POLYURIA WITH INCREASED URINARY CREATININE CLEARANCE COMPLICATING POSTURAL-ORTHOSTATIC-TACHYCARDIA-SYNDROME AND PELVIC-FLOOR-DYSFUNCTION ON PYRIDOSTIGMINE AND BUSPIRONE – IS THIS POLYDIPSIA VERSUS UNRECOGNIZED HYPERFILTRATION SYNDROME VERSUS “OVER-COLLECT

Clinically, hyperfiltration induces mechanical stress on the glomeruli, leading to basement membrane expansion, podocyte injury, increased albuminuria, and progression to glomerulosclerosis and tubular damage. In early diabetic nephropathy, hyperfiltration is associated with an increased tubular metabolic load and oxygen consumption.

Despite its importance, a universally accepted definition of hyperfiltration is lacking. Commonly reported thresholds range from 130 to 140 mL/min/1.73 m² in individuals with two functional kidneys, corresponding to renal function exceeding two standard deviations above the mean GFR in healthy individuals. However, fixed thresholds fail to account for factors such as sex, ethnicity, nephron number at birth, or age-related GFR decline. 

We recently encountered polyuria with high 24-hr urine creatinine clearance in a 22-yo male which raised questions regarding hyperfiltration syndrome as a distinct renal disease entity. Polyuria is defined as excessive urine production exceeding 3 liters per day in adults.

CASE REPORT

Please see results below.

A 22-year-old male who was diagnosed with symptomatic pelvic floor dysfunction in 2020, with pain after urinating, urinary urgency, and inability to empty the urinary bladder together with unsteady urinary stream, was subsequently diagnosed in the following year with postural orthostatic syndrome (POTS). He started oral Pyridostigmine for POTS in late 2021. He initially started with the short-acting Pyridostigmine and later transitioned to the longer-acting oral Pyridostigmine in 2022. At the time of the Nephrology consultation in July 2025, he was on Pyridostigmine SR 180+30 mg daily. He had also started taking Buspirone for anxiety in March 2025, initially at 5 mg twice daily, and was now taking Buspirone 7.5 mg three times a day at the time of the Nephrology consultation. For the pelvic floor dysfunction, he had all along been advised to drink more water/fluids to help with the symptoms. At the same time, following the POTS diagnosis, he was again further counseled on the need to maintain adequate hydration status by again drinking more water/fluids. He was indeed drinking a mix of lots of water and two or more 20-oz electrolyte drinks daily. The mother had kidney stones but there was no family history of polyuria or other kidney disease. He noticed increasing urine in May 2025. At the first Nephrology visit, he reported increased urine volumes plus urinary frequency of up to 10 times during the day. Most significantly, he had emphatically confirmed that he did not wake up at night to pass urine. He had not experienced any weight loss. He had a fuzzy feeling in the head sometimes but was otherwise not orthostatic. 

Vital signs were stable with blood pressure 113/73 mm Hg, pulse was 84/min, and respiratory rate was 14/min. He was not orthostatic. Height 1.803 m, weight 144 lb, and BSA was 1.83 square meters. 

Laboratory testing in July 2025 revealed the following pertinent values: Plasma sodium 144 mmol/L, measured serum osmolality 294 mOsm/kg (275-295), potassium 4.0 mmol/L, bicarbonate 29 mmol/L, creatinine 0.89 mg/dL, eGFR Creatinine 124 ml/min/1.73 square meters BSA, albumin 4.6 g/dL, phosphorus 3.1 mg/dL, calcium 10.2 mg/dL, Cystatin C 0.84 (0.63 - 1.03) mg/L, eGFR by serum Cystatin C 114 (>60) ml/min/BSA, urine albumin creatinine ratio 5 micrograms/mg (<30) and plasma COPEPTIN PROAVP was 4.7 pmol/L (<15.2 pmol/L). 24-hr urine creatinine data from May 2025 revealed urine volume of 7,200 mL, urine creatinine 28.5 mg/dL, 24-hr urine creatinine 2.1 gm and 24-hr urine creatinine clearance 152 ml/min. 24-hr urine creatinine clearance was 143 ml/min/1.73 square meters BSA. From early May 2025, urine sodium was 22.5 mmol/L and urine osmolality was 226 mOsm/kg (150-1150). At other times, in late May 2025 urine osmolality was 750 mOsm/kg and in mid-July 2025, urine osmolality was 746 mOsm/kg. Importantly, kidney function has been stable in the past 7 years (FIGURE 1). Renal sonogram in July 2025 revealed right kidney measuring 10.7 cm in length and left kidney was 10.5 cm in length, no calculus, but both kidneys showed trace pelvocaliectasis.

The likelihood of compulsive self-driven polydipsia driving the clearly daytime polyuria was discussed amicably with the patient during the July 2025 Nephrology meeting. When he was seen again in Nephrology in August 2025, to review all the investigational data, he had already experienced reduced urine volumes simply by cutting back on the quantity of water/electrolyte drinks consumed daily to about 3 L a day. He had noted at this visit: “Definitely when I drink less water, I pee less”.

Polyuria can be driven by polydipsia or can result from renal dysfunction with loss of urinary concentration ability. Patients with postural orthostatic syndrome (POTS) are encouraged to drink upwards of 3 Liters of fluid daily to mitigate dehydration and worsening orthostatism. Similarly, patients with pelvic floor dysfunction are encouraged and motivated to drink more fluids to again lessen their symptoms. Furthermore, Pyridostigmine, a cholinesterase inhibitor, used to treat POTS, can cause or exacerbate urinary urgency and urinary frequency. Moreover, Buspirone, a nonbenzodiazepine anxiolytic agent, is also known to cause or aggravate nocturia, pelvic inflammatory disease, urinary spotting, urinary frequency, urinary hesitancy and urinary incontinence. The 22-year-old male patient was diagnosed with pelvic floor dysfunction in 2020, with pain after urinating, urinary urgency, and not emptying the urinary bladder with unsteady urinary stream. He was diagnosed with POTS the following year in 2021 and started taking Pyridostigmine for POTS in late 2021. More recently, about March 2025, he started Buspirone for worsening anxiety and depression. About two months after starting Buspirone, he had reported increasing urine output and was referred to Nephrology for polyuria following the completion of a 24-hour urine collection for creatinine clearance studies. The interplay of pelvic floor dysfunction, POTS, counseling to increase fluid intake to mitigate the symptoms of pelvic floor dysfunction and POTS, together with concurrent administration of Pyridostigmine and Buspirone, produced what we have dubbed the Polyuria Quadruple Whammy Syndrome (PQWS).

We posit that our patient had exhibited features of compulsive intentional polydipsia driving polyuria in a bid to compensate and mitigate the symptoms of pelvic floor dysfunction and POTS. Furthermore, the pharmacological effects of Pyridostigmine and Buspirone on urinary bladder physiology had also created urinary retention and that possibly, the patient had experienced an “over-collection” of 24-hour urine during the 24-hr urine collection assay in May 2025. This “over-collection syndrome” could have falsely added more to the measured urine volume that returned as high as 7,200 mL. The concordance of measured eGFR by both creatinine and measured eGFR by Cystatin C, taken together with the stable serum creatinine over the years clearly argue against a true hyperfiltration syndrome. This thus represents a pseudo-hyperfiltration syndrome. Most importantly, the daytime-nighttime desynchrony with 10 x daytime urinary frequency versus zero night-time urinary frequency was most consistent with daytime polydipsia-driven polyuria. The plasma COPEPTIN PROAVP level of 4.7 pmol/L in July 2025 was within normal range and was not suppressed as would be expected in polydipsia states. This would be explained by the fact that in July 2025, following the nephrology visit, the patient was now complying with nephrology advice to cut back significantly on the quantity of daily fluid intake to nearer 3 liters, compared to 7 liters earlier in May 2025, when he completed the 24-hour urine collection. Furthermore, the demonstration of trace pelvocaliectasis in both kidneys on renal sonogram in July 2025 supports the speculation that drug-induced urinary retention, coupled with significantly increased polydipsia was contributory to this pseudo-hyperfiltration syndrome. It is speculated that if he were to maintain the current daily fluid intake of about 3 liters, over time, the bilateral pelvocaliectasis will spontaneously resolve. Finally, the rapid improvement in polyuria following the intentional cutback of water/electrolyte drinks further confirmed that this was polydipsia-polyuria syndrome. Simply put!