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246 SECTION IV Preoperative and Postoperative Care
concerns are drug-induced hepatotoxicity, precipitating decompensation of liver cirrhosis and/or development of fulminant liver
failure. Perioperative management involves treatment of the complications of liver disease, including coagulopathy, ascites, encephalopathy, and malnutrition.
• Elective procedures in patients with asymptomatic hepatic dys-
function should be postponed pending additional evaluation and
reassessment of operative risk.
• Patientswithacutehepaticinammationorhepatocellularand/or
cholestatic injury should have elective procedures postponed until
there is evidence of recovery.
• Patientswithchronicliverdiseasewithpreservedhepaticfunction
require close monitoring although their operative risk is minimal.
Cirrhosis is a chronic liver disease, which results in impaired syn-
thetic and metabolic functions.
SBP antibiotic prophylaxis is required for patients with low ascitic
fluid protein levels (<1 g/L) for the duration of hospitalization perioperatively. Additional indications for SBP prophylaxis include prior history
of SBP and patients with evidence of upper gastrointestinal blood loss.
Patients with ascites due to portal hypertension who may require
therapeutic paracentesis will need albumin infusion if more than 5 L is
drained to reduce risk for AKI, and the rapid reaccumulation of ascitic
fluid.
Diuretic regimens should be adjusted as needed to help maintain
required volume status and to keep serum electrolytes within normal
limits.
Precipitants of hepatic encephalopathy in patients with cirrhosis
need to be avoided as much as possible. Elective procedures in patients
who are encephalopathic should be postponed while their clinical condition is managed with the aid of a hepatologist.
Coagulopathy is one of the primary features of chronic advanced
liver disease. The etiology is often multifactorial, including hepatic
synthetic dysfunction, thrombocytopenia, malnutrition, and the effect
of cholestasis on vitamin K absorption. The following measures should
be taken to address coagulopathy in the perioperative period.
1. Vitamin K supplementation with or without fresh-frozen plasma
(FFP) is often used to correct coagulopathy before surgery. Use of
FFP is mainly limited to instances where massive blood transfusion
(>4 units) raises concern for dilutional coagulopathy.
2. Cryoprecipitate can address hypofibrinogenemia if serum fibrino-
gen is less than 100 mg/dL.
3. Platelet transfusion can be used to attain a desired serum platelet
level depending on the type of surgical procedure, greater than
50,000 μL for most surgical interventions, but greater than 100,000
μL for neurosurgical procedures.
4. NR values tend to be elevated due to hepatic dysfunction, but this
does not confer any antithrombotic properties due to the concept
of rebalanced hemostasis. Patients who require deep vein thrombo-
sis (DVT) prophylaxis should still receive subcutaneous heparin or
other pharmacologic interventions to reduce DVT risk.
The Model for End-Stage Liver Disease (MELD) and Child-Pugh score/
classification (also referred to as Child criteria) have been used for risk
assessment of patients with liver disease. The MELD score is calculated
using total bilirubin, international normalized ratio (INR), and serum
creatinine. This results in four MELD levels, with scores greater than 25
indicating highest mortality risk. Child-Pugh scores are calculated using
five clinical measures: total bilirubin, serum albumin, prothrombin time
(PT), ascites, and hepatic encephalopathy. The scoring of these clinical
measures results in classification of patients in Child class A, B, or C.
Patients in class C have the highest mortality risk.
More recently, the integrated MELD score (iMELD), which incorporates serum sodium level for MELD scores less than 12, has been
adapted and has been shown to have a better prognostic strength compared with the MELD or Child-Pugh scores.
Surgery is contraindicated in patients with Child-Pugh class C,
high MELD/iMELD score (>20), acute hepatitis, severe coagulopathy,
or severe extrahepatic manifestations of liver disease (e.g., acute renal
failure, hypoxia). Avoid surgery, if possible, in patients with a MELD
score of greater than or equal to 18 or Child-Pugh class B unless they
have undergone a thorough preoperative evaluation and preparation.
• Usesedativesandneuromuscularblockingagentscautiously.
• Optimizenutritionandmedicaltherapyforcirrhotics:
• Correctcoagulopathy with vitamin Kwith or without FFP to
achieve an INR less than 1.6.
• Thegoalplateletcountisgreater than 50 to 100 × 103/L. This
may vary depending on the type of surgical procedure.
• Addressascitic uidvolume to reducerisk of abdominalwall
herniation, wound dehiscence, and compartment syndrome.
• Postoperatively,emphasisshouldbeplacedon:
• Signs of acute liver failure, including worsening jaundice,
encephalopathy, and ascites.
• Monitoringforandcorrectionofrenaldysfunctionand/orelec-
trolyte abnormalities.
• SomepatientsmayrequireIVtranexamicacidtoaddresspost-
operative bleeding due to the altered fibrinolytic system.
PULMONARY DISEASE
The major components of effective preoperative care are measures to
prevent or reduce perioperative complications including pulmonary
infections, exacerbation of underlying pulmonary disease, hypoxic
hypercarbic respiratory episodes, and avoidance of pulmonary
embolism.
For asymptomatic patients there is generally no need for preoperative chest radiographs or pulmonary function tests (PFTs).
Preoperative PFTs are, however, essential in patients who are scheduled to have lung resection procedures to help predict postoperative
lung function.
Patients with unexplained dyspnea need to be evaluated before having surgical procedures that require general anesthesia.
A combined cardiopulmonary risk index is proposed for risk stratification of pulmonary complications. Pulmonary risk factors have
been added to the Goldman Cardiac Risk Index; patients with a combined score of greater than 4 points (of a total of 10) are 17 times more
likely to develop complications. These pulmonary risk factors include
the following:
• Obesity(i.e.,bodymassindex>27kg/m2)
• Cigarettesmokingwithin8weeksofsurgery
• Productivecoughwithin5daysofsurgery
• Diffusewheezingwithin5daysofsurgery
• FEV1/FVC ratio less than 70% and Paco2 greater than 45 mm Hg
In the preoperative history and physical exam, patients should be
screened for obstructive sleep apnea (OSA). Adequate management of
OSA is critical to prevent cardiopulmonary and neurovascular complications. The commonly used tool is the STOP-BANG score. A formal
sleep study is needed in high-risk patients who are scheduled for elective procedures.
COPD/Bronchial Asthma
Patients with these conditions should have their treatment regimen
optimized and be instructed to continue with their medications up to
the morning of their procedures. Patients with features of exacerbation should be started on systemic corticosteroids. Planned procedures
should be rescheduled if possible.
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247
HPA axis suppression should be assumed to be present in patients
who have received systemic steroids for more than 3 weeks in the
past 6 months. These patients should receive stress-dose coverage
perioperatively.
There is no role for prophylactic perioperative use of antibiotics. Elective procedures should be cancelled in patients with active
infections.
Obstructive Sleep Apnea
Patients require CPAP (continuous positive airway pressure) perioperatively. Blood gas monitoring is required.
Smoking cessation does reduce pulmonary complications and
should be encouraged several weeks before planned elective procedures.
Breathing exercises including use of incentive spirometry are
worthwhile risk-reduction measures that should be used.
Postoperative management is based on:
• Appropriateuseofantibioticstotreatinfections
• Useofhigh-dosesteroidsofmanagementofare-upofunder-
lying lung diseases
• Maintenanceofadequateoxygenation.
Prevention of Venous Thromboembolism
In patients undergoing major orthopedic surgery such as hip and knee
joint replacement, venous thromboembolism (VTE) prophylaxis with
low-molecular-weight heparin (LMWH), adjusted dose warfarin,
apixaban, rivaroxaban or aspirin should be initiated postoperatively
and continued for a period of up to 35 days. Placement of inferior vena
cava filters is unlikely to offer added benefit to patients with contraindications to thromboprophylaxis. Patients undergoing nonorthopedic surgeries should be risk stratified for VTE and those at high risk
receive prophylaxis with LMWH or low-dose unfractionated heparin.
See American College of Chest Physicians guidelines in the suggested
readings section.
ENDOCRINE DISEASE
Diabetes Mellitus
Diabetes mellitus is a common condition requiring preoperative management because uncontrolled diabetes is associated
with hyperglycemic crises, infection, reduced wound healing, and
increased mortality. Optimal perioperative glucose targets vary but
generally fall between 80 to 180 mg/dL. Evaluation includes known
complications of diabetes including neuropathy, chronic kidney
disease, and heart disease. Hemoglobin A1C measurement will correlate with recent (1-3 months) blood glucose levels and may be
helpful with assessment of hyperglycemia risk. Oral and noninsulin
injectable medications are generally continued until the morning
of surgery at which time they are temporarily discontinued. Longacting basal insulin is continued but may require dose reduction by
20% to 30% if a fasting period is required. Withholding of long-acting insulin in type 1 diabetics may result in onset of ketoacidosis
and should be avoided. Short-acting insulin doses may be reduced
or temporarily eliminated depending on oral intake restrictions.
Intraoperative and postoperative monitoring of blood glucose
via fingerstick (every 2-4 hours) will help identify occurrence of
hypo- or hyperglycemia. Long- and short-acting insulin should be
used to treat and prevent hyperglycemia while being mindful of the
patient’s insulin sensitivity to avoid hypoglycemia. Transition back
to home regimen may begin when the patient is clinically stable,
resumes steady oral intake and no further procedures/operations
are planned (see Chapter 68).
Thyroid Disease
Hypo- and hyperthyroidism are each associated with worsening of associated symptoms, morbidity, and even death. Although routine laboratory screening is not recommended, evaluation should be done when
symptoms of thyroid dysfunction are noted in patient assessments. Mild
to moderate hypothyroidism should be treated with preoperative oral
levothyroxine. Treatment of severe hypothyroidism including myxedema coma include IV levothyroxine and IV liothyronine and postponement of elective surgery until thyroid hormone levels are stable.
Untreated hyperthyroidism may result in postoperative thyroid storm,
which is characterized by tachycardia, confusion, fever, and cardiovascular collapse. Patients with thyrotoxicosis should be treated with β-blockers and antithyroid medications preoperatively (see Chapter 65).
Adrenal Insufficiency and Long-Term Corticosteroid Use
The adrenal glands produce cortisol and various catecholamines in
response to stimulation from the HPA axis. Patients receiving long-term
exogenous corticosteroids (20 mg daily of prednisone or equivalent for
>3 weeks) are considered at risk of adrenal insufficiency due to HPA axis
suppression. Because surgery is a state of induced stress, an IV corticosteroid regimen (intravenous hydrocortisone 50-100 mg and up to three
times daily) is required with a plan to taper to routine doses based on
hemodynamic response (see Chapter 66).
HEMATOLOGIC DISEASE
Screening for disorders of bleeding hemostasis includes questions
identifying episodes of bleeding diathesis, medications posing high
bleeding risk, and family history of hemophilia or other inherited
bleeding disorders. Patients with liver disease, end-stage renal disease,
and collagen vascular disease may have higher perioperative bleeding
risk. Commonly obtained laboratory testing includes PT, INR, activated prothrombin time (aPTT), and platelet count.
Management of anticoagulants and antithrombotics in the perioperative setting is a frequent concern given their frequent use in clinical
practice. Perioperative risk of bleeding and thromboembolic events
should be evaluated because not all surgical procedures require discontinuation of anticoagulation (Table 22.4). In situations of high risk
of bleeding, the vitamin K antagonist warfarin is held 5 days prior to
the planned procedure. Direct oral anticoagulants such as apixaban,
dabigatran, and rivaroxaban may be discontinued within 24 to 48
hours of the procedure depending on overall bleeding risk and renal
function. In situations of high risk of thromboembolism due to interruption of therapy, bridging therapy may be provided with heparin
infusion or LMWH injection until oral therapy may be safely resumed
(Table 22.5). Perioperative management of antithrombotics, such as
aspirin, clopidogrel, and other P2Y12 inhibitors should be based upon
the indications for antithrombotic use and the type of surgery to be
performed as noted in the section on cardiologic disease.
Preoperative anemia is associated with an increase in postoperative
transfusion, morbidity, and mortality. A target preoperative hemoglobin is
not well established and may depend on the expected blood loss, but most
patients will likely tolerate levels as low as 7 g/dL. Screening, work-up, and
optimization of anemia should occur with enough lead time to allow for
correction and optimization prior to elective surgical procedures.
INFECTIOUS DISEASE
Surgical site infections (SSIs) complicate up to 20% of operations leading to significant morbidity and mortality. SSIs occur within 30 days of
surgery and are defined as affecting the superficial, deep or organ/space
248 SECTION IV Preoperative and Postoperative Care
TABLE 22.4 Risk Factors for Bleeding and Thrombosis in the Anticoagulated Patient
INDICATIONS FOR ANTICOAGULATION THERAPY
Atrial Fibrillation Mechanical Heart Valve VTE
High-risk features for periprocedural
bleeding: Consider interruption of
therapy
High-risk features for perioperative
thromboembolism: Consider bridging therapy
CHADS2-VASC, Clinical prediction rule for estimating the risk of stroke in patients with nonrheumatic atrial fibrillation.
a
Decisions on bridging therapy are clinically based—evaluate thrombotic risk balanced by patient bleeding risk, consider additional information, and
use clinical judgement.
Procedure-related bleeding risk: Consult surgeon or surgical society guidelines for procedure bleeding risk classification. Common
high-risk procedures include: vascular surgery, pacemaker lead extraction, kidney biopsy, radical hysterectomy, total hip replacement, and many others.
Patient-related bleed risk increased if: Major bleed or intracranial hemorrhage <3 months; thrombocytopenia or abnormal platelet
function (uremia and aspirin use); supratherapeutic INR; history of periprocedural bleeding
• CHADS2-Vasc 7+
• CVA/TIA/VTE <3 months prior
• Rheumatic valvular heart disease
• Mitral valve prosthesis
• CVA/TIA <6 months prior
• Cage-ball or tilting disk aortic valve
prosthesis
• VTE <3 months prior
• Severe thrombophilia (protein C
a
or S deficiency, antiphospholipid
syndrome, history of recurrent thrombosis when off anticoagulation)
TABLE 22.5 Interruption of Therapy and Bridging of Anticoagulation
Anticoagulant Class
Vitamin K Antagonists
• Warfarin
Interruption of therapy
Bridging therapy
Reinitiation of therapy
Special considerations
LMWH, Low-molecular-weight heparin; UFH, unfractionated heparin.
• INR 2.0-3.0, discontinue 5 days prior to procedure
• INR 1.5-1.9, discontinue 3-4 days prior to procedure
• Therapeutic UFH or LMWH
• Start UFH when INR <2
• UFH: Stop >4 hours prior to procedure
• LMWH: Stop 12-24 hours prior to procedure
• LMWH use and dosing must be renally adjusted
• Restart at patient’s regular dose
• Timing is procedure specific: consult with surgeon
(most within 24 hours)
• Postprocedure bridging therapy may be considered in
patients with moderate or high risk
• Discontinue bridging therapy once INR >2.0
Direct Oral Anticoagulants (DOACs)
• Dabigatran
• Apixaban
• Rivaroxaban
• Dependent on creatinine clearance
• If renal function is normal, stop 1-2 days prior to surgery
• Therapeutic UFH or LMWH
• Start UFH when INR <2
• UFH: Stop >4 hours prior to procedure
• LMWH: Stop 12-24 hours prior to procedure
• LMWH use and dosing must be renally adjusted
• Will render patient therapeutically anticoagulated within
hours
• Discuss timing of reinitiation with surgeon/proceduralist
(most within 24 hours)
• Inability to take PO: may use UFH or LMWH
• Obviates need for DVT prophylaxis
• Special caution in setting of spinal anesthesia due to risk
of hematoma formation
areas of the wound. Patient risk factors for SSIs include age, nutritional
status, and diabetes while operative risk factors include initial contamination of surgical wound, operative technique, and many others.
Perioperative care is focused on prevention through the implementation
of care bundles (small sets of straightforward evidence-based interventions) including preoperative antibiotics, hair removal, avoidance of
hypothermia, and glycemic control. Preoperative antibiotic coverage
should include Staphylococcus aureus for clean wounds and expand to
cover other organisms depending on wound type and risk of contamination. Skin decontamination with topical agents such as chlorhexidine
has become routine but may not confer benefit in all patients.
NEUROLOGIC DISEASE
Neurologic conditions that may become exacerbated in the perioperative period include neuromuscular diseases, Parkinson’s disease, and
stroke.
Neuromuscular Diseases
Conditions such as myasthenia gravis, amyotrophic lateral sclerosis (ALS), and muscular dystrophies predispose patients to a variety
of complications. Myasthenia gravis, an autoimmune disease affecting acetylcholine receptors at the neuromuscular junction that leads
to skeletal muscle weakness, may worsen acutely in the perioperative
period. Respiratory insufficiency or failure due to myasthenic crisis
requires assessment of inspiratory function by measuring the negative
inspiratory force at the bedside.
Dysphagia, which accompanies many neuromuscular diseases,
may lead to aspiration pneumonitis/pneumonia. Swallow evaluation is necessary in the perioperative setting to mitigate this risk in
patients with ALS, which is characterized by motor neuron degeneration and may be complicated by postoperative aspiration pneumonia and respiratory failure. Patients with muscular dystrophies
are at risk for cardiac arrhythmias and may require cardiac rhythm
monitoring. Malignant hyperthermia syndrome is a rare inherited
CHAPTER 22 Preoperative and Postoperative Care
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249
condition presenting as perioperative muscle rigidity, fever, and cardiac arrhythmias.
Parkinson’s Disease
Parkinson’s disease is a common neurodegenerative disorder associated with dyskinesia, dysphagia, dysmetria, and loss of function. Missed
doses of levodopa, a common therapy for Parkinson’s, may result in
fever, dysautonomia, and worsening of Parkinson’s disease symptoms.
Levodopa therapy should be continued without interruption if possible, depending on the clinical situation. Patients with Parkinson’s disease may require longer rehabilitation following surgical procedures.
Stroke
Perioperative stroke incidence is low but carries a high rate of mortality
and morbidity. Most perioperative strokes are embolic in mechanism.
Risk factors include history of stroke, diabetes mellitus, hypertension,
atrial fibrillation, and advanced age. Addressing modifiable risk factors
and appropriate management including use of aspirin and statin therapy for known intracranial atheromatous disease should be pursued.
In high-risk patients with atrial fibrillation, perioperative bridging
of anticoagulation therapy should be considered to minimize risk of
stroke.
RHEUMATOLOGIC DISEASE
Autoimmune conditions such as rheumatoid arthritis and lupus are
commonly treated with medications aimed at reducing the activity of
the immune system. Disease-modifying antirheumatic drugs such as
methotrexate, azathioprine, mycophenolate mofetil, which are used in
a range of rheumatic conditions, may be continued in the perioperative period. Biologic agents such as adalimumab, infliximab, and other
similar agents are thought to raise the risk of perioperative infection
and should be held perioperatively. In addition, surgery should ideally
be scheduled for the end of the dosing cycle.
SPECIAL NEEDS OF THE GERIATRIC PATIENT
One third of inpatient surgeries in the United States are performed on
adults older than age 65. Patients in the geriatric population have a
greater risk of perioperative morbidity and mortality. Geriatric preoperative risk assessment should focus on function, cognition, and evaluation of medications, in addition to the systems-based approach in
this chapter. Impairment of activities of daily living (ADLs) is directly
associated with increased postoperative mortality. Screening for function may be performed with a variety of scales developed for this purpose. Gait speed and the timed Up and Go test are useful objective
assessments. Underlying cognitive impairment is an independent risk
factor for postoperative delirium. Cognition may be evaluated with
the Mini-Cog scale or Montreal Cognitive Assessment. Identification
of concerns in the patient’s functional status and/or cognition preoperatively may lead to reevaluation of the surgical management plan.
Postoperatively, strategies should focus on physical rehabilitation and
measures to reduce risk of delirium including minimal use of medications that promote delirium, frequent reorientation, multicomponent
interventions, and judicious use of antipsychotic medications.
Review of medications with a view toward postoperative complications should especially include antihypertensives (hypotension),
diuretics (volume depletion), diabetes medications (hypo- or hyperglycemia), antithrombotic agents (bleeding or thrombosis), benzodiazepines, opiates, and other sedative hypnotics (sedation and delirium).
Indications for each medication should be reviewed and assessment of
the risks and benefits should be performed.
SUMMARY
The success of standardized evidence-based preoperative and postoperative risk reduction strategies in patients undergoing noncardiac surgery depends on collaborative teamwork and careful communication
among the surgeons, the anesthesiologist, the patient’s primary care
physician, and the consultant.
The risk for a perioperative cardiac complication varies with
the severity of the surgical procedure and with RCRI stratification. A systematic, stepwise approach for preoperative cardiac risk
assessment in patients undergoing noncardiac surgery facilitates a
decision as to whether the risk for perioperative cardiac events is
sufficiently low to proceed with the surgery. The patient’s comorbid
conditions and risk factors must be assessed for risk of exacerbation
and steps taken to reduce risk to the patient in the perioperative
period. Postoperatively, close monitoring of the patient’s condition
is required. Patients who develop complications after the operation
will require timely and appropriate interventions by the surgical and
medical teams. Finally, cardiac and medical perioperative care are
evolving fields and practitioners must strive to keep their knowledge and practices current through literature review and guideline
awareness.
For a deeper discussion on this topic, please see Chapters 403,
“Preoperative Evaluation,” and 405, “Postoperative Care and
Complications,” in Goldman-Cecil Medicine, 26th Edition.
SUGGESTED READINGS
Auerbach A, Goldman L: Assessing and reducing the cardiac risk of
noncardiac surgery, Circulation 113:1361–1376, 2006.
Boersma E, Kertai MD, Schouten O, et al.: Perioperative cardiovascular
mortality in noncardiac surgery: validation of the Lee cardiac risk index,
Am J Med 118:1134–1141, 2005.
Doherty JU, Gluckman TJ, Hucker WJ, et al.: 2017 ACC expert consensus
decision pathway for periprocedural management of anticoagulation
in patients with nonvalvular atrial fibrillation: a report of the American
College of Cardiology Clinical Expert Consensus Document Task Force,
J Am Coll Cardiol 69:871–898, 2017.
Falck-Ytter Y, Francis CW, Johanson NA, Curley C, Dahl OE, Schulman S,
et al.: Prevention of VTE in orthopedic surgery patients: Antithrombotic
Therapy and Prevention of Thrombosis, 9th ed: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines, Chest 141(Suppl
2):e278S–325S, 2012 Feb.
Fleisher LA, Fleischmann KE, Auerbach AD, et al.: 2014 ACC/AHA guideline
on perioperative cardiovascular evaluation and management of patients
undergoing noncardiac surgery: a report of the American College of
Cardiology/American Heart Association task force on practice guidelines, J
Am Coll Cardiol S0735- 1097(14), 2014, 05536-3.
Hassan SA, Hlatky MA, Boothroyd DB, et al.: Outcomes of noncardiac surgery
after coronary bypass surgery or coronary angioplasty in the Bypass
Angioplasty Revascularization Investigation (BARI), Am J Med 110:
260–266, 2001.
Kristensen SD, Knuuti J, Saraste A, et al.: 2014 ESC/ESA guidelines on
non-cardiac surgery: cardiovascular assessment and management:
the joint task force on non-cardiac surgery: cardiovascular assessment
and management of the European Society of Cardiology (ESC) and
the European Society of Anesthesiology (ESA), Eur Heart J
35(35):2382–2431, 2014.
McFalls EO, Ward HB, Moritz TE, et al.: Coronary-artery revascularization
before elective major vascular surgery, N Engl J Med 351:2795–2804, 2004.
POISE Study Group: Effects of extended-release metoprolol succinate in
patients undergoing non-cardiac surgery (POISE trial): a randomized
controlled trial, Lancet 371:1839–1847, 2008.
Rechenmacher SJ, Fang JC: Bridging anticoagulation: primum non nocere, J
Am Coll Cardiol 66:1392–1403, 2015.
SECTION V
Renal Disease
23 Renal Structure and Function, 251
24 Approach to the Patient With Renal
Disease, 258
25 Fluid and Electrolyte Disorders, 268
26 Glomerular Diseases, 282
27 Major Nonglomerular Disorders of the
Kidney, 298
28 Vascular Disorders of the Kidney, 312
29 Acute Kidney Injury, 324
30 Chronic Kidney Disease, 334
250
23
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Renal Structure and Function
Orson W. Moe, Javier A. Neyra
INTRODUCTION
The kidney maintains the composition and quantity of body fluids,
and kidney failure is manifested by dysfunction of multiple organs.
Chronic kidney disease is approaching epidemic proportions worldwide, and acute kidney injury affects a very high percentage of hospital
admissions and ambulatory patients, with high rates of morbidity and
mortality. The etiologies of these conditions are very diverse and often
geographically specific. In addition to loss of glomerular filtration and
tubular function, kidney diseases include hypertension, urolithiasis,
and a host of electrolyte disorders that do not affect the glomerular
filtration rate (GFR) but nonetheless cause significant morbidity and
mortality. To understand these conditions, a thorough knowledge of
the anatomy and function of the kidney is requisite.
Approximately 25% of the cardiac output is distributed to the kidneys, where the blood is continuously cleansed of toxins. In addition
to excretion, the kidney is an important metabolic organ and a source
of endocrine molecules. Renal failure represents a disruption of all of
these functions. Selected aspects of renal structure and function are
reviewed briefly in this chapter to set the foundation for the subsequent chapters that deal with specific renal diseases.
RENAL STRUCTURE
Macroscopic Anatomy
The kidneys are seated against the posterior wall of the abdomen in
the retroperitoneal space, rendering them readily accessible for percutaneous biopsy. The lower poles may be palpable on deep inspiration
in a lean individual. Each human kidney weighs about 120 to 170 g;
is about 11 cm long, 6 cm wide, and 3 cm thick; and is endowed with
approximately 1 million nephrons with interindividual variations. The
“kidney size” commonly referred to in clinical sonographic reports is
actually the cephalocaudal renal length, which is not an accurate surrogate for renal volume and mass and may be influenced by patients’
body habitus. Despite this caveat, renal length is an acceptable clinical
surrogate of renal volume.
The kidney is surrounded by a fibrous capsule (anteriorly, Gerota
fascia and posteriorly, fascia retro renalis). The renal arteries enter the
kidney and the renal vein and ureters leave the kidney in the renal pelvis. The bisected surface consists of the lighter-colored outer cortex and
the darker inner medulla (Fig. 23.1A). A sample from a clinical biopsy
typically originates from the cortex in the lower pole. The medulla is
divided into outer and inner regions, and the outer medulla is subdivided into outer and inner stripes. The medulla has multiple conical contours, called pyramids, with their apices abutting on the renal
pelvis as papillae. The contact points of the renal pelvis with the renal
papillae are cup-like structures called calyces. Interpolated between the
pyramids are centripetal extensions of cortical tissue called columns of
Bertin (see Fig. 23.1A).
Renal Circulation
Each kidney receives blood from a single renal artery, although supernumerary arteries are present in up to one third of individuals. Just
before or after the renal artery enters the kidney, it divides into interlobar arteries that pass between the pyramids of the kidney radially up
the columns of Bertin (see Fig. 23.1A). The interlobar arteries further
divide into arcuate arteries, which arch along the corticomedullary
junction (see Fig. 23.1B). Arcuate arteries give rise to cortical ascending
arteries, which bring blood to the glomeruli. Afferent arterioles ramify
into glomerular capillaries, distributing blood to individual glomeruli.
Features of the renal circulation are summarized in Table 23.1.
The glomerular capillary is the site for glomerular ultrafiltration.
Even though the efferent arteriole is downstream from the glomerular capillary, it is not a venule because it has arteriolar walls and is
upstream of the second capillary system surrounding the tubules.
The peritubular capillaries provide oxygen and nutrients for the kidney, collect the fluid and solutes reabsorbed by tubules to return into
the circulation, and deliver the solutes to be secreted by tubule into
the tubule fluid. The peritubular capillaries surrounding the cortical
and juxtamedullary nephrons originate from the efferent arterioles of
cortical and juxtamedullary glomeruli, respectively. In certain pathologic settings, peritubular capillary flow or integrity can be disrupted,
decreasing oxygenation and promoting ischemic injury.
The vessels that run parallel to loops of Henle are called vasa recta
(see Fig. 23.1D) because of their long, straight structures. Blood from
the peritubular capillaries is returned to the circulation by a venous
system that mirrors the architectural structure of the arterial supply:
interlobular vein, arcuate vein, interlobar vein, and renal vein. The
parallel countercurrent nature of the vasculature provides the basis for
the very high medullar tonicity, which allows urine concentration but
also direct arteriovenous diffusion of oxygen, giving rise to the very
low oxygen tension in the medulla. This low oxygen tension renders
the kidney prone to ischemic injury, which is one of the most common
causes of acute kidney injury (see Chapter 29).
Renal Nerves
The capsules of the kidney and the ureters have pain fibers derived
from splanchnic nerves. This explains the costovertebral angle pain
that occurs when the kidneys are inflamed and during renal colic
during kidney stone passage. The renal parenchyma does not have
pain fibers but is richly innervated with sympathetic nerves that enter
the renal parenchyma with the renal artery. The sympathetic nerves
251
252 SECTION V Renal Disease
Superficial nephron
A B
CD
Cortex
PCT
PST
tDL
Vasa recta
Juxtamedullary nephron
Medulla
LOH
CCD
Aff Art
DCT
TAL
tAL
DCT
OMCD
IMCD
CNT
Eff Art
Glom capillary
Fig. 23.1 (A) Gross anatomy of the kidney. (B) Schematic representation of the vasculature within a column
of Bertin. (C) Structural components of the glomerulus. (D) Schematic representation of a superficial and a
juxtamedullary nephron based on the location of their glomeruli. The tubules are intimately intertwined with
the capillary system. The peritubular capillaries come off the efferent arteriole leaving the glomerular capillary. The capillaries that bathe the long descending and ascending limbs of the Henle loop are called the vasa
recta due to their straight nature. The tubular segments are named axially: CCD, Cortical collecting duct; CNT,
connecting tubule; DCT, distal convoluted tubule; IMCD, inner medullary collecting duct; LOH, loop of Henle;
OMCD, outer medullary collecting duct; PCT, proximal convoluted tubule; PST, proximal straight tubule; TAL,
thick ascending limb; tAL, thin ascending limb; tDL, thin descending limb.
PCT
Peritubular
capillaries
TABLE 23.1 Characteristics of the Renal Circulation
Feature Implications
Few or no anastomoses Very prone to regional disruption of blood supply
Among the highest blood flow rates per gram of tissue Lowest oxygen extraction (lowest arteriovenous O2 difference)
Functional arteriovenous shunts Solutes and gases (e.g., O2) can diffuse directly from artery to vein without passing
through capillaries
Two capillary systems in tandem The two capillaries serve completely different functions, in the glomeruli and
tubules in sequence
abut on the arterioles (see Fig. 23.1C), stimulate renin release, decrease
renal blood flow, and promote renal retention of sodium (Na+). Renal
sympathetic denervation has been proposed as a novel treatment of
resistant hypertension using radiofrequency energy delivered via an
intrarenal arterial catheter radially to disrupt the nerve fibers on the
renal artery, but thus far the data have not been conclusive.
CHAPTER 23 Renal Structure and Function
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253
Walk the Nephron
The functional unit of the kidney is the nephron. Each human kidney
has approximately 1 million nephrons. Approximately 30% of these
have their glomeruli situated deep in the cortex and are referred to
as juxtamedullary nephrons; the rest are in the outer cortex and are
referred to as superficial nephrons. Each nephron is a glomerulus followed by a tubule that ends in the renal pelvis. The surrounding capillaries and the interstitial space are important functional components
of the nephron.
Glomerulus
The glomerulus consists of the glomerular vasculature (arterioles and
capillaries) supported by the mesangium (mesangial cells and matrix)
inside Bowman’s capsule (parietal and visceral epithelial cells) (see
Fig. 23.1C). The visceral cells of Bowman’s capsule are the podocytes, so
named because of their numerous “foot processes.” The smooth muscle layers of the afferent and efferent arterioles are critical in determining arteriolar tone. The glomerular capillary contacts the mesangium
on one side and is separated from the foot processes of the podocytes
on the opposite side by the glomerular basement membrane (GBM).
The glomerulus filters large volumes of water and small solutes while
retaining most of the proteins and all of the cells in the blood. The
glomerular filtration barrier is a tripartite structure composed of the
capillary endothelium, the GBM, and the podocyte slit diaphragm.
Lining the inside of the GBM is a single layer of fenestrated endothelial cells. The fenestrations (50 to 100 nm in diameter) provide a
barrier to negatively charged large molecules in the blood. The GBM
contains laminin, type IV collagen, entactin (nidogen), and proteoglycans that restrict movement of large molecules (e.g., albumin) from
the capillary into Bowman’s space. The GBM contains dense negative
charges due to glycoproteins with sialic acid residues that restrict the
passage of anionic plasma solutes. It can be the site of deposition of
immunocomplexes that cause glomerulonephritis (e.g., membranous glomerulonephritis, membranoproliferative glomerulonephritis, lupus nephritis). Autoantibodies against the GBM cause severe
inflammation and loss of filtration. Autoantibodies against a podocyte
membrane glycoprotein (M-type phospholipase A2 receptor, PLA2R)
can cause antibody-mediated primary membranous nephropathy.
The epithelial layer consists of podocytes and the parietal epithelium,
which is flat and squamous with few organelles. At the vascular pole,
the parietal epithelium is contiguous with a completely different epithelium—the proximal convoluted tubule.
On the visceral side of Bowman’s space are the podocytes, which
constitute part of the filtration barrier. These cells have a highly interdigitating system of foot processes that rest against the basement membrane. The podocyte cell bodies lie within the extracellular matrix. The
spaces between foot processes are filtration slits of approximately 40
nm in diameter bridged by slit diaphragms, which are also negatively
charged, contributing to the containment of middle-size negatively
charged particles in the capillary. In the last decade, there have been
momentous advances in identifying the components of the slit diaphragm complex and understanding their functions. A full discussion
is not possible here, but major slit diaphragm–associated proteins
include nephrin, podocin, neph-1/2/3, FAT-1, R-cadherin, catenin,
CD2AP, ZO-1, and α-actinin 4. Mutations of many of these genes
cause congenital proteinuric kidney disease (see Chapter 26).
Tubules
The parietal epithelium of Bowman’s capsule becomes the renal tubule
(see Fig. 23.1D) as it leaves the glomerulus. The renal tubule is a prototypical polarized epithelium. Its salient characteristics are summarized
in Fig. 23.2. A simple cylinder would not suffice in terms of surface area
for transport. In the luminal apical membrane, surface amplification is
achieved either by protrusions or by a more extensive form of protrusions called the brush border in the proximal tubule. Between cells are
structures called tight junctions. Although they are called tight junctions, some are truly tight (with high resistance to solute and charge
movement), whereas others are quite leaky to solutes. In addition to
resistance, these complexes also regulate whether the junction is more
permeable to one ion type compared with another selective permeability. On the other side of the tight junction is the intercellular space,
which is contiguous with the interstitial space. The basolateral cell
membrane on the interstitial-capillary side amplifies its surface area by
infoldings into the cell and interdigitations between two cells.
The movement of a solute can be through a cell (transcellular
transport) or around the cell (paracellular transport) (see Fig. 23.2A).
Solute transport is an energy-consuming process that requires metabolic fuels. There are many kinds of transport proteins (see Fig. 23.2B).
ATPases directly couple hydrolysis of adenosine triphosphate (ATP)
to transport. Cotransporters (or symporters) move two solutes in the
same direction, and countertransporters (antiporters) move two different solutes in opposite directions. Channels function as protein-lined
“holes” that allows specific solutes to permeate. Different transporters
can also be coupled together to form a new transport system. Finally,
there are proteins that protrude outside the cell in the junctional area
to provide a conduit for paracellular transport.
Specialized Structures
Interstitium
The space between the tubules and peritubular capillaries constitutes
about 5% to 10% of renal volume and harbors interstitial fibroblasts and
dendritic cells. In diseases such as interstitial nephritis (see Chapter 27),
the interstitium is full of inflammatory cells, which elaborate cytokines
and chemokines that profoundly affect filtration and tubular function.
The resident fibroblasts are stellate cells with projections that physically
contact tubules and capillaries, provide scaffold support, and secrete and
maintain matrix. These cells, when stimulated by cytokines, can transform into myofibroblasts and contribute to interstitial fibrosis, a common
pathobiologic feature of kidney disease. Some specialized fibroblasts in
the deep cortex are sensors of oxygen and producers of circulating erythropoietin. The dendritic cells are antigen-presenting cells that express
major histocompatibility complex (MHC) class II molecules. They are
in intimate communication with the renal parenchyma, constantly sampling and responding to the local antigenic environment. Dendritic cells
are involved with innate and adaptive immunity and are major players in
immunologic homeostasis and diseases of the renal parenchyma.
Juxtaglomerular Apparatus
A unique feature of the nephron is that each thick ascending limb traverses
back to and engages in physical contact with its parent glomerulus. The
tubular cell at the point of contact is different from the rest of the thick
ascending limb and is called the macula densa. The tripartite structure
comprising the macula densa, the afferent and efferent glomerular arterioles, and the extraglomerular mesangium, a special part of the mesangium that protrudes outside the glomerulus, is called the juxtaglomerular
apparatus (JGA) (see Fig. 23.1C). The JGA is an important structure in
the maintenance of GFR by tubuloglomerular feedback and regulation of
afferent arteriole resistance and is the site of endocrine renin production.
Organelles Such as Mitochondria and Endoplasmic Reticulum
The kidney is second to the heart in mitochondrial content and
oxygen consumption per unit mass. In addition to their role as the
254 SECTION V Renal Disease
A
C
B
Fig. 23.2 (A) Top, Transcellular and paracellular transport of solutes. Solute transport is an energy-consum-
ing process that requires metabolic fuels; a sodium cotransporter and a sodium-potassium countertransporter are shown. (B) Transport proteins. Top, Adenosine triphosphatases (ATPases) directly couple ATP
hydrolysis to transport. Cotransporters (symporters) move two solutes in the same direction (e.g., Na+-glucose cotransporter or sodium-glucose linked transporter [SGLT]), and countertransporters (antiporters)
move two different solutes in opposite directions. Channels function as protein-lined “holes” that allow
specific solutes to permeate. Lower left, Different transporters can be coupled together to form a new
transport system. Lower right, Proteins that protrude outside the cell in the junctional area provide a conduit for paracellular transport. (C) Comparison of a pure filtration (or secretion) design (top) and a filtrationreabsorption design (bottom). See text for details.
power generator of a cell, mitochondria serve many roles as regulatory, synthetic, and adaptive functions in the cell. Mitochondria
are under complex regulation and undergo a plethora of abnormalities in many kidney diseases. Mitochondria-targeted therapeutics
are emerging with the notion that maintenance of mitochondria
health can prevent pathogenesis and progression of chronic kidney disease. The endoplasmic reticulum (ER) helps maintain the
quality of proteins through the unfolded protein response (UPR)
pathway, and ER dysfunction with maladaptive UPR activation is
named ER stress. ER stress is now known to be present in a wide
variety of kidney diseases, and modulators of ER stress will assume
important therapeutic roles.
RENAL FUNCTION
Excretory Function
Renal excretion of a substance can be mediated and modified by one
or a combination of three processes: filtration, secretion, and reabsorption. Fig. 23.2C compares two designs—pure filtration (or secretion) and filtration-reabsorption—and their implications in terms of
demands on regulation. The filtration-reabsorption mechanism allows
high filtration rates to be achieved, and the coupling with reabsorption
prevents loss of valuable fluid and electrolytes. This design also enables
economy in transport mechanisms through adaptive targeting of key
solutes while allowing the rest to be excreted. However, there is a price
CHAPTER 23 Renal Structure and Function
GFR K P
f
= × −( )∆ ∆Π
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255
to be paid for this configuration. Consider the excretion of 1 L/day by
pure filtration (or secretion). If there is a 5% error (reduction in filtration or secretion), only 0.95 L/day will be excreted—a difference of 50
mL. Compare this to a filtration-reabsorption mechanism wherein 170
L/day is filtered and 169 L/day is reabsorbed, resulting in the same 1 L/
day excretion. A 5% error (reduction) in reabsorption would result in
reabsorption of 160 L/day and excretion of 10 L/day, with an absolute
error of 9 L. One consequence of a filtration-reabsorption design is
that regulation has to have exquisite fidelity, and even small errors are
not tolerated.
Filtration
Filtration occurs exclusively at the glomerulus. The GFR, measured as
volume per unit time, has been the standard quantitative surrogate for
overall kidney function, although there are many disturbances of renal
function that are not associated with a decrease in GFR (e.g., nephrotic
syndrome, tubulopathies, renovascular hypertension, kidney stones).
Numerically, GFR can be conceptualized as an equation:
where the ultrafiltration coefficient, Kf, is equal to the surface area for
filtration multiplied by the hydraulic permeability; the hydrostatic
driving force, ΔP, is the pressure gradient between the glomerular capillary and Bowman’s space, which drives fluid to go into Bowman’s
space to form urine; and the osmotic driving force, ΔΠ, is the osmotic
pressure gradient between the glomerular capillary and Bowman’s
space, which holds fluid back in the capillary and slows down filtration.
Many renal diseases affect the determinants of GFR. Glomerular
disease (see Chapter 26) decreases Kf by affecting both the filtration surface area and the hydraulic permeability. Changes in ΔP are commonly
involved in diseases that reduce GFR. Changes in renal blood flow and
more importantly in afferent and efferent arteriolar resistances can
drastically affect ΔP and GFR. Functional changes in ΔP, such as prerenal failure from hypovolemia, hepatorenal syndrome (see Chapter
29), or intra-abdominal hypertension can radically lower GFR simply
by hemodynamic changes without any structural glomerular lesions.
Reabsorption
High GFR, which is required to maintain a high metabolic rate, can be
sustained only if there is high reclamation to maintain intravascular
volume and prevent circulatory collapse. Tubular reabsorption thwarts
the loss of valuable solutes and allows for finer tuning of the water and
solutes not reabsorbed. The resulting tubular contents are excreted. In
the mammalian kidney, tubular reabsorption assumes critical roles in
the regulation of excretion of many solutes (Table 23.2). A universal
mechanism of reabsorption is energy-dependent transepithelial transport, which is mostly Na+ dependent but can be Na+ independent.
The proximal tubules participate in the reabsorption of all solutes, but
some solutes are sequentially reabsorbed by the proximal and distal
segments; in these cases, the generic design tends to be high-capacity reabsorption proximally and more of a high-gradient reabsorption
for fine tuning distally. The axial difference can occur within the same
nephron segment (e.g., early vs. late proximal tubule) or across different segments (e.g., proximal vs. distal nephron segments).
Secretion
Secretion is an ancient mode of excretion that is found in lower-order
organisms. Although the human nephron is not primarily secretory in
nature, a number of solutes are still handled by secretion. For example,
the renal excretion of potassium (K+), hydrogen ions (H+), and uric
acid involves secretion. Many organic cations and anions are secreted
by the proximal tubule, and so are many exogenous toxins such as
xenobiotics. The secretion of creatinine by organic cation transporters
in the proximal tubule is the reason why creatinine clearance overestimates GFR. The secretion of furosemide by organic cation transporters
in the proximal tubule is why response to this drug is attenuated in
settings of renal hypoperfusion and/or proximal tubular damage such
in acute kidney injury.
Integrated Models of Excretion
The modes of excretion are coordinated in a precise, complex, and concerted fashion to effect excretion with exquisite accuracy (see Table 23.2).
The kidney is capable of a large range of urinary tonicity (<50 to 1200
mOsm), depending on the need of the organism to excrete or conserve
electrolyte-free water. Water is filtered at the glomerulus and is handled isotonically in the proximal tubule. At the lumen of the distal convoluted tubule, urine is maximally dilute as a consequence of low water
permeability throughout the thick ascending limb of Henle. The subsequent fate of the urine determines whether there is electrolyte-free
water excretion (dilute urine), achieved by low water permeability of
the collecting duct, or electrolyte-free water conservation (concentrated urine), effected by the action of antidiuretic hormone (ADH),
which renders the collecting tubule permeable to water.
Na+ homeostasis basically occurs via filtration-reabsorption; it is
regulated by changes in effective arterial blood volume (EABV) mediated by neurohormonal afferent signals (e.g., renin-angiotensin-aldosterone system [RAAS]) that act directly on tubules. In the proximal
tubule, Na+ reabsorption is also regulated by peritubular physical factors. K+ undergoes an interesting sequence in which the filtered load is
largely reabsorbed in the proximal tubule and the thick ascending limb;
the final determinant of excretion is secretion by the collecting duct,
for which aldosterone and distal Na+ delivery are major regulators.
Only Ca2+ that is not bound to plasma protein is filtered; it is reabsorbed largely via paracellular pathways in the proximal tubule and
thick ascending limb and via transcellular pathways in the distal convoluted tubule.
A massive amount of bicarbonate (HCO
−
) is filtered and must be
3
reclaimed to forestall catastrophic acidosis. H+ secretion provides the
mechanism for HCO
−
reclamation as well as acid excretion, with the
3
H+ being carried by urinary buffers such as ammonia.
Metabolic Function
The kidney is a major metabolic organ. It consumes a wide range of fuels,
regulates plasma levels of metabolic substrates, and is a major source
of gluconeogenesis. Metabolic substrates such as amino acids, glucose,
organic anions, and fatty acids are converted to ATP, the universal
energy unit for all cells (see Fig. 23.2A). ATP is directly hydrolyzed by
proteins such as Na+/K+-ATPase to create a low intracellular Na+ concentration ([Na+]) and a negative interior cell voltage, thus translating
the chemical energy into chemical gradients. About 80% to 90% of the
oxygen consumption of the kidney can be attributed to Na+ transport.
For example, a protein such as the Na+-glucose cotransporter (sodium-glucose linked transporter [SGLT], see Fig. 23.2B) on the proximal
tubule luminal membrane, couples the movement of Na+ ions to glucose molecule (carrying a net positive charge). The low cell [Na+] and
negative voltage energize glucose uptake, allowing the proximal tubule
to capture most of the filtered glucose that otherwise would be lost in
the urine. In normal physiology, this glucose reclamation is beneficial
to conserve calories. The pharmacologic inhibition of Na+-coupled glucose reabsorption (SGLT-2 inhibitors) leads to low glycosuric threshold
and creation of a “glucose sink” to control glycemia. Surprisingly, many
additional beneficial cardiovascular and renal effects have been observed
with SGLT-2 inhibitors that are not explained by glycemic control.
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