Neuromodulation for the Treatment of Refractory Chronic Renal Pain: Clinical Report and Literature Review

Abstract

Background: Chronic renal pain secondary to urological pathology can severely affect a patient’s quality of life. Utero Pelvic Junction Obstruction (UPJO) and Loin Pain Hematuria Syndrome (LPHS) are two conditions known to cause chronic renal pain that can be refractory to conventional treatments. Recent publications demonstrate neuromodulation as an effective treatment option for refractory renal pain. The purpose of this review is to (1) provide evidence from a patient case demonstrating the expanding clinical application of spinal cord stimulation (SCS) for refractory renal pain; (2) provide a review of the literature surrounding UPJO/LPHS and SCS; and (3) express a call to action to investigate the clinical applications of neuromodulation and SCS to treatment-resistant genitourinary pathologies. Methods: We performed a search across PubMed and Web of Science databases to search for patients with UPJO/LPHS who had chronic renal/flank pain and were treated with SCS. Results: In our review, we included five case reports/series (including our own) of eight patients who had chronic flank pain secondary to the genitourinary pathologies UPJO and LPHS. Some patients have been having renal pain for up to 20 years, with all patients experiencing significant or complete alleviation of pain after SCS despite multiple failed attempts with other modalities. Five patients had complete resolution of pain and four patients were able to discontinue their pain medications entirely. Conclusions: SCS is gaining traction in its versatility in the management of various chronic pathologies beyond just CNS conditions. Specifically, UPJO and LPHS are examples of urogenital conditions that may benefit from using SCS. Our case shows an exciting opportunity for managing clinical symptoms in patients who have these conditions but have not undergone surgery for many reasons. Our review and clinical report suggest more research is needed in the application of SCS to genitourinary conditions and those experiencing refractory chronic pain.

1. Introduction

Chronic, untreated flank pain secondary to urological pathology is debilitating. The causes of flank pain related to genitourinary pathology range from ureteropelvic junction obstruction (UPJO) to rarer conditions such as Loin Pain Hematuria Syndrome (LPHS). UPJO is a genitourinary condition characterized by impaired urine flow from the renal pelvis to the ureter due to blockage. The etiologies can be categorized as intrinsic vs. extrinsic or congenital vs. acquired [1]. LPHS, a rarer condition, is defined by cryptogenic, debilitating flank pain and hematuria, although its pathophysiology remains poorly understood [2].

The incidence of UPJO in adults is not well-defined, but it occurs in approximately 1 in 1000–2000 live births, with a male-to-female ratio of 2:1 [1,2]. In contrast, LPHS is even rarer, affecting approximately 0.011% of the population [3]. Despite the low prevalence of these conditions, their sequelae can be profoundly debilitating, significantly impairing daily activities and quality of life. The standard treatment for UPJO is surgical, including open pyeloplasty, endopyelotomy, and endoscopic pyeloplasty [1]. Conversely, LPHS is primarily managed conservatively using a multimodal approach, which includes non-opioid analgesics, cognitive behavioral therapy, physical therapy, and antihypertensives [4]. In cases where conservative management fails, minimally invasive therapies such as neuromodulation may be considered, while more aggressive surgical interventions, such as renal denervation or renal auto transplantation, serve as last-resort options [4]. Our review and clinical report are unique in that the management of UPJO and LPHS is traditionally limited to either conservative therapy or surgical intervention, yet recent publications highlight neuromodulation as a promising treatment for refractory renal pain.

The objectives of this review and clinical report are as follows: (1) provide evidence from a patient case demonstrating the expanding clinical application of neuromodulation, specifically for the management of refractory flank pain of urological origin; (2) provide a review of the literature surrounding the epidemiology, risk factors, pathophysiology, and treatment of the underlying urologic pathologies (UPJO and LPHS); and (3) highlight the advantages and considerations of neuromodulation for patients with treatment-resistant genitourinary pathologies.

2. Methods

This study is a case report and descriptive review of the literature regarding the epidemiology, pathophysiology, and treatment of chronic renal pain secondary to genitourinary conditions (UPJO, LPHS). In January 2024, we conducted a computer-aided search across PubMed and Web of Science databases to search for other patients with refractory flank pain managed with neuromodulation. Our search strategy included the following key words and corresponding format: [“Renal Pain” or “Flank Pain”] AND [“Electrical stimulation” or “Spinal Cord Stimulation” or “Neuromodulation” or “Epidural Stimulation”].

We included all articles with reports of patients with chronic renal/flank pain that were treated with neuromodulation. We manually reviewed the references of these articles and selected all relevant articles to include in our review and summary of the literature. All articles that did not contain information in relation to renal/flank pain and neuromodulation were excluded. The articles we sought to include were case reports or case series and were descriptive reports of the clinical outcomes. In these reports, there were no controls and the efficacy of neuromodulation across groups was not able to be assessed. Moreover, there were a small number of reports that only included UPJO and LPHS cases. Provided with these limitations, we decided to conduct a descriptive approach that highlighted the substantial improvements patients made on a case-by-case basis.

3. Results

3.1. Case Report

Our patient is a 36-year-old male with a diverse medical history including hepatitis C, opioid dependence, epilepsy (managed with levetiracetam 1500 mg twice daily), traumatic brain injury (TBI), and chronic flank pain secondary to UPJO. The patient’s UPJO was secondary to kidney stones, which were diagnosed at 13 years old. Since the initial diagnosis, the patient underwent multiple lithotripsies (6-7x), stenting, and eventual Medtronic spinal cord stimulator implantation in 2014. The initial presentation and evaluation to our hospital was in March 2022 due to an acute flare in his flank pain. He expressed experiencing constant pain 5/10, parallel to acute flares. The patient explained his father had a history of similar symptoms. Previous interventions include pain medications and a spinal cord stimulator that was previously implanted and very effective until the battery became completely depleted.

On physical examination, the patient exhibited normal neurological and musculoskeletal function. He reported bladder and bowel function remaining unaffected. He did not report pain on palpation in the flank region. Radiological studies revealed mild degenerative disc disease and SCS leads up to T6, with the generator located in the left upper gluteus. A CT lumbar spine scan indicated known lumbar disc disease and facet arthropathy, along with mild central canal stenosis at L3–4 and L4–5 and minimal stenosis at L2–L3. Additionally, non-obstructing renal calculi were identified.

Interrogation of his spinal cord stimulator (Medtronic, Model 97715), which was implanted over 10 years ago, was appreciated and confirmed to lack any charge. He stated when it was fully functional it offered more than 70% relief in his flank pain. The patient underwent preop evaluation in June 2022 and ultimately surgery to replace the system’s battery. The spinal cord stimulator leads entered the spinal canal at T11–12, with the tip of the array lying in the T6 region.

The patient had a post-operative follow-up in February 2023. During the appointment, he reported a favorable condition and a return to baseline with no focal pain or signs of infection. From his perspective, he was content with the outcomes and explained following the stimulator “everything has gone really well.” The patient appeared stable and showed no signs of distress. Notably, there was non-troubling prominence of the underlying SCS wiring. Overall, the initial implantation of the spinal cord stimulator and revision provided significant pain relief and self-reported improved quality of life. Of note, the stimulation parameters were not documented, and no validated pain or quality of life measure was taken. There were no ethical approvals necessary, all patient data were de-identified, and the patient provided informed consent.

3.2. Clinical Data and Tables

In our review, we included 5 case-reports/series (including our own), spanning 8 total patients (

Table 1. Spinal cord stimulation for patients with refractory renal pain secondary to UPJO/LPHS.

Author/Year	Pathology	Age	Sex	Clinical Presentation	Time-Course	Failed Therapies	SCS Device and Settings	Clinical Outcome
Urreola et al., 2024	UPJO	36	M	5/10 chronic flank pain	10 years	Long-Acting Opioids	Medtronic Spinal Cord Stimulator	“Significant Pain Relief” “Improved Quality of Life”
Kim et al., 2011 [5]	UPJO	38	F	8/10 chronic R-sided flank pain 10/10 pain during flare ups	15 years	Long-Acting Opioids Renal Stents Physical Therapy Celiac Plexus Block	Boston Scientific Octad lead Placement: T7 Vertebral Body Amplitude: 7.0 mA Pulse Width: 160 ms Frequency: 60 Hz	85% relief in pain Discontinuation of pain medications Improved sleep Improvement of mood
Zuidema et al., 2017 [4]	LPHS	37	F	9/10 R-sided flank pain	2 Years	Go	Spinal Modulation Inc(Abbott, Sylmar California, USA). Quadripolar Stimulation Lead & Modulation Axium, Implantable Pulse Generator Placement: DRG T12 & L1 on Right side Amplitude: 0.2, 0.35 mA Pulse Width: 180, 180 ms Frequency: 20, 20 Hz Impedance: <600, <700	4 weeks-100% pain relief 36 weeks-over 50% pain reduction 3/10 pain Discontinuation of pain medications
Goroszeniuk et al., 2009 [6]	LPHS	35	M	10/10 pain radiating from loin to groin	NA	Ureteric Stent Lithotripsy Long-Acting Opioids	Two Medtronic 33 cm Pisces Quad Electrodes at L3 & Medtronic IPG-Synergy SCS System Current: 2–3.5 amps Pulse Width: 450 ms Frequency: 5 Hz	3 months pain-free 1 year pain-free 0/10 pain
Goroszeniuk et al., 2009 [6]	LPHS	44	F	8–10/10 Bilateral loin pain Microscopic hematuria	8 Years	Physiotherapy Facet Join Injections Lumbar Epidural Long-Acting Opioids	Two Medtronic 33 cm Pisces Quad Electrodes & Medtronic IPG-Synergy SCS System Placement: L4/L5 lumbar sympathetic chain Current: 2–3 amps Pulse Width: 450 ms Frequency: 5 Hz	1 year complete pain relief 0/10 pain
Goroszeniuk et al., 2009 [6]	LPHS	43	M	10/10 bilateral groin and loin pain Sleep disturbances	20 years	Left Pyloroplasty Bilateral Nephrostomies Ureteric Stents Transcutaneous Electrical Nerve Stimulation Long-Acting Opioids Local Anesthetic Patches	Stimulong Monoelectrode catheter Placement: L3-Left Lumbar Sympathetic Plexus Frequency: 2 Hz Timing: 5 min, 3–4 times daily	7 months complete pain relief 0/10 pain Discontinuation of pain medications
Goroszeniuk et al., 2009 [6]	LPHS	44	F	2–8/10 left loin pain Hematuria	5.5 years	Long-acting opioids	Pajunk, Stimulong monoelectrode catheter	Complete pain relief 0/10 pain
Richter et al., 2018 [3]	LPHS	24	F	10/10 flank pain Hematuria Severe pain attacks	6 Years	Long-Acting Opioids Radiofrequency Ablation of renal nerves	Abbott PENTA 5-column paddle lead T10-R lateral dorsal epidural space	Improved quality of life 25–50% pain reduction Discontinuation of pain medications

NA = Not applicable.

). All 8 of the patients included had chronic flank pain secondary to the genitourinary pathologies UPJO and LPHS. Notably, patients had substantial flank pain for 2 years up to 20 years with multiple failed treatment attempts. Our patient had 5/10 chronic pain, while the other 7 patients all had pain greater than or equal to 8/10.

All 8 patients had failed trials of long-acting opioids. Furthermore, other failed treatment modalities included ureteric stents, lithotripsy, nerve blocks, renal denervation, physical therapy, pyloroplasty, physiotherapy, transcutaneous electrical nerve stimulation, and radiofrequency nerve ablation. All 8 patients had significant or complete alleviation of pain after neuromodulation and SCS despite multiple failed attempts with other modalities. Specifically, 5 patients had complete resolution of pain, and 4 patients were able to discontinue their pain medications entirely. Long-term efficacy was evident, with patients seeing reductions in pain from a few months to an entire year.

Although the settings and SCS devices varied between patients, all devices were implanted in the lower thoracic or upper lumbar regions. Device leads were implanted in T7 and as low as L3, with many of them targeting the lumbar sympathetic chain. SCS devices included the Medtronic IPG-Synergy SCS system, Abbott Spinal Modulation Axium implantable pulse generator, Boston Scientific Octad leads, Abbott PENTA 5-column paddle lead, and Pajunk Stimulong Mono electrode system.

4. Discussion

4.1. Epidemiology and Risk Factors

Ureteropelvic junction obstruction (UPJO) occurs sporadically and is the most common cause of pathological antenatal hydronephrosis, although it may also have a genetic component [5]. The condition affects approximately 1 in 750–1500 live births, with a male-to-female ratio of 2:1 and a left-sided predominance, while bilateral cases are reported in 10–46% of cases [7]. The overall prevalence of UPJO is estimated at 0.08% in the general population but accounts for 7.7% of patients diagnosed with hydronephrosis [7]. Notably, among patients who undergo surgical repair for UPJO, the majority do so within the first year following diagnosis [8]. However, the epidemiology of UPJO remains incompletely understood, with its first report dating back to 1967 by Little et al. [9]. The prevalence for LPHS is significantly lower, affecting only 0.0012% of the population. However, recent studies indicate a rising incidence in the Ohio region [3].

Interestingly, new epidemiological analyses of UPJO have identified an association with vesicoureteral reflux, urinary tract infections (UTIs), developmental kidney disease, chronic kidney disease, and urinary stone disease [8]. While statistical significance was not determined, a retrospective review provided notable clinical data on patients with UPJO and hydronephrosis. Among a cohort of 368 patients, 13% were premature, 17% had a history of UTIs, and 41% had perinatal complications [10]. This study found that the severity of hydronephrosis was a key predictor for closer clinical surveillance and the likelihood of requiring surgical intervention [11].

Although some risk factors and etiologies of UPJO have been identified, additional considerations are warranted for patients requiring more intensive care. Notably, anteroposterior diameter, differential renal function, and febrile UTIs have been significant predictors for surgical intervention [10]. Another study demonstrated that patients with right-sided UPJO presenting after pain episodes, as well as those with larger anteroposterior diameters but thinner parenchymal tissue, exhibited diminished renal function [10]. Regarding LPHS, little is known about specific risk factors, but Caucasian women appear to be the most affected demographic [3].

4.2. Pathophysiology of LPHS and UPJO

The mechanisms underlying LPHS and its associated flank pain remain unclear since its initial description in 1967. Debate continues regarding whether LPHS is a somatoform disorder or a physiological condition [6]. Standard hematologic and rheumatologic investigations typically yield normal results, with renal angiographic findings varying among patients [6]. Some patients exhibit avascular regions and microaneurysms on renal angiography, while renal biopsies have demonstrated findings ranging from IgA nephropathy to thin glomerular basement membranes (GBMs) or even normal histology [12].

Herbert et al. proposed that thin GBMs may be responsible for gross hematuria, with membrane rupture contributing to the pain experienced by patients [13]. Additionally, Leaker et al. found that the histological appearance of renal vessels in LPHS patients resembled that seen in cyclosporin toxicity, supporting the hypothesis that LPHS may share a vasospastic mechanism analogous to migraines [14]. Hematologic studies have identified statistically significant elevations in β-thromboglobulin, platelet aggregation, plasma D-dimer, and C-reactive protein concentrations, suggesting a potential role of coagulopathy in LPHS pathophysiology [14].

Spetie et al. reported that structurally abnormal GBMs may contribute to LPHS, with two-thirds of affected patients exhibiting either unusually thin or thick membranes [15]. Furthermore, an association has been identified between thin GBMs and metabolic abnormalities such as hypercalciuria, hyperuricosuria, and nephrolithiasis [16]. Notably, Spetie et al. suggest that LPHS patients who test positive for glomerular hematuria may have a distinct pathology compared to those with negative findings [15]. Overall, further research is needed to elucidate the exact mechanisms underlying LPHS. Current hypotheses focus on GBM abnormalities, autoimmune processes, and vascular disturbances as potential contributors to severe flank pain.

In contrast, the pathophysiology and etiology of UPJO have been more consistently studied and established. Although the precise mechanism remains under investigation, UPJO is broadly classified based on intrinsic or extrinsic obstruction and can be categorized as either acquired or genetic [1]. Intrinsic causes of UPJO include an aperistaltic ureteric segment, ureteral strictures, scarring of the ureteric valve, renal calculi, and urothelial neoplasms [1]. Extrinsic causes include lower pole crossing vessels, horseshoe kidney, post-surgical scarring, and fibro-epithelial polyps [1]. These factors can contribute to chronic, debilitating flank and renal pain.

The pathogenesis of UPJO is likely multifactorial, with studies suggesting that mechanisms may involve incomplete recanalization, fetal vessel compression leading to impaired musculature development, abnormal innervation, or muscular discontinuity [17]. Isali et al. identified a potential link between hypoxia, fibrous tissue formation, and inflammation in the development of UPJO [18]. This mechanism aligns with our patient case, which includes a history of kidney stones at a young age. Additionally, a paternal history of similar symptoms supports other proposed theories that a genetic predisposition may underlie UPJO in some patients. If left untreated, UPJO can present with chronic or acute symptoms, including abdominal or back pain, recurrent UTIs, renal calculi, pyelonephritis, hematuria, and, in rare cases, hypertension.

4.3. Diagnosis and Treatment

The gold standard for the initial workup of UPJO is diuretic nephrography [19]. Although still emerging in prognostic and clinical value, biomarkers identified by Kostic et al. have shown promise in identifying infants who may benefit from early intervention [20]. Some of these biomarkers include neutrophil gelatinase-associated lipocalin (NGAL), retinol-binding protein (RBP), transforming growth factor-beta 1 (TGF-β1), and kidney injury molecule-1 (KIM-1) [20].

Passoni et al. propose a treatment algorithm in which patients with severe or worsening mild-to-moderate hydronephrosis and a differential renal function below 35% are considered ideal candidates for surgery [19]. Infants meeting these criteria can undergo minimally invasive surgical approaches to prevent serious long-term complications. Notably, infants with bilateral UPJO-associated hydronephrosis should be evaluated for posterior urethral valves and vesicoureteral reflux using voiding cystourethrography (VCUG) [19]. An important consideration is the management of adults with chronic complications associated with UPJO. Symptoms such as intermittent flank or abdominal pain are diagnosed using ultrasound, similar to pediatric cases. Current treatment options include open pyeloplasty (previously the standard of care) and newer, minimally invasive techniques such as endopyelotomy, laparoscopic pyeloplasty, and robot-assisted pyeloplasty [1].

There is limited information on the pathophysiology of LPHS, making treatment particularly challenging. Currently, no definitive treatment has been established. Instead, a conservative, multidisciplinary approach remains the first-line strategy [21]. Some of the commonly used treatment modalities include analgesics, opioids, cognitive behavioral therapy (CBT), ACE inhibitors, and, in severe cases, surgical options such as renal denervation and auto transplantation [21].

Although many patients achieve favorable outcomes with surgical and medical therapies, an important question remains: what treatment options exist for patients who are not surgical candidates or who continue to experience chronic pain despite intervention? Our case report presents an essential alternative treatment option for patients suffering from severely diminished quality of life due to UPJO or LPHS.

4.3.1. Neuromodulation as an Alternative Treatment

Chronic pain is often a result of dysregulated pain pathways originating in either the peripheral or central nervous system [22]. Spinal cord stimulation (SCS) was first developed in the 1970s based on the gate control theory of pain [23]. Over the next four decades, SCS and neuromodulation has evolved into a widely used technique for managing various chronic pain syndromes and physiological disease states. More recently, SCS has gained attention for its role in managing clinical symptoms secondary to spinal cord injury, including spasticity, locomotion, pain, respiratory function, cardiovascular function, and urological function. Clinical trials are currently underway to further explore its potential applications [22].

Emerging clinical reports suggest that neuromodulation could potentially alleviate visceral organ pain. Recently, neuromodulation has been successfully applied to chronic gastrointestinal pain caused by conditions such as chronic pancreatitis, irritable bowel syndrome, postural abdominal pain, sphincter of Oddi dysfunction, and abdominal neuropathic pain [24]. Furthermore, SCS has been used in patients with neuropathic groin pain, bladder dysfunction, prostatitis, orchialgia, and prostatodynia [24]. The application of SCS for urogenital conditions is now being explored, including its use for UPJO and LPHS. Our case report contributes to this expanding body of literature by demonstrating the therapeutic potential of SCS. Our patient, who suffered from recurrent ureteropelvic junction obstruction and chronic pain, experienced a 70% reduction in pain symptoms following SCS therapy. To our knowledge, this is only the second documented case in which SCS successfully alleviated UPJO-related pain. These promising results highlight the need for further research and clinical trials.

4.3.2. Mechanisms of Neuromodulation

While the precise mechanisms of neuromodulation and SCS remain under investigation, four primary hypotheses have been proposed regarding its role in pain relief:

• Modulation of Neuroinflammation: SCS may regulate systemic and local inflammatory mediators through gene expression and glial cell modulation [22].
• Neurotransmitter Regulation: Multiple studies indicate that SCS alters the release and reuptake of key neurotransmitters, including serotonin, GABA, norepinephrine, and endogenous opioids, thereby contributing to pain relief [22].
• Neuronal Circuit Restoration: Despite incomplete understanding of cortical neurocircuit stimulation, both basic and clinical studies have demonstrated long-term alterations in neuronal firing patterns. West et al. propose that electrical stimulation of the spinal cord increases the resting membrane potential of neurons, thereby restoring effective action potential firing that was previously impaired [25].
• Inhibition of Noxious Stimuli: Studies suggest that neuromodulation and SCS can modulate ascending and descending pain pathways, thereby inhibiting noxious stimuli transmission via electrical stimulation [25].

These ongoing advancements in understanding SCS highlight its growing clinical applications in the treatment of UPJO and LPHS, conditions that can lead to severe, treatment-resistant renal pain.

Our case report highlights an innovative approach for treating chronic pain associated with UPJO and LPHS, emphasizing neuromodulation as a viable alternative for patients who do not respond to conventional medical or surgical therapies. Given the promising outcomes observed in this case and the growing body of evidence supporting SCS for visceral and neuropathic pain conditions, further randomized controlled trials are warranted to fully establish the efficacy of SCS in refractory urological pain syndromes.

4.4. Limitations

Our case report is, to our knowledge, only the second documented instance of UPJO being treated with neuromodulation. A key strength of our report is that our patient underwent multiple surgical and non-surgical therapies for chronic flank pain, yet meaningful relief was only achieved after spinal cord stimulation. However, an inherent limitation of our study represents a single clinical case, and further research is required to establish causation. Additionally, we did not collect detailed clinical data on SCS settings or utilize a standardized implantation protocol. It is also possible that other patients have undergone SCS trials for UPJO, but due to reporting bias, negative results may not have been published. This limitation was similarly observed in other studies included in our review. While our literature review and case report provide valuable insights into the potential of neuromodulation for refractory urological pain, further randomized controlled trials are necessary to determine its efficacy and additional laboratory research is needed to elucidate the underlying mechanisms.

5. Conclusions

Chronic renal pain refractory to treatment can cause debilitating symptomatology. UPJO and LPHS are two genitourinary conditions in which management of renal pain is managed through conservative treatment or surgery. Although minimally invasive surgery is an option, not all patients qualify for, want, or need surgical intervention. We believe SCS is an attractive option due to its versatility in the management of various chronic pathologies beyond just CNS conditions. Specifically, we believe UPJO/LPHS are examples of urogenital conditions that may benefit from the use of SCS. Our case shows an exciting opportunity for managing clinical symptoms in patients who have chronic and refractory pain secondary to genitourinary conditions but have not undergone or cannot undergo surgery for many reasons. Our review and clinical report suggest that more research is needed in the application of SCS to genitourinary conditions that may benefit from alternative management.