrast volume

  • Never delay a necessary procedure or image out of concern for worsening renal function

Iodinated contrast in CKD-5/ESRD patients

  • While hemodialysis can remove contrast media, it is not recommended as a prophylactic measure to prevent contrast-induced nephropathy due to the rapid onset of kidney damage post-contrast administration

  • Avoid giving if you are trying to preserve residual kidney function in ESRD particularly with patients on PD

Gadolinium contrast for MRI

  • The risk of nephrogenic systemic fibrosis (NSF) has been significantly reduced with the use of newer gadolinium based contrast agents (GBCAs) that have a higher binding affinity for free gadolinium, such as group II and III agents.

  • Contemporary studies have not reported any new cases of NSF with the use of these agents, though there remains concern about gadolinium deposition in the brain and a possible systemic syndrome attributed to GBCAs, which warrants consideration of alternative imaging modalities when feasible

  • If a patient with eGFR <30 mL/min per 1.73m² requires contrasted MRI discuss with Nephrology

Approach to Chronic Kidney Disease

Author: Terra Swanson

Definition of CKD

  • Decreased kidney function or one or more markers of kidney damage for 3 or more months
  • History of kidney transplant
  • GFR < 60. Staging helps risk-stratify pts likely to progress or develop complications of CKD
  • CKD IIIa: eGFR 45-60
  • CKD IIIb: eGFR 30-44
  • CKD IV: eGFR 15-30

  • CKD V: eGFR < 15

  • Markers of kidney damage

  • Urine Albumin/Cr ratio
    • Mild: 0-30 mg/g
    • Moderate: 30-300 mg/g
    • Severe: >300 mg/g
  • Urine sediment: RBC casts, WBC casts, oval fat bodies or fatty casts, granular casts
  • Electrolyte derangements
  • Abnormalities on histology
  • Structural abnormalities: cysts, hydronephrosis, scarring, masses, renal artery stenosis

When to refer to Nephrology Clinic

  • eGFR < 45
  • Persistent urine albumin/creatinine ratio > 300 mg/g
  • Urine protein/creatinine ratio greater than 500 mg/g
  • Rapid loss of kidney function (> 30% decline over 4 months)
  • Hematuria not secondary urologic condition or if there are RBC casts on UA
  • Inability to identify presumed cause of renal dysfunction
  • Difficult to manage complications: hyperkalemia, anemia, bone-mineral disease, HTN
  • Confirmed or presumed hereditary kidney disease (PCKD suspected)

Complications of CKD

Imbalance of water homeostasis

  • As renal mass declines, the ability to both concentrate and dilute the urine is impaired
  • This manifests as hyponatremia (no end-organ to respond to ADH) and edema
  • Treat this with water restriction, diuretics or, eventually, ultrafiltration

Chronic NAGMA in CKD

  • Some data support that correcting serum bicarbonate slows decline in renal function and protects against bone-mineral complications of chronic metabolic acidosis (bone breakdown is an alternate buffer that the body uses in chronic acidemia)
  • Current KDIGO guidelines recommend bicarb goal 18. However, practice patterns vary. For instance, Dr. Gould starts repletion if bicarb <20 on 2 consecutive BMPs in the outpt setting.
  • Sodium bicarb 650 mg TID (8mEq bicarb per 650mg tablet) up to 5850mg/day (70 mEq or 3 tabs TID)
  • Sodium citrate (Bicitra): 1mL = 1 mEq * Careful in cirrhosis since citrate cannot be metabolized
  • Baking soda (sodium bicarbonate): 1 teaspoon = 59 mEq HCO3 (careful of Na load)

HTN in CKD

  • Goal BP < 120/80 (Class 2B recommendation) based on SPRINT trial, ACC/AHA 2017, and KDIGO 2021 guidelines
  • All comers: diet (e.g. DASH) and lifestyle modifications
  • CKD without albuminuria or DM:
  • Start pharmacotherapy based on ASCVD risk as well as risk for other target organ damage
  • CKD with moderate to severe albuminuria w/ or w/out DM
  • ACEi or ARB titrated to maximally tolerated dose (Class 1B recommendation)
  • Thiazide-like diuretics (see CLICK trial for chlorthalidone in advanced CKD)
  • Loop diuretics can assist with volume driven HTN in patients with CKD 4-5
  • HTN in kidney transplant
  • CCBs or ARBs are first line (Class 1C recommendation)
  • Consider stopping ACE-i/ARB if:
  • GFR declines >30% over 4 months. Consider evaluation for renal artery stenosis
  • K > 5.5 despite low K diet, optimizing dose of diuretics, or adding K-binders

Anemia in CKD

  • Multifactorial: decreased EPO production, impaired iron absorption, uremic toxins suppressing bone marrow, loss of blood in dialysis circuit, and from GI AVMs

  • Indications for iron supplementation in non-dialysis patients

  • ALL patients with TSAT <20% and ferritin <100 ng/mL

  • Patients with Hb <13 and TSAT <30% and ferritin <500 ng/mL

    • Can start with PO supplementation (see Anemia section). Reassess iron levels in 1-3 mos; if not appropriately ↑, consider IV iron repletion

  • Dialysis patients

  • IV iron preferred method of repletion for HD patients with
    • TSAT < 20% and ferritin < 200
    • TSAT <30% and ferritin <500 AND with Hb < 10 OR are on EPO
  • Dosing: usually administered at HD sessions
    • 125 mg ferric gluconate at consecutive HD sessions x 8 doses
    • 100 mg iron sucrose at consecutive HD sessions x 10 doses
    • Ferumoxytol 510mg at the end of two HD sessions 1-4 weeks apart
  • Indications for EPO
    • Pts with Hb <10 who are not iron deficient (ferritin >500) or whose anemia persists despite adequate iron repletion

Hyperkalemia (Goal K < 5.5)

  • Patients with diabetic nephropathy (T4 RTA) and CKD 5-ESRD are at the highest risk

  • Strategies to mitigate hyperK

  • Low K diet (< 40-70 mEq/day or 1500-2700 mg/day)
  • Loop diuretics
  • GI cation exchangers
    • Patiromer (Veltassa): binds K in colon in exchange for calcium
    • Sodium zirconium cyclosilicate (Lokelma): binds K throughout intestine in exchange for sodium and H+
    • Sodium polystyrene sulfonate (Kayexelate): binds K throughout intestine in exchange for sodium; do not use as chronic therapy due to risk of intestinal ischemia/necrosis
  • Treat metabolic acidosis

Mineral bone disease in ESRD

  • Avoid calcium supplementation in mild or asymptomatic hypocalcemia
  • Replace vitamin D to >20 (weak evidence)
  • Phos goal < 5.5
  • Sevelamer: use lowest dose effective to achieve Phos < 5.5
    • Phos 5.5-7.5: initial dose 800 TID with meals
    • Phos 7.5-9.0: initial dose 1200-1600 TID with meals
    • Phos > 9: initial dose 1600 TID
    • Can titrate dosing by 400 to 800 mg per meal at 2-week intervals
  • Restrict dietary phos to 900 mg/day
  • PTH goal in CKD3: 2x ULN
  • PTH Goal in ESRD: 2-10x ULN

Diabetes in CKD

  • Individualize A1C goals. Both the ADA and VA-DOD have guidelines for selecting A1C targets

  • Treatment

  • Metformin remains first-line but should be dose-reduced based on eGFR
    • eGFR > 45: Maximum daily dose of 2000mg/day (1000mg bid)
    • eGFR < 45: Reduce max daily dose to 1000mg/day (500mg bid)
    • eGFR < 30: Discontinue if high risk for volume mediated AKI/chronically ill
  • SGLT-2 inhibitors for patients with eGFR >25 reduces progression to ESRD and death from renal or cardiovascular causes (Evidence: DAPA-CKD, EMPA-KIDNEY, CREDENCE)
    • Expect a GFR decline of up to 30% after initiation
  • Finerenone (non-steroidal MRA): initiate if eGFR >25 and UACR > 30 on maximally tolerated ACEi/ARB + SGLT2i (and pt is not already on other MRA for other indication). Check K in 2 weeks (Evidence: FIDELIO)

Dialysis initiation

  • Early (CKD3a or 3b) referral to Nephrology has better outcomes
  • Uremic symptoms: fatigue, sleep disturbance, n/v, decreased appetite, dysgeusia, itching, hiccupping
  • Refractory hyper K
  • Refractory hypertension
  • Plot your patient's eGFR using the graph function in EPIC or CPRS to determine trajectory (normal age-related decline after age 60 is ~ 1ml/min/m²)

Renal Replacement Therapy (RRT) Basics

Author: Daniel Motta

Background/Terminology

  • Dialysis (diffusive clearance): solutes diffuse down concentration gradients through a semipermeable membrane separating blood and dialysate

  • Dialysate (dialysis bath): electrolyte solution used to create concentration gradient for dialysis. Customizable to treat specific electrolyte and acid-base derangements

  • Effluent: fluid removed during dialysis or ultrafiltration

  • Ultrafiltration Hydrostatic pressure "pushing" water through a membrane. There is no dialysate solution used during ultrafiltration. There is some associated cponvective clearance, as solutes are removed via solvent drag. The effluent in this case is isotonic to plasma.

  • Total ultrafiltration (UF): overall ultrafiltration volume produced during treatment

  • UF net: net ultrafiltrate volume removed from the patient by the machine. The overall volume can be completely replaced (net even), partially replaced, or not replaced at all. UF net is the difference between UF and the volume replaced in the circuit

  • Timing of dialysis: There are several studies in this space (IDEAL, IDEAL-ICU, AKIKI, STARRT, ELAINE). In both the outpatient and the inpatient setting, there is no compelling evidence that early start dialysis improves mortality compared to later starts

Outpatient modalities

  • Intermittent hemodialysis (iHD)
  • In home hemodialysis
  • Peritoneal dialysis (PD)

If someone with ESRD is admitted

  • Urgent ESRD consult if acute need (AEIOU), otherwise can consult them routinely
  • Routine orders include MWF phos checks and a renal diet
  • For PD patients, their diet can be more liberal and include low phos only or even regular diet (Can just ask what diet he/she follows at home)

Acute Setting

Indications (AEIOU): AKI leading to life-threatening changes in fluid, electrolyte, and acid-base balance or toxic ingestion

  • Acidosis: severe metabolic acidosis (serum pH<7.1) refractory to correcting volume status or other electrolyte derangements

  • Electrolytes: severe hyperkalemia >6.5 despite medical management (e.g. loop diuretics, IV fluids, GI cation exchangers, correcting acidemia, etc.)

  • Intoxication: dialyzable toxins and medications

  • Alcohols: ethylene glycol, methanol, isopropyl alcohol, diethylene glycol, and propylene glycol

  • Medications: lithium, salicylates, valproic acid, phenytoin, barbiturates, carbamazepine, vancomycin, aminoglycosides, etc.

  • Overload: Severe fluid overload (e.g. pulmonary edema) refractory to diuretics

  • Uremia: uremic complications include encephalopathy, pericarditis, platelet dysfunction

  • Can perform furosemide stress test to help predict who is likely to recover kidney function

  • If Lasix naïve, administer 1mg/kg as a bolus. If on a loop diuretic, administer 1.5 mg/kg as a bolus
  • If within the hour they have made 200 cc of urine, then they are likely to regain kidney function

Modalities

  • iHD: Ideal for removal of toxins (e.g. alcohols, dialyzable meds). Use with caution in hypotensive patients

  • CRRT: Set a rate of volume removal (typically 0-200 cc/hr)→ less rapid fluid/electrolytes shifts→ better tolerated in patients with hemodynamic instability

  • Anti-coagulation options to prevent clotting of circuit
    • None
    • Heparin (preferred). Can be either within the circuit or systemic if indicated for another reason (e.g. DVT/PE)
    • Citrate (need to monitor calcium frequently)
  • Complications of CRRT: infections, hypophosphatemia

Access

  • Dialysis catheter (aka: Vascath)
  • Non-tunneled catheter (Trialysis) used for acute dialysis

  • Different lengths depending on site (see procedures section)

  • Tunneled dialysis catheter (ex: Permcath)

  • Typically used as a bridge to fistula/graft placement
  • Placed by IR

Peritoneal Dialysis Peritonitis

Background

  • Typically occurs due to contamination with pathogenic skin bacteria during exchanges or due to exit-site/tunnel infection

  • Usually presents with cloudy effluent fluid and abdominal pain. Can also be asymptomatic

  • Important history to obtain: recent contamination, accidental disconnection, endoscopic or gynecologic procedure, as well as the presence of constipation or diarrhea

  • Definitive diagnosis requires 2 of the following:

  • Clinical features consistent with peritonitis, Positive dialysis effluent culture, Dialysis effluent with WBC > 100 with PMN > 50%

Evaluation

  • Examine catheter exit site
  • Culture peritoneal fluid (requires specific technique, done by Nephrology)
  • Peritoneal cell count with diff, gram stain and culture
  • Obtain peripheral blood cultures if there is concern for sepsis

Management (requires Nephrology involvement)

  • All PD orders, intraperitoneal antibiotics, and prescription adjustments should be directed by ESRD consult service (page them overnight if concerns)

  • Treatment with intraperitoneal antibiotics should be started immediately after specimens have been obtained if there is high clinical suspicion

  • Empiric antibiotics regimen should cover both gram-positive and gram-negative organisms, typically with Vancomycin and third generation cephalosporin

  • Systemic antibiotics are generally not necessary unless pts have systemic signs of sepsis

  • Patients with relapsing, recurrent or repeat peritonitis will likely need catheter removal

Secondary prevention

  • Treatment with intraperitoneal OR IV antibiotics (for any infection requiring > 1 dose of antibiotics) requires prophylaxis for fungal peritonitis with either
  • Nystatin 400,000 to 500,000 units orally TID

  • Fluconazole 200 mg every other day or 100 mg qdaily

  • Dialysate should be drained the day of endoscopies or gynecological procedures

Intravenous Fluids

Author: Chandler Montgomery

Indications for IV fluid

  • Restoration or maintenance of tissue perfusion
  • Correction of electrolyte abnormalities
  • Nutritional supplementation in those without reliable enteric access

Categorized into crystalloids and colloids

  • Crystalloid = water + electrolytes
  • Colloid = water + proteins/large molecules

Terms

  • Osmolality: osmoles of solute per L of solution
  • Tonicity: ability to induce movement of water across a membrane (i.e., effective osmolality)
  • Buffer: anions such as lactate, acetate, gluconate which are metabolized to bicarbonate in vivo with the goal of sustaining normal plasma pH

Crystalloids

  • Isotonic fluids used for volume resuscitation

  • After ~ 30 mins, redistribute such that only 25% remains w/in intravascular space

  • Balanced solutions (e.g. Lactated Ringer's [LR], Plasma-Lyte)= have electrolytes concentrations similar to plasma

  • NS may lead to renal vasoconstriction, AKI, hemodynamic instability, increased mortality

    • SMART and SALT-ED: balanced solutions had lower rates of death, new renal replacement therapy, or persistent renal dysfunction compared to NS

  • Situations where NS may be preferred

  • Cerebral edema/traumatic brain injury
  • Hypovolemic hyponatremia

  • Pre-existing hypochloremic metabolic alkalosis (e.g. after vomiting or over diuresis)

  • Notes on LR

  • The small amount of K in LR (~4 mEq/L) is unlikely to significantly exacerbate hyperkalemia
  • Lactate in LR is sodium lactate. No hydrogen ions are being added to plasma

Common crystalloid solutions

Fluid Na Cl K Ca Mg Glucose Buffer Osmolarity Tonicity
Plasma ~140 ~100 ~4 ~2.4 1.0 ~0.85 Bicarb ~24 ~290 NA
Normal 0.9% saline 154 154 0 0 0 0 0 308 Isotonic
Lactated Ringer's 130 109 4.0 2.7 0 0 Lactate 28 273 Isotonic
Plasma-Lyte/ Normosol 140 98 5.0 0 3.0 0 Gluconate 23
Acetate 27		 295 Isotonic
D5W + 150 mEq HCO3- 150 0 0 0 0 50 Bicarb 150 300 Isotonic
3% Saline 513 513 0 0 0 0 0 1026 Hypertonic
D5W 0 0 0 0 0 50 0 252 Hypotonic

Colloids

  • Albumin: extracted from human plasma
  • 5%: use after plasma exchange

  • 25%: more concentrated; raises oncotic pressure and restores intravascular volume

    • Uses: post-LVP, diagnosis and treatment of hepatorenal syndrome, SBP (see Hepatology section)
    • Evidence base for use outside of above indications is poor (SAFE trial)

  • Blood products: packed RBCs, FFP, cryoprecipitate

Acid-Base

Authors: Ned Hardison, Trey Richardson

Background

  • Abnormal serum H+ concentrations lead to impaired cellular function (cardiac arrest, vasodilation, decreased response to catecholamines), electrolyte abnormalities (e.g. hypo- and hyperkalemia, hypo- and hypercalcemia), impaired glucose metabolism, impaired drug metabolism, and other complications that translate to increased morbidity and mortality

  • ABG/VBG reference ranges

  • pH = 7.36-7.44 (~7.32-7.40)
  • PCO2 = 36-44 mmHg
  • pO2: 60-100 mmHg

  • HCO3 = 22-26 mEq/L

  • Useful formulas

  • pH on ABG = VBG pH + 0.035
  • Anion Gap= Na-(Cl+Bicarb), normal = 12-14
  • Calculated Osmolarity= 2[Na]+ ([Glucose]/18) + ([BUN]/2.8)
  • Osmolar gap= Measured osmolarity – Calculated osmolarity
  • Winter's formula for respiratory compensation for AGMA: expected pCO2 = 1.5 (serum bicarb) +8 ± 2
    • Shortcut: Expected pCO2 = last two digits of pH

General Approach to Acid-Base Derangements

  1. Determine if the patient is acidemic or alkalemic (look at the pH)
  2. Determine the primary disorder (metabolic or respiratory)
  3. Calculate anion gap (see section below)
  4. Is there appropriate compensation?
  5. Evaluate for secondary disorders

Anion Gap Metabolic Acidosis (AGMA)

Background

  • Na+ is the predominant cation in normal plasma. Cl- and HCO3- are the predominant anions. There are anions that are not directly measured (e.g. most binding globulins, immunoglobulins, clotting factors, and other proteins). These unmeasured anions are responsible for the normal anion gap of ~12 meq/L. When there are extra unmeasured anions within the plasma, the anion gap increases

Differential

  • GOLDMARK: Glycols, oxyproline (acetaminophen metabolite), L-lactate, D-lactate, methanol, ASA, renal failure/uremia, ketoacids

Evaluate for secondary disorders

  • Corrected bicarbonate
  • Corrected HCO3 = patient's HCO3 + (patient's anion gap - 12)
    • Corrected HCO3 > 26, coexisting metabolic alkalosis,
    • Corrected HCO3 < 22 coexisting non-AG metabolic acidosis

Osmolar Gap

  • If there is an anion gap, it is worthwhile to always calculate an osmolar gap. You will be surprised the number of toxic ingestions you catch this way

Non-Anion Gap Metabolic Acidosis (NAGMA)

Differential

  • HARDUP: hyperalimentation (starting TPN), acetazolamide use, RTA, diarrhea, uretosigmoid fistula, pancreatic fistula

  • There are two places from which people can waste bicarbonate- the kidneys and the gut

  • The urine anion-gap, which corresponds to unmeasured urinary NH4+ (primary means of renal acid excretion), can differentiate between the two.

  • Urine anion gap (only useful In setting of NAGMA) = Unmeasured cations (NH4+) – unmeasured anions = UNa + UK – UCl

    • Positive value ◊ low NH4+ ◊ renal losses
    • RTA
    • Carbonic anhydrase inhibition: acetazolamide, topiramate
    • Adrenal insufficiency
    • Normal saline infusion
    • Ne-GUT-ive value ◊ high NH4+ ◊ kidneys working appropriately ◊ GI losses
    • Diarrhea
    • Pancreatic fistula
    • Ureterosigmoidostomy

  • Caveat: Proximal RTA has a normal distal urine acidification and has a negative urine AG

Managing Metabolic Acidosis

  • Lactic acidosis is the most common cause AGMA that we encounter

  • In general, avoid use of bicarbonate to treat lactic acidosis

  • Remember: H+ + HCO3- <-> H2CO3 <-> H2O + CO2. While administering bicarbonate will transiently improve pH, carbonic acid will eventually form and ultimately worsen acidemia

  • In acute NAGMA, reasonable to give bicarbonate when bicarb <12 or pH <7.1-7.2

  • Pay close attention to other electrolyte levels, especially K+ as it shifts back into cells

Metabolic Alkalosis

Background

  • Metabolic alkalosis occurs as a primary disorder or as compensation for respiratory acidosis. A thorough history and exam can usually clarify which of these two scenarios is occurring

  • In order for metabolic alkalosis to occur, there has to be both an inciting phase (e.g. volume depletion) and a maintenance phase (e.g. hypochloremia or hypokalemia)

Presentation

  • Most symptoms of metabolic alkalosis (confusion, nausea, vomiting, tremors) occur as a result of other electrolyte abnormalities (hypocalcemia, hypokalemia)
  • Serum pH of >7.55 is likely the threshold where symptoms will develop

Causes

  • Saline responsive (e.g. hypochloremia)
  • True volume depletion
  • NG suction/nausea/vomiting

  • Diuretic use

  • Saline refractory

  • Hypokalemia
  • Milk-alkali syndrome
  • Mineralocorticoid excess states
  • Bartters syndrome
  • Gitelman's syndrome

Treatment

  • Saline responsive/hypochloremia
  • If volume deplete, then normal saline is treatment of choice

  • If alkalosis develops in setting of diuresis, then make sure replacing KCl and consider acetazolamide

  • Saline refractory

  • Hypokalemia: replenish potassium stores
  • Hyperaldosteronism: see Endocrinology section for more detail
  • Bartter syndrome and Gitelman syndrome: replace electrolytes and refer to Nephrology

Electrolytes

Hypercalcemia

Authors: Trevor Stevens, Madison Bandler

Evaluation

  • Total serum calcium >10.5 (normal 8.5-10.5g/dl)

  • Most (99%) Ca2+ is anhydrous and stored in bone.

  • The remaining 1% is 60% bound (mostly to albumin) and 40% ionized and able to exert a physiologic effect

  • There is an inverse relationship between pH and free Ca2+. As pH declines, serum Ca increases due to H+ binding to albumin and releasing Ca2+

  • Don't forget to correct calcium level if hypoalbuminemia (or check ionized calcium level)

  • Corrected Ca2+ = ((Normal albumin – Patient's albumin) x 0.8)) + Patient's Ca2+

  • It is not unusual to have pseudohypercalcemia in the setting of dehydration due to an increased concentration of albumin, in which case ionized calcium would remain normal

  • Hypercalcemia of malignancy may occur through multiple mechanisms:

  • Osteolytic lesions (as in multiple myeloma or bony metastatic disease)
  • Activation of vitamin D (as in lymphoma)
  • PTHrP mediated (most commonly squamous cell carcinoma of lung, head and neck/renal and bladder cancer/breast and ovarian cancer)

Presentation

  • Ca2+ > 12 can cause shortened QT interval, 2nd and 3rd degree heart block, ventricular arrhythmias, and ST elevations mimicking MI
  • Severe manifestations uncommon at Ca2+ < 14
  • "Stones, bones, thrones, belly groans, and psychiatric overtones"
  • Bone pain, Polydipsia/polyuria: due to nephrogenic DI, Nausea/constipation, Depressed mood/cognitive impairment, Decreased level of consciousness

Physical Exam

  • Examine mucous membrane dryness
  • Eye exam for band keratopathy or corenal degeneration from calcium deposits if chronic
  • Skin exam for calcinosis cutis
  • GI exam for abdominal tenderness
  • MSK exam for bone pain, especially along spine
  • GU exam for CVA tenderness suggestive of kidney stones

Labs & Imaging

  • PTH level can help distinguish between PTH-dependent and PTH-independent causes of hypercalcemia

  • Normal or ↑ PTH

    • Primary hyperparathyroidism: ↑ Ca+2 and ↓ PO4-3
    • Tertiary hyperparathyroidism (autologous secretion of PTH in CKD/ESRD)
    • Familial hypercalciuric hypercalcemia (often asymptomatic, no treatment required)
    • Li toxicity

  • ↓ PTH

    • Humoral hypercalcemia of malignancy (PTHrP)
    • Malignancy (boney metastases)
    • Excess vitamin D intake
    • Granulomatous disease: 1,25-dihydroxy vitamin D, 25-hydroxyvitamin D, or ACE level
    • Milk-alkali syndrome
    • Medications (classically HCTZ)
    • Thyrotoxicosis
    • Adrenal insufficiency

  • Serum phosphate, creatinine, and alkaline phosphatase levels to assess renal function and bone turnover

  • Remember- phosphorus should be lower end of normal if hypercalcemia is PTH dependent

  • Serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels can help identify vitamin D-related causes of hypercalcemia, such as vitamin D intoxication or granulomatous diseases

  • 24-hour urinary calcium excretion helps differentiate primary hyperparathyroidism (PHPT) from FHH. In PHPT, urinary calcium excretion is typically normal or elevated, whereas it is low in FHH

  • Imaging studies, such as neck ultrasound or Tc-sestamibi scan may be indicated to localize parathyroid adenomas in cases of primary hyperparathyroidism

  • Bone density measurement, particularly at the distal third of the radius, and renal ultrasound to detect nephrolithiasis or nephrocalcinosis

Management

  • If Ca+2 < 12 and asymptomatic
  • Encourage PO hydration
  • Normal saline if hypovolemic
    • NS provides a higher sodium load that LR
    • Sodium delivery to the distal tubule enhances calcium clearance by the kidneys

  • Evaluate for underlying cause

  • If Ca+2 > 12 with symptoms or Ca > 14

  • Trend Ca q8 hrs, EKG, monitor on telemetry; strict I/Os ± foley catheter
  • Volume expansion with NS bolus followed by continuous infusion at ~ 200cc/hr
    • Goal UOP 100-150cc/hr
  • Add loop diuretic (Lasix) once patient is volume expanded

  • Bisphosphonates

    • Zoledronic acid 4mg IV (EGFR >60) given over 15 minutes normalized calcium in 80-90% of patients over 48-72 hours, with a median treatment duration of 30-40 days.
    • Pamidronate 90mg IV (EGFR 15-60) given over 2 hours normalizes calcium in 60-70% of patients over 48-72 hours, with a median treatment duration of 11-14 days

  • If Ca+2 >14 or neurologic symptoms, consider subq (not intranasal) calcitonin

  • VUMC: requires approval from an oncology or endocrine attending

  • Tachyphylaxis after ~48H

  • If etiology of hyperparathyroidism is due to primary hyperparathyroidism, indications for parathyroidectomy include:

  • Age <50
  • Calcium level >1mg/dL above ULN
  • Renal dysfunction
  • Kidney stones or high risk of kidney stones
  • Fragility fractures or osteoporosis

Additional Information

  • CHF: consider early addition of a loop diuretic, especially if volume overloaded
  • ESRD with hypercalcemia (rare), oliguric AKI not responsive to IVF, or severely elevated Ca 16-18: consult Endocrine and Nephrology early
  • Sarcoidosis or lymphoma: consider glucocorticoids

Hypocalcemia

Author: Trey Richardson

Background

  • Can be divided into low PTH and high PTH states

  • Low PTH

    • Magnesium deficiency
    • Post-operative for parathyroidectomy
    • DiGeorge syndrome
    • Medications: bisphosphonates, denosumab, aminoglycosides, gadolinium
    • Infiltrative disease: sarcoid, hemochromatosis, malignancies
    • Autoimmune hypoparathyroidism
    • CRRT (if using regional citrate anticoagulation)

  • High PTH

    • Late-stage CKD
    • Hyperphosphatemia
    • Vitamin D deficiency
    • Alkalemia (Serum Ca is inversely proportional to pH)
    • Pseudohypoparathyroidism/Parathyroid resistance
    • Consumption/deposition: pancreatitis, rhabdomyolysis, some osteoblastic metastases
    • Sepsis or critical illness

Presentation

  • Chvostek (facial muscle twitching), Trousseau's sign (carpopedal spasm) , laryngospasm, seizures, widened QRS and arrhythmias
  • Hemodynamic instability

Evaluation

  • Check PTH, albumin, iCal, VBG, Vitamin D
  • Review medications for possible offenders

Management

  • Under most circumstances there is no need to replace calcium. Instead, focus on correcting the underlying perturbation (e.g. acidemia, hypomagnesemia, treating pancreatitis, etc. )

  • If hemodynamic instability, cardiac electrical instability, or seizures, then aggressive intravenous replacement is warranted.

  • Also consider preemptive repletion for patients requiring high-volume of blood transfusions (citrate in blood products can cause hypocalcemia)

  • 1 g of CaCl is equivalent to 3 grams of Ca Gluconate

  • Avoid treatment in hyperphosphatemia, advanced CKD/ESRD, and rhabdomyolysis

Hypernatremia

Author: Lauren Chan

Overview of dysnatremias

  • Fluctuations in serum Na reflect fluctuations in plasma free water
  • Sodium is the major driver of tonicity. The clinical signs and symptoms of serum Na fluctuations are related to changes in tonicity with most profound effects on cerebral tissue
  • Two major mechanisms maintain plasma osmolarity between 275 and 290: Thirst and secretion of ADH. When these mechanisms malfunction, dysnatremias occur

Background

  • Definition: Na+ >145
  • Hypernatremia = decreased free water
  • Almost always due to inadequate free water intake (ICU patients, dementia, limited mobility, tube feeding/TPN, impaired thirst/adipsia from hypothalamic stroke). Hospital acquired hypernatremia is iatrogenic and correlates with poor outcomes
  • Can also occur from: Na+ overload (salt poisoning, iatrogenic from NS infusion, over correction), osmotic diuresis (hyperglycemia, SGLT-2 inhibitors, urea, mannitol), diabetes insipidus

Presentation

  • Lethargy, irritability, confusion
  • Seizures, coma, hemorrhagic stroke, or subarachnoid hemorrhage (from the effects of hypertonic serum on cerebral vasculature)

Evaluation

  • Step 1: Treat underlying cause (vomiting, hyperglycemia, medications)
  • Step 2: Determine volume status. If severely hypovolemic, the patient will need IV crystalloid to restore volume in addition to free water
  • Step 3: Estimate and replace free water deficit (FWD):
  • FWD = TBW x [(serum Na/140) - 1]
  • Step 4: Account for ongoing insensible losses and electrolyte free water clearance

  • Rule of thumb for accounting for electrolyte free water clearance. This is in addition to replacing free water deficit

    • 0-1 Liter of urine output: ignore, no need to replace
    • 1-3 Liters of urine output: replace half of the losses
    • More than 3 liters of urine output: replace all urine losses

  • No evidence that overcorrecting hypernatremia is harmful. In fact, there is increased mortality with overly cautious correction or under correction

  • If able, replace free water enterally. Otherwise, administer D5W intravenously

Additional Information

  • Suspected DI: Consult Nephrology (may require desmopressin or may receive desmopressin once stabilized to differentiate between central and nephrogenic DI)
  • Hypokalemia: giving K decreases total amount of free water you are giving the patient

Hyponatremia

Author: Lauren Chan

Background

Definition:

  • Mild: Na+ 130-134
  • Moderate: Na+ 125-129
  • Severe: Na+ <125

Hyponatremia occurs when free water reabsorption (i.e ADH is on) or intake exceeds free water excretion

Presentation

  • Mild to moderate symptoms: lethargy, N/V, dizziness, confusion, fatigue, cramping
  • Severe symptoms: obtundation, coma, respiratory arrest, seizure

Evaluation and Management

Step 1: Serum osm

>295: Hyper-osmolar - presence of other molecules that contribute to serum osmolarity - Glucose, mannitol, iodinated contrast - If hyperglycemic, corrected serum Na+ = measured Na+ + 1.6*[(glucose – 100)/100] - If corrected Na+ is normal, treat hyperglycemia; not a water balance problem - If corrected Na+ is low, there is hypotonic hyponatremia + coexisting hyperglycemia - Renal failure (urea) and ethanol: Ineffective osmoles that can freely diffuse across cells and do NOT lead to hyponatremia

275-295: Iso-osmolar - Pseudohyponatremia due to hypertriglyceridemia, paraproteinemia, or lipoprotein X: Serum Na not actually low, due to how the lab is calculated

<275: Hypo-osmolar → step 2

Step 2: Urine osm

Surrogate for ADH activity

Uosm <100 or Uosm < Sosm - correlates with low ADH (the body is appropriately trying to get rid of water so ADH is appropriately suppressed) - Primary polydipsia: free water intake>output - Tea and toast: lack solute to effectively concentrate urine - Beer drinkers' potomania: mixture of the two above

Uosm >100 or Uosm > Sosm - correlates with high ADH → Step 3 (the body is retaining water, so ADH is elevated)

Step 3: Urine Na

Is ADH on in the setting of decreased effective arterial blood volume (EABV) or decreased mean arterial pressure (i.e. appropriate ADH)?

UNa <20: Low EABV → RAAS upregulation with Na avidity → appropriate ADH release - If true volume depletion, then trial 500cc-1L NS bolus and monitor serum Na. IVF bolus → increase EABV → decrease ADH release → ↑ free water excretion - If edematous state (e.g. heart failure or cirrhosis), then decongestion with diuretics may improve serum Na

UNa >40: euvolemic with no stimulus for ADH → SIADH - SIADH from: n/v, malignancy, meds, surgery, pulmonary disease, hormones, pain, bladder distension: → ADH out of proportion to stimulus - Treat with water restriction. Can add NaCl or urea tabs if fluid restriction is severe - Water restriction (L/day) = 600 / uosm (600 mEq Na in American diet/day) - Salt wasting: diuretics, cerebral salt wasting (aka hypovolemic SIADH), SSRIs - Get a Chest Xray – look for treatable pulmonary etiologies (effusions, pneumonia etc.) - Other: hypothyroidism, adrenal insufficiency

If still stumped, can check a FeNa and measure a serum uric acid - FeNa <0.5 % suggests appropriate ADH activity - High uric acid suggests some degree of volume depletion and appropriate ADH activity

Rate of correction

Acute (<48 hrs)

  • If symptomatic, give 150 cc bolus 3% NaCl up to two times
  • Monitor Na+ q1-2 hr
  • Goal is an initial rapid 4-6 mEq/L correction and then hold
  • May require Hypertonic Saline infusion with DDAVP clamp if at risk of over-correcting

Chronic (>48 hrs or unknown, higher risk for osmotic demyelination if corrected too quickly):

  • Goal Na+ correction rate 4-6 mEq/L over 24 hrs (Max 8mEq/L)

When to call Nephrology

If you are worried about rapid over-correction

High risk patients are those with rapidly reversible causes: - Low solute states (Beer drinker's potomania, psychogenic polydipsia, tea-toast) as soon as they decrease their excess free water intake, they will rapidly clear free water - Volume depletion: As volume is replaced and the stimulus for ADH release is switched off, then patients will rapidly clear the excess free water if they have normal underlying kidney function

High risk for ODS includes chronic liver disease, Na <105 meq/dL, alcoholism, and malnutrition

Consideration of DDAVP clamp

Hyperkalemia

Author: Mengyao Tang, Amanda Morrison

Background

Causes:

  • Cellular shifts: acidemia, rhabdomyolysis, TLS, beta blockade
  • Aldosterone deficient states: T4 RTA, primary adrenal insufficiency
  • Decreased distal tubular delivery: volume depletion
  • Decreased clearance: AKI, CKD, ESRD
  • Excessive intake
  • Medication-related: ACEi, ARB, MRA, NSAIDs, TMP/SMX, digoxin, heparin
  • Pseudo-Hyperkalemia: hemolysis, severe leukocytosis

Symptoms are rare, but usually manifest as cardiac dysrhythmias

Evaluation

  • Confirm hyperkalemia with repeat BMP
  • Check EKG for hyperkalemic changes (sensitivity for EKG findings in hyper K is poor)
  • K+ 5.5-6.5: peaked T waves, prolonged PR interval
  • K+ 6.5-8: prolonged QRS, loss of P wave, ST elevation, ectopic beats
  • K+ >8: sine wave pattern, asystole, PEA, VF

Management

If EKG changes or signs of instability

  • Calcium gluconate 1g IV (effective within 3-5 min)
  • Stabilizes cardiac membrane for ~60mins
  • SHOULD BE REPEATED HOURLY while hyperkalemic

Shift K+ (temporizing measures)

  • D50 with regular insulin 10 units (can order using Adult Hyperkalemia order set in Epic)
  • Use 5 units if there is renal impairment
  • Lasts for 4-6hrs (can be longer in renal impairment)
  • Correct acidosis: consider using isotonic bicarb
  • Beta agonists (e.g. high-dose albuterol nebulizer); lasts 2-4 hrs
  • Note that typical albuterol nebulizer is 2.5mg, need 10-20mg to have an effect

Increase K+ excretion

  • Loop diuretic: if the kidneys work, use them
  • If there is AKI or a volume deficit can administer with IVF
  • Volume expansion with IVF: increases distal Na delivery and K excretion. NS and LR are likely equally effective
  • GI cation exchangers
  • Kayexalate (Polystyrene sulfonate): only effective if having BMs. 60g PO q2h until bowel movement (If using oral, ensure patient is having bowel movements and is not obstructed, could cause bowel injury/ necrosis). PO can take up to 6hrs to work. Consider per rectal administration for faster action but DO NOT GIVE WITH SORBITOL per rectum
  • Lokelma (Sodium-zirconium-cyclosilicate) 10 g PO TID for 48 H. Actively exchanges K for Na within the small bowel and works within 2 hours. Remember to stop once the K is normal since can cause hypokalemia. Also keep in mind the high Na content of Lokelma (400mg/5g dose of lokelma). Valtessa (Patiromer) Is an alternative, though not on VUMC Inpatient formulary
  • Hemodialysis: Consult Nephrology early if severe hyper K+

Hypokalemia

Author: Peter Thorne, Patrick Steadman

Background

  • Potassium (K+) < 3.5 mEq/L
  • 98% of total body K+ is intracellular (majority in muscle cells)
  • Goal: prevent life threatening complication (e.g. arrhythmia), replace deficit, elucidate cause
  • Insulin and catecholamines (beta adrenoreceptors) are key drivers of transcellular shifts
  • H+ and K+ will trade places to maintain electroneutrality

Presentation

  • Malaise, weakness, myalgias, decreased gastrointestinal motility
  • EKG changes:
  • Mild: ST segment depression, decreased T wave amplitude
  • Severe: U-waves (most commonly seen in precordial leads V2 and V3)
  • Severe hypokalemia can lead to rhabdomyolysis

Evaluation

  • History: decreased K+ intake, increased entry into cells (e.g. elevated beta-adrenergic activity, hypothermia), GI losses, urinary losses (diuretics, hypomagnesemia, RTA, tubular defects, hyperaldosteronism)
  • If concomitant metabolic alkalosis: Normal/low BP suggests diuretic use, vomiting or Gitelman/Bartter syndromes
  • Hypertension suggests renovascular disease or primary mineralocorticoid excess
  • Labs: BMP, CBC, VBG, urine electrolytes, magnesium, POC glucose, CK. Possibly aldosterone, renin, cortisol pending clinical context
  • Imaging: Renal US, CT AP

Management

  • Check Mg, replete to 2. Give empirically while waiting for serum Mg
  • K+ preparation (route); replete to 4

Choice of agent:

  • KCl is used for repletion in the hospital
  • PO tablets for mild asymptomatic hypokalemia
  • IV can be given through peripheral (rate is 10mEq/hr, may have burning sensation) or central access
  • K+ bicarbonate can be dissolved and put through G tube
  • Useful in patients with hypokalemia and metabolic acidosis

Dose:

  • Normal renal function: 10 mEq K+ is expected to raise serum [K+] by 0.1 mEq/L
  • Significant CKD or AKI: at risk of overcorrection
  • Shortcut: multiply the mEq by the Cr = how much K+ expected to rise
  • Once K+ higher than 5.5, K+ increases much faster and rules above do not apply

Hyperphosphatemia

Author: Peter Thorne, Amanda Morrison

Background

  • Phosphate (PO4-3) > 4.5mg/dL

Etiologies

  • Cellular shifts: cellular lysis (TLS, rhabdomyolysis), acidemia (lactic acidosis, DKA)
  • Increased intake/absorption or iatrogenic hyperphosphatemia (over repletion, vitamin D toxicity, use of Fleet's enemas, etc.)
  • Decreased phosphate clearance (acute or chronic renal disease, hypoparathyroidism, pseudohypoparathyroidism)

Presentation

  • Symptoms are usually secondary to coexistent hypocalcemia (psychosis, seizure, perioral paresthesias, muscle weakness)
  • Can cause acute phosphate nephropathy with phosphate containing laxatives
  • Calciphylaxis if concurrent hypercalcemia (high Ca+2 x PO4-3product)

Evaluation

  • Labs: BMP (calcium, creatinine), VBG, Vit D, PTH, PTHrP, lactate

Management

Acute

  • If renal function normal, can often treat with IVF (promote PO4-3 excretion)
  • Consider need for calcium supplementation (see hypocalcemia section)
  • If renal function impaired and severe hypocalcemia present, consider hemodialysis

Chronic

  • Usually secondary to chronic renal failure, goal PO4-3 3.5-5.5 in CKD patients
  • Renal diet (low PO4-3)
  • PO4-3 binders: Ca+2 containing (calcium carbonate and calcium acetate) and non Ca+2 containing (sevelamer, lanthanum, and iron based such as ferric citrate)
  • Sevelamer is significantly more expensive than calcium containing binders
    • Given 3 times daily with meals, started at 800mg (Can be ↑ to 1,600mg TID)
    • Should not be given if patient is not eating
  • Calcium acetate: started at 1334mg TID with meals
  • Limit dose changes to chronic binders upon discharge
  • Need to avoid calcium containing binders in patients with calciphylaxis

Hypophosphatemia

Author: Peter Thorne

Background

  • Required for metabolic pathways (ATP production)
  • Most renal reabsorption occurs in proximal tubule via sodium-phosphate cotransporter

Common causes

  • Internal redistribution, reduced intestinal absorption
  • Refeeding syndrome
  • Alkalemia
  • Phos binders on purpose or inadvertently (calcium, aluminum, magnesium antacids)
  • Excessive loss (diarrhea, CRRT, increased urinary excretion)
  • Proximal tubular dysfunction such as in Fanconi Syndrome
  • Hyperparathyroidism causes renal phos wasting
  • Post-parathyroidectomy leading to hungry bone syndrome
  • Vitamin D deficiency or resistance

Presentation

  • Mild hypophosphatemia (serum >2.0) rarely symptomatic
  • PO4-3< 2.0: muscle weakness
  • PO4-3< 1.0: heart failure, respiratory failure, rhabdomyolysis, seizures
  • Failure to wean from ventilator

Evaluation

  • Urine PO4-3 level if cause not readily apparent
  • Calculate Fe PO4-3 ([U PO4-3 x PCr x 100]/[P PO4-3x UCr])
  • Fe PO4-3 < 5% = normal renal response to hypophos: redistribution or ↓ absorption
  • Fe PO4-3 > 5% = renal phos wasting

Management

  • Caution replacing in patients with impaired renal function. Start with half suggested dose
  • If K+ > 4 and patient requires IV repletion, may need to use sodium PO4-3 in place of K+ PO4-3 IV; PO preferred unless severe or symptomatic, or patient cannot take PO
  • K-Phos neutral: oral, each 250mg tablet has 8 mmol of PO4-3 and 1.1mEq of K+
  • K+ PO4-3: IV, each mL has 3mmol PO4-3, 4.4 meq K+
  • Na+ PO4-3: IV, each mL has 3mmol PO4-3
  • PO4-3>1.5: PO: 40 – 80 mmol K+Phos neutral (aim for 1 mmol/kg) divided into 3-4 doses/day
  • PO4-3 1.25 - 1.5: oral 100 mmol K+ PO4-3neutral in 3-4 divided doses if asymptomatic
  • IV: 30 mmol K+ PO4-3over 6 hours (aim for 0.4mmol/kg) if symptomatic
  • PO4-3<1.25: IV: 80mmol K+Phos over approximately 12 hours (aim for 0.5mmol/kg)
  • Check serum PO4-3 2-12 hrs after last dose of PO4-3 to determine if additional needs

Hypomagnesemia

Author: Mike Tozier

Background

  • Definition: Mg+2 < 1.8 mg/dL, most patients asymptomatic until <1.2 mg/dL. Severe [Mg+2] < 1 mg/dL

Causes

  • GI losses: diarrhea, malabsorption, acute pancreatitis, EtOH use, TPN, vomiting, NG suction, GI fistulas, anorexia, short gut syndrome, small bowel bypass
  • Drugs: PPIs, loop diuretics, thiazides, digoxin, amphotericin, aminoglycosides, foscarnet, cisplatin, calcineurin inhibitors, laxatives, pentamidine
  • Kidney losses: post-ATN diuresis, Bartter syndrome and Gitelman syndrome
  • Cellular shifts: DKA treatment/recovery, refeeding, hungry bone syndrome, correction of metabolic acidosis, pancreatitis, EtOH withdrawal
  • Other: DM, hyper Ca, hyperthyroid, hyperaldosteronism, burns, lactation, Vit D deficiency, heat, prolonged exercise, mitral valve prolapse, pseudohypomagnesemia due to EDTA tube, lactation

Presentation

  • Refractory hypocalcemia or hypokalemia, arrhythmias, muscle weakness
  • Severe symptoms: seizures, drowsiness, confusion, coma, arrhythmias
  • Vertical nystagmus, tetany (Chvostek sign, Trousseau), tremors, fasciculations

Evaluation

  • EKG: Initially wide QRS, peaked Ts. Progresses to wide PR, diminished T, arrhythmias
  • Labs: Ca+2, K+, can use FEMg (order urine Mg+2 and Cr, serum Cr and Mg) or 24-hour urine for Mg to distinguish renal vs GI etiology (FEMg >2% renal, <2% GI)

Management

  • Correct underlying cause, replete based on severity (Dosing below for normal GFR)

Oral: asymptomatic patients, can cause GI symptoms, not well absorbed

  • Sustained release (Mg Chloride or Mg L-lactate) better tolerated and absorbed, though standard preparations (Mg oxide) are faster acting
  • Mg chloride: 3-4 tabs BID (total 30 to 56 meq [15 to 28 mmol]) for severe hypo Mg
  • 2-4 tabs daily (total 10 to 28 meq [5 to 14 mmol]) for mild hypo Mg
  • Mg oxide: 400-800 mg BID (20 to 40 mmol [40 to 80 meq]) for mod-severe hypo Mg

Intravenous: for symptomatic patients or if GI intolerance to oral

  • Mg <1 mg/dL: 4 to 8g of MgSO4 (32 to 64 meq [16 to 32 mmol]) over 12 to 24 hrs
  • Mg 1 to 1.5 mg/dL: 4 g MgSO4 (16 to 32 meq [8 to 16 mmol]) over 4 to 12 hrs
  • Mg 1.6 to 1.9 give 1 to 2 grams MgSO4 (8 to 16 meq [4 to 8 mmol]) 1-2 hrs
  • VUMC only has 4g bags of IV mag so would need to ask nurses to only infuse 1/2 bag
  • Infusion rate should not exceed 2 g/hr to minimize urinary excretion

Additional Information

  • Renal impairment: replete with caution, reduce dose by 50-75% and monitor closely
  • If persistent hypo Mg in patients requiring diuresis, try K-sparing diuretic (e.g. amiloride)
  • Treat concomitant hypokalemia, hypocalcemia or hypophosphatemia
  • In patients with concomitant hypophos and hypocalcemia, IV Mg alone may worsen hypophos

Approach to Urinalysis

Author: Madelaine Behrens, Laura Binari, Patrick Steadman

Background

  • 3 components: Gross evaluation, dipstick analysis, microscopic exam or urinary sediment
  • Indications: dysuria, gross hematuria, fever + GU symptoms, AKI, volume overload
  • If foley, obtain sample from catheter, not the urine bag

Spinning urine

  • At VUMC, take sample to lab on 4th floor to centrifuge the sample at 1500 rpm for 5 minutes, remove supernatant and then resuspend sediment, place drops of urine on the slide, examine with microscope
  • At the VA, there is a microscopy room where you can spin urine as well
  • Ideally, the specimen should be a fresh catch (<2-4 hours old); Beware: casts like to migrate to the edges of the coverslip

Gross Evaluation

  • Turbid: infection, precipitated crystals, or chyluria
  • Color:
  • Red urine (broad DDx, see "Hematuria" section, includes certain meds, porphyrias, myo/hemoglobinuria)
  • White (chlyuria, phosphate crystals, propofol)
  • Green (methylene blue, amitriptyline, propofol)
  • Pink (uric acid crystals, post-propofol infusion)
  • Black (hemoglobinuria/myoglobinuria)

Dipstick Analysis

Quality of sample: should have zero squamous epithelial cells

Specific gravity: normal = 1.010 - Surrogate for urine osmolality and hydration: can have falsely high specific gravity if large particles (contrast, glucose) present - Trick: Last 2 digits of S.G. x 30 = Uosm. For example: S.G. is 1.013; 13 x 30 = 390 mOsm/L

Urinary pH: normal pH is 5.5-6.5 - Alkaline pH: bicarb suppl, vegan diet, urease producing organisms (staghorn calculi) - Acidic pH: uric acid stones, appropriate response to acidemia

Proteinuria: dipstick detects albumin ONLY (not paraproteins) - Ddx: primary glomerular dx vs secondary glomerular dx (DM, amyloid, infxn, sickle cell, etc.) vs tubular vs overflow (multiple myeloma) - Transient: due to volume depletion, CHF, fever, postural, exercise-induced - Mild albuminuria (30-300 mg/day) not detected by standard dipsticks - Degree of dilution affects semiquantitative measurement (1+,2+,3+) - Follow up with spot protein to Cr ratio or 24 hr urine collection (nephrotic range >3.5 g/day)

Heme (see "Hematuria" section): False (+) if semen, false (-) w/ ascorbic acid

WBC - Possibilities: False (+) due to contamination with squamous cells. If bacteria → consider UTI/pyelo with hematuria → inflammation - Ddx includes UTI: gram positive/negative, chlamydia, ureaplasma; TB, malignancy, viral infxn, kidney stones, GN, urethritis, steroids, cyclophosphamide use - Sterile pyuria (no bacteria): DDx interstitial nephritis, renal tuberculosis, nephrolithiasis, recently treated UTI, prostatitis

Ketones - Never normal in urine; only detects acetic acid - Ddx: DKA, starvation ketoacidosis, pregnancy, keto diet

Glucose: max threshold at proximal tubule exceeded (~serum glucose 180 mg/dL) - DM, Cushing's, liver/pancreatic dx, SGLT2i use; or a primary defect of proximal reabsorption (w/phosphaturia, uricosuria, amino aciduria think Fanconi syndrome) - False (-) with ascorbic acid

Leukocyte esterase: enzyme released by lysed neutrophils, macrophages - Associated with pyuria and infections - False (-) from hematuria, glucosuria, or concentrated urine

Nitrites: reduction of urinary nitrates by nitrate reductase - Certain bacteria (e.g. Enterobacteriaceae) express, others (e.g. Enterococci) do not

Bilirubin: conjugated = water soluble (passes through glomerulus), unlike unconjugated - Liver dysfunction and biliary obstruction

Urobilinogen: end product of conjugated bilirubin, normally ~1.0mg/dL is normal - Can be elevated due to hepatocellular dx or hemolysis

Microscopic Examination of the Urine Sediment

Cells

  • Dysmorphic RBCs (sign of GN)
  • Squamous epithelial cells (contamination)
  • Tubular cells (abnormal, indicates renal dx)
  • Neutrophils (UTI, AIN, TB, sterile pyuria)
  • Eosinophils (think AIN, not sensitive thus cannot exclude diagnosis)

Casts

  • Hyaline (pyelo, CKD, prerenal azotemia, normal subjects)
  • RBC (GN, interstitial disease)
  • WBC (acute interstitial nephritis, GN, pyelo, inflammation)
  • Epithelial - renal tubular cells (ATN, interstitial nephritis, nephritic sx, heavy metal ingestion)
  • Granular or waxy (presence of kidney disease, but nonspecific)
  • Muddy brown casts (ATN)
  • Fatty (nephrotic syndrome)

Crystals

  • Ca+2 oxalate (envelope/dumbbell shape)
  • Uric acid (rhombic/rosette shaped, classically formed in acidic urine)
  • Cystine (hexagonal, found in cystinuria)
  • Mg+2 ammonium phosphate (aka struvite stones, from increased ammonia production, in setting of urease producing bacteria such as Proteus or Klebsiella UTIs)
  • Calcium oxalate crystals + AKI, consider ethylene glycol intoxication
  • Uric acid crystals + AKI, consider tumor lysis syndrome

Hematuria

Authors: Madelaine Behrens, Laura Binari, Patrick Steadman

Background

Definition: 3 urinalyses with three or more RBC/hpf; 1 urinalysis with 100 RBC/hpf or gross hematuria (1 cc blood/L urine can induce color change)

Causes:

  • Transient hematuria: exercise-induced, menses, trauma, cystitis/prostatitis
  • Concurrent pyuria/dysuria: consider urinary tract infection or bladder malignancy
  • Malignancy risk factors: male sex, age > 50, smoking Hx, exposures to benzene/aromatic amine, cyclophosphamide, indwelling foreign body, pelvic irradiation, chronic UTIs, heavy NSAID use, urologic disorders (nephrolithiasis, BPH)
  • Recent URI: think infection related glomerulonephritis, IgA, vasculitis, anti-GBM
  • Positive family Hx of hematuria: consider PKD, sickle cell disease
  • Bleeding from other sites: think inherited/acquired bleeding disorder, anticoagulation
  • Unilateral flank pain: ureteral calculus, renal malignancy, IgA nephropathy

Evaluation

Step 1: Confirm the presence of hematuria

  • Dipstick positive heme: urinary RBCs (hematuria), free myoglobin or free hgb
  • Centrifuge the urine
  • Red sediment → true hematuria (urinary RBCs)
  • Red supernatant +
    • Positive dipstick: myoglobulin or hemoglobin
    • Negative dipstick: porphyria, pyridium, beets, rhubarb, or ingestion of food dyes

Step 2: Determine if there is a GLOMERULAR or NON-GLOMERULAR source of bleeding

Glomerular bleeding - Isolated hematuria: differential includes IgA nephropathy, thin BM dx, Alport's - Nephritic syndrome (new proteinuria, pyuria, HTN, edema, rise in Cr): post-infectious GN, MPGN, ANCA vasculitis, Goodpasture's, lupus nephritis - Workup: anti-GMB, anti-DNase/ASO, ANA, ANCA, C3, C4, cryo, Hep B/C, HIV - Indications for renal biopsy: glomerular bleeding + risk factors for progressive disease, including albuminuria > 30 mg/day, new hypertension > 140/90 or significant elevation over baseline BP, rise in serum creatinine

Source Etiology
Glomerular IgA Nephropathy, IgA Vasculitis, Lupus Nephritis, Infection related glomerulonephritis, ANCA-associated, Anti-GBM disease, Genetic (thin Basement Membrane Nephropathy/Alport Syndrome), MPGN
Kidney Pyelo, RCC, PKD, sickle cell disease, papillary necrosis, Malignant HTN, arterial embolism, vein thrombus
Ureter/Bladder Cystitis, Urothelial Malignancy, nephrolithiasis, ureteral stricture, hemorrhagic cystitis (chemo/rads), traumatic Foley/procedure
Prostate/Urethra BPH, prostate cancer, TURP, urethritis (STI)
Other Exercise-induced, bleeding diathesis, meds (AC), menses, TB, schistosomiasis

Characteristics of Glomerular vs Extraglomerular Bleeding

Glomerular Extraglomerular
Color (if gross hematuria) Red, Cola, Smoky Red/Pink
Clots Absent Present/Absent
Proteinuria May be >500 mg/day <500 mg/day
RBC morphology Dysmorphic RBCs present Normal (isomorphic)
RBC casts May be present Absent

Extraglomerular bleeding - If historical clues suggest nephrolithiasis, start with non-con CT A/P - Gross hematuria otherwise should be evaluated with CT A/P w/ and w/o contrast (CT urography); will need to see Urology for cystoscopy (often done as outpatient referral) - CT Urography is more sensitive than IV pyelogram for renal masses and stones - Pregnant patients: renal and bladder ultrasound preferred over CT - If clots are passed, more likely to be secondary to lower urinary source; high burden of clots poses a risk of obstruction (urologic emergency) - If extraglomerular bleeding with clots: hematuria catheter needs to be placed ASAP (2 valve catheter, 20-24 Fr (!); page urology if nursing unable to obtain)

Who needs cystoscopy: All patients with clots and all patients with gross, nonglomerular hematuria in whom infection has been ruled out

Nephrolithiasis

Author: Madison Bandler

Background

Formation of kidney stones occurs when urine becomes supersaturated with stone-forming substances, leading to crystallization. This process can be influenced by various factors, including metabolic disorders, genetic predispositions, dietary habits, and dehydration

Classified into four main types based on their composition:

Calcium stones (oxalate or phosphate) - ~75-80% of stones - Driven by increased intestinal absorption of calcium, enhanced bone resorption, or decreased renal tubular reabsorption of calcium with low levels of urinary citrate further increasing risk

Uric acid stones - ~9-10% of stones - Primary risk factors are high levels of uric acid in the urine, low urinary volume, and persistently low urinary pH, which makes uric acid less soluble

Cystine stones - ~1% of stones - Occur in setting of genetic disorder with defective reabsorption of cystine and other dibasic amino acids (ornithine, lysine, and arginine) in the renal proximal tubules

Struvite stones - ~10% of stones - Typically take months to years to form, more common in women with recurrent UTIs from urease producing bacteria

Evaluation

  • BMP
  • Uric acid
  • Parathyroid Hormone level should be measured if primary hyperparathyroidism is suspected, particularly when serum calcium is high or high normal
  • Urinalysis for pH, erythrocytes, leukocyte esterase, citrate, nitrites, urine culture
  • Patients with uric acid stones may have persistent urine pH of 5-5.5 rather than the expected variation in pH of 5 in the morning and 6.5 in the evening
  • Patients with RTAs usually have urine pH of 6.5
  • Patients with struvite stones usually have urine pH of 8.5
  • For high-risk or recurrent stone formers, additional metabolic testing is recommended. At VUMC most commonly will see Litholink, which is a send out Labcorp test. This includes one or two 24-hour urine collections analyzed for total volume, pH, calcium, oxalate, uric acid, citrate, sodium, potassium, and creatinine. This testing helps identify metabolic and environmental risk factors, informing dietary and medical therapy

Imaging

  • CT abdomen and pelvis w/o contrast is typically first line
  • MR urography (MRU) without and with IV contrast or CT abdomen and pelvis with IV contrast may be appropriate as the next imaging study if CT w/o cntrast is inconclusive
  • Renal and bladder ultrasound may be used in pregnant patients

Management

  • Stones less than 5 mm often pass spontaneously. Follow-up imaging within 14 days is recommended to monitor stone position and assess for hydronephrosis
  • Alpha blockers, such as tamsulosin, may be used to facilitate the passage of distal ureteral stones less than 10 mm
  • NSAIDs are ideal for acute pain control if no contraindications
  • Thiazide Diuretics are indicated for patients with recurrent calcium stones and hypercalciuria
  • Potassium Citrate is recommended for patients with hypocitraturia and calcium phosphate stones, as well as for uric acid and cystine stones to raise urinary pH
  • Allopurinol for patients with recurrent calcium oxalate stones and hyperuricosuria

Operative Management

  • Extracorporeal Shock Wave Lithotripsy (ESWL): Suitable for renal stones between 10 and 20 mm, especially in favorable anatomical locations
  • Ureteroscopy: An option for lower pole stones between 1.5 and 2 cm, and for stones resistant to ESWL
  • Percutaneous Nephrolithotomy (PCNL): Indicated for stones larger than 20 mm, staghorn calculi, and stones in patients with CKD

Prevention of recurrent urinary tract stones

  • 50% of patients will have recurrent stone at 10 years and 80% will have recurrent stone at 20 years
  • Increase fluid intake to achieve a urine volume of more than 2.5 L/day and adhere to a low-sodium diet
  • Weight loss and exercise
  • Diets consisting of low sodium, low animal protein (source of uric acid), and low oxalate (beets, berries, chocolate, rhubarb, nuts and leafy greens) with no calcium restriction may be beneficial. During a meal it may help to combine calcium rich food with oxalates that will bind in the intestinal lumen and be excreted in stool
  • Adding citrus fruits may increase citrate and reduce stone formation

Kidney Transplant Medicine

Authors: Trey Richardson, Madison Bandler

Introduction

The goal of this section is to serve as a guide for tackling the most common transplant complications as well as offer a few tips for managing immunosuppression while kidney transplant patients are admitted to the hospital

Alphabet soup

  • PRA: panel reactive antibodies
  • DSA: donor specific antibodies
  • SCD/ECD: standard or expanded criteria donors reflects quality of organ and risk of graft loss
  • DCD: donation after circulatory death
  • DGF: delayed graft function (required dialysis within 7 days post-transplant)
  • CMV (-/+): indicates the CMV status of both the recipient and the donor
  • FK506 or FK: another name for tacrolimus
  • KDPI: Kidney donor profile index used to "grade" the quality of the donated organ
  • X/6 MM: indicates the number of HLA subtypes that are mismatched between donor and recipient
  • CAN: chronic allograft nephropathy

Infections in Kidney Transplant Recipients

Infection Prophylaxis

Agent Purpose
Trimethoprim-Sulfamethoxazole (TMP-SMX) 80/400mg one tablet daily for at least six months for PJP ppx (12 months for toxo ppx) Routine use reduces or eliminates the incidence of Pneumocystis jirovecii, Listeria monocytogenes, Nocardia asteroids, and Toxoplasma gondii and TMP-SMX is also effective as UTI prophylaxis
Monthly IV or aerosolized pentamidine, dapsone* or atovaquone Replace TMP-SMX as PJP prophylaxis for patients with sulfa allergies or if treatment complications such as hyperkalemia or leukopenia arise. *pentamidine and dapsone are not sufficient for toxo ppx
Nystatin 100,000 units/mL, 4mL after meals and before bedtime OR Fluconazole 200mg one tablet daily generally 3 months after transplant For fungal prophylaxis. **closely monitor cyclosporine and tacrolimus levels when starting and stopping antifungals (azoles)
Valganciclovir for 4-6 months after transplant For CMV prophylaxis (also prevents HSV). *Acyclovir for 3 months for HSV ppx in CMV recipient negative/donor negative individuals
Letermovir An alternative for CMV prophylaxis in patients with significant myelosuppression. *would need HSV ppx with acyclovir

Background

Infections in a kidney transplant recipient can be divided into 3 phases:

<1-month post-transplant - Surgical site infections, nosocomial infections (e.g. C. Diff, CAUTIs, and CLABSIs), and donor-derived infections/reactivation of latent recipient infections predominate

1-6 months post-transplant - Depleted immune-system regenerates increased risk for disseminated fungal (e.g. PJP, histo/blasto) and viral infections (HSV, adenovirus)

>6 months post-transplant - Risk for atypical infections persists, but common community acquired syndromes should still be on the differential

This section will focus on the most common infection in kidney transplant recipients—infections of the urinary tract

Evaluation

  • UA with culture
  • Examine the native kidneys (CVA tenderness) AND the allograft (almost always in RLQ, denervated so the graft itself will not be tender, but the surrounding soft-tissue may)
  • Renal U/S (of both allograft and native kidneys) or CT AP if:
  • Early post-op (1 month)
  • Recurrent (2+ episodes in year)
  • History of nephrolithiasis or if sepsis/bacteremia
  • Blood cultures if systemic signs/symptoms
  • Consider testing for C. urealyticum, and sending fungal and AFB urine cultures if UA is recurrently positive but culture negative. Differential includes BK and adenovirus if hemorrhagic cystitis (test urine PCR)

Management

  • Remove or replace indwelling catheters
  • Review prior culture susceptibilities (if available)

Empiric antibiotic regimens

Asymptomatic bacteriuria: treat with fluoroquinolone or beta lactam for 5-7 days if <3 mo post-transplant

Simple cystitis: Fluoroquinolones (ciprofloxacin 250 BID or Levaquin 500 mg daily), Augmentin (500 mg BID), 3rd gen cephalosporin (cefpodoxime 100 mg BID or cefixime 400 mg daily) or nitrofurantoin 100 mg BID (if GFR>30, only treats cystitis since drug only concentrates in the urine) - < 6 mos post-transplant: treat for 10-14 days - >6 mos post-transplant: treat for 5-7 days

Complicated UTI/Pyelonephritis (cover Pseudomonas, gram negatives and Enterococcus): Ceftriaxone 2g daily (preferred), Cefepime 2g q8hrs (add Vancomycin when using cephalosporin if suspicious for enterococcus) or Pip-tazo 3.75g q6hrs, can also use meropenem 1g q8h (need ID approval) - Treat for 14-21 days - For stable pts with mild complicated UTI, can consider giving more narrow empiric antibiotics: Augmentin 875 mg BID or ciprofloxacin 500 mg q12h - MDR UTI: Consult transplant ID - Options: meropenem-vaborbactam, ceftolozone-tazobactam, ceftazidime-avibactam - In pts with PCKD, include lipophilic antibiotic (such as ciprofloxacin) to penetrate cysts

Viral Infections

CMV

  • Most common opportunistic viral infection, typically in the first 6 months post-transplant
  • CMV infection can lead to acute rejection and graft failure
  • May manifest as a nonspecific febrile syndrome, gastrointestinal symptoms, or tissue-invasive infection, which may not cause CMV viremia but requires histologic diagnosis
  • In patients with active disease, weekly monitoring of CMV PCR, CBC and kidney function recommended
  • For severe disease treat with IV ganciclovir vs oral valganciclovir for mild or moderate disease
  • Ganciclovir and valganciclovir are renally dosed
  • Alternative treatments: IV Foscarnet (if resistant to ganciclovir) or maribavir in patients with severe leukopenia or ganciclovir-resistant
  • Check a resistance panel if CMV viral load not improving after first 2-3 weeks of treatment

BK Virus

  • Disease manifestations include BKV-associated nephropathy (BKVAN), ureteric stenosis, and hemorrhagic cystitis
  • Monitored by checking serum BK DNA PCR. BK nephropathy diagnosed by renal biopsy
  • Managed by reducing immunosuppression

EBV and post-transplant lymphoproliferative disease (PTLD)

  • Manifestations can include lymphadenopathy, fever, weight loss, and organ-specific symptoms such as gastrointestinal disturbances or respiratory issues
  • Key risk factors include EBV seronegativity at the time of transplantation, primary EBV infection post-transplant, and the overall level of immunosuppression
  • Monitoring EBV DNA levels may be used for early detection

Fungal Infections

  • Candida species infections account for up to 70% of fungal infections in kidney transplant recipients
  • Aspergillus
  • Cryptococcus
  • Pneumocystis jiroveci
  • Histoplasmosis, blastomycosis, and coccidioidomycosis

Acute Kidney Injury of Kidney Transplant

Background

Most patients admitted to medicine services with kidney transplants are >3 months post-op. Therefore, we are typically not managing perioperative complications such as delayed graft function, or hyper-acute rejection. Below are the most common causes of acute kidney injury in kidney transplant recipients

Evaluation

  • Signs and symptoms of UTI?
  • Assess volume status
  • Review meds for recent medication changes
  • Common offenders: NSAIDs, ACEi, diuretics, azole antifungals
  • Medication non-adherence
  • Tacrolimus (FK) or cyclosporine (CsA) level
  • FK levels increase with n/v, diarrhea due to alterations in p-glycoprotein expression within inflamed GI tract
  • FK toxicity also causes diarrhea and volume depletion
  • Proteinuria
  • Transplant patients with 1 g/day proteinuria usually get biopsies
  • Review donor characteristics (CMV status, PRA, % HLA antibodies present, DSAs)
  • BK PCR: consider only if unclear source of AKI and no recent titers
  • Serum PCR is test of choice
  • Renal transplant U/S (costly and not always warranted)

< 1 week post-transplant:

If acute graft dysfunction, look for thrombosis, urine/ureter leak

> 1 week post-transplant

  • Cr does not respond to 48 hours of current management
  • Lack of clear, reversible causes
  • Hydronephrosis (can occur after stent removal 4-6 wks after transplant or due to perinephric fluid collection)
  • Arterial stenosis (↑ velocities in renal artery -- very concerning when velocity >300), tardus parvus waveforms)
  • Perinephric abscess with recurrent UTI/pyelonephritis
  • Urinoma (usually first 2-3 weeks), hematoma (after a biopsy)

Unique findings

  • Resistive indices: Reflect central renal vascular compliance. High indices in transplant patients signify parenchymal problem (rejection, infection, ATN)

Biopsy

  • To differentiate ATN vs. rejection vs. BK nephropathy vs. recurrent disease (FSGS, lupus, etc.)

Post biopsy care

  • Watch for bleeding and HTN
  • Blood can get into collecting system, then the capsule, and into the perinephric space causing Page Kidney (aka Pressure Tamponade)
  • Compressed renal vessels → RAAS surge → rapid, severe HTN (STAT page the renal fellow)

Kidney Transplant Rejection

Background

Rejection is divided into acute vs. chronic and T-cell mediated or antibody mediated - Pathologists can determine the type of rejection and the chronicity by observing the structures that are acutely involved (e.g. tubulitis, glomerulitis, arteritis, and capillaritis) as well as the time course of involvement (e.g. presence of fibrosis) - Structures exhibiting fibrosis represent chronic rejection that is unlikely to respond to treatment, whereas acute inflammation may be amenable to acute therapies - This section will focus on acute rejection since this is the clinical entity we will most likely manage while on the wards

Acute Rejection

Acute T cell mediated rejection

Infiltration of the graft by lymphocytes and inflammatory cells characterized by tubulitis, interstitial inflammation, and arteritis (on occasion)

Treatment - High dose glucocorticoids (methyl prednisolone) is first line (~ 5 days) - Thymoglobulin (polyclonal Ig anti-T cell) - Use depends on severity of rejection - Indicated if Cr fails to improve after steroids - T cell subsets are measured during treatment until depleted - Tacro target levels are reset to ~8-10 if treated for acute T cell mediated rejection

Acute antibody mediated rejection (ABMR)

Donor specific antibody mediated rejection characterized by glomerulitis, peri-tubular capillaritis (microcirculation inflammation), complement deposition (C4d staining), and presence of DSA

Treatment = B-cell depletion therapy - IV methyl prednisone 500 mg IV x 3-5 days - Plasmapheresis (If with high titers of DSA) - IVIG 2 g/kg (max 140 g) - Rituximab 375 mg/m2

Kidney Transplant Immunosuppression

Background

  • Induction therapy, which is administered at the time of transplantation, includes biologic agents such as rabbit anti-thymocyte globulin, anti-CD52 antibody alemtuzumab, or the anti-CD25 monoclonal antibody basiliximab, to provide an initial high level of immunosuppression
  • Maintenance therapy is continued long term and often involves triple therapy with an anti-metabolite (azathioprine or mycophenolate compound) or mTOR inhibitor + calcineurin inhibitor + corticosteroids
  • You may also come across patients who are on monthly infusions with belatacept, a selective T-cell co-stimulation blocker
  • Belatacept is only for use in patients who are EBV seropositive due to increased risk of post-transplant lymphoproliferative disorder (PTLD) in EBV seronegative patients

Calcineurin Inhibitors

Tacrolimus (FK), cyclosporine (CsA) - Envarsus XR is a once a day long acting formulation of tacrolimus

Common side effects: - Nephrotoxicity: mediated by vasoconstriction to the afferent arterioles and interstitial fibrosis - Hypertension - treat with CCBs - Diabetes - Neurotoxicity: Hand tremors, headache, seizures, PRES - Diarrhea, nausea - Thrombotic microangiopathy - T4 RTA - hyperkalemia - Gingival hyperplasia (more associated with cyclosporine)

MTOR Inhibitors

Sirolimus, Everolimus

Major side effects: poor wound healing, rarely pneumonitis, dyslipidemia, bone marrow suppression, proteinuria

Reduced incidence of nephrotoxicity, lower incidence of certain viral infections and malignancies, and decreased alloantibody production (useful in patients at risk for antibody mediated rejection) relative to CNI's, though there are higher rates of delayed graft function, acute rejection and proteinuria

Increases nephrotoxicity when given with standard doses of CNIs so target trough levels are adjusted when patients are on both meds

Anti-metabolites

Azathioprine

Mycophenolate preparations: mycophenolate mofetil (Cellcept, MMF), Mycophenolic acid (Myfortic)

Side effects: bone marrow suppression (hold if lymphopenia), GI upset (hold if diarrhea)

Mycophonolate generally preferred for superior efficacy in preventing acute rejection and improving graft survival, but azathioprine may be considered in specific patient scenarios (pregnancy, G intolerance/IBD, high cost of medications)

Additional Information for Overnight Admits:

  • Do not change immunosuppression unless discussed with fellow
  • When to consider holding medications: known CMV infection or COVID infection w/ hypoxia (hold mycophenolate); if pt has multiple signs of CNI toxicity (AKI, severe diarrhea, and tremors/neurotoxicity)
  • If holding mycophenolate/anti-metabolite, prednisone is increased to 10 mg daily
  • Daily tacrolimus or cyclosporine level (order qam at 0500). Always order tacrolimus or cyclosporine dose at 6:00 am and 6:00 pm (regardless of what time patient takes at home, lab can only run am tacro levels at a certain time in batches) *check an everolimus or sirolimus AM level if patient takes an MTOR inhibitor
  • Transplant patients with normal kidney function can have regular diet
  • Renal transplant is consulted on every post-transplant patient admitted to the hospital