Chronic renal insufficiency and Nocardia brasiliensis infection: A call for heightened vigilance and multidisciplinary management

Abstract

This letter discusses the critical yet underrecognized intersection of chronic renal insufficiency and Nocardia brasiliensis skin infection in the case reported by Zhang et al, emphasizing the diagnostic challenges and therapeutic complexities in the context of advanced age, comorbidities, and immunocompromised populations. The study’s strengths included its integration of immunological profiling and precision medicine, demonstrating that a tailored low-dose trimethoprim-sulfamethoxazole regimen with pharmacokinetic monitoring can improve outcomes in geriatric patients with chronic renal insufficiency while mitigating nephrotoxicity risks. However, its limitations included a single-case design, reliance on phenotypic diagnostics, and the lack of information regarding comorbidity interactions. The findings support the use of advanced molecular tools for rapid pathogen identification and identification of co-infection. Future studies should prioritize elucidating the synergistic effects of chronic kidney disease-uremia and immunosuppression on Nocardia colonization, developing biomarkers for early detection, and conducting global epidemiological studies in endemic regions. This case underscores the importance of interdisciplinary collaboration and innovative diagnostics to optimize management of nocardiosis in vulnerable populations.

Key Words: Chronic renal insufficiency; Nocardia brasiliensis; Skin infection; Immunocompromised patients; Multidisciplinary management

Core Tip: This study highlights the interplay of chronic renal insufficiency and Nocardia brasiliensis infection in immunocompromised patients. A tailored low-dose sulfamethoxazole-trimethoprim regimen with pharmacokinetic monitoring improved outcomes in a geriatric patient. Future research needs advanced diagnostics, biomarker development, and global epidemiological studies.

TO THE EDITOR

Chronic renal insufficiency (CRI) is a well-established risk factor for opportunistic infections caused by impaired immune function, including humoral (hypogammaglobulinemia) and cellular (T-cell dysfunction) deficits. Nocardia brasiliensis, a saprophytic actinomycete, primarily causes localized skin and soft tissue infections in immunocompromised hosts. The case reported by Zhang et al[1] underscores the diagnostic challenges and therapeutic complexities of Nocardia brasiliensis in elderly patients with CRI.

Significance of the case report

The case reported by Zhang et al[1] underscores the critical yet underrecognized intersection of CRI and Nocardia brasiliensis skin infection, a clinically relevant association attributable to the immunological dysregulation inherent to CRI. Advanced age (93 years), comorbidities (hypertension, gout), and immunosuppressive medications (e.g., corticosteroids) created a “perfect storm” for opportunistic infection. The patient’s refractory cutaneous lesions, despite the initial misdiagnosis, highlight the diagnostic pitfalls of nocardiosis, which often mimics bacterial cellulitis or fungal infections in immunocompromised hosts. Notably, the tailored use of a low-dose sulfamethoxazole-trimethoprim (SMZ-TMP) regimen with pharmacokinetic monitoring exemplifies precision medicine in elderly patients with renal impairment, balancing efficacy against Nocardia while mitigating nephrotoxicity and hepatotoxicity risks. This approach is in line with the findings of recent studies that recommend dose adjustments in cases of renal dysfunction in order to achieve optimal therapeutic outcomes[2,3].

Strengths and innovations

The case reported by Zhang et al[1] presents two pivotal innovations in the management of patients with CRI, particularly those at risk of nocardiosis or those diagnosed with it.

Immunological profiling for assessment of immune competence: The study pioneers the integration of immunological parameters, specifically CD4(+) T-cell counts (212 cells/μL; reference range: 500-1600 cells/μL) and immunoglobulin G levels (680 mg/dL; reference range: 700-1600 mg/dL), to comprehensively evaluate immune competence in patients with CRI. This approach provides a nuanced understanding of the immunological landscape in these patients and corroborates existing evidence linking hypogammaglobulinemia and T-cell dysfunction to an elevated risk of nocardiosis in chronic kidney disease (CKD) populations[4]. By employing these biomarkers, the study offers a novel framework for risk stratification and personalized care in patients with CRI.

Precision medicine-based long-term therapeutic strategy: The study introduces a tailored, pharmacokinetically monitored, low-dose SMZ-TMP regimen that was meticulously adjusted for renal clearance in the geriatric patient with CRI. This strategy significantly reduced the risk of recurrence of nocardiosis over a 6-month treatment period, underscoring the importance of prolonged antimicrobial therapy in immunocompromised hosts[3]. The integration of pharmacokinetic monitoring ensured optimal drug exposure while minimizing nephrotoxic risks, thereby exemplifying the application of precision medicine principles to enhance therapeutic outcomes in this vulnerable patient cohort. Furthermore, the case study underscores the indispensable role of interdisciplinary collaboration and advanced diagnostic modalities for effective management of nocardiosis in CRI patients, highlighting the clinical relevance and translational potential of these findings.

Limitations and critiques

While impactful, this study had some limitations that are summarized below.

Lack of long-term follow-up data: Although the current investigation included a 6-month follow-up period, during which relevant data were meticulously presented and analyzed, it is acknowledged that this duration may be insufficient for a comprehensive evaluation of the enduring therapeutic effects and potential long-term adverse events associated with the treatment. The relatively brief follow-up timeframe imposes certain constraints on the ability to fully ascertain the treatment’s long-term outcomes (12-24 months). To mitigate this limitation, the manuscript should incorporate a detailed discussion explicitly highlighting the need for future research to extend follow-up periods. Such extended studies would enable a more nuanced understanding of the treatment’s sustained efficacy, durability of response, and any latent safety concerns that may emerge over time. By providing a more comprehensive perspective on the treatment’s risk-benefit profile, these future endeavors will be instrumental in guiding clinical decision-making and optimizing patient care.

Single-center observational design: The limitations inherent to this single-case design underscore the constrained generalizability of findings, particularly in non-endemic regions where Nocardia epidemiology, antimicrobial susceptibility patterns, and clinical management strategies differ substantially from those observed in the study cohort. While case reports offer critical insights into rare infections, the absence of comparative data across heterogeneous populations limits the ability to extrapolate conclusions to broader clinical contexts. Multicenter studies with expanded cohorts are imperative to address this methodological gap, as they would enable systematic evaluation of regional variability in diagnostic delays, therapeutic responses, and prognostic outcomes. Prospective cohort designs, such as the inclusion of consecutive CRI patients with culture-confirmed Nocardia infections across geographically distinct centers, would mitigate selection bias while facilitating subgroup analyses to identify region-specific risk modifiers. Registry-based surveillance systems, leveraging existing platforms like the European Centre for Disease Prevention and Control’s Antimicrobial Resistance Surveillance Network or the World Health Organization’s Global Antimicrobial Resistance and Use Surveillance System, could provide standardized data collection frameworks to validate our observations. Establishing international consortia, akin to the Global Invasive Fungal Infections Observatory, would foster collaborative data-sharing networks, particularly in underrepresented regions, while securing funding through competitive grants such as the National Institutes of Health R01 mechanisms or the European Research Council’s Horizon Europe program would ensure sustained resource allocation. Such multicenter initiatives would not only enhance external validity but also provide methodological rigor through standardized protocols for diagnostic confirmation, treatment regimens, and follow-up intervals, thereby enabling robust comparisons to refine evidence-based guidelines for managing Nocardia-associated CRI.

Absence of molecular diagnostics: In the current study, species-level classification of pathogens was primarily performed using phenotypic methods, including acid-fast staining. While these approaches are established and widely accessible, their diagnostic specificity is notably inferior to advanced molecular techniques such as 16S ribosomal RNA (rRNA) sequencing or matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS)[5]. This limitation introduces a critical risk of misclassification, since the lower specificity of phenotypic methods may lead to either false-positive or false-negative diagnoses, with potential downstream consequences for patient management, including suboptimal treatment decision-making and compromised clinical outcomes. The absence of molecular tools in this study reflects resource constraints or logistical challenges, but also underscores the necessity of incorporating such technologies in future investigations. By integrating 16S rRNA sequencing or MALDI-TOF MS, researchers could achieve higher diagnostic accuracy, thereby improving the reliability of species identification and enabling more precise epidemiological and therapeutic assessments. The reliance on phenotypic diagnostics in this study was driven by pragmatic considerations, including limited access to molecular platforms in clinical network, budgetary restrictions limiting high-throughput sequencing, and the need for rapid turnaround times in acute care settings. However, these constraints underscore a broader gap in equitable access to advanced diagnostic infrastructure. To bridge this divide, future studies should prioritize scalable solutions such as establishing regional diagnostic hubs equipped with shared molecular platforms, fostering partnerships between tertiary care centers and smaller facilities to enable knowledge transfer and resource pooling. Additionally, investing in cost-effective point-of-care technologies, such as lateral flow assays targeting conserved Nocardia antigens or portable MALDI-TOF MS systems, could enhance diagnostic accuracy without overwhelming existing workflows. For instance, a tiered diagnostic algorithm could be proposed: Initial phenotypic screening followed by molecular confirmation in selected high-risk cases, optimizing both resource utilization and diagnostic yield. Such strategies would not only address the limitations of phenotypic methods but also provide a framework for implementing molecular diagnostics in diverse healthcare settings, aligning with global efforts to reduce diagnostic inequities.

Unexplored comorbidity interactions: The complex interplay among CKD, hypertension, and gout in the modulation of immune responses remains an unresolved issue in the current study. In patients with CRI, uremic toxins accumulate due to reduced renal clearance, directly affecting macrophage activity and, consequently, the body’s first line of defense against pathogens. Additionally, the use of immunosuppressive agents such as corticosteroids, which are commonly prescribed in the management of these comorbidities, may exacerbate neutrophil dysfunction. Neutrophils play a vital role in the early stages of the immune response, and impaired neutrophil function can have a detrimental impact on the body’s ability to combat infections and other pathogens. The unresolved nature of these comorbidity interactions poses a substantial challenge since it may lead to suboptimal treatment outcomes and an increased risk of complications for patients. For example, the compromised phagocytic ability of macrophages and dysfunctional neutrophils can result in prolonged infections and a heightened susceptibility to opportunistic pathogens. Therefore, additional research is warranted to elucidate the underlying mechanisms of these interactions and to develop more effective treatment strategies that take into account the complex interplay of these comorbidities, including the potential impact of uremic toxins and immunosuppressive agents on immune cell function.

In summary, the interplay between CKD, hypertension, and gout is multifaceted and involves both direct and indirect effects on immune function (Table 1). Uremic toxins and hyperuricemia are key factors that contribute to immune dysregulation, while the use of immunosuppressive agents further complicates the immune response. Future research should focus on the mechanistic details of how these comorbidities synergistically impair immunity, particularly through the effects of uremic toxins on macrophage function and the role of hyperuricemia in promoting inflammation and immune dysregulation.

Table 1 The complex interplay among chronic kidney disease, hypertension, and gout significantly impacts immune function through various mechanisms.

Factor	Mechanism of action	Specific manifestations	Impact on immune function
CKD	Reduced renal function leads to accumulation of uremic toxins	Uremic toxins directly impair macrophage activity	Weaken the body’s first line of defense against pathogens, reduce macrophage phagocytic capacity
Hypertension	No direct mechanism specified, but often coexists with CKD and gout	Commonly managed with immunosuppressive agents (e.g., corticosteroids)	Exacerbate neutrophil dysfunction, impact early immune response
Gout	Hyperuricemia triggers inflammatory responses	Urate crystal deposition induces local inflammation and activates the immune system	Promotes inflammation and immune dysregulation, may further affect immune cell function
Immunosuppressive agents	Commonly used in the management of these comorbidities	Suppress immune cell functions, particularly neutrophils	Exacerbate neutrophil dysfunction, reduce the body’s ability to fight infections

CKD: Chronic kidney disease.

Clinical implications and future directions

This case highlights the critical need for a multidisciplinary approach to manage Nocardia brasiliensis infections in patients with CRI. Nocardia infections have a global presence but are more prevalent in tropical regions, with notable geographic variations in species distribution observed in studies from Western Australia, China, Pakistan, and Portugal[5-8]. Tropical regions such as northern Australia and subtropical zones exhibit elevated disease burden compared to temperate climates, with notable differences in incidence patterns across geographic areas[5]. In China, immunocompromised populations demonstrate higher Nocardia colonization rates, predominantly attributed to Nocardia farcinica and Nippostrongylus brasiliensis[6,7]. Similarly, clinical outcomes in Pakistani cohorts reveal significant mortality associated with pulmonary nocardiosis, often linked to diagnostic delays and antimicrobial resistance challenges[8]. These regional variations underscore the influence of environmental exposure, host immunity, and healthcare accessibility on disease prevalence and severity. Immunocompromised individuals, including solid organ (lung, kidney, heart) and hematopoietic stem cell transplant recipients, are at the highest risk, with incidence rates of 0.4%-1.7% in transplant populations[9]. Occupational soil exposure and climatic factors contribute to transmission, underscoring the need for global epidemiological surveillance to better understand environmental risk factors driving nocardiosis in different regions. Diagnostic challenges include non-specific presentations, frequent misdiagnosis as tuberculosis in endemic areas, and high mortality in central nervous system infections. Given these complexities, early diagnosis remains paramount, particularly in immunocompromised hosts with refractory skin lesions, highlighting the urgent need for standardized global monitoring networks incorporating molecular epidemiology. The integration of MALDI-TOF MS and 16S rRNA sequencing has enabled rapid species-level identification, while metagenomic next-generation sequencing can reveal co-infections (e.g., Pneumocystis jirovecii) that may have otherwise gone undetected[10,11]. These advanced diagnostics should be prioritized in high-risk patients, especially those with unexplained granulomatous lesions or persistent infections despite empiric therapy. Future advancements may include artificial intelligence-driven diagnostic algorithms capable of analyzing radiographic patterns and biomolecular datasets to predict Nocardia species infection risk, particularly in endemic regions where clinical mimics like tuberculosis predominate. Cytokine profiling platforms could identify immunological signatures preceding infection onset, offering potential biomarkers for early intervention in high-risk cohorts.

In terms of therapeutic optimization, the tailored SMZ-TMP regimen (2.5-5 mg/kg/day adjusted for renal clearance) exemplifies precision medicine in geriatric patients with CRI. Pharmacokinetic monitoring ensured therapeutic sulfamethoxazole blood concentrations (54-95 μg/mL) while avoiding nephrotoxicity. In this regard, the use of population pharmacokinetic modeling represents a promising avenue to further refine SMZ-TMP dosing algorithms in patients with CKD. By integrating variables such as the estimated glomerular filtration rate and albuminuria into these models, clinicians can account for the dynamic changes in drug clearance and protein binding that occur in renal impairment. This approach can enhance the accuracy of dose predictions and minimize the risk of sub-therapeutic exposure or toxicity, thereby optimizing treatment outcomes. Additionally, surgical drainage of cutaneous abscesses and nutritional support played pivotal roles in resolving inflammation and preventing systemic dissemination.

Future studies should focus on diagnostic and therapeutic innovations for nocardiosis in patients with CRI (Table 2). For example, longitudinal cytokine profiling may help identify the immune dysregulation preceding infection. In resource-limited settings, point-of-care tests (e.g., lateral flow assays) could improve access to rapid diagnostics. Regarding treatment, population pharmacokinetic modeling could help refine SMZ-TMP dosing algorithms in CKD, integrating variables like epidermal growth factor receptor and albuminuria. Global epidemiological surveillance is also required to elucidate environmental risk factors (e.g., soil exposure) driving nocardiosis in tropical regions.

Table 2 Diagnostic and therapeutic innovations in Nocardia brasiliensis infection.

Aspect	Key innovations	Impact
Diagnostic modalities	MALDI-TOF MS: Rapid species identification (< 1 hour)	Reduced time-to-treatment compared to culture-based methods
	mNGS: Detection of polymicrobial infections and co-pathogens (e.g.,Pneumocystis jirovecii)	Enhanced diagnostic yield in immunocompromised hosts
	E-test: Guided antibiotic susceptibility testing	Optimized SMZ-TMP dosing based on local resistance patterns
Therapeutic strategies	Low-dose SMZ-TMP: Reduced nephrotoxicity risk in CRI patients	Improved tolerability and adherence in elderly populations
	Surgical drainage: Adjunctive management of cutaneous abscesses	Hastened resolution of localized infections
	Pharmacokinetic monitoring: Targeted SMZ trough levels (50-100 μg/mL)	Minimized toxicity while

MALDI-TOF MS: Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry; mNGS: Metagenomic next-generation sequencing; SMZ-TMP: Sulfamethoxazole-trimethoprim; CRI: Chronic renal insufficiency; SMZ: Sulfamethoxazole.

Ethical statement

Patient anonymity has been strictly maintained throughout the manuscript. As the study did not involve experimental interventions or procedures requiring formal institutional oversight, institutional review board approval was not applicable.