- •Preface and Acknowledgments
- •Contents
- •Contributors
- •1: Embryology for Urologists
- •Introduction
- •Renal Development
- •Pronephros
- •Mesonephros
- •Metanephros
- •Development of the Collecting System
- •Critical Steps in Further Development
- •Anomalies of the Kidney
- •Renal Agenesis
- •Renal Aplasia
- •Renal Hypoplasia
- •Renal Ectopia
- •Renal Fusion
- •Ureteral Development
- •Anomalies of Origin
- •Anomalies of Number
- •Incomplete Ureteral Duplication
- •Complete Ureteral Duplication
- •Ureteral Ectopia
- •Embryology of Ectopia
- •Clinical Correlation
- •Location of Ectopic Ureteral Orifices – Male (in Descending Order According to Incidence)
- •Symptoms
- •Ureteroceles
- •Congenital Ureteral Obstruction
- •Pipestem Ureter
- •Megaureter-Megacystis Syndrome
- •Prune Belly Syndrome
- •Vascular Ureteral Obstructions
- •Division of the Urogenital Sinus
- •Bladder Development
- •Urachal Anomalies
- •Cloacal Duct Anomalies
- •Other Bladder Anomalies
- •Bladder Diverticula
- •Bladder Extrophy
- •Gonadal Development
- •Testicular Differentiation
- •Ovarian Differentiation
- •Gonadal Anomalies
- •Genital Duct System
- •Disorders of Testicular Function
- •Female Ductal Development
- •Prostatic Urethral Valves
- •Gonadal Duct Anomalies
- •External Genital Development
- •Male External Genital Development
- •Female External Genital Development
- •Anomalies of the External Genitalia
- •References
- •2: Gross and Laparoscopic Anatomy of the Upper Urinary Tract and Retroperitoneum
- •Overview
- •The Kidneys
- •The Renal Vasculature
- •The Renal Collecting System
- •The Ureters
- •Retroperitoneal Lymphatics
- •Retroperitoneal Nerves
- •The Adrenal Glands
- •References
- •3: Gross and Laparoscopic Anatomy of the Lower Urinary Tract and Pelvis
- •Introduction
- •Female Pelvis
- •Male Pelvis
- •Pelvic Floor
- •Urinary Bladder
- •Urethra
- •Male Urethra
- •Female Urethra
- •Sphincter Mechanisms
- •The Bladder Neck Component
- •The Urethral Wall Component
- •The External Urethral Sphincter
- •Summary
- •References
- •4: Anatomy of the Male Reproductive System
- •Testis and Scrotum
- •Spermatogenesis
- •Hormonal Regulation of Spermatogenesis
- •Genetic Regulation of Spermatogenesis
- •Epididymis and Ductus Deferens
- •Accessory Sex Glands
- •Prostate
- •Seminal Vesicles
- •Bulbourethral Glands
- •Penis
- •Erection and Ejaculation
- •References
- •5: Imaging of the Upper Tracts
- •Anatomy of the Upper Tracts and Introduction to Imaging Modalities
- •Introduction
- •Renal Upper Tract Basic Anatomy
- •Modalities Used for Imaging the Upper Tracts
- •Ultrasound
- •Radiation Issues
- •Contrast Issues
- •Renal and Upper Tract Tumors
- •Benign Renal Tumors
- •Transitional Cell Carcinoma
- •Renal Mass Biopsy
- •Renal Stone Disease
- •Ultrasound
- •Plain Radiographs and IVU
- •Renal Cystic Disease
- •Benign Renal Cysts
- •Hereditary Renal Cystic Disease
- •Complex Renal Cysts
- •Renal Trauma
- •References
- •Introduction
- •Pathophysiology
- •Susceptibility and Resistance
- •Epidemiological Breakpoints
- •Clinical Breakpoints
- •Pharmacodynamic Parameters
- •Pharmacokinetic Parameters
- •Fosfomycin
- •Nitrofurantoin
- •Pivmecillinam
- •b-Lactam-Antibiotics
- •Penicillins
- •Cephalosporins
- •Carbapenems
- •Aminoglycosides
- •Fluoroquinolones
- •Trimethoprim, Cotrimoxazole
- •Glycopeptides
- •Linezolid
- •Conclusion
- •References
- •7: An Overview of Renal Physiology
- •Introduction
- •Body Fluid Compartments
- •Regulation of Potassium Balance
- •Regulation of Acid–Base Balance
- •Diuretics
- •Suggested Reading
- •8: Ureteral Physiology and Pharmacology
- •Ureteral Anatomy
- •Modulation of Peristalsis
- •Ureteral Pharmacology
- •Conclusion
- •References
- •Introduction
- •Afferent Signaling Pathways
- •Efferent Signaling
- •Parasympathetic Nerves
- •Sympathetic Nerves
- •Vesico-Spinal-Vesical Micturition Reflex
- •Peripheral Targets
- •Afferent Signaling Mechanisms
- •Urothelium
- •Myocytes
- •Cholinergic Receptors
- •Muscarinic Receptors
- •Nicotinic Receptors
- •Adrenergic Receptors (ARs)
- •a-Adrenoceptors
- •b-Adrenoceptors
- •Transient Receptor Potential (TRP) Receptors
- •Phosphodiesterases (PDEs)
- •CNS Targets
- •Opioid Receptors
- •Serotonin (5-HT) Mechanisms
- •g-Amino Butyric Acid (GABA) Mechanisms
- •Gabapentin
- •Neurokinin and Neurokinin Receptors
- •Summary
- •References
- •10: Pharmacology of Sexual Function
- •Introduction
- •Sexual Desire/Arousal
- •Endocrinology
- •Steroids in the Male
- •Steroids in the Female
- •Neurohormones
- •Neurotransmitters
- •Dopamine
- •Serotonin
- •Pharmacological Strategies
- •CNS Drugs
- •Enzyme-inducing Antiepileptic Drugs
- •Erectile Function
- •Ejaculatory Function
- •Premature Ejaculation
- •Abnormal Ejaculation
- •Conclusions
- •References
- •Epidemiology
- •Calcium-Based Urolithiasis
- •Uric Acid Urolithiasis
- •Infectious Urolithiasis
- •Cystine-Based Urolithiasis
- •Aims
- •Who Deserves Metabolic Evaluation?
- •Metabolic Workup for Stone Producers
- •Medical History and Physical Examination
- •Stone Analysis
- •Serum Chemistry
- •Urine Evaluation
- •Urine Cultures
- •Urinalysis
- •Twenty-Four Hour Urine Collections
- •Radiologic Imaging
- •Medical Management
- •Conservative Management
- •Increased Fluid Intake
- •Citrus Juices
- •Dietary Restrictions
- •Restricted Oxalate Diet
- •Conservative Measures
- •Selective Medical Therapy
- •Absorptive Hypercalciuria
- •Thiazide
- •Orthophosphate
- •Renal Hypercalciuria
- •Primary Hyperparathyroidism
- •Hyperuricosuric Calcium Oxalate Nephrolithiasis
- •Enteric Hyperoxaluria
- •Hypocitraturic Calcium Oxalate Nephrolithiasis
- •Distal Renal Tubular Acidosis
- •Chronic Diarrheal States
- •Thiazide-Induced Hypocitraturia
- •Idiopathic Hypocitraturic Calcium Oxalate Nephrolithiasis
- •Hypomagnesiuric Calcium Nephrolithiasis
- •Gouty Diathesis
- •Cystinuria
- •Infection Lithiasis
- •Summary
- •References
- •12: Molecular Biology for Urologists
- •Introduction
- •Inherited Changes in Cancer Cells
- •VEGR and Cell Signaling
- •Targeting mTOR
- •Conclusion
- •References
- •13: Chemotherapeutic Agents for Urologic Oncology
- •Introduction
- •Bladder Cancer
- •Muscle Invasive Bladder Cancer
- •Metastatic Bladder Cancer
- •Conclusion
- •Prostate Cancer
- •Other Chemotherapeutic Drugs or Combinations for Treating HRPC
- •Conclusion
- •Renal Cell Carcinoma
- •Chemotherapy
- •Immunotherapy
- •Angiogenesis Inhibitor Drugs
- •Conclusion
- •Testicular Cancer
- •Stage I Seminoma
- •Stage I non-seminomatous Germ Cell Tumours (NSGCT)
- •Metastatic Germ Cell Tumours
- •Low-Volume Metastatic Disease (Stage II A/B)
- •Advanced Metastatic Disease
- •Salvage Chemotherapy for Relapsed or Refractory Disease
- •Conclusion
- •Penile Cancer
- •Side Effects of Chemotherapy
- •Conclusion
- •References
- •14: Tumor and Transplant Immunology
- •Antibodies
- •Cytotoxic and T-helper Cells
- •Immunosuppression
- •Induction Therapy
- •Maintenance Therapy
- •Rejection
- •Posttransplant Lymphoproliferative Disease
- •Summary
- •References
- •15: Pathophysiology of Renal Obstruction
- •Causes of Renal Obstruction
- •Effects on Prenatal Development
- •Prenatal Hydronephrosis
- •Spectrum of Renal Abnormalities
- •Renal Functional Changes
- •Renal Growth/Counterbalance
- •Vascular Changes
- •Inflammatory Mediators
- •Glomerular Development Changes
- •Mechanical Stretch of Renal Tubules
- •Unilateral Versus Bilateral
- •Limitations of Animal Models
- •Future Research
- •Issues in Patient Management
- •Diagnostic Imaging
- •Ultrasound
- •Intravenous Urography
- •Antegrade Urography and the Whitaker Test
- •Nuclear Renography
- •Computed Tomography
- •Magnetic Resonance Urography
- •Hypertension
- •Postobstructive Diuresis
- •References
- •Introduction
- •The Normal Lower Urinary Tract
- •Anatomy
- •Storage Function
- •Voiding Function
- •Neural Control
- •Symptoms
- •Flow Rate and Post-void Residual
- •Voiding Cystometry
- •Male
- •Female
- •Neurourology
- •Conclusions
- •References
- •17: Urologic Endocrinology
- •The Testis
- •Normal Androgen Metabolism
- •Epidemiological Aspects
- •Prostate
- •Brain
- •Muscle Mass and Adipose Tissue
- •Bones
- •Ematopoiesis
- •Metabolism
- •Cardiovascular System
- •Clinical Assessment
- •Biochemical Assessment
- •Treatment Modalities
- •Oral Preparations
- •Parenteral Preparations
- •Transdermal Preparations
- •Side Effects and Treatment Monitoring
- •Body Composition
- •Cognitive Decline
- •Bone Metabolism
- •The Kidneys
- •Endocrine Functions of the Kidney
- •Erythropoietin
- •Calcitriol
- •Renin
- •Paraneoplastic Syndromes
- •Hypercalcemia
- •Hypertension
- •Polycythemia
- •Other Endocrine Abnormalities
- •References
- •General Physiology
- •Prostate Innervation
- •Summary
- •References
- •Wound Healing
- •Inflammation
- •Proliferation
- •Remodeling
- •Principles of Plastic Surgery
- •Tissue Characteristics
- •Grafts
- •Flap
- •References
- •Lower Urinary Tract Symptoms
- •Storage Phase
- •Voiding Phase
- •Return to Storage Phase
- •Urodynamic Parameters
- •Urodynamic Techniques
- •Volume Voided Charts
- •Pad Testing
- •Typical Test Schedule
- •Uroflowmetry
- •Post Voiding Residual
- •Further Diagnostic Evaluation of Patients
- •Cystometry with or Without Video
- •Cystometry
- •Videocystometrography (Cystometry + Cystourethrography)
- •Cystometric Findings
- •Comment:
- •Measurements During the Storage Phase:
- •Measurements During the Voiding Phase:
- •Abnormal Function
- •Disorders of Sensation
- •Causes of Hypersensitive Bladder Sensation
- •Causes of Hyposensitive Bladder Sensation
- •Disorders of Detrusor Motor Function
- •Bladder Outflow Tract Dysfunction
- •Detrusor–Urethral Dyssynergia
- •Detrusor–Bladder Neck Dyssynergia
- •Detrusor–Sphincter Dyssynergia
- •Complex Urodynamic Investigation
- •Urethral Pressure Measurement
- •Technique
- •Neurophysiological Evaluation
- •Conclusion
- •References
- •Endoscopy
- •Cystourethroscopy
- •Ureteroscopy and Ureteropyeloscopy
- •Nephroscopy
- •Virtual Reality Simulators
- •Lasers
- •Clinical Application of Lasers
- •Condylomata Acuminata
- •Urolithiasis
- •Benign Prostatic Hyperplasia
- •Ureteral and Urethral Strictures
- •Conclusion
- •References
- •Introduction
- •The Prostatitis Syndromes
- •The Scope of the Problem
- •Category III CP/CPPS
- •The Goal of Treatment
- •Conservative Management
- •Drug Therapy
- •Antibiotics
- •Anti-inflammatories
- •Alpha blockers
- •Hormone Therapies
- •Phytotherapies
- •Analgesics, muscle relaxants and neuromodulators
- •Surgery
- •A Practical Management Plan
- •References
- •Orchitis
- •Definition and Etiology
- •Clinical Signs and Symptoms
- •Diagnostic Evaluation
- •Treatment of Infectious Orchitis
- •Epididymitis
- •Definition and Etiology
- •Clinical Signs and Symptoms
- •Diagnostic Evaluation of Epididymitis
- •Treatment of Acute Epididymitis
- •Treatment of Chronic Epididymitis
- •Treatment of Spermatic Cord Torsion
- •Fournier’s Gangrene
- •Definition and Etiology
- •Risk Factors
- •Clinical Signs and Symptoms
- •Diagnostic Evaluation
- •Treatment
- •References
- •Fungal Infections
- •Candidiasis
- •Aspergillosis
- •Cryptococcosis
- •Blastomycosis
- •Coccidioidomycosis
- •Histoplasmosis
- •Radiographic Findings
- •Treatment
- •Tuberculosis
- •Clinical Manifestations
- •Diagnosis
- •Treatment
- •Schistosomiasis
- •Clinical Manifestations
- •Diagnosis
- •Treatment
- •Filariasis
- •Clinical Manifestations
- •Diagnosis
- •Treatment
- •Onchocerciasis
- •References
- •25: Sexually Transmitted Infections
- •Introduction
- •STIs Associated with Genital Ulcers
- •Herpes Simplex Virus
- •Diagnosis
- •Treatment
- •Chancroid
- •Diagnosis
- •Treatment
- •Syphilis
- •Diagnosis
- •Treatment
- •Lymphogranuloma Venereum
- •Diagnosis
- •Treatment
- •Chlamydia
- •Diagnosis
- •Treatment
- •Gonorrhea
- •Diagnosis
- •Treatment
- •Trichomoniasis
- •Diagnosis
- •Treatment
- •Human Papilloma Virus
- •Diagnosis
- •Treatment
- •Scabies
- •Diagnosis
- •Treatment
- •References
- •26: Hematuria: Evaluation and Management
- •Introduction
- •Classification of Hematuria
- •Macroscopic Hematuria
- •Microscopic Hematuria
- •Dipstick Hematuria
- •Pseudohematuria
- •Factitious Hematuria
- •Menstruation
- •Aetiology
- •Malignancy
- •Urinary Calculi
- •Infection and Inflammation
- •Benign Prostatic Hyperplasia
- •Trauma
- •Drugs
- •Nephrological Causes
- •Assessment
- •History
- •Examination
- •Investigations
- •Dipstick Urinalysis
- •Cytology
- •Molecular Tests
- •Blood Tests
- •Flexible Cystoscopy
- •Upper Urinary Tract Evaluation
- •Renal USS
- •KUB Abdominal X-Ray
- •Intravenous Urography (IVU)
- •Computed Tomography (CT)
- •Retrograde Urogram Studies
- •Magnetic Resonance Imaging (MRI)
- •Additional Tests and Renal Biopsy
- •Intractable Hematuria
- •Loin Pain Hematuria Syndrome
- •References
- •27: Benign Prostatic Hyperplasia (BPH)
- •Historical Background
- •Pathophysiology
- •Patient Assessment
- •Treatment of BPH
- •Watchful Waiting
- •Drug Therapy
- •Interventional Therapies
- •Conclusions
- •References
- •28: Practical Guidelines for the Treatment of Erectile Dysfunction and Peyronie´s Disease
- •Erectile Dysfunction
- •Introduction
- •Diagnosis
- •Basic Evaluation
- •Cardiovascular System and Sexual Activity
- •Optional Tests
- •Treatment
- •Medical Treatment
- •Oral Agents
- •Phosphodiesterase Type 5 (PDE 5) Inhibitors
- •Nonresponders to PDE5 Inhibitors
- •Apomorphine SL
- •Yohimbine
- •Intracavernosal and Intraurethral Therapy
- •Intracavernosal Injection (ICI) Therapy
- •Intraurethral Therapy
- •Vacuum Constriction Devices
- •Surgical Therapy
- •Conclusion
- •Peyronie´s Disease (PD)
- •Introduction
- •Oral Drug Therapy
- •Intralesional Drug Therapy
- •Iontophoresis
- •Radiation Therapy
- •Surgical Therapy
- •References
- •29: Premature Ejaculation
- •Introduction
- •Epidemiology
- •Defining Premature Ejaculation
- •Voluntary Control
- •Sexual Satisfaction
- •Distress
- •Psychosexual Counseling
- •Pharmacological Treatment
- •On-Demand Treatment with Tramadol
- •Topical Anesthetics
- •Phosphodiesterase Inhibitors
- •Surgery
- •Conclusion
- •References
- •30: The Role of Interventional Management for Urinary Tract Calculi
- •Contraindications to ESWL
- •Complications of ESWL
- •PCNL Access
- •Instrumentation for PCNL
- •Nephrostomy Drains Post PCNL
- •Contraindications to PCNL
- •Complications of PCNL
- •Semirigid Ureteroscopy
- •Flexible Ureteroscopy
- •Electrohydraulic Lithotripsy (EHL)
- •Ultrasound
- •Ballistic Lithotripsy
- •Laser Lithotripsy
- •Ureteric Stents
- •Staghorn Calculi
- •Lower Pole Stones
- •Horseshoe Kidneys and Stones
- •Calyceal Diverticula Stones
- •Stones and PUJ Obstruction
- •Treatment of Ureteric Colic
- •Medical Expulsive Therapy (MET)
- •Intervention for Ureteric Stones
- •Stones in Pregnancy
- •Morbid Obesity
- •References
- •Anatomy and Function
- •Pathophysiology
- •Management
- •Optical Urethrotomy/Dilatation
- •Urethral Stents
- •Preoperative Assessment
- •Urethroplasty
- •Anastomotic Urethroplasty
- •Substitution Urethroplasty
- •Grafts Versus Flaps
- •Oral Mucosal Grafts
- •Tissue Engineering
- •Graft Position
- •Conclusion
- •References
- •32: Urinary Incontinence
- •Epidemiology and Risk Factors
- •Pathophysiology
- •Urge Incontinence
- •Conservative Treatments
- •Pharmacotherapy
- •Invasive/ Surgical Therapies
- •Stress Urinary Incontinence
- •Male SUI Therapies
- •Female SUI Therapies
- •Mixed Urinary Incontinence
- •Conclusions
- •References
- •33: Neurogenic Bladder
- •Introduction
- •Examination and Diagnostic Tests
- •History and Physical Examination
- •Imaging
- •Urodynamics (UDS)
- •Evoked Potentials
- •Classifications
- •Somatic Pathways
- •Brain Lesions
- •Cerebrovascular Accident (CVA)
- •Parkinson’s Disease (PD)
- •Multiple Sclerosis
- •Huntington’s Disease
- •Dementias
- •Normal Pressure Hydrocephalus (NPH)
- •Tumors
- •Psychiatric Disorders
- •Spinal Lesions and Pathology
- •Intervertebral Disk Prolapse
- •Spinal Cord Injury (SCI)
- •Transverse Myelitis
- •Peripheral Neuropathies
- •Metabolic Neuropathies
- •Pelvic Surgery
- •Treatment
- •Summary
- •References
- •34: Pelvic Prolapse
- •Introduction
- •Epidemiology
- •Anatomy and Pathophysiology
- •Evaluation and Diagnosis
- •Outcome Measures
- •Imaging
- •Urodynamics
- •Indications for Management
- •Biosynthetics
- •Surgical Management
- •Anterior Compartment Repair
- •Uterine/Apical Prolapse
- •Enterocele Repair
- •Conclusion
- •References
- •35: Urinary Tract Fistula
- •Introduction
- •Urogynecologic Fistula
- •Vesicovaginal Fistula
- •Etiology and Risk Factors
- •Clinical Factors
- •Evaluation and Diagnosis
- •Pelvic Examination
- •Cystoscopy
- •Imaging
- •Treatment
- •Conservative Management
- •Surgical Management
- •Urethrovaginal Fistula
- •Etiology and Presentation
- •Diagnosis and Management
- •Ureterovaginal Fistula
- •Etiology and Presentation
- •Diagnosis and Management
- •Vesicouterine Fistula
- •Etiology and Presentation
- •Diagnosis and Management
- •Uro-Enteric Fistula
- •Vesicoenteric Fistula
- •Pyeloenteric Fistula
- •Urethrorectal Fistula
- •References
- •36: Urologic Trauma
- •Introduction
- •Kidney
- •Expectant Management
- •Endovascular Therapy
- •Operative Intervention
- •Operative Management: Follow-up
- •Reno-Vascular Injuries
- •Pediatric Renal Injuries
- •Adrenal
- •Ureter
- •Diagnosis
- •Treatment
- •Delayed Diagnosis
- •Bladder and Posterior Urethra
- •Bladder Injuries: Initial Management
- •Bladder Injuries: Formal Repair
- •Anterior Urethral Trauma
- •Fractured Penis
- •Penile Amputation
- •Scrotal and Testicular Trauma
- •Imaging
- •CT-IVP (CT with Delayed Images)
- •Technique
- •Cystogram
- •Technique
- •Retrograde Urethrogram (RUG)
- •Technique
- •Retrograde Pyelogram (RPG)
- •Technique
- •One-Shot IVP
- •Technique
- •References
- •37: Bladder Cancer
- •Who Should Be Investigated?
- •Epidemiology
- •Risk Factors
- •Role of Screening
- •Signs and Symptoms
- •Imaging
- •Cystoscopy
- •Urine Tests
- •PDD-Assisted TUR
- •Pathology
- •NMIBC and Risk Groups
- •Intravesical Chemotherapy
- •Intravesical Immunotherapy
- •Immediate Cystectomy and CIS
- •Radical Cystectomy with Pelvic Lymph Node Dissection
- •sexual function-preserving techniques
- •Bladder-Preservation Treatments
- •Neoadjuvant Chemotherapy
- •Adjuvant Chemotherapy
- •Preoperative Radiotherapy
- •Follow-up After TUR in NMIBC
- •References
- •38: Prostate Cancer
- •Introduction
- •Epidemiology
- •Race
- •Geographic Variation
- •Risk Factors and Prevention
- •Family History
- •Diet and Lifestyle
- •Prevention
- •Screening and Diagnosis
- •Current Screening Recommendations
- •Biopsy
- •Pathology
- •Prognosis
- •Treatment of Prostate Cancer
- •Treatment for Localized Prostate Cancer (T1, T2)
- •Radical Prostatectomy
- •EBRT
- •IMRT
- •Brachytherapy
- •Treatment for Locally Advanced Prostate Cancer (T3, T4)
- •EBRT with ADT
- •Radical Prostatectomy
- •Androgen-Deprivation Therapy
- •Summary
- •References
- •39: The Management of Testis Cancer
- •Presentation and Diagnosis
- •Serum Tumor Markers
- •Primary Surgery
- •Testis Preserving Surgery
- •Risk Stratification
- •Surveillance Versus Primary RPLND
- •Primary RPLND
- •Adjuvant Treatment for High Risk
- •Clinical Stage 1 Seminoma
- •Risk-Stratified Adjuvant Treatment
- •Adjuvant Radiotherapy
- •Adjuvant Low Dose Chemotherapy
- •Primary Combination Chemotherapy
- •Late Toxicity
- •Salvage Strategies
- •Conclusion
- •References
- •Index
190
Practical Urology: EssEntial PrinciPlEs and PracticE
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while attempting to prevent rejection and main- |
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drug to utilize. There is significant bias from one |
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tain the immune system’s integrity. This is a |
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transplant center to another, and pharmaceuti- |
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delicate balance to strike. Complicating the issue |
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cal companies compete actively. |
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is individualizing patients’sensitivities to immu- |
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Modern immunosuppressive therapy may be |
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broken down into three distinct types. The initial |
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physiologic states that may affect their levels of |
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apy. This entails the use of antibody preparations |
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successful renal |
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within the first week posttransplant to reduce |
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long-term function was performed by Joseph |
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exposure to calcineurin inhibitor toxicity or to |
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Murray between twin males in 1954. During this |
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decrease the incidence of rejection within the |
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organs were |
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first 6 months. Maintenance therapy is the life- |
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long use of immunosuppression to prevent rejec- |
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matching between twin siblings during this era |
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tion. This therapy is frequently fine-tuned over |
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of transplantation. The progression of immuno- |
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the lifetime of the allograft. Often, the therapy is |
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suppression began with the institution of total |
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weaned to lower levels as some level of tolerance |
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body irradiation, thoracic duct drainage, and |
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is achieved. Furthermore, the incidence of rejec- |
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splenectomy. During the late 1950s and early |
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tion is highest during the first 6 months of trans- |
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1960s, pharmacologic methods of immune sup- |
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plantation. Finally, rejection is observed when |
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pression became prevalent.Corticosteroids were |
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the innate immune system recognizes the foreign |
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employed in 1956 and azathioprine was intro- |
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organ and begins to mount a response. This |
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duced in 1962. Polyclonal antibodies were devel- |
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occurs secondary to many causes including drug |
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oped in the mid-1960s. These advances were |
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noncompliance,malabsorption of drug,etc.Most |
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brought from the basic science laboratories to |
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often, |
use of high-dose steroids |
or antibody |
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the clinical bedside and permitted for the pre- |
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preparations are employed to reverse rejection. |
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vention of rejection and long-term maintenance |
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of the functioning allograft. |
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Major advances in the field of transplantation |
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mirrored such advancements in immunosup- |
Induction Therapy |
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pression. With the discoveries of cyclosporine |
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and tacrolimus, the field of transplantation was |
The goal of induction therapy is to provide potent |
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transformed. It became commonplace to expect |
immunosuppressive activity during the initial |
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and achieve long-term graft survival with more |
7–14 days following transplantation. This allows |
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easily treatable and less frequent allograft rejec- |
for coverage of the patient while introducing and |
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tions. The mechanism of action of cyclosporine |
titratingmaintenanceimmunosuppressivedrugs. |
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and tacrolimus is the inhibition of calcineurin. |
Induction has been demonstrated to be extremely |
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This prevents the transcription of IL-2, and its |
effective in decreasing rates of rejection. Its use |
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subsequent actions on T-cells as described |
has increased as has its effectiveness. Polyclonal |
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above. |
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antibody preparations include Atgam and |
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The pharmacologic principles of immuno- |
Thymoglobulin, while monoclonal preparations |
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suppression have evolved since their inception. |
include OKT3, Basiliximab, Alemtuzumab, and |
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The goal is to titrate the immune response to |
Daclizumab. Standard for induction therapy has |
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prevent rejection while attempting not to over- |
been the use of high-dose steroids and, in some |
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immunosuppress and elicit infection. Immu- |
cases, an antilymphocyte antibody preparation. |
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nosuppression is usually initiated before or |
Unfortunately, it is an expensive endeavor, cost- |
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during surgery. Furthermore, other drugs have |
ing $1,000–$1,500 per day of treatment. |
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been developed such as mycophenolate mofetil, |
Thymoglobulin |
induces dose-dependent |
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an inosine |
monophosphate |
dehydrogenase |
T-cell depletion in both the blood and periph- |
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inhibitor, to assist as antirejection therapies. The |
eral lymphoid tissues. This depletion is thought |
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concomitant use of all of these therapies has |
to involve complement-dependent lysis and |
191
tUmor and transPlant immUnology
activation-associated apoptosis. Thymoglobulin |
period, while other centers administer the doses |
also modulates several functional molecules |
split over several days. Of course, many centers |
that mediate the interaction between leukocytes |
fall in between these two extremes. Others advo- |
and the endothelium. As a result, there is decre- |
cate the use of induction in only select cases. |
ased leukocyte adhesion and translocation into |
What is clear is that highly sensitized patients |
sites of inflammation (Figs. 14.2 and 14.3)8-11). |
benefit from the use of a combined steroid and |
The monoclonal antibody preparations have |
antilymphocyte regimen as induction. These |
gained some acceptance as well. The original |
highly sensitized patients include those with |
monoclonal antibody, OKT3, is T-cell directed. It |
previous exposure to blood transfusions, previ- |
binds CD3 and was historically used for induc- |
ous transplantation, and African-Americans. |
tion as well as treatment of rejection. Unfor- |
Induction therapy occasionally prolongs hos- |
tunately, it may cause a cytokine release |
pitalization.As a result,some centers have begun |
syndrome initiating a life-threatening anaphy- |
to alter the administration schedule as outlined |
lactoid reaction resulting in hypotension and |
above. Antilymphocyte antibody preparations |
pulmonary edema. Newer monoclonal prepara- |
are often given as a single dose initiated periop- |
tions include Daclizumab and Basiliximab. They |
eratively and continued until the final and goal |
are monoclonal antibodies directed at the IL-2 |
dose is achieved. Many agree that a full dose |
receptor. They are primarily utilized for induc- |
constitutes 6 mg/kg. Significant side effects can |
tion and have few, if any, side effects. |
be observed secondary to induction therapy. |
There are as many derivations of induction |
Many cytokines are released as a consequence |
therapy as there are transplant centers. There is |
of induction. Potential opportunistic infections |
obviously no clear and correct manner to |
occur at an increased rate and pose a significant |
administer induction therapy. Some centers will |
threat to the patient as well as the allograft via- |
administer the entire induction at once during |
bility. Rarely, a patient may also develop anti- |
the operative and immediate postoperative |
bodies to the antilymphocyte antibody. |
Thymoglobulin® |
Thymoglobulin® |
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Thymoglobulin® |
Human |
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iC3b |
Complement |
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(C1q...) |
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T cell |
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T cell |
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T cell |
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FcR |
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CR3 |
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CD14 |
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Macrophage |
Complement |
CD36 |
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anb3 |
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cascade |
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PS-R |
Macrophage |
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ABC-1 |
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Opsonization |
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etc. |
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Membrane attack |
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Apoptosis |
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complex |
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Lysis |
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Phagocytosis |
Phagocytosis |
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Demonstrated |
Demonstrated |
Hypothetical |
Figure 14.2. thymoglobulin® t-cell depletion: possible mechanisms (adapted from Brennan8 and von andrian9).
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192 |
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Practical Urology: EssEntial PrinciPlEs and PracticE |
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Leukocytes |
Endothelium |
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PSGL-1 (CD162) |
P-selectin (CD62-P) |
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L-selectin (CD62-L) |
CD34 (on HEV) |
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Sialyl Lewis X |
E-selectin (CD62-E) |
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7 TM |
Chemokines, |
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receptors |
PAF, CD5a |
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LFA-1 |
ICAM-1 |
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(CD54) |
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(CD11a/CD18) |
ICAM-2 |
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(CD102) |
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VLA-4 |
VCAM-1 |
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(CD49d/CD29) |
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(CD106) |
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a4b7 |
MAdCAM-1 |
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(CD49d/b7) |
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Down-modulation of adhesion molecules by
Thymoglobulin®
Figure 14.3. thymoglobulin® down-modulation: interactions between leukocytes and endothelium. (courtesy of genzyme corporation; adapted from genestier et al.10 and Préville et al.11)
Maintenance Therapy
Allograft tolerance remains the “Holy Grail” for the field of transplantation. Unfortunately, only limited success has been achieved with regard to this goal. Consequently, maintenance therapy is required for the life of the allograft. Commonly accepted practice with regards to posttransplant immunosuppression involves the use of one to three drugs for the life of the allograft. The decision to utilize one drug versus another depends on the type of organ transplanted and is often transplant center dependent. If no rejection is encountered, the general premise is to reduce the dose of immunosuppression or discontinue the use of some of the drugs with time. If the patient experiences rejection, the immunosuppression is most often increased or different drug therapies are employed.
The discussion on which immunosuppressants to utilize usually begins with the calcineurin inhibitors, namely, Cyclosporine and Tacrolimus. The calcineurin inhibitors exert their mechanism of action as inhibition of T-cells by preventing the transcription and subsequent release of IL-2. They have transformed solid organ transplant significantly. The rates of
rejection have plummeted since their inception. Furthermore, allograft survival has greatly increasedsincetheirintroduction.Unfortunately, they do have common and significant side effect profiles. Cyclosporine has been associated with hirsutism, gingival hyperplasia, hyperlipidemia, hypertension, hypomagnesemia, and nephrotoxicity. Tacrolimus is slightly more potent than cyclosporine. It has similar drug interactions as cyclosporine but has a greater propensity to cause hyperglycemia. Tacrolimus also has better bioavailability than cyclosporine and has enabled steroid reduction protocols. With renal transplantation, there appears to be a less rapid decline in glomerular filtration rates.12 Furthermore, several studies have suggested that lower rates of rejection are observed with tacrolimus use.13,14 As a result, tacrolimus has gained wider acceptance nationally. Another immunomodulator, Sirolimus, has gained recent acceptance for having less nephrotoxicity and less likelihood in causing PTLD. Sirolimus binds to immunophilin (FK Binding Protein-12) to generate an immunosuppressive complex. The sirolimus:FKBP-12 complex does not affect calcineurin activity. Rather, this complex binds to and inhibits the activation of the mammalian
193
tUmor and transPlant immUnology
Target Of Rapamycin (mTOR), a key regulatory |
gain, ulcers, and nausea. They cause hyperglyce- |
kinase. This inhibition suppresses cytokine- |
mia and promote diabetes mellitus. Acne, hir- |
driven T-cell proliferation, inhibiting the pro- |
sutism, skin atrophy, and easy bruising are |
gression from the G1 to the S phase of the cell |
frequent side effects. Muscle weakness and |
cycle. Its main side effect is the inhibition of the |
osteoporosis often ensue. Many patients experi- |
healing process; however, it may also cause |
ence edema, hypertension, and hypernatremia. |
hyperlipidemia and bone marrow suppression. |
Ultimately, a subset of patients with long-term |
Sirolimus use has become more popular because |
steroid use may develop Cushing’s syndrome. |
of lower rates of chronic rejection relative to |
Transplant physicians and surgeons are con- |
cyclosporine-based therapy.15 |
stantly adjusting immunosuppression on a per- |
The second drug added to the immunosup- |
sonalized patient basis for the life of the allograft |
pression regimen is often mycophenolate mofetil |
and patient. These judgments are made based |
(Cellcept, MMF), mycophenolic acid (Myfortic, |
on each patient’s clinical presentation, labora- |
enteric-coated MMF), or azathioprine (Imuran). |
tory values, and other associated or unassoci- |
Azathioprine was one of the first drugs devel- |
ated illnesses. In general, patients require higher |
oped for immunosuppression and has a storied |
levels of immunosuppression early in their post- |
role in the early progression of kidney and liver |
operative course; however, immunosuppression |
transplantation. It decreases both T- and B-cell |
may be weaned to lower levels within 3–6 months |
production by antagonizing purine metabolism. |
posttransplant in most cases. The balance |
As a result, it inhibits synthesis of DNA, RNA, |
between excessive and inadequate imunosup- |
and proteins. Azathioprine may also interfere |
pression must be found. A steady-state immu- |
with cellular metabolism and inhibit mitosis. |
nosuppressive regimen may be altered by the |
Azathioprine unfortunately has been associated |
patient’s pharmacokinetics and dynamics or |
with bone marrow suppression, pancreatitis, |
a concomitant illness. As a result, immuno- |
and has significant drug interactions. Myco- |
suppression should be adjusted accordingly. |
phenolate mofetil and mycophenolic acid pri- |
Over-immunosuppression may result in an opp- |
marily decrease B-cell production, although |
ortunistic infection, malignancy, or PTLD. |
they exert some effect on T-cells. They are selec- |
Under-immunosuppression will almost inevita- |
tive but reversible inhibitors of inosine mono- |
bly result in organ rejection. |
phosphate dehydrogenase, which is a critical |
|
enzyme for the de novo synthesis of guanosine |
Rejection |
nucleotides. They have been found to decrease |
|
the incidence of antibody-mediated rejection |
Organ rejection manifests as an innate immu- |
and reduce the prevalence of chronic rejec- |
nologic reaction to donor tissue. There are four |
tion.13,16 They have some minor bone marrow |
main types: hyperacute, accelerated, acute, and |
suppressive effects, but their primary side effect |
chronic. The outcome may result in organ dam- |
is gastrointestinal disturbance, which may be |
age with the possible eventual loss of the |
decreased with the enteric-coated form. |
allograft. Moreover, only acute rejection is com- |
Corticosteroids are the third drug class in the |
pletely responsive to therapy. Hyperacute rejec- |
armamentarium of maintenance therapy. They |
tion is extremely rare and, in most cases, |
are usually used in the IV or PO forms, methyl- |
preventable. These are the so-called pre-formed |
prednisolone or prednisone, respectively. Ster- |
antibodies that immediately attack the foreign |
oids have a broad set of physiologic effects and |
organ.Anti-HLA antibodies within the serum of |
subsequent side effects. In the field of solid |
the recipient react towards the donor organ. The |
organ transplantation, they are employed in the |
onset is nearly immediate within minutes to |
prevention as well as the treatment of rejection. |
hours. Vascular damage begins immediately |
With regard to immunosuppression, they inhibit |
resulting in inflammation, congestion, throm- |
T-cells, IL-2, and antibody formation. Unfor- |
bosis, and necrosis. Unfortunately, the only |
tunately,steroids have serious deleterious effects. |
recourse is to remove the offending organ. |
Centrally, they can often cause mood swings and |
Accelerated rejection is a more indolent form |
psychoses as well as cataracts and glaucoma. |
of hyperacute rejection. There is usually a low |
From a gastrointestinal standpoint, they are |
level of circulating non-HLA antibody against |
associated with increased appetite and weight |
donor tissue. The onset occurs 3–10 days |