Urinary Frequency and Polydipsia Mimicking Diabetes Mellitus: Obesity-Related Secondary Focal Segmental Glomerulosclerosis with Concurrent Overactive Bladder — A Case Report

Technical Summary: Urinary Frequency and Polydipsia Mimicking Diabetes Mellitus in Obesity-Related Secondary FSGS with Concurrent Overactive Bladder

Problem Statement
The case report addresses two concurrent diagnostic challenges in a young adult with class II obesity: the differentiation of nephrotic-range proteinuria caused by secondary (adaptive) focal segmental glomerulosclerosis (FSGS) versus primary immune-mediated disease, and the distinction between true metabolic polyuria (suggestive of diabetes mellitus or insipidus) and lower urinary tract dysfunction (overactive bladder). The patient presented with a two-year history of urinary frequency, polydipsia, and hand paraesthesia, initially raising suspicion for diabetes mellitus. The clinical complexity lay in the coexistence of heavy proteinuria with preserved serum albumin (atypical for primary nephrotic syndrome) and urinary symptoms that mimicked osmotic diuresis but were ultimately attributed to bladder dysfunction.

Methodology
This is a single-patient case report utilizing a comprehensive clinicopathological correlation approach.

• Clinical Evaluation: Detailed history taking, physical examination, and anthropometric measurements (BMI 36.2 kg/m²) were performed.
• Laboratory Workup: Extensive serological and immunological testing excluded autoimmune, viral (HIV, Hepatitis B/C), and genetic causes (sickle cell trait). Metabolic panels assessed renal function, lipid profiles, uric acid, and glycemic control (HbA1c).
• Quantitative Urinalysis: 24-hour urine protein collection and spot urine protein-to-creatinine ratio (UPCR) were utilized to quantify proteinuria.
• Imaging: Trans-abdominal ultrasound evaluated renal morphology and bladder dynamics (pre-void and post-void volumes).
• Histopathology: An ultrasound-guided kidney biopsy was performed. Tissue was analyzed via light microscopy (H&E, PAS, silver stains), immunofluorescence (for IgA, IgM, IgG, C3, C1q, C4d), and clinical correlation with the Columbia classification system. Electron microscopy was noted as unavailable.
• Therapeutic Intervention: Management followed KDIGO guidelines for secondary FSGS, avoiding immunosuppression. The regimen included:
  • Renin-angiotensin system (RAS) blockade (Losartan).
  • SGLT2 inhibition (Empagliflozin).
  • Lipid management (Rosuvastatin, later Rosuvastatin/Ezetimibe).
  • Urate-lowering therapy (Febuxostat).
  • Weight reduction via Tirzepatide (off-label use).
  • Antimuscarinic therapy (Oxybutynin) for urinary symptoms.
• Follow-up: Longitudinal monitoring of renal function, proteinuria, metabolic parameters, and urinary symptoms over several months.

Key Results

• Renal Pathology: The biopsy revealed segmental sclerosis with perihilar and arteriolar hyalinosis, intracapillary foam cells, and capsular adhesions. Immunofluorescence showed only focal trace mesangial IgA/IgM. These findings were consistent with the perihilar variant of FSGS, indicative of a secondary (adaptive) process driven by obesity-related hyperfiltration, rather than primary immune-mediated FSGS.
• Metabolic Profile: The patient exhibited nephrotic-range proteinuria (4320 mg/24h) but maintained preserved serum albumin (4.6 g/dL) and no edema. He had dyslipidemia, hyperuricemia, and elevated liver enzymes consistent with metabolic dysfunction-associated steatotic liver disease. HbA1c was normal (5.1%), ruling out diabetes mellitus.
• Urinary Symptoms: Initial evaluation suggested polyuria, but 24-hour urine volume was within normal limits (3000 mL), and urine specific gravity was not inappropriately dilute. The patient's ability to tolerate prolonged fasting (Ramadan) without symptoms further argued against diabetes insipidus.
• Treatment Outcomes:
  • Renal: Weight loss (16 kg reduction) and RAS/SGLT2 blockade improved metabolic parameters and transiently lowered creatinine, but proteinuria fluctuated and did not achieve durable remission.
  • Urinary: Empagliflozin initially worsened urinary frequency due to glycosuria. Upon re-evaluation, the patient recalled urgency at low bladder volumes. A clinical diagnosis of overactive bladder (OAB) was made. Low-dose oxybutynin resulted in marked symptomatic improvement.
  • Neurological: Intermittent hand paraesthesia remained unexplained but was deemed benign and unrelated to the renal/urological diagnoses.

Key Contributions

1. Diagnostic Differentiation: The report highlights the critical distinction between true polyuria (excessive urine volume) and urinary frequency (excessive voiding of normal volumes), demonstrating how the latter can mimic metabolic disease in obese patients.
2. Histopathological Correlation: It reinforces that obesity-related glomerulopathy can present with heavy, nephrotic-range proteinuria while preserving serum albumin, a phenotype that often leads to misdiagnosis of primary FSGS.
3. Therapeutic Implications: The case demonstrates that in secondary (adaptive) FSGS, immunosuppression is inappropriate; management should focus on hemodynamic and metabolic drivers (weight loss, RAS blockade, SGLT2 inhibition).
4. Clinical Caution: It illustrates how SGLT2 inhibitors, while beneficial for renal protection, can transiently obscure the underlying etiology of urinary symptoms by inducing glycosuria, necessitating careful re-evaluation of bladder function.

Significance and Claims
The authors claim that this case serves as a reminder to clinicians to avoid "diagnostic anchoring" in young adults with obesity, where renal disease is attributed solely to obesity and urinary symptoms to diabetes without rigorous differentiation. The paper emphasizes that:

• Correct classification of FSGS (primary vs. secondary) is essential to avoid unnecessary and potentially harmful immunosuppression.
• A preserved serum albumin does not rule out significant glomerular disease.
• Chronic urinary frequency must be evaluated as a lower urinary tract symptom (e.g., overactive bladder) distinct from metabolic polyuria.
• Histology, timed urine quantification, and bladder assessment are distinct tools that must be used to answer specific clinical questions.

The authors modestly note limitations, including the lack of electron microscopy for definitive foot-process effacement grading, the absence of formal urodynamic studies or water-deprivation tests, and the relatively short follow-up period where proteinuria remained active. The conclusion is that the patient's condition represents an active, partially controlled glomerular lesion driven by metabolic factors, coexisting with a treatable bladder dysfunction, rather than a remitted disease state.