Nathan Roberts, MD
Patrick J. Shenot, MD, FACS
BASICS
DESCRIPTION
• Immunocompromised patients have attenuated immune responses caused by:
– Immunosuppressive drugs (chemotherapy)
– Radiation (bone marrow irradiation)
– Hematopoietic stem cell transplant
– Malnutrition
– Disease processes (HIV, lymphoma, congenital immune deficiencies, autoimmune disorders)
• Immunocompromised patients are at risk for opportunistic infections
• Hematopoietic stem cell transplant
– Need preparative regimens to prevent rejection of transplanted graft: Complete myeloablative, Nonmyeloablative or +/– chemotherapy
• Miliary tuberculosis
– Hematogenous dissemination of Mycobacterium tuberculosis
– HIV coinfection is common; 38% with military TB patients also have HIV
EPIDEMIOLOGY
Incidence
• HIV infections
– 2.7 million new HIV infections worldwide
• Tuberculosis
– 11,182 reported cases in US in 2010
– 22% of cases were extrapulmonary
– 2.7% were miliary TB
Prevalence
HIV/AIDS: 1.2 million Americans
RISK FACTORS
• Hemorrhagic cystitis (HC) (1)
– Increased degree of immunosuppression
BK virus Hemorrhagic cystitis (HC)
– Early onset Hemorrhagic cystitis (HC)
Conditioning regimen used for Hematopoetic stem cell transplant (HSCT) with cyclophosphamide, busulfan, or with antithymocyte globulin (4)
Donor–recipient gender mismatch
– Late onset Hemorrhagic cystitis (HC)
Allogenic HSCT transplant
Graft versus host disease (GVHD)
– Use of corticosteroids or cyclosporine for GVHD
Use of T-cell depleted grafts
Need for blood transfusions
• HIV/AIDS
– Unprotected high-risk sexual contact
– Blood transfusion
– Uncircumcised Men
– Occupational exposure
• Tuberculosis
– HIV infections: 14% of TB patients have HIV
PATHOPHYSIOLOGY
• Cyclophosphamide/busulfan
– Metabolized in the liver to acrolein
toxic to urothelium; prolonged exposure in the bladder causes increased inflammatory mediators: Bladder mucosal edema, vascular dilation, and increased capillary fragility
Long-term increased bladder cancer risk
• Polyoma virus–related hematuria (see Polyoma virus [BK, JC]), urologic considerations
• HIV/AIDS
– Virus targets CD4+ T cells
Virus targets CCR5 expressing CD4+ cells;
with decreased CD4 lymphocyte count. Mucosal tissues preferentially targeted, leads to immunosuppression
• TB genitourinary involvement
– Hematogenous spread → renal capillaries → renal cortex → immune response → chronic inflammation → granuloma with central caseous necrosis → inflammation into renal tubules and medulla → renal papilla sloughing → calyceal ulceration → fibrosis from healing → calyceal infundibular narrowing or UPJ scarring → hydronephrosis
– Tubercles can also form in distal ureter leading to stricture
ASSOCIATED CONDITIONS
• HIV/AIDS; indinavir calculus
• TB
• Any cause requiring bone marrow transplant
• Urethritis: Reiter syndrome, arthritis
GENERAL PREVENTION
• HIV/AIDS: Protection during sexual activity; universal precautions for healthcare professionals
• Miliary tuberculosis: Treatment of latent TB can prevent miliary TB
DIAGNOSIS
HISTORY
• HC
– Ranging from pink urine to clot retention
– Can also have bladder pain and or lower urinary tract symptoms (LUTS)
• HIV/AIDS (2)
– Increased risk of transmission and acquisition of sexually transmitted infections
Atypical and prolonged course; genital lesions do not respond to normal treatments
Can present with symptomatic genitourinary tract infections
Testicular pain: Epididymitis/orchitis are common findings
Can be positive for LUTS with prostatitis
Cystitis: Increased risk of bladder infections
Urolithiasis: Can present with typical complaints of ureteral calculus (flank pain, nausea, vomiting, dysuria, increased frequency, urgency)
Can present with voiding dysfunction
Commonly present with urinary retention
Detrusor hyperreflexia, LUTS for bladder outlet syndrome
• Miliary tuberculosis
– Failure to thrive, fever of unknown origin and night sweats, anorexia, weight loss
Subacute or chronic presentation more common; can have dysfunction of one or more organ system
50% have pulmonary disease with dyspnea or cough
– Genitourinary involvement
Hematuria; small percentage may be passing material in urine (caseous material)
Flank pain, symptoms of cystitis, LUTS (storage symptoms), scrotal pain, male infertility workup; hematospermia
PHYSICAL EXAM
• HC
– May present with palpable bladder if in clot retention
• HIV/AIDS
– Most common intrascrotal pathology in AIDS is testicular atrophy
Secondary to endocrine imbalances, febrile episodes, malnutrition, testicular infections, and toxic effects of therapeutic agents
– Prostatitis
Boggy prostate
– Scrotal swelling/testicular pain
Epididymitis/orchitis caused by common and uncommon organisms (Candida, CMV, toxoplasmosis)
– Voiding dysfunction
May have enlarged prostate
• Miliary tuberculosis
– Pulmonary: Course breath sounds on auscultation, may have lymphadenopathy
– Genitourinary involvement
Possible costovertebral angle tenderness
Epididymal/prostate tenderness
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• HIV/AIDS
– HIV ELISA for anti-HIV-1 and 2
>99% sensitivity; Western blot to exclude false-positive but also to confirm HIV diagnosis
– Plasma HIV RNA
Detectable by day 12; antibodies detected day 21
Used to assess treatment response/failure HIV-associated nephropathy: Proteinuria-increased creatinine
• Tuberculosis
– PPD; may be false negative
– Mycobacterial blood cultures
Urinalysis: Sterile pyuria, possible hematuria
Urine acid fast bacilli (AFB) culture
Imaging
• HC
– CT with and without contrast: Can show clot, filling defect, calculus
• HIV/AIDS
– Urolithiasis
CT non contrast may be associated with minimal findings with indinavir calculus
– Kidney infection
CT scan: Can see striated nephrogram in pyelonephritis, abscess
• Tuberculosis
– Chest radiograph (miliary disease)
Faint, reticulonodular infiltrate distributed fairly uniformly throughout the lungs
– GU findings: Disparity in renal size. Larger may indicate caseous lesions or shrunken and fibrotic from autonephrectomy
Autonephrectomy: Diffuse, uniform, extensive parenchymal, putty-like calcification, a lobar cast of the kidney
Calcifications in 30–50% of cases (seen in caseating lesions)
Calculi may also be seen in the collecting system or ureter secondary to stricture formation
Ureteral calcifications are rare and are characteristically intraluminal
Bladder wall calcifications are not very common except in late cases of bladder contraction
Calcifications of the prostate and seminal vesicles are seen in 10% of cases
– Contrast-enhanced computed tomography
Renal parenchymal masses and scarring
Thick urinary tract walls
Tuberculoma: Renal mass coalescing caseating granulomas
Can see hydronephrosis
Sensitive in seeing the calcifications
Contrast can evaluate function of the kidney
– Ultrasound: Limited in diagnosis, Can be used for monitoring disease progression
Diagnostic Procedures/Surgery
• HC
– Cystoscopy, possible ureteroscopy
• HIV/AIDS
– Kidney biopsy: Help to diagnose HIV-associated nephropathy (HIVAN)
– Voiding dysfunction
May warrant UDS, may uncover neurogenic voiding dysfunction
Post-void residuals, cystoscopy
• Tuberculosis
– Biopsy of the following can demonstrate granulomas and be used for culture: lung, bone marrow, lymph nodes, bones, joints, liver, brain, and other tissues
– Cystoscopy/retrograde pyelograms
Limited in diagnosis: Stricture, acute UO inflammation, acute tuberculous ulcer. Golf hole ureter: Circular and often excessively lateral ureteral orifice
Pathologic Findings
• Tuberculosis
– Granulomatous inflammation
Contain epithelioid macrophages, Langhans giant cells, and lymphocytes
Contain caseation necrosis
Organisms may or may not be seen with acid fast staining
• HIV
– HIV-associated nephropathy (HIVAN)
Collapsing form of focal segmental glomerulosclerosis
Dilated tubules and interstitial inflammation
DIFFERENTIAL DIAGNOSIS
• HC
– Infectious source
Bacterial
Viral BK vs. adenovirus, CMV, JC, and herpes
• HIV
– Voiding dysfunction
Patient may have underlying neurologic opportunistic infection
TREATMENT
GENERAL MEASURES
• Reduction of immunosuppression (if possible) can help to reduce clinical sequelae
• HIV patients have higher risk of bladder infections than non-HIV patients
– Associated with typical uropathogens
– Salmonella is of particular concern due to high-risk fatal recurrence (may need chronic suppression)
MEDICATION
First Line
• HC
– Increased hydration
– Catheter placement with clot evacuation
– Continuous bladder irrigation (CBI)
• HIV/AIDS
– Antiretroviral therapy (ART)
• Miliary TB (3)
– Standard pulmonary therapy
– Often directly observed therapy
– Isoniazid (INH), rifamycin (rifampin), pyrazinamide, and ethambutol for 2 mo
– Isoniazid and rifamycin for additional 4 mo
Second Line
• HC
– Conjugated estrogens
Act by stabilization of microvasculature
Oral vs. intravenous administration
– Intravesical instillation of Alum
An astringent precipitates protein over bleeding surface
1% Alum solution in continuous bladdder irrigation (CBI)
Can be used in presence of vesico ureteral reflux (VUR)
– Intravesical instillation of silver nitrate
Chemical coagulation and eschar at bleeding sites
0.5–1% instilled for 10–20 min
VUR may lead to renal failure due to precipitation and obstruction of upper tracts
– E-aminocaproic acid
Inhibits fibrinolysis preventing activation of plasminogen to plasmin
Given orally, parenterally, or intravesically
Patients can form hard clots that are difficult to flush from the bladder
– Intravesical instillation of prostaglandin
PGE2: May encourage platelet aggregation and induce vasoconstriction
PGE2: 0.75 mg in 200 mL of normal saline and left indwelling
May cause bladder spasms
– Intravesical instillation of formalin (40% formaldehyde)
Hydrolyzes proteins and coagulates tissue on superficial level
Painful and needs to be done with general anesthesia
Should not be done with VUR. Can fibrose the ureters, cause obstruction, hydronephrosis and also papillary necrosis
Can result in small contracted bladder
• HIV/AIDS
– Urinary tract infection (UTI)
Can treat with prolonged 7–10-day course of antibiotics
If patients do not respond to empiric antibiotics attention should be turned and patients screened for atypical and opportunistic infections (ie, fungi, parasites, TB, and viruses)
– Prostatitis/Epididymitis/Orchitis
Should be treated with antibiotics
Opportunistic infections should be suspected if not resolving
– Voiding dysfunction
Individualized for the patient
Males: α-blockers possibly 5α-reductase inhibitors
Irritative symptoms: Anticholinergics if low PVR’s
Surgery
• HIV/AIDS
– Kidney infection abscess (Aspergillus and toxoplasma)
Percutaneous or open drainage
Nephrectomy
– Prostatic abscess
Percutaneous (transperineal vs. transrectal aspiration)
Transurethral unroofing (TUR)
– Testicular and epididymal infections
If intractable pain may warrant epididymectomy or orchiectomy
• Tuberculosis
– Often will proceed 3–6 wk after medications
Abscess drainage
Ureteral stenting for strictures (41% successful)
PCN: TB fistula can form
Nephrectomy: If kidney is nonfunctioning, there is extensive disease involving the whole kidney, coexisting renal carcinoma
Partial nephrectomy
Epididymectomy: Caseating abscess that has not responded to medical therapy or firm swelling that has remained unchanged or increased in size with medial therapy
Augmentation cystoplasty (<100 cc capacity) vs. orthotopic bladder substitution (20 cc capacity)
SURGERY/OTHER PROCEDURES
• HC
– Hyperbaric oxygen therapy
100% oxygen in a hyperbaric chamber at 2.5 atmospheres absolute for 90 min 5 days a week.
– Cystectomy if refractory life-threatening cases
– Selective embolization
Vesical or internal iliac artery
ADDITIONAL TREATMENT
Additional Therapies
• Oxazaphosphorine (cyclophosphamide)-induced HC
– Mesna
Binds to acrolein and inactivates it
– Supra hydration
– Prophylactic Continuous bladder irrigation (CBI)
Often occurs within 72 hr
ONGOING CARE
PROGNOSIS
• HIV/AIDS
– Greatly improved in the era of HAART therapy
– Cancer
Penile: 8-fold higher incidence
Testicular cancer: 2-fold increase in seminoma
• Miliary tuberculosis
– Greatly improved with the introduction of antibiotics
– Mortality previously 100% (preantibiotics) now 20%
COMPLICATIONS
• Increased risk for malignancy in immunosuppressed patients
• HIV/AIDS
– 3.5% of HIV-infected patients will experience HIV-associated nephropathy
Caucasian patients 12:1 risk
Intravenous drug use and men who have sex with men association
• Tuberculosis
– Percutanous nephrostomy (PCN)
Tuberculosis fistula formation
– Ureteral stenting
Limit high-pressure contrast injection during retrograde pyelogram may disseminate infection
FOLLOW-UP
Patient Monitoring
• Hemorrhagic cystitis (HC)
– Cyclophosphamide
9-fold increase in urothelial carcinoma
10-yr latency period
REFERENCES
1. Manikandan R, Kumar S, Dorairajan LN. Hemorrhagic cystitis: A challenge to the urologist. Indian J Urol. 2010;26:159–166.
2. Shindel AW, Akhavan A, Sharlip ID. Urologic aspects of HIV infection. Med Clin North Am. 2011;95(1):129–151.
3. Cek M, Lenk S, Naber KG, et al. EAU guidelines for the management of genitourinary tuberculosis. Eur Urol. 2005;48(3):353–362.
4. Gyurkocz B, Rezvani A, Storb RF. Allogeneic hematopoietic cell transplantation: the state of the art. Expert Rev Hematol. 2010;3(3):285–299.
ADDITIONAL READING
Lee SH, Hong SH, Lee JY, et al. Asymptomatic hematuria associated with urinary polyomavirus infection in immunocompetent patients. J Med Virol. 2014;86(2):347–353.
See Also (Topic, Algorithm, Media)
• Cystitis, Hemorrhagic (Infectious, Non-Infectious, Radiation)
• HIV/AIDS, Urologic Considerations
• HIV/AIDS, Urologic Considerations Image 
• Polyoma Virus (BK, JC), Urologic Considerations
• Tuberculosis, Genitourinary, General Considerations
• Tuberculosis, Kidney and Ureter
CODES
ICD9
• 279.9 Unspecified disorder of immune mechanism
• 279.49 Autoimmune disease, not elsewhere classified
• 279.50 Graft-versus-host disease, unspecified
ICD10
• D89.9 Disorder involving the immune mechanism, unspecified
• D89.813 Graft-versus-host disease, unspecified
• M35.9 Systemic involvement of connective tissue, unspecified
CLINICAL/SURGICAL PEARLS
• Recurrent UTI in the absence of infections in other organ systems, is not a typical presentation of an immunocompromised patient.
• Most common intrascrotal pathology in AIDS is testicular atrophy.