Alexander Small, MD

Disruptions in renal solute/solvent excretion and reabsorption caused by metabolic, biophysical, environmental, and genetic factors can result in solute supersaturation and ultimately can lead to kidney stone formation. Although the etiology of kidney stone disease is multifactorial, emerging evidence suggests that the prevalence of genetically linked kidney stone disorders is much higher than previously realized.

 Population studies of twins have shown that heritability accounts for 45% to 56% of kidney stone prevalence.

 Likewise, genome-wide association studies and high-throughput sequencing have implicated a myriad of genetic variants linked to stone formation. As more genes are classified and catalogued, diagnosis and treatment of kidney stones inches further and further toward “precision medicine.”

The precision medicine approach allows clinicians to tailor disease management to patients’ unique genetic, metabolic, and environmental risk factors. In fact, a rudimentary form of precision medicine is already considered standard practice for stone formers—24-hour urine collection can detect major systemic causes of stone disease and allow for more specific dietary recommendations.

 However, 24-hour urine collections can lack consistency due to their reliance on patient diet. The day-to-day variability in lithogenic-factor excretion has been noted to be as high as 50%.

 To overcome these deficits, novel diagnostic tools are under investigation.

One such innovation is the kidney injury test (KIT), a point-of-care urine spot analysis assay developed at the University of California, San Francisco. The KIT assay measures the levels of 4 biomarkers and provides a composite “KIT score.” The score has been shown to accurately diagnose calcium-based stones in patients with imaging-confirmed stones,

 and at the 2022 American Urological Association Annual Meeting, investigators showed that the score could distinguish between stone events and nonstone events in known stone formers.

 Although more research is still required, the KIT assay could represent a useful, less expensive diagnostic alternative to imaging, as well as another step toward a precision medicine approach.

Genomic sequencing can also provide a less invasive and more reliable means of diagnosing and educating patients. The 2015 landmark study by Halbritter et al of 272 consecutive patients with kidney stones was able to isolate 14 monogenetic mutations that led to molecular diagnoses of 15% of patients (including 21% of pediatric patients and 11% of adults). The most common variant was at the 

 locus, resulting in dysfunctional transport of cystine and predisposing patients to cysteine stones.

 Other clinically significant variants affected the renal calcium transport (

 Although several individual genes have been implicated, Patel et al’s 2022 genome-wise and phenome-wide association study shows that phenome expression is not equal.

 Due to the highly variable phenotypic expression, their results support the hypothesis that genetic causes of kidney stone disease are more likely polygenetic and that expression is dependent on a complex interplay of several factors.

For now, many precision medicine approaches to the management of kidney stone disease are restricted to research centers and university hospitals. Clinicians may find that commercially available sequencing services for kidney stone formers are not only rare, but also cost prohibitive.

 Moreover, diagnosing genomic variants does not guarantee novel prophylaxis or treatment. To better serve patients with stones, identification of genomic culprits should be simultaneous with investigation of personalized dietary and pharmaceutical interventions.

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2. Goldfarb DS, Fischer ME, Keich Y, Goldberg J. A twin study of genetic and dietary influences on nephrolithiasis: a report from the Vietnam Era Twin (VET) Registry. 

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3. Goldfarb DS. The search for monogenic causes of kidney stones. 

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4. Gambaro G, Croppi E, Coe F, et al; Consensus Conference Group. Metabolic diagnosis and medical prevention of calcium nephrolithiasis and its systemic manifestations: a consensus statement. 

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5. Parks JH, Goldfisher E, Asplin JR, Coe FL. A single 24-hour urine collection is inadequate for the medical evaluation of nephrolithiasis. 

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6. Watson D, Yang JYC, Sarwal RD, et al. A novel multi-biomarker assay for non-invasive quantitative monitoring of kidney injury. 

7. Cortez X, Ghosh S, Sarwal R, et al. Validating the kidney injury test (kit) as a point of care diagnostic for urinary stone recurrence. 

. 2022;207(suppl 5):e67. doi:10.1097/JU.0000000000002522.01

8. Halbritter J, Baum M, Hynes AM, et al. Fourteen monogenic genes account for 15% of nephrolithiasis/nephrocalcinosis. 

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9. Halbritter J. Genetics of kidney stone disease-polygenic meets monogenic. 

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10. Patel P, Venkateswaran V, Pasanuic B, Scotland K. Genetic analysis of kidney stone disease in a multi-ethnic cohort: insights from genome-wide and phenome-wide association studies. 

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11. Goldfarb DS. Empiric therapy for kidney stones. 

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Articles

"As more genes are classified and catalogued, diagnosis and treatment of kidney stones inches further and further toward 'precision medicine,' " write Rutul Patel, DO, MS, and Alexander Small, MD.

Kidney stone treatment inches toward precision medicine

Small is a minimally invasive urology fellow at Mount Sinai Health System, New York, and Matulewicz is a clinical instructor in urology and population health, NYU Langone Medical Center, New York. Urology Times blogs present opinions, advice, and news from urologists and other urology professionals. Opinions expressed by bloggers are their own, and do not necessarily reflect the views of Urology Times or its parent company, MJH Life Sciences.

The worldwide spread of the novel coronavirus SARS-CoV-2 and its constellation of COVID-19 disease manifestations has dramatically disrupted normal life and has altered many aspects of medical practice. Specialty physicians in disease “hot spots,” including many urologists, have nobly performed outside of their normal scopes of practice to support our health systems’ efforts to treat the massive influx of patients with COVID-19.

As urologists at two large New York City academic medical centers with associated public city hospitals, we were responsible for on-call urology coverage during several weeks and stages of the COVID-19 pandemic. Others have described their experiences as off-service frontline physicians and highlighted the changes to outpatient urology care, including the rapid adoption of telemedicine. The goal of this narrative is to share details and lessons learned during our on-call urology coverage in the midst of the current pandemic so we can help others by informing planning.

On March 22, Gov. Andrew Cuomo signed an executive order banning any “elective surgeries” in the state of New York after March 25, 2020. Prior to this hard stop, many institutions had already begun triaging the most urgent cases as ancillary personnel, personal protective equipment (PPE), and operative space resources became scarce. Given the swell of cases that were expected, many areas normally reserved for preoperative holding, post-anesthesia care, and even operating rooms were retrofit for COVID wards and intensive care units. This required a coordinated effort among all surgical services, hospitals leadership, and engineers who made dramatic changes to the physical interior of many hospital areas and reverse airflow to create negative pressure rooms.

All non-emergent cases were prioritized based on consensus decision-making. Risks of surgical delays had to be weighed against the complex risks of disease progression and patient/physician viral exposure. Several weeks ahead of us in their experience, urologists in Asia and Europe suggested tiered systems that accounted for these risks as well as resource utilization. Several institutional guidelines were disseminated online that helped standardize this initial effort. Nevertheless, the vast majority of urologic surgery virtually stopped overnight.

Identifying COVID-positive patients and taking appropriate precautions has become critically important in controlling the spread of this virus. At the onset of the crisis, testing was limited to acutely ill patients with high suspicion of COVID, and results could take up to several days to return. This precluded our ability to systematically test patients with urgent surgical indications and required the use of contact screening and fever testing as a proxy.

While we awaited more widespread use of rapid testing, patients were given designations based on suspicion that included “patients under observation” (PUO) or “patients under investigation” (PUI). As we learned more about asymptomatic spread, universal precautions that included masking and eye protection eventually replaced this risk-adapted approach.

Our first add-on cases with COVID-suspected or COVID-positive patients were learning experiences. Clear communication was essential. A system was instituted that prior to a case being posted for surgery, an attending-level “huddle” among the surgical team, anesthesia, and the charge nurse was required. This conversation mitigated confusion about procedural indications and perioperative needs. Transportation of patients throughout the hospital was a challenge as we attempted to eliminate or reduce contact with non-COVID patients and staff. Likewise, allocating holding areas and recovery rooms required intense coordination.

In the OR, appropriate PPE (i.e., N95 masks, gloves, gowns, and face shields) was required by the entire team, and during intubation/extubation when droplet production is highest, only the anesthesia team remained in the room. Cases were performed expeditiously to minimize risk for all involved. Coronavirus has been rarely detected in blood and never in urine, although theoretical concerns exist about fecal viral loads and risk of aerosolization in cautery smoke and pneumoperitoneum. These new issues have added increased complexity and need for coordination for once-routine interventions.

Special considerations needed to be taken during general urology call. Protecting our frontline residents was highest priority, and many residency programs instituted rotating resident teams to minimize exposure and team outbreak risk. Additionally, several urology trainees dutifully volunteered for “redeployment” to other areas of the hospital, including COVID wards and ICUs. Working with skeleton crews, we encouraged our teams to triage consults and embrace inpatient telehealth consultations where appropriate.

We seemed to receive fewer non-urgent calls, and those that did come through were referred for outpatient follow-up. A reinvigorated spirit of collegiality among specialties has been a welcome silver lining to this crisis.

There are unique diagnostic conundrums during this time. A COVID diagnosis is a potential red herring and could lead to an overlooked urologic problem. For example, a patient may present obtunded with fever and be designated a PUO/PUI, when in fact he or she could have an obstructing ureteral stone and urosepsis. Given many of the vague clinical signs and symptoms mutual to COVID and urologic conditions, a high index of suspicion remains necessary to identify and treat urologic problems appropriately.

Accordingly, synchronous urologic diagnoses with COVID have become common during this time. In addition to the well-recognized pneumonia and acute respiratory distress syndrome, the virus can cause profound coagulopathy, acute kidney injury, and renal failure. Workup often includes lung CT and other imaging, and patients may have incidental urologic findings detected on their COVID evaluation. The management of almost all asymptomatic stones, small renal masses, microhematuria, etc. can be safely deferred until the virus improves.

Anecdotally, gross hematuria consults have become more frequent, as patients with severe COVID can develop a hypercoagulable disseminated intravascular coagulation (DIC), which many institutions are treating with therapeutic anticoagulation. Unfortunately, DIC is a sign of advanced disease and a prognostic factor of poor outcome. In these very sick patients on heparin drips or therapeutic enoxaparin, hematuria treatment can be challenging. Principles of managing hematuria remain and often only temporizing measures are required, such as an upsized catheter or gentle bladder irrigation.

As other physicians have also noted decreases in “routine” emergencies such as heart attacks and appendicitis, we have anecdotally noted fewer urologic emergencies such as obstructing stones and testicular torsion in the emergency room. Are patients staying home due to coronavirus fear? Seeking care outside of New York City? Will delays in care result in worse outcomes for some patients? Or once things normalize, will we see a deluge of patients seeking urologic care? The downstream consequences of COVID-19 disruptions to society and health care will take years to fully understand.

At this time, we are working with our colleagues to determine protocols to optimize universal preoperative COVID testing as the initial surge abates and we are again able to perform more routine clinical care. Lastly, the true extent of our colleagues’ heroic frontline efforts will probably never be adequately appreciated, but they have our unrelenting admiration and respect for the care they’ve provided to all affected by this crisis.

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"The goal of this narrative is to share details and lessons learned during our on-call urology coverage in the midst of the current pandemic so we can help others by informing planning," write Alexander Small, MD, and Rich Matulewicz, MD.

Alexander Small, MD

Articles

Kidney stone treatment inches toward precision medicine

Acute-care urology during the pandemic: Lessons learned