The Potential Role of Sodium/Glucose Cotransporter 2 Inhibitors in the Treatment of Cystinuria

doi:10.21203/rs.3.rs-4706572/v1

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The Potential Role of Sodium/Glucose Cotransporter 2 Inhibitors in the Treatment of Cystinuria

https://doi.org/10.21203/rs.3.rs-4706572/v1

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Introduction The Maillard reaction is a non-enzymatic reaction between an amino acid and carbohydrate. We hypothesized that continuous washing of cystine stones with glucose could theoretically prevent growth of an existing cystine stone or even reduce its size leading to a decrease in stone events. Sodium/Glucose Cotransporter 2 (SGLT2) inhibitors, well known for inducing glucosuria, were used to test this hypothesis in an initial series of patients. Materials and methods Patients with cystinuria from September 2019 to May 2023 who received off-label dapaglifozin (Farxiga™) were identified. Patients were allowed to continue thiol and alkalinizing agents per standard of care. A symptomatic stone event was defined by stone passage or surgical intervention. Results Ten cystinuric patients were prescribed SGLT2 inhibitors with a median follow up of 13.5 months. Each patients’ historic stone event rate was compared to the event rate while prescribed SGLT2 medication. Overall, 80% of patients experienced fewer or equivalent stone events and half had stable stone volume during therapy. Eight patients had negative cystine capacity at baseline, yet seven experienced fewer stone events while on medication: four experienced no stone growth. One patient was taken off the SGLT2 inhibitor due to an adverse reaction; three others experienced mild, self-resolving effects and yet stayed on the medication. Conclusions Cystinuric patients treated with a SGLT2 inhibitor experienced fewer stone events while on medication compared to their historic rates and exhibited decreased or stable stone growth. There were few medication related side effects. SGLT2 inhibitors may be a promising long-term therapy for patients with cystinuria.

Cystinuria

Maillard reaction

nephrolithiasis

The disulfide bond of cystine, a dimer of the amino acid cysteine, has long been the target of pharmacologic management in patients with cystinuria. Thiol containing medications undergo a thiol exchange reaction to compete with this bond resulting in a drug-cystine complex that is more soluble than cystine.^1–3 These medications however, are associated with severe side effects including liver abnormalities, nephrotic syndrome, blood dyscrasias and skin disorders limiting their use to those who fail dietary or alkali therapy.⁴ Since the first report of the use of thiol medications for cystinuria in 1963, there have been no prospective, randomized data for these medications and development of alternative medications for this disease have been limited.^1,4–6

The Maillard reaction, which is a non-enzymatic reaction between the amine of an amino acid and carbohydrate has been widely used in the food industry. While the reaction requires heating, we hypothesized even if a small amount of cysteine/cystine reacts with glucose at body temperature, continuous exposure of cystine stones to glucose could prevent growth of an existing cystine stone and perhaps could reduce its size to facilitate excretion. To this end, the popular class of medications for treatment of diabetes called Sodium/Glucose Cotransporter 2 (SGLT2) inhibitors may be useful.^7–9 These medications block SGLT2, a protein found in the renal proximal tubules which facilitates excretion of glucose into the urine reducing systemic levels; this has been used for many purposes, especially for certain types of diabetes mellitus. Approximately 60–100 grams of glucose are eliminated daily while this medication is therapeutic. Boasting a low-risk safety profile, once daily dosing and cardiovascular and renal benefits, these medications have rapidly grown in popularity.^8,10

Here we present a novel approach to medical management of cystinuria with SGLT2 inhibitors. We hypothesize that the glucosuria and diuretic effects of SGTL2 inhibitors would lead to a Maillard reaction between cysteine/cystine and glucose in the urinary system leading to a reduction in kidney stone events, possible stone dissolution and stabilization of stone growth.

Setting and participants

Starting in November 2015, the University of California San Francisco (UCSF) Urology Clinic has been enrolling new patients with urinary stone disease into a prospective registry called the Registry for Stones of the Kidney and Ureter (ReSKU). The data points are derived from the EMR notes created by healthcare providers during clinic visits, surgical encounters, and follow-up visits as part of their regular care. The methodology and structure of this registry have been previously described.¹¹ All individuals participating in ReSKU provide written consent, and the study has received approval from the Committee on Human Research (Protocol 14–14533).

Exposure & predictors

We performed a retrospective review of consecutive patients with a history of cystinuria who were started on dapafligozin 10mg daily (Farxiga™) off-label from 2019 to May 2023. Patients were counseled that this medication would be used off-label and the risks, benefits and alternatives of this approach were discussed in detail. Given the widespread use of these medications in diabetes, the associated minimal side effect profile and the close clinical monitoring of these patients, we felt the potential benefits outweighed the risks. These patients had previously failed, did not tolerate or did not wish to start a thiol medication. If patients were on a thiol and wished to stop or were previously enrolled in a clinical trial, they were asked to pause these medications for at least 30 days before starting dapafligozin. We additionally extracted demographic and clinical information including past medical history, prior operative procedures. Twenty-four hour urine study (Litholink Corporation, Chicago IL) results were abstracted prior to medication administration and also while on the SGLT2 inhibitor.

Outcomes

The primary outcome was symptomatic stone events defined by patient report of stone passage or documented surgical intervention. The secondary outcome was silent stone events defined by stone growth. Two trained endourologists reviewed consecutive computed tomography scans and calculated stone growth by the longest stone axis. Baseline size was calculated within 3 months of SGLT2 inhibitor initiation. Final size was calculated at time of last follow up or prior to surgical intervention.

Statistical analysis

For continuous variables, paired T-tests were used to compare means while chi-square tests were used for categorical variables. All analyses were performed using SPSS™ v27.

The SGLT2 inhibitor was prescribed to ten consecutive cystinuric patients in our comprehensive stone clinic. The majority were generally healthy, female (70%), white (90%) with a mean age of 45 years (Table 1). While taking the SGLT2 inhibitor, seven remained on potassium citrate and no additional stone-related medications.

Table 1

Demographic characteristics of the study cohort
	% (n = 10)
Age at medication initiation in years (median, range)	41 (27–71)
Sex
Male	30 (3)
Female	70 (7)
Race
White	90 (10)
Non-white	9 (1)
Past medical history
HTN	10 (1)
T2DM	10 (1)
CKD	0 (0)
HLD	10 (1)
Anxiety/MDD	30 (3)
Cystinuria-specific history
Age at first stone in years (median, range)	19 (6–28)
Number of prior stone surgeries (median, range)	10 (5–25)
Prior medications for cystinuria
Potassium citrate	100 (10)
Tiopronin	80 (8)
Other	20 (2)
Reason for cessation of thiol medication (n = 8)
Side effect	75 (6)
Cost	12 (1)
Unknown	12 (1)

The median time on the SGLT2 inhibitor was 13.5 months and overall follow up since enrollment in ReSKU was 64 months (Table 2). While on the SGLT2 inhibitor, seven patients experienced a symptomatic stone event; three of whom underwent surgical intervention. One procedure was due to an acute stone episode while the other two underwent prophylactic treatment due to stone growth.

Table 2

Stone events and growth while on SGLT-2 inhibitor
	Prior to SGLT-2 inhibitor % (n = 10)	On SGLT-2 inhibitor % (n = 10)
Mean time on medication (months)		12.6 ± 4.1
Citrate utilization	70 (7)	70 (7)
Stone events
Stone event rate per person-years	1.8	1.1
Proportion with fewer stone events on treatment		70 (7)
Surgical event rate per person-years	0.5	0.3
Proportion who underwent surgery on treatment		30 (3)
Stone growth
Stone growth (mm) per person-years	7.3	4.8
Proportion with stable stone volume on treatment		50 (5)

The number of stone events were tallied and annualized from the time of registry enrollment through medication initiation and subsequent follow ups. Each patient’s historical stone event rate prior to medication initiation was compared to their stone event rate while on medication expressed as stone events per person year. Seven of ten patients experienced fewer spontaneous stone passage events while taking the SGLT2 inhibitor (Fig. 1). Prior to SGLT-2 inhibitor use, the stone event rate per person-year was 1.8 compared to 1.1 while on SGLT-2 inhibitor. The surgical event rate (0.5 surgeries per person year versus 0.3 surgeries per person year) and stone growth (7.3 mm per person year versus 4.8mm per person year) were also improved while on medication compared to their historical values. Importantly, due to small sample size, poisson modeling could not be done to compare stone or surgical events.

We therefore performed a comparison of mean stone events per patient. Participants averaged 1.8 ± 1.3 stone events per year prior to initiating the SGLT2 inhibitor compared to 1.2 ± 1.5 stone events per year while taking SGLT2 inhibitors (paired T-test p = 0.313). Half of patients had stable stone volume while on medication while the rest experienced stone growth with a mean stone growth rate of 10mm ± 10.8mm per year (Fig. 2).

The baseline mean 24-hour urine volumes, quantitative urinary cystine and capacities were 3L, 1000 mg, and − 58mg/L respectively in our cohort (Table 3). While on SGLT2 inhibitor, eight patients underwent a repeat 24-hour urine collection which were compared to the baseline studies. There were no significant differences in any of the 24-hour urine analytes except for a significantly higher mean citrate while on medication (719mg ± 254 vs 1172mg ± 649, paired T-test p = 0.03). Interestingly, of the eight patients with negative capacity at baseline, seven had fewer stone events while on medication and four experienced no stone growth while under observation. Only one patient was taken off the SGLT2 inhibitor due to side effects (syncope) while 3 others experienced temporary adverse reactions that resolved spontaneously (nausea, dysuria and lethargy).

Table 3. Comparison of 24-hour urine characteristics

	Baseline		On SGLT-2 inhibitor
	Mean	SD	Mean	SD	p-value
Volume (L)	3.1	1.0	3.5	1.1	0.206
Cystine (mg)	1000.4	208.7	999.3	342.5	0.965
Capacity (mg/L)	-57.9	112.1	-39.5	128.0	0.696
pH	6.9	0.4	6.9	0.5	0.65
Sodium (mmol)	133.3	34.5	173.6	61.2	0.108
Urine Urea Nitrogen (g)	9.4	1.8	10.6	3.9	0.274
PCR (g/kg)	1.0	0.2	1.0	0.2	0.695
Creatinine (mg)	1442.0	354.0	1421.0	475.0	0.888
Calcium (mg)	131.1	53.2	182.5	91.5	0.129
Phosphorus (g)	0.8	0.2	1.0	0.4	0.339
Citrate (mg)	719.0	254.0	1172.0	649.0	0.03
Creatinine (mg) per Kg	17.8	2.7	17.2	4.1	0.795
Calcium (mg) per Kg	1.6	0.7	2.1	1.1	0.277
Supersaturation
Cystine	1.1	0.4	1.2	0.5	0.783
Brushite	0.6	0.6	0.5	0.2	0.658

This retrospective review of ten cystinuric patients who received off-label SGLT2 inhibitors showed 70% of patients experienced fewer stone events after initiating the medication compared to their historic rate. In addition, half of our patients experienced no stone growth while on the medication. The medication was well tolerated with limited adverse effects.

Cystine is formed by the oxidation of two cysteine molecules connected by a disulfide bond. The initial management of cystinuria has traditionally relied on aggressive hydration, dietary modifications and alkalinization of urine.⁵ Failing these preliminary strategies, targeted medication management has relied solely on the use of thiol (-SH) containing medications targeting the disulfide bond to form a more soluble drug-cysteine complex. Use of these medications however has been limited by side effects such as fatigue, arthritis, mucosal ulcers, liver abnormalities, blood dyscrasias, nephrotic syndrome, and skin rashes.^4,5 These medications are also expensive and require frequent dosing throughout the day limiting patient compliance. Though these medications were first used in treatment of cystinuria in 1963, these substantial limitations have restricted their widespread use and there have not been meaningful advances in alternative medication strategies.

We considered a novel approach to treat cystinuria and hypothesized that the Maillard reaction may be an alternative, effective mechanism to impact stone growth and stone recurrence. The biochemical basis for this reaction was initially reported in 1912 when Louis-Camille Maillard was the first to describe that mixtures of amino acids and sugars would become intensely brown with heating; laying the foundation for the understanding of non-enzymatic browning reactions that occur during food preparation.¹² These same reactions occur at body temperature (37^oC) and underly the formation of hemoglobin A1c through glycation of hemoglobin and other advanced-glycation end products (AGEs).^13,14 These AGEs are a heterogeneous group of molecules implicated in diabetes^15,16 and autoimmune or rheumatic diseases.^17,18 As an amino acid, cysteine will also undergo the Maillard reaction when exposed to glucose at physiologic temperatures to form adducts which are expected to be more soluble than cystine. With this hypothetical mechanism to inhibit precipitation of cysteine and possibly induce crystal breakdown leveraging glucosuria, the question was then then how to safely induce this state in our patients.

Sodium/Glucose Cotransporter 2 inhibitors block renal glucose reabsorption, leading to a significant increase in glycosuria.^8,9 These inhibitors predominantly target SGLT2, a protein found in the renal proximal tubules. When administered at therapeutic doses, these inhibitors facilitate the excretion of approximately 60–100 grams of glucose per day (equivalent to 40-70mgs of glucose/mL of urine, assuming 1.5Lit of 24h urine volume) in the urine leading to lower systemic levels of glucose. The glucosuria indued by SGLT2 inhibitors is far in excess to the plasma glucose (1.5-2.0mg/mL) in blood of diabetic patients responsible for the formation of hemoglobin A1c through glycation of hemoglobin and other advanced-glycation end products (AGEs) suggesting bimolecular reaction between cystine and glucose should be favored. The enhanced urinary glucose excretion induces an osmotic diuresis that also may promote increased fluid intake. While these medications were initially developed to treat type 2 diabetes, there is a growing body of literature to support its cardiovascular and renal benefits as well.^7,8

While SGLT2 inhibitors are well tolerated and widely prescribed, they do have adverse reactions including polyuria due to diuresis and fungal genital infections.⁷ There also may be an increased risk of bacterial urinary tract infections however meta-analyses and observational studies suggest the risk is similar to that of type 2 diabetes.^10,19 Our patients tolerated the medication well with three experiencing self-resolving minor adverse reactions and only one patient discontinuing the treatment due to adverse reaction. No patients experienced perineal or urinary tract infections while on medication. These medications are also well reported to cause weight loss which several of our patients reported as a positive ancillary effect of taking these medications.

Urinary citrate excretion was significantly increased in patients while on SGLT2 inhibitors. Citrate reabsorption is tightly regulated by pH such that even small decreases in cellular proximal tubule pH from 7.4 to 7.2 will significantly increase citrate reabsorption whereas alkalosis will limit this reabsorption resulting in increased urinary citrate.²⁰ Therefore, the increase in urinary citrate we observed may be due to decreases in serum potassium leading to a chronic metabolic alkalosis from SGLT2 inhibitor use leading to increases in urinary citrate.²¹ While we did not find any differences in cystine capacity or supersaturation as measured with 24-hour urine collections, sulfhydryl medications are known to cause interference with these measurements in vitro so it is possible imines may have a similar effect.²² Additionally, we observed a modest increase in voided volume and decrease in capacity though neither was statistically significant. The absolute increase in fluid intake is likely limited as our cystinuria patients already demonstrate excellent hydration. It is possible that in a larger study, these differences would become more apparent.

In this context, we hypothesize that SGLT2 inhibitors may be able to induce sufficient levels of glucosuria to inhibit stone growth in patients with cystinuria. In our cohort of patients who received this medication off-label, most experienced fewer symptomatic stone events compared to their own historic event rate and there were few minor side effects from the medication. An alternative mechanism or at least a synergistic aspect of SGLT2 inhibitors is that they induce an osmotic diuresis (due to the increased excretion of both glucose and sodium) which also may have led to increased urinary excretion of cystine and/or encouraged fluid intake.

Our study has several important limitations. First, this was a retrospective study with a limited follow up duration on SGLT2 inhibitors. Our patients were managed with standard of care follow up which meant that the follow-up intervals and duration were not as rigid as that of a rigid clinical trial. Nonetheless, our patients had a median of 1 year of follow up while on medication and 64 months overall which points to good patient compliance with rigorous follow up. Second, treating the stone event rate as its own control may introduce healthcare utilization bias as interfacing with the medical system could have led to improved dietary habits which had a major impact on stone event rates. Most patients were typically registered on ReSKU for several years before initiating the SGLT2 inhibitor, so their historic stone event rate was less subject to variations in control of their cystinuria. In addition, most of our patients had a negative cystine capacity at baseline before starting the SGLT2 inhibitor signifying severe disease. Third, patients with cystinuria are known to develop symptomatic calculi in clusters for unknown reasons. It is possible that we captured our patients during a period of quiescence however as stated previously, we had a median follow up of over five years, so this is less likely. Fourth, our overall sample size was small. Yet cystinuria is a rare disease and our practice at UCSF has amassed a large cystinuric patient cohort of at least 60 patients that have enrolled in numerous trials in hopes of finding an alternative to the thiol-type prophylactic medications. Lastly, part of the historic data collected on the stone event rate includes time on clinical trials however all patients had at least 30 days off trial medication prior to starting the SGLT2 inhibitor. In addition, 90% were previously on randomized trials so the effect of these trial medications on their baseline stone rate would have decreased any detectable difference in the event rate on the SGLT2 inhibitor making the difference we captured an underestimate.

Dapaglifozin (Farxiga™) appears to be a well-tolerated medication for the treatment of cystinuric patients. Most patients experienced fewer stone events and had stable radiographic stone disease on interval imaging. Patients experienced few medication-limiting side effects. The mechanism of action of this medication appears to occur independently of any identifiable findings on twenty-four hour urine analysis aside from an increase in urinary citrate.

Conceptualization: Wilson Sui, Marshall Stoller, Manoj Desai; Methodology: Wilson Sui, Heiko Yang, Marshall Stoller; Formal analysis and investigation: Thomas Chi, Wilson Sui, Marshall Stoller; Writing - original draft preparation: Wilson Sui, Marshall Stoller, Manoj Desai; Writing - review and editing: Wilson Sui, Marshall Stoller, Thomas Chi, Heiko Yang, Manoj Desai; Supervision: Thomas Chi, Marshall Stoller

AGE

advanced-glycation end product

EMR

electronic medical record

ReSKU

Registry for Stones of the Kidney and Ureter

SGLT2

Sodium/Glucose Cotransporter 2

UCSF

University of California, San Francisco

Funding:

none

Author Contribution

Acknowledgement

n/a

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No competing interests reported.

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The Potential Role of Sodium/Glucose Cotransporter 2 Inhibitors in the Treatment of Cystinuria

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