Renal infections in cancer patients





Introduction


Epidemiology


Cancer patients are at a higher risk of infections with a mean annual incidence rate of 1465 cases per 100,000 cancer patients and a relative risk [RR] of 9.77 compared with noncancer patients (95% confidence interval [CI], 9.67–9.88). Bacterial urinary tract infections (UTIs) can commonly be seen both in patients with genitourinary tract cancers and nongenitourinary tract malignancies. Because of their immunosuppression, both hematopoietic stem cell transplant and solid organ transplant patients are at increased risk of viral, fungal, and other atypical bacterial infections, in addition to bacterial infections. Very few studies have described the incidence of kidney infections in cancer patients. In a study among 3355 French patients with primarily hematologic malignancies, 170 UTIs were observed, with an attack rate (number of diagnosed infections/100 patients) of 5.1 and an incidence rate of 2.9 per 1000 patient-days at risk. In this study enterobacteria (60%) were the predominant pathogens. Some 10% of the patients had fungal infections, whereas viruses accounted for only 3%. These rates are higher than the documented UTI rates among hospitalized patients in both the United States of 0.34% (2015) and Europe 1.32% (2010). ,


Although early recognition and management of sepsis in an intensive care setting has improved survival in cancer patients, cancer patients with sepsis continue to have disproportionately higher rates of mortality and morbidity and consequently, incur higher health care costs compared with noncancer patients with sepsis.


Infections including UTIs leading to sepsis have been well described in cancer patients and can lead to significant morbidity and mortality. Sepsis is the most common cause of intensive care admissions in cancer patients. In some studies, about 20% of the cancer patients admitted to ICUs had sepsis. In a study of 1332 patients that were admitted to an oncology-dedicated ICU, 563 (42%) patients met criteria for sepsis. Of these, 8% of patients had UTIs. Patients with UTIs were shown to have lower mortality rates in this study than those with pneumonias or bacteremias.




Risk factors for infections in cancer patients


Many factors contribute to a higher risk of infections in cancer patients and involve a complex interplay between the body’s natural defenses and microorganisms colonizing the patients.


Immune dysfunction caused by cancer


The innate immune system is the first line of defense of the body and refers to immune responses that are present from birth and are not acquired or adapted as a result of exposure to microorganisms. Host components include mucosal barriers, secretory enzymes, such as lysozyme, certain inflammatory proteins including C-reactive protein, antimicrobial peptides, cell receptors such as Toll-like receptors, phagocytic cells, like neutrophils and macrophages, mast cells and natural killer cells, which release cytokines. On the other hand, the adaptive immune system consists of the T and B lymphocytes, which continually learn, adapt, and help mount immune responses upon recognition of different foreign and tumor antigens. A variety of microorganisms that colonize the skin, respiratory tract, and the gastrointestinal tract constitute the human microbiome and are thought to contribute to the maturation of immune response and controlling the overgrowth of pathogenic microbes.


Cancers can alter both innate and adaptive immune responses. In certain hematologic cancers, like multiple myeloma and chronic lymphocytic leukemia, reduced antibody production and clearance of immune complexes can lead to an increased risk of infections from encapsulated bacteria like Streptococcus pneumoniae and Haemophilus influenzae . Other malignancies like lymphomas can cause defects in cell-mediated immunity, and lead to increased risk of infections with intracellular organisms, like listeria, salmonella, cryptococcus, and mycobacteria.


Chemotherapy and radiotherapy


Chemotherapy can have several effects on the immune system, leading to infections. The suppression of hematopoiesis by chemotherapy can lead to pancytopenia and functional impairment, thereby decreasing the quantitative and qualitative ability of the immune system to contain infections.


Neutropenia with an absolute neutrophil count (ANC) below 500 cells/microliter increases the risk of bacterial infections in patients. If neutropenia is prolonged, the risk of fungal infections also increases in these patients. In addition to causing neutropenia, chemotherapeutic agents may impair chemotaxis and phagocytosis and decrease the ability of neutrophils to eliminate intracellular pathogens. Other chemotherapeutic agents, such as calcineurin inhibitors, which inhibit T-cell activation, or fludarabine, which affects lymphocyte function, can have severe and longstanding effects on the cell-mediated immunity and can increase the risk for certain infections like Pneumocystis jiroveci pneumonia, and viral infections.


Stem cell transplants can have a profound effect on cell-mediated immunity; the use of aggressive chemotherapy and prolonged immunosuppression after stem cell transplants can impair immunity further, leading to increased susceptibility to infection.


Radiotherapy-induced inflammation also contributes to UTIs. In one prospective study, pelvic radiotherapy led to development of UTIs in 17% of the patients studied. Even though patients of both sexes with various pelvic malignancies were included, there was an increased risk of infections in women with bladder and cervical malignancies. In another study of 36 patients with gynecologic malignancies, 25% of patients developed bacteriuria during radiotherapy; a higher risk of infection was associated with advanced stages of cancer. The authors suggested preradiation urine cultures, particularly in patients undergoing cystoscopy and periodic screening in women with advanced cervical cancers, as they were at higher risk.


Glucocorticoids and other medication-induced immune dysfunction


The use of glucocorticoids can impair migration of granulocytes to sites of inflammation and negatively affect phagocytosis and intracellular killing. The opsonization of bacteria and phagocytosis of pathogens by neutrophils and macrophages is also affected adversely by the use of steroids. Furthermore, the introduction of monoclonal antibodies, like alemtuzumab, ibritumomab, and rituximab, has also resulted in an increase in opportunistic infections because of lymphopenia, impaired T-lymphocyte response, and phagocyte dysfunction.


Mucositis


Cachexia and malnutrition are frequently seen in cancer patients and lead to a catabolic state. This is further exacerbated by anorexia because of malignancy and chemotherapy-induced gastrointestinal effects, including nausea and vomiting. All these together cause mucosal atrophy and loss of the epithelial lining, leading to mucositis.


Mucositis results in decreases in secretory defenses, including lysozymes and immunoglobulin (Ig)A, and alterations in the classic and alternative complement pathway. The associated loss of inhibitory substances, such as lactoferrin, lysozyme, defensins, peroxidase, and IgA, can contribute to the impaired clearance of pathogenic organisms and increase the risk of infections.


Chemotherapy and radiotherapy-induced mucositis


Chemotherapy and radiation therapy can cause mucositis and translocation of the normal microbial flora of the gastrointestinal and genitourinary tract; this in turn leads to invasive infections and bacteremia. , Chemotherapy-induced hematopoiesis suppression can cause pancytopenia and functional impairment, thereby decreasing the quantitative and qualitative ability of the immune system to contain infections. Various chemotherapeutic agents, including anthracyclines (daunorubicin and doxorubicin), plant alkaloids (vinblastine and vincristine), paclitaxel, cisplatin, melphalan, bleomycin, etoposides, and radiation, have been shown to cause aberrant activation of the immune cascade by activation of nuclear factor (NF)-κβ. Activation of NF-κβ in turn results in macrophages and endothelial cells releasing various proinflammatory cytokines and chemokines like interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor-α, and interferon-gamma. The activation of NF-κβ can lead to apoptosis and both tumor and “innocent bystander” mucosal cell death. As a consequence, ulceration, crypt hypoplasia, and villous atrophy follows, and matrix metalloproteinases are activated, which in turn leads to cleavage of collagen and fibronectin. Mucositis is further amplified by the breaching of natural barriers by bacteria and their proinflammatory cell wall products, such as peptidoglycan and lipopolysaccharides. The destruction of residual symbiotic microflora disrupts the microbiome and leads to the overgrowth of pathogenic microorganisms, thereby causing infections.


Mechanical factors, devices


Cancer patients have an elevated risk of infections because of the increased use of medical devices, including catheters, stents, and prostheses. The anatomic changes associated with transplantation and various postsurgical complications also predispose these patients to infections. The risk of inflammation is increased in malignancies. UTIs may be caused by invasive gynecologic surgery (for malignancy), associated surgical complications, and invasive instrumentation, which also includes catheterization or cystoscopy. Tumors, by obstructing and invading normal tissue, can cause local organ dysfunction and predispose patients to infections.




Bacterial infections


Bacterial UTIs are common in cancer patients. In a study of 399 patients with solid tumors, UTIs were significantly more common among patients on glucocorticosteroids and needed a median duration of 11 days to treat. UTIs also led to a 14-day length of hospital stay; a total of 28 patients died in this study.


The microbiology of UTIs is similar in cancer and noncancer patients, although more antimicrobial resistance is seen in cancer patients. In a retrospective study, 100 out of 497 urine samples from cancer patients who were suspected to have UTI had growth on cultures. Escherichia coli was the predominant organism in 40% of the cases, followed by Klebsiella pneumoniae (25%), Pseudomonas aeruginosa (11%), Enterococcus spp (11%), and Proteus mirabilis (5%). Resistance to antimicrobials was high; 90% of the isolates were resistant to fluoroquinolones, 67% to cephalosporins, 46% to aminoglycosides, and 28% to carbapenems. E. coli was also the predominant isolate in another study accounting for 28/66 isolates. Resistance to fluoroquinolones, sulfamethoxazole, and some other antimicrobials and multidrug resistance have also been described and have contributed to a longer length of stay. The low yield of cultures could be caused by obtaining them after antimicrobials are started and this makes obtaining cultures before initiating empiric antimicrobials essential. Antimicrobial susceptibility data (local antibiograms) can be used to guide initial antimicrobial therapy. If a patient was on antimicrobials for prophylaxis, a different class of antimicrobial should be chosen for empiric treatment. Also the presence of resistance above 20% to an antimicrobial class in a particular area is thought to preclude its use empirically. ,


In another study of 462 patients hospitalized with Enterobacteriaceae bacteremia, K. pneumoniae bacteremia (odds ratio [OR], 6.13; p =.007), APACHE II score (OR, 1.18; p =.007), and exposure to aminopenicillins (OR, 28.84; p =.015) were more commonly associated with neoplasms. Among these patients, a genitourinary source of bacteremia was identified in 111 patients (25.5%).


Cystitis


The signs and symptoms of UTIs in patients with cancer are similar to those in patients without malignancies. Lower tract UTIs may present with dysuria, urgent or frequent urination, and suprapubic pain or tenderness. In general, the presence of fevers in UTIs is indicative of parenchymal inflammation or upper tract involvement.


Separate guidelines for diagnosis and management of UTIs in cancer patients have not been published. Thus management is mostly based on guidelines in noncancer patients ( Table 36.1 ). For uncomplicated lower tract infections including cystitis, nitrofurantoin, trimethoprim-sulfamethoxazole (160/800 mg [1 double-strength tablet] twice daily for 3 days) or fosfomycin trometamol (3-g single dose) have been recommended in recent guidelines for nonimmunocompromised and noncancer patients. The presence of resistance above 20% to an antimicrobial class in a particular area is thought to preclude its use empirically. , , Given the higher prevalence of antimicrobial resistance in cancer patients to fluoroquinolones, cephalosporins, aminoglycosides, and sulfa agents, the use of these agents empirically is thus not recommended. The higher prevalence of resistance, including to carbapenems, and even multidrug resistance necessitates obtaining urine cultures in these cases essential. , ,



Table 36.1

Treatment of Uncomplicated Cystitis











































Antibiotic Dose & Duration Adverse Effects Dose Adjustment for Renal Function
EMPIRIC AGENTS
Nitrofurantoin 100 mg twice daily × 5–7 days Nausea, headache Yes a
Trimethoprim-sulfamethoxazole 160/800 mg twice daily × 3 days Nausea, vomiting, cytopenia, rash Yes
Fosfomycin 3-g single dose Nausea, diarrhea, headache Not defined
ALTERNATE AGENTS
Ciprofloxacin b 500 mg twice a day × 3 days Nausea, vomiting, headache, diarrhea Yes
Levofloxacin b 250–500 mg daily × 3 days Nausea, vomiting, headache, diarrhea Yes
Beta-lactams c , d Dose varies by agent × 3–5 days Nausea, vomiting, diarrhea, rash Yes

a Contraindicated when creatinine clearance less than 60 mL/min.


b High rates of resistance, confirm sensitivity before use. Highly efficacious but also high incidence of adverse effects—considered as alternate agents.


c Amoxicillin and ampicillin have high rates of resistance, also relatively poor efficacy; do not use for empiric therapy.


d Amoxicillin-clavulanate, cefaclor, cefopodoxime-proxetil, and cefdinir can be used if other agents not available. Lower efficacy and higher adverse effects as compared with other agents.



There is frequent resistance to fluoroquinolones, and they have higher potential for Clostridium difficile . Hence alternatives are preferred. There have been studies documenting inferior efficacy of amoxicillin-clavulanate in shorter 3 day courses as compared with fluoroquinolones. However, beta-lactam antibiotics including cephalosporins such as cefdinir, cefaclor, and cefpodoxime-proxetil, and aminopenicillin derivatives including amoxicillin-clavulanate are considered reasonable alternatives in 3- to 7-day regimens, when other agents cannot be used. Other beta-lactams, such as first-generation cephalosporins, including cephalexin, have a narrower gram-negative spectrum, and data supporting their use are scant. However, if susceptibility is confirmed, their use may be reasonable in certain situations. , , ,


Upper urinary tract infections including pyelonephritis


Upper tract infections manifest with new onset or worsening of fever, rigors, altered mental status, malaise, or lethargy with no other identified cause, flank pain, costovertebral angle tenderness, acute hematuria, or pelvic discomfort. Catheter-associated UTIs have similar signs.


In patients suspected of having pyelonephritis, a urine culture and susceptibility test should always be performed, and initial empirical therapy should be tailored appropriately based on the infecting pathogen. Guidelines in nonimmunocompromised patients indicate that oral ciprofloxacin is an appropriate therapeutic choice in patients not requiring hospitalization, provided the prevalence of resistance of community-acquired bacteria to fluoroquinolones is known to be below 10% ( Table 36.2 ). The higher resistance and increasing use of fluoroquinolones for prophylaxis in cancer patients makes them unreliable empiric options. In the presence of more than 10% fluoroquinolone resistance, an initial intravenous dose of a long-acting antimicrobial, such as ceftriaxone or an aminoglycoside, is considered reasonable. If susceptibility is confirmed, oral trimethoprim-sulfamethoxazole for 14 days is considered a reasonable option.



Table 36.2

Treatment of Upper Tract Infections/Pyelonephritis


































































Antibiotic Dose & Duration Adverse Effects Dose Adjustment for Renal Function
EMPIRIC AGENTS – OUTPATIENT a
Trimethoprim-sulfamethoxazole b 160/800 mg twice daily × 3 days Nausea, vomiting, cytopenia, rash Yes
Levofloxacin c 250–500 mg daily × 3 days Nausea, vomiting, headache, diarrhea Yes
Ciprofloxacin c 500 mg twice a day × 3 days Nausea, vomiting, headache, diarrhea Yes
INPATIENT REGIMENS d , e , f
Ceftriaxone ± aminoglycoside as later 1 g IV daily Nausea, vomiting, allergy, neutropenia Yes
Levofloxacin b ± aminoglycoside 250–750 mg IV/po daily Nausea, vomiting, headache, diarrhea Yes
Ciprofloxacin b ± aminoglycoside as below 200–400 mg IV q 12 hours or 250–750 mg po q 12 hours Nausea, vomiting, headache, diarrhea
Piperacillin/tazobactam 3.375 g IV q 6 hours Allergic reaction, myelosuppression, interstitial nephritis Yes



  • Carbapenem



  • Imipenem/cilastatin



  • Meropenem




  • 500 mg IV q 6 hours



  • 500–1000 mg IV q 8 hours

Allergic reactions, seizures, myelosuppression Yes
AMINOGLYCOSIDES
Gentamicin 5–7 mg/kg IV daily Nephrotoxicity, ototoxicity Yes
Amikacin 7.5 mg/kg IV q 12–24 hours Nephrotoxicity, ototoxicity Yes

IV , Intravenous; po , by mouth; q , every.

a Urine cultures and susceptibility data should always be obtained.


b Only if local resistance rates are less than 10%.


c Can be used in a 14-day course if susceptibility is confirmed.


d Initial intravenous therapy is recommended. Use based on local antimicrobial resistance data. Modify treatment based on susceptibility data.


e 7 day regimens of fluoroquinolones may be sufficient.


f 10–14 day courses of beta-lactams may be needed.



Awaiting susceptibilities, an initial parenteral antimicrobial, like 1-g ceftriaxone or a once-a-day aminoglycoside, is recommended in noncancer patients and would be considered necessary in immunocompromised patients, given the higher probability of resistance. As in cystitis, beta-lactam agents are less effective than other available agents for treatment of pyelonephritis. Efficacy/outcomes for beta-lactams, including cephalosporins, were inferior compared with trimethoprim-sulfamethoxazole and fluoroquinolones. ,


Seven-day regimens for fluoroquinolones in noncancer patients have been recommended to treat pyelonephritis. However, most recent guidelines suggest that there are not enough data to treat pyelonephritis with a similar short course of a beta-lactam agent. , , Patients with pyelonephritis requiring hospitalization should be initially treated with intravenous antibiotics, such as a fluoroquinolone, an aminoglycoside (with or without ampicillin), an extended-spectrum cephalosporin or extended-spectrum penicillin (with or without an aminoglycoside), or a carbapenem. The choice between these agents should be based on local resistance data, and the regimen should be tailored based on susceptibility results (see Table 36.2 ). ,


Treatment with agents for longer periods (> 14 days) may result in the development of resistant pathogens by selection pressure. Two weeks of trimethoprim-sulfamethoxazole were shown to be as efficacious as a 6-week course of ampicillin in a study of 60 women with uncomplicated pyelonephritis. The shorter course had fewer adverse effects, lower costs, and also led to the selection of fewer resistant organisms.


Catheter-associated urinary tract infections


Guidelines indicate that if an indwelling catheter has been in place for more than 2 weeks and still needs to be retained, replacement of the catheter helps in treatment of the episode and the prevention of any future recurrences. Urine culture should be obtained from the newly placed catheter before starting antibiotics and used to tailor the antimicrobial choice. However, if the catheter can be removed, a midstream urine sample should be obtained before starting antibiotics and the result used to guide the choice. ,


If symptoms resolve rapidly, 7 days of treatment is considered adequate for most patients with catheter-associated (CA)-UTI. Shorter duration of fluoroquinolones, particularly levofloxacin, has been recommended in patients who are not severely ill. There is some literature supporting a shorter duration (3 days) in nonimmunocompromised patients with no upper tract symptoms in whom the catheter has been removed, although there are no trials to guide therapy in cancer patients. , In patients with delayed response and immunocompromised patients, a longer (10–14 day) course of treatment may be considered, but data on the optimal duration of therapy are scant, particularly in cancer patients. Given the immunocompromised state, we feel that a 10- to 14-day course would be reasonable in these cases.


Prostatitis


In men, the majority of febrile UTIs are associated with prostatitis. The diagnosis of acute prostatitis can be established by urine cultures and prostate examinations. However, the diagnosis of chronic prostatitis may require obtaining prostatic fluid and a urine sample after prostatic massage. Other methods, including the Meares-Stamey four-glass test and the simpler “two-glass” test have been described, but are infrequently used in clinical practice. Prolonged symptoms or refractory cases may require a urologist referral and evaluation. Antimicrobials used to treat UTIs in men should be able to achieve sufficient concentration in the prostatic tissues. Fluoroquinolones and trimethoprim-sulfamethoxazole have excellent penetration, but the increasing resistance may preclude their use. Beta-lactams may result in less optimal outcomes.


Although there is paucity of data on the treatment of UTIs in men, some studies have shown that patients with urologic issues requiring surgical intervention had more recurrences of UTIs (26% vs. 12%). A 2-week antimicrobial course was shown to be adequate in most cases.


Mechanical aspects – infections caused by obstruction, reconstruction


Anatomic obstructions, either via tumor burden or impaired physiology, can lead to inadequate emptying, retention, and reflux, which can lead to development of infections. Surgical procedures can lead to altered anatomy, thereby compromising natural defenses against infection bladder surgeries, for example, reflux.


Obstructive uropathy can also lead to urinary stasis, which encourages bacterial colonization and can further lead to retrograde ascending urinary infections. Complicated infections of this nature will need rapid decompression with placement of stents or percutaneous nephrostomy catheters. Organisms seen in these infections include the expected urinary flora like E. coli, klebsiella species, and staphylococci, enterococci, pseudomonas, and candida. Eradication of these infections in the presence of prior foreign bodies often requires removal or replacement of the indwelling devices. ,


Patients with reconstructive surgery and either neobladders or ileoanal conduits have been shown to have persistent bacteriuria after surgery. It can be difficult to distinguish between colonization and infections in these cases and the presence of symptoms is essential in making the distinction between colonization and infections in these cases.


Patients with nephrostomy tubes are at increased risk for development of UTIs. In a tertiary cancer center study, among 200 patients with nephrostomy tubes, 38 (19%) developed pyelonephritis and 15 (7.5%) had asymptomatic bacteriuria. The presence of prior episodes and neutropenia were significant risk factors ( p =.047 and p =.03), respectively.


Asymptomatic bacteriuria in cancer patients


Current guidelines do not support treatment of asymptomatic bacteriuria in cancer patients. , However, neutropenia, a recent transplant, or other factors causing immunosuppression may necessitate treatment consideration in some patients. Guidelines are not very clear on this, however; an evaluation should be done, and clinical judgment used on a case-by-case basis, especially for indwelling catheters, where catheter-related colonization is common. Urine cultures should be obtained only if there is a clinical suspicion of UTI in these cases.


Prophylaxis


Presently, there are no studies to help guide prophylaxis in patients with cancer and frequent or recurrent UTIs. In nonimmunocompromised patients, prophylactic or suppressive antimicrobials should be considered in case of more than two episodes of lower tract infections in 6 months or more than three episodes in 12 months. A workup for reversible anatomic or functional factors including obstruction is required before suppressive therapy. The risk of adverse effects and the development of resistance needs to be considered, as such risks may be higher in cancer patients. Emerging data suggest that there may be significant pathologic consequences like the development of antimicrobial resistance, vitamin K deficiency, increased susceptibility to infections, and diarrhea, because of the altered microbiome from suppressive/prophylactic antibiotics. ,




Mycobacterial infections


Bacillus calmette-guérin


Bacillus Calmette-Guérin (BCG) is a live attenuated vaccine obtained from Mycobacterium bovis . Use of intravesical BCG for the treatment of superficial bladder cancer was first described in 1976. Its use increased after the U.S. Food and Drug Administration approval in 1990, and currently there are more data on its safety and efficacy with its use over the past quarter of a century. The treatment is usually well tolerated, but rarely, systemic complications, such as fatal BCGosis, occur. Specific side effects involving the kidney are well described. Granulomatous cystitis has been well described after BCG instillation and bladder pathology is useful in establishing diagnosis ( Fig. 36.1 ). Asymptomatic renal granulomas—often detected on follow-up imaging—occur in 1 in 1000 cases. These are thought to likely be related to reflux of the intravesical BCG rather than hematogenous spread. The treatment of these granulomas is not well established; they were commonly treated with antitubercular therapy in the past and some authors still advocate early treatment of renal BCGosis even in asymptomatic patients. However, other studies have demonstrated no progression with no treatment and close observation.




Fig. 36.1


Bladder biopsy showing granulomatous cystitis after intravesical Bacillus Calmette-Guérin (BCG) therapy.


BCG instillation can also lead to interstitial nephritis with or without granuloma. Patients usually present with elevated creatinine. A few case reports have described other pathologies, including acute kidney injury with glomerulonephritis, membranous nephropathy, hemolytic uremic syndrome, rhabdomyolysis, and multiorgan failure after BCG treatment. It has been recommended that a decline in renal function, hematuria, or proteinuria during BCG treatment in the absence of other etiologies warrants consideration of renal biopsy.


There are no reliable data available about the incidence of renal toxicity after intravesical BCG; this is in part because of underreporting and in part because other variables influence the occurrence. These other factors include the strain type of BCG used (they have different immunogenicity, virulence, and toxicity), the dose used, repetitive injury, and patient factors.


Tuberculosis


Approximately 1.7 billion individuals are latently infected with Mycobacterium tuberculosis. Tuberculosis (TB) is the ninth leading cause of death worldwide, and the leading cause of death from a single infectious agent. In 2016 an estimated 1.7 million people died from TB. It is an infection of major relevance.


Although TB primarily affects the lung, other organs may also be involved. After lymphadenitis, the most common form of nonpulmonary TB is genitourinary disease, accounting for 27% of nonpulmonary cases in the United States, Canada, and the United Kingdom. Respiratory infection with TB can be followed by hematogenous dissemination to the kidneys, epididymis, and the prostate. Implantation usually occurs in the more vascular parts, such as the cortex of the kidney and the globus minor of the epididymis, and is bilateral. Cancer patients are at increased risk for reactivation of their latent tuberculosis, either caused by inherent immunodeficiency from their underlying malignancy or from effects of the cancer treatment—such as fludarabine and glucocorticosteroids that might impair T-cell immunity.


The incidence of TB is 10 to 40 times more common in patients with hematopoietic stem cell transplantation (HSCT) compared with the general population, but the incidence varies depending on geographic location and is directly proportional to the incidence of TB in the general population. Incidences of M. tuberculosis in HSCT recipients have been reported to be as low as 0.0014% in the United States and as high as 16% in Pakistan. Risk factors for the development of TB after HSCT include certain leukemias, like acute myeloid leukemia, chronic myeloid leukemia, and myelodysplastic syndrome, the use of certain conditioning therapies, such as busulfan, cyclophosphamide, total body irradiation, corticosteroid therapy, mismatched allografts, graft-versus-host disease (GVHD), or a history of previous TB infection. At least one-third of M. tuberculosis infections in HSCT patients are disseminated at presentation.


A high index of suspicion for genitourinary TB is required for timely diagnosis and treatment. Clinical findings are variable, but patients commonly present with dysuria with sterile pyuria or a painless scrotal mass. Diagnosis of genitourinary TB without any systemic involvement can be difficult. Collection of urine, expressed prostatic secretions, postmassage urine and ejaculate for acid fast bacilli smear and mycobacterial culture, and polymerase chain reaction (PCR) may be helpful, although these have a low sensitivity. The gold standard for establishing the diagnosis would be isolation of mycobacteria from the urine. Sterile pyuria may suggest urinary tract TB infection, but a superimposed bacterial infection may delay diagnosis in up to 30% of cases. There is poor sensitivity with traditional staining (Ziehl-Neelsen and auramine stain, being positive in 37%–52% of cases). Furthermore, contamination with Mycobacterium smegmatis or fragments of sperm can cause a false positive smear. Nucleic acid amplification can be sensitive and specific, although some urine specimens contain inhibitory substances. Early diagnosis and treatment may prevent the loss of organ function.


Treatment is generally with medical therapy with the standard four drugs (isoniazid, rifampin, pyrazinamide, ethambutol); surgery is rarely required. Special considerations apply to the treatment of TB in patients with renal insufficiency; dose adjustments of some antitubercular drugs, like ethambutol are needed to avoid toxicity, such as optic neuritis ( Table 36.3 ). Aminoglycosides are renally excreted and nephrotoxic and should be avoided in these patients. Rifampin has a number of drug interactions and can increase the metabolism of a wide range of drugs, including steroids, cyclosporine, and tacrolimus. Thus its use may require drug level monitoring and dose adjustment.



Table 36.3

Antimycobacterial Agents and Dose Adjustments With Renal Impairment




























































Drug Major Toxicities Adjust for Renal Function
Isoniazid Hepatitis, neuritis, drug-induced lupus, drowsiness, mood changes No dose adjustment
Rifampin Multiple drug interactions, hepatitis, flushing, thrombocytopenia, diarrhea, brownish discoloration of skin and secretions, flu-like syndrome No dose adjustment
Ethambutol Optic neuritis, rash, abdominal distress Adjust
Pyrizinamide Hepatitis rash, arthralgias or arthritis, hyperuricemia Adjust
Moxifloxacin Tremors, thrush, diarrhea, interstitial nephritis, Achilles tendon rupture, aneurysm, QTc prolongation, hepatotoxicity Adjust
Capreomycin Hearing loss, ataxia, nystagmus, azotemia proteinuria, eosinophilia, serum electrolyte abnormality Adjust
Amikacin, kanamycin Hearing loss, ataxia, nystagmus, azotemia proteinuria, eosinophilia, serum electrolyte abnormality Adjust
Ethionamide Abdominal pain, nausea, anorexia, dysgeusia, diarrhea, rash, edema, arthralgias, neuropathy, hypothyroidism, temporary alopecia, gynecomastia Adjust for CrCl < 30 mL/min
Para-aminosalicyclic acid Abdominal pain, hypothyroid, diarrhea Adjust
Cycloserine Mood and cognitive decline, psychosis, tremors, seizures (all concentration dependent) Use contraindicated in severe renal impairment, some people adjust for severe impairment
Bedaquiline QTc prolongation, nausea, joint pains, liver dysfunction No dose adjustment, use with caution for severe renal failure
Linezolid Bone marrow suppression—especially thrombocytopenia, neuropathy, GI symptoms, serotonin syndrome No dose adjustment
Clofazamine Nausea, vomiting, skin discoloration, QTc prolongation No dose adjustment

CrCl , Creatinine clearance; GI , gastrointestinal.




Fungal infections


Fungal infections can be caused by yeasts or molds. Several factors render cancer patients at an increased risk for fungal infections. Prolonged neutropenia, the use of broad-spectrum antibiotics, the presence of indwelling venous catheters, and chemotherapy-associated mucosal injuries put patients at increased risk for invasive candidiasis. GVHD after allogeneic transplantation and prolonged neutropenia pose a risk for mold infections. Aspergillus is the most common mold isolated, but other molds, such as Fusarium , zygomycetes ( Mucor, Rhizopus , and Rhizomucor ) and less commonly, Scedosporium/Pseudoallescheria and Trichosporon can also be seen. Other risk factors for fungal infection include the underlying malignancy, comorbidities, such as diabetes or underlying lung disease, and the types of treatments used.


Candida


The presence of candiduria is a therapeutic challenge. It can represent asymptomatic colonization or be a harbinger of severe sepsis. There are no clear guidelines about treatment. A positive culture often represents colonization, although the distinction between colonization and infection can be difficult to make. Untreated patients also have the risk of progression to disseminated candidiasis. Foley catheters should be removed, and if possible, broad spectrum antibiotics should be discontinued. If there is persistent candiduria, then imaging to look for renal abscess, fungal balls, or evidence of urologic obstruction should be considered.


The significance of candiduria in patients with hematologic malignancies is as confusing as it is in the general population. Neutropenic patients may not have pyuria even with candiduria, and in the presence of indwelling Foley catheters, the diagnosis of candida UTIs becomes very challenging. In a 10-year retrospective study in nonintensive care patients with hematologic malignancies and candiduria, only 4% developed candidemia and the crude mortality was low. The authors concluded that isolated candiduria in patients with hematologic malignancies was not a predictor of subsequent invasive candidiasis. Their conclusion, however, is hard to support, because 88% of the patients in this study were treated with systemic antifungals.


Renal involvement with fungi can be either caused by hematogenous spread or from retrograde extension. Fungi can disseminate to the collecting system and rarely coalesce to form bezoars or fungus balls, which can cause obstructive uropathy. Although candida are the most frequently isolated fungal pathogen species, there are reports of aspergillus bezoar causing bilateral ureteral obstruction. The characteristic radiologic features of fungus balls and intraluminal filling defects are not pathognomonic, and the differential is broad ( Fig. 36.2 ). Fungal infections should always be included in the differential diagnosis of renal obstruction in an immunocompromised patient.




Fig. 36.2


Coronal excretory phase computed tomography with multiple filling defects in the right renal pelvis consistent with a candida fungal ball.


Fluconazole is the drug of choice for candida cystitis because of its favorable pharmacokinetics. Because other azoles and all echinocandins (caspofungin, micafungin, and anidulafungin) are poorly excreted in urine, they have been found to be less effective in candiduric patients. Other options include bladder irrigation with amphotericin B, flucytosine, or parenteral amphotericin B preparations; however, these are more toxic options. Candiduria caused by more resistant non- Candida albicans species makes treatment even more challenging as few options exist. There have been successful case reports of treating candiduria with echinocandins, but because of their low urinary concentrations, they are not generally recommended. Fungal prostatitis is uncommon, and the collective experience from case reports emphasizes the role of surgical intervention in conjunction with antifungal therapy.


Aspergillus


Aspergillus spp are among the most common mold pathogens in patients with cancer, but they are seen mostly with patients after prolonged neutropenia or in patients with GVHD after allogeneic transplantation. The vast majority of aspergillus infections occur in the lung, the usual portal of entry, but subsequent dissemination to other organs including the kidneys can be seen. The Aspergillus spp have angioinvasive properties. The usual presentation of renal aspergillus includes the formation of multiple abscesses (bezoars). Clinically the renal involvement is seen as bezoars in the renal pelvis. Rarely, renal infarcts have also been described. Early diagnosis and bezoar debulking along with systemic antifungal therapy may avert the need for an open resection. Surgical management includes irrigation, lavage, and debulking from either an antegrade or retrograde approach. Refractory cases may end up with partial or complete nephrectomy.


Cryptococcus


The incidence of cryptococcal renal disease is not well documented. In 1972, a single center evaluated 32 patients with a serologic or pathologic diagnosis of Cryptococcus neoformans . Eight (25%) of the patients had disseminated disease and five had renal involvement. One-third of these patients had lymphoma. The urinary tract can possibly serve as a reservoir for cryptococcus, even after successful treatment for meningitis. It is felt to be sequestered in the prostate and can be found in the urine, or in prostatic secretions after prostatic massage. Unless treated specifically, the patient is at risk for systemic relapse of disease. Transurethral drainage is sometimes needed.


Patients who undergo organ transplantation—either solid or HSCT—are known to be at increased risk of cryptococcal disease. In solid organ transplant recipients, including renal transplants, cryptococcus is one of the most common causes of fungal infection. However, because of the effective fungal prophylaxis, it is not as common in HSCT recipients, representing less than 1% of fungal infections in this population. A rare case of acute kidney injury resulting from disseminated cryptococcal infection in an allogeneic stem cell transplant recipient has been described. The renal failure in this patient was multifactorial and was caused by the acute and evolving thrombotic microangiopathy secondary to the presence of GVHD, tacrolimus, and possibly caused by the cryptococcus infection. The authors were able to document parenchymal invasion by the cryptococcus in this study.


Mucor


The hallmarks of mucormycosis are vascular invasion and tissue necrosis. The fungi typically appear as broad nonseptate hyphae with branches occurring at right angles. Therapy of mucormycosis includes rapid correction of the predisposing factors, surgical debridement of the necrotic tissue when feasible, and antifungal therapy. Adjunctive therapy may include hyperbaric oxygen, granulocyte stimulating factor, and granulocyte transfusion. Lee et al. described two cases of disseminated mucormycosis after HSCT. The first patient had an abscess in the kidney from the mucor and splenic involvement. He was successfully treated with splenectomy, liposomal amphotericin and 5-flucytosine, and discontinuation of cyclosporine and prednisolone.

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Mar 16, 2020 | Posted by in NEPHROLOGY | Comments Off on Renal infections in cancer patients
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