Nephrotic-Nephritic Syndrome Possibly Linked to Tramadol and Occupational Chemical Exposure in a Resource-Limited Setting: A Case Report and Public Health Perspective.

ABSTRACT

We report a case of nephrotic-nephritic syndrome in a 20-year-old male apprentice with a history of chronic tramadol use and prolonged occupational exposure to automotive chemicals. He presented with generalised swelling, fever, and body aches lasting one month. Clinical evaluation revealed anasarca and hypertension, while laboratory investigations showed hypoalbuminemia (1.7 g/dL), significant proteinuria (3.7 g/24 hours), and hyperlipidemia (Total Cholesterol: 380 mg/dL, LDL: 302 mg/dL), consistent with nephrotic-nephritic syndrome. The patient received intravenous diuretics, antibiotics, antihypertensives, and dietary modifications, leading to marked clinical improvement over five days. This case draws attention to the nephrotoxic effects of tramadol and chemical exposures, which may play a synergistic role in the development of glomerular disease. It also highlights the challenges of managing such conditions in resource-limited settings, where socioeconomic constraints hinder long-term follow-up and care. Addressing environmental risks and improving healthcare access are essential for effective prevention and management.

Keywords: Automotive Chemicals, Nephrotic Syndrome, Nephritic Syndrome, Occupational Health Hazards, Tramadol

INTRODUCTION:

Nephrotic syndrome (NS) is a clinical condition characterised by excessive protein excretion in the urine, leading to low blood albumin levels. This causes high blood lipid levels, fluid retention, and various complications. The underlying mechanism involves increased permeability of the glomerular basement membrane in the kidneys, often due to infections or thromboembolic events. The abnormal glomerular permeability can be a primary renal disorder or secondary to congenital infections, diabetes, systemic lupus erythematosus, malignancies, or certain medications. [1,2,3] Nephritic syndrome is a kidney disorder characterised by inflammation of the glomeruli, leading to hematuria (blood in the urine), proteinuria (protein in the urine), hypertension (high blood pressure), and reduced kidney function. Its clinical presentation includes: hematuria, proteinuria which is typically less severe than in nephrotic syndrome, hypertension, oliguria and oedema, particularly in the face and hands. [4,5]

This case report emphasises the distinctive challenges and considerations when managing renal conditions. One of them is nephrotic syndrome in rural areas, a population that is frequently underrepresented in medical literature. The findings from this report can serve as a valuable resource for clinicians practising in comparable settings, assisting them in optimising the care they provide to their patients. Also, this work can serve as a basis for future research, linking tramadol and common chemical substances used in the day-to-day activities in an automobile workshop to the onset of NS. [6,7]

CASE PRESENTATION

History:

The patient was a 20-year-old male apprentice at an electrical store, Bini by tribe and a Christian. He was brought into the emergency room by his relatives on account of fever, generalised body swelling and body aches of one-month duration. His fever was insidious in onset, high grade and associated with chills and rigour. It was relieved by the use of over-the-counter paracetamol. However, fever was recurrent over this period and associated with body aches. Generalised swelling started about the same time and was progressive. There was a positive history of facial puffiness and periorbital swelling. There was also a given history of sore throat before the onset of symptoms, which resolved spontaneously. There was also urgency, frequency and nocturia. There was no history of tobacco smoking or alcohol usage; however, the patient admits to daily indiscriminate use of tramadol over the last 3 months, at least 4 tablets daily (each tablet was 200mg), gotten over-the-counter. This exceeded the recommended therapeutic dose and posed a significant risk of nephrotoxicity. [49]

Physical Examination:

The patient was conscious and had a bloated look with facial puffiness and marked periorbital swelling. He was febrile with a temperature of 40.4⸰C, dyspneic (respiratory rate (RR)- 36cpm), tachycardic (pulse rate (PR)- 120bpm), and elevated blood pressure of 190/110mmHg. He was not pale, icteric, nor cyanosed but was mildly dehydrated and had no palpable lymph node enlargements. However, bilateral pitting pedal oedema was present up to the sacral region. Shifting dullness and fluid thrill were positive with an abdominal circumference (AC) of 43 inches, indicating ascites. Liver span was difficult to ascertain due to the presence of ascites, and there was the presence of right costovertebral angle tenderness. The lung fields were clinically clear on auscultation. A tentative diagnosis of post-infectious glomerulonephritis (PIGN) and right pyelonephritis was made.

Laboratory and Diagnostic Test Results:

Blood Investigations:

Complete Blood Count:

• HAEMOGLOBIN- 11.5g/dL (13-18g/dL), PCV- 34% (40-54%), RBC- 4.0 x 10¹²/L (4.6-6.2 x 10¹²/L), MCV- 84FL (80-90FL), MCH- 29Pg (27-32Pg), MCHC- 34g/dL (31.5-36g/dL), WBC- 12.2 x 10⁹/L (4-11 x 10⁹/L), LYMPHOCYTE- 5% (20-45%), MONOCYTE- 3% (2-10%), GRANULOCYTES- 92% (50-70%), PLATELET- 452 x 10⁹/L (150-400 x 10⁹/L)

  
  

Viral Markers (all rapid diagnostic):

• RVS (negative), VDRL (negative), HBsAg (negative), Anti-HCV (negative)

  
  

Liver Function Test (LFT):

• Total protein- 5.1g/dL (6.4-8.3g/dL), Albumin- 1.7g/dL (3.8-4.5g/dL), Globulin- 0.2g/dL (0.1-1.0g/dL), Alkaline Phosphatase (ALP)- 96U/L (60-170U/L), Aspartate Transaminase (AST)- 6U/L (0-12U/L), Alanine aminotransferase (ALT)- 4U/L (0-12U/L)

  
  

Renal Function Test (RFT):

• Sodium- 149mmol/L (135-155mmol/L), Potassium- 4.5mmol/L (3.6-5.5mmol/L), Chloride- 101mmol/L (97-102mmol/L), Urea- 21mg/dL (10-55mg/dL), Creatinine- 0.9mg/dL (0.6-1.2mg/dL), eGFR (CKD-EPI 2021)- 125.39 ml/min/1.73m² (Normal)

  
  

Lipid Profile

• Total cholesterol- 380mg/dL (150-220mg/dL), Triglyceride- 128mg/dL (60-165mg/dL), HDL- 52mg/dL (35-55mg/dL), LDL- 302mg/dL (≤150mg/dL)

Urine Investigations:

Urinalysis (urinalysis strip, combi 11):

• Appearance- cloudy, Protein- +++, Nitrate- +, Leukocyte- +, Bilirubin- trace, Urobilinogen- absent, Blood- absent, Glucose- absent, Ascorbic acid- absent, Ketones- absent, pH- 7.0, specific gravity- 1.020

  
  

Urine Protein: Creatinine Ratio (UPCR) - 4.2mg/mg (< 0.2mg/mg)

24hr Urine Protein- 3.7g (< 0.15g/day)

Imaging Study:

2.3.3.1 Abdominopelvic USS revealed that the liver was enlarged in size, measuring 17cm with homogenous parenchymal echotexture. It also revealed that the right kidney was enlarged in size, measuring 12.12 x 4.74cm with increases in cortico echotexture and loss of cortico-medullary differentiation. There was moderate ascites noted in the peritoneal cavity of the abdomen. All these features were suggestive of Right Pyelonephritis, Ascites and hepatomegaly (17cm).

Laboratory Limitaion:

A throat swab or an assay for Streptococcus O antigen wasn’t done as well as a toxicological screening, due to the unavailability of a screening unit at the managing facility and the patient’s limited resources to do it elsewhere.

Diagnosis:

The history (sore throat, occupational history, and drug history), clinical presentation (anasarca, facial puffiness, and hypertension) and laboratory investigations (hypercholesterolemia, hypoalbuminaemia, nephrotic range proteinuria) gave a working diagnosis of Nephrotic-Nephritic Syndrome. Also, a secondary diagnosis of Right Pyelonephritis was made from clinical findings (right renal angle tenderness) and laboratory results (urinalysis- nitrates and leukocytes, CBC - granulocytosis and leukocytosis, abdominopelvic USS).

Management

• IV paracetamol 600mg 8hourly

• IV furosemide 60mg every 8 hours, to be adjusted based on the patient’s blood pressure response and not to exceed 600mg in 24 hours

• IV ceftriaxone 1g every 12 hours

• Tabs bisoprolol 5mg daily

• Tabs spironolactone 25mg daily

• Salt intake restriction and strict fluid input and output monitoring

• By the second day of admission, his blood pressure was 130/70mmHg and IV furosemide was adjusted to 40mg every 8 hours.

• On the third day of admission, Tabs rosuvastatin 10mg daily was included in the treatment regimen. They were purchased on the third day of admission due to financial constraints experienced by the patient and his family.

• On the 5^th day of admission, the patient was discharged home on oral medications:

• Tabs torsemide 10mg daily

• Tabs cefuroxime 500mg BD

• Tabs clopidogrel 75mg daily                   All for one week          

• Tabs rosuvastatin 10mg daily

• Caps livolin forte 1 caps BD

He was given a one-week clinic appointment where he would have to repeat RFT, lipid profile, and LFT for monitoring, but he never showed up. When he was called, he said he didn’t have money to run those investigations.

Treatment Outcome

The patient spent five days on admission, and his clinical vitals were progressively on a downward trend since treatment commenced, as seen in Table 1 below. Also, his right costovertebral angle tenderness had abated at the end of 5 days.

Table 1: Treatment Outcome of Patient Being Managed for Nephrotic-Nephritic Syndrome and Right Pyelonephritis on Hospital Admission

Figure 1: Treatment Outcome for the Patient Managed for Nephrotic Syndrome in This Case Study:

Keys: RR-respiratory rate; AC-abdominal circumference; mmHg-millimetre of mercury; bpm-beats per minute; cpm-cycles per minute; ⸰c-degree celcius

Figure 2: The patient’s face before and after treatment showing marked facial puffiness before treatment and reduced facial swelling after treatment

Photo credit: Dr. Harmony Ibezim, used with patient consent

DISCUSSION

The patient’s history of exposure to tramadol and automobile chemicals raises concerns about a possible association with his presentation of nephrotic-nephritic syndrome. Although a toxicological screening to confirm specific nephrotoxic agents was not done due to the unavailability of testing kits/equipment at the rural facility and the financial constraint of the patient to have it done elsewhere, previous studies have documented renal complications linked to these substances. The temporal relationship between exposure and symptom onset suggests a potential contributing role, warranting further investigation into these exposures as possible risk factors for nephrotic, nephritic or nephrotic-nephritic syndromes.

Nephrotic syndrome (NS) is a condition characterised by significant proteinuria (exceeding 40 mg/m² per hour) or, on a single spot urine sample, 2 g of protein per gram of urinary creatinine. This proteinuria can also result from other systemic diseases, such as amyloidosis, leading to hypoalbuminemia (˂3g/dL), accompanied by hyperlipidemia, oedema, and associated complications. This occurs due to the increased permeability of the renal glomerular basement membrane. The syndrome can be primary, arising from kidney-specific diseases, or secondary to factors such as congenital infections, diabetes, systemic lupus erythematosus, malignancies, or the use of certain medications just as it is suspected in this patient. [8] Primary nephrotic syndrome commonly arises from intrinsic kidney diseases such as membranous nephropathy, minimal-change disease, and focal segmental glomerulosclerosis. Secondary causes include systemic conditions like lupus erythematosus, diabetes mellitus, and amyloidosis. Congenital or hereditary focal segmental glomerulosclerosis may result from genetic mutations in podocyte proteins, including podocin, nephrin, or the cation channel 6 protein. [9] In approximately half of cases, triggers such as upper respiratory tract infections play a significant role, while allergic reactions account for about one-third of cases. Less commonly, events like insect bites or vaccinations can act as triggers. Additionally, nephrotic syndrome may be associated with drug abuse, such as heroin use. [10] Nephritic syndrome is traditionally identified by the presence of hematuria (blood in the urine), hypertension (elevated blood pressure), reduced urine output (<400 ml/day, oliguria), red blood cell casts, pyuria, and mild to moderate proteinuria. Without timely intervention, the condition may progress to azotemia and uremic symptoms. These clinical features differ from those observed in nephrotic syndrome as listed above. [11,12] It is caused by significant inflammatory injury to the glomerular capillaries, often linked to various underlying autoimmune, infectious or thrombotic medical conditions in children such as IgA nephropathy, post-streptococcal glomerulonephritis (PSGN), hemolytic uremic syndrome (HUS) and in adults such as systemic lupus erythematosus (SLE), rapidly progressive glomerulonephritis, infective endocarditis, membranoproliferative glomerulonephritis, cryoglobulinemia, etc. [13,14]

Although direct evidence connecting tramadol abuse or overdose to nephrotic or nephritic syndrome is limited, several studies have examined tramadol's nephrotoxic effects, especially regarding acute kidney injury (AKI). Tramadol, an opioid analgesic, has been associated with various forms of kidney injury through multiple mechanisms. Tramadol overdose or misuse can result in acute tubular necrosis (ATN) due to rhabdomyolysis, a condition marked by the breakdown of muscle tissue and the release of myoglobin into the bloodstream, which is harmful to the kidneys. [15] Mitochondrial dysfunction in renal cells has also been implicated, leading to increased oxidative stress. This oxidative stress damages renal tubular cells, contributing to nephrotoxicity. [16] Abuse of this opioid may cause direct injury to renal tubular cells via inflammatory pathways. It increases pro-inflammatory cytokines like TNF-α and IL-6, which can damage kidney tissue. These substances promote inflammation in the kidney, which can disrupt the normal function of the glomeruli and damage the filtration barrier. [17,18]

A study conducted among Palestinian tramadol abusers in 2014 assessed the drug's effects on liver and kidney functions. The findings indicated that tramadol abuse led to significant alterations in renal function markers, suggesting potential nephrotoxic effects. [21]

With potential chemical exposure in an automobile workshop, the nephrotoxic effects of tramadol metabolites could synergise with solvents like toluene and xylene and heavy metals like lead or cadmium. These co-exposures may amplify oxidative stress and inflammatory responses in the kidney. Many chemicals used in automobile workshops can cause direct toxicity via oxidative stress, inflammation, or direct cellular injury to renal tissues or via immune-mediated reactions whereby chemicals can act as haptens, triggering immune responses that damage glomeruli. The development of nephrotic, nephritic or nephrotic-nephritic syndrome due to chemical exposure depends on various factors, including the level and duration of exposure, individual susceptibility, and the presence of other risk factors. [22]

Chronic exposure to heavy metals such as lead, which is commonly found in batteries, paints, and contaminated soils in older workshops or cadmium present in metal coatings and certain batteries, has been associated with nephrotoxicity, leading to conditions such as nephrotic, nephritic or nephrotic-nephritic syndrome. [23] Organic solvents such as toluene, which is found in paints, adhesives, and fuel additives and trichloroethylene, used as a degreasing agent in automotive workshops have been associated with nephrotoxicity. [24,25] Also, Continuous inhalation or dermal exposure to exhaust fumes in poorly ventilated workshops can lead to the absorption of hydrocarbons and other nephrotoxic substances, potentially resulting in kidney damage. Studies have shown that occupational exposure to diesel and gasoline engine exhausts is associated with an increased risk of kidney cancer. For instance, a study found that individuals with high cumulative exposure to both gasoline and diesel exhaust had a 76% increased odds of kidney cancer. [26]

One of the most common metals to which automobile mechanics are exposed and most frequently reported to be associated with nephropathies is mercury. The mechanism by which mercury causes glomerulopathies is not fully understood. It has been suggested that mercury induces immunomodulatory activity in patients exhibiting such glomerulopathies, activating an immune response to the heavy metal. [27,28] A case report in 2024 describes a 38-year-old woman with nephrotic syndrome suspected to be related to heavy metal toxicity, specifically mercury exposure. After ruling out other secondary causes, heavy metal toxicity was considered a potential etiological factor. From 2002 to 2024, there has been more than enough scientific evidence linking heavy metal exposure to the aetiology of nephrotic syndrome. [23]

Acute pyelonephritis is an upper urinary tract infection, specifically of the renal parenchyma and renal pelvis. [29] Pyelonephritis, nephrotic or nephritic syndrome are distinct conditions, but in rare cases, pyelonephritis can indirectly contribute to the development of nephrotic, nephritic or both syndromes through specific mechanisms such as secondary glomerular damage. While pyelonephritis primarily affects the tubules, severe or chronic infections can lead to inflammation and scarring, which may eventually affect the glomeruli. [30] In some cases, immune complex deposition from prolonged infections could lead to secondary glomerular diseases like membranoproliferative glomerulonephritis (MPGN), which can cause nephritic syndrome. [31] Prolonged or recurrent pyelonephritis can lead to immune complex formation, where antigens and antibodies form deposits in the glomeruli. This mechanism may trigger post-infectious glomerulonephritis, which, in rare cases, can present with nephrotic-range proteinuria. [32] Also, Infections, such as pyelonephritis, can trigger minimal change disease (MCD), especially in children. Although uncommon, MCD may present as a secondary glomerular disease following infections. [33]

The patient’s presentation was in keeping with the typical features of nephrotic and nephritic syndrome. Oedema is the hallmark of both nephrotic and nephritic syndrome, initially appearing around the eyes and legs. As the condition progresses, the oedema becomes more widespread, resulting in weight gain and the formation of ascites or pleural effusions. Hypertension is less common in nephrotic syndrome but may occur with nephritic syndrome. [34] Nephrotic-range proteinuria is indicated by 3+ or 4+ results on a dipstick test or through semiquantitative assessment using sulfosalicylic acid. A 3+ result corresponds to a urinary protein concentration of 300 mg/dL or higher, equating to a daily protein loss of 3 g or more, which falls within the nephrotic range. A 24-hour urine collection showing proteinuria of 3 g or more is considered diagnostic. [35,36,37] Serum albumin levels are typically reduced in nephrotic syndrome, often falling below the normal range of 3.5 to 4.5 g/dL. Creatinine levels vary depending on the extent of renal impairment, while total cholesterol and triglyceride levels are generally elevated. [38]

The treatment of nephrotic syndrome is tailored to its underlying cause, and management approaches differ between adults and children. In 2012, the Kidney Disease Improving Global Outcomes (KDIGO) organization provided guidelines outlining recommendations for the treatment of nephrotic syndrome. The treatment principles include diuretics such as furosemide, spironolactone, and occasionally metolazone may be required. However, diuretic use can result in volume depletion, which should be evaluated by monitoring the patient’s symptoms, weight, pulse, and blood pressure. The use of anticoagulants to prevent thromboembolic complications has been proposed, though their role in primary prevention remains unproven. Hypolipidemic agents may also be considered. The dietary approach for patients with nephrotic or nephritic syndrome focuses on providing adequate calories and protein (approximately 1 g/kg/day). [39] There is no evidence to support the benefit of supplemental dietary proteins. A low-sodium diet is recommended to minimize fluid retention and oedema. The management of oedema and proteinuria involves adjusting diuretics and angiotensin antagonists. [40,41] This was implemented in the management of this patient.

No renal biopsy was done due to contraindications such as hypertension and active kidney infection (right pyelonephritis). No corticosteroid was given because of his active pyelonephritis. Some investigations were moved to other days within the five days of admission, or were never done due to the patient’s financial status. Also, the patient missed his clinic follow-up due to financial constraints. This can significantly impact clinical outcomes and contribute to the relapse of disease states. Limited financial resources often prevent patients from accessing necessary healthcare services, medications, and diagnostic tests, leading to poor disease management and increased risk of complications. Studies have shown that patients experiencing financial difficulties are more likely to miss appointments, skip medications, or delay seeking medical care, which exacerbates their condition and increases the likelihood of disease relapse, which might be a possibility in this patient. [42,43] These are some of the challenges faced in the management of most cases in rural settings.

The managing team was able to work with resources available at their disposal to achieve the best outcomes for the patient. A referral attempt could have been fatal because financial constraints significantly impact patients' adherence to medical referrals, particularly in rural settings. Studies indicate that patients often forgo recommended specialist consultations or treatments due to the inability to afford associated costs, including transportation, medical fees, and time away from work. This financial burden leads many to return home without pursuing further care, potentially exacerbating their health conditions. For instance, research has shown that in rural areas, financial hardship is a major barrier to accessing specialty referrals, with patients frequently unable to follow through with recommended care due to cost-related issues. [44,45] Additionally, the lack of health insurance and higher rates of un- or under-insurance in rural populations further impede access to necessary healthcare services. This financial insecurity contributes to lower utilization of healthcare services and higher rates of potentially preventable hospitalizations. [46] Moreover, the failure of referral systems in sub-Saharan rural Africa has been attributed to transport problems and financial barriers, with patients often unable to access higher levels of care due to these constraints. [47,48]

CONCLUSION

This case highlights the multifactorial nature of nephrotic-nephritic syndrome, which can arise from a combination of predisposing factors, such as indiscriminate tramadol use and occupational exposure to automotive chemicals and fumes, as seen in this patient. These factors likely contributed to the development of the condition, alongside pyelonephritis. Despite significant financial and logistical barriers, the managing team employed a resource-efficient approach that led to stabilization and improvement in the patient’s clinical condition. However, financial constraints severely limited the patient's ability to procure medications and attend follow-up appointments, thereby increasing the likelihood of relapse or undetected complications. Addressing these systemic barriers requires a comprehensive approach, including subsidised healthcare services, better occupational health policies, and improved insurance coverage.

Recommendations:

Community and Occupational Health Interventions

• Strengthen public health education on the risks of indiscriminate tramadol use, particularly among young adults in high-risk occupations.

• Implement occupational safety regulations to minimise exposure to harmful automotive chemicals and fumes, including the provision of personal protective equipment (PPE).

• Conduct workplace health screenings for early detection of renal impairment in individuals with chronic chemical exposure.

  
  

Policy and Healthcare System Improvements

• Advocate for government policies to regulate the sale and misuse of tramadol, including stricter prescription guidelines and awareness campaigns.

• Expand access to nephrology care by establishing subsidized dialysis and medication programs for low-income patients.

• Strengthen national health insurance schemes to ensure coverage for chronic kidney disease (CKD) management.

  
  

Clinical and Research Recommendations

• Encourage longitudinal studies on the renal effects of tramadol and chronic exposure to automotive chemicals to establish clearer causal relationships.

• Promote toxicological studies to determine safe exposure limits for automotive workers and mechanics.

• Develop clinical guidelines for early screening and management of nephrotic-nephritic syndrome in at-risk populations.

Patient-Centered Strategies

• Introduce financial assistance programs or patient support groups to help individuals afford essential medications and follow-up care.

• Implement telemedicine follow-ups for patients with financial or logistical barriers to in-person visits.

• Educate patients and caregivers on lifestyle modifications, such as adequate hydration, reduced NSAID use, and dietary modifications to slow disease progression.

ETHICAL CONSIDERATION

The patient provided informed consent for the use of their medical information for this case report. All efforts were made to ensure confidentiality and ethical standards were upheld.

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