Nephrolithiasis—New Directions in 2011

Introduction

Kidney stones are a disease with an identity crisis. The very name itself gives it away. What should the branding strategy be? A low-key, blue collar approach with the simple term “kidney stones” or more upscale marketing with the exotic name “nephrolithiasis”?

I have never personally experienced having a kidney stone, but from what I have been told, I should consider myself fortunate. Those who experience recurrent kidney stones can vouch for the excruciating pain and the unpredictable impact that this problem has on their day-to-day living. As a disease predominantly affecting middle-aged men, it can disrupt family vacations, attendance at work, and the global economy. Even though I have never had a kidney stone, I am caring for more children with this problem with each passing year. My colleagues have documented this trend and have shown that over the past 10 years, the incidence of kidney stones at our center has increased nearly fivefold (¹). Moreover, computer modeling of anticipated climate changes in response to global warming suggests that there will be a profound increase in the incidence and the economic burden of nephrolithiasis throughout the current stone belt in the southeastern United States. In addition, it is anticipated that there will be a significant expansion of this geographic zone of high incidence of kidney stones into more temperate regions of the United States (²). Finally, the occurrence of renal stones has been linked to a higher risk for myocardial infarction (³). Thus, kidney stone disease should shed its inferiority complex and step forward as a full-fledged clinical disorder worthy of investigation by the best and the brightest in nephrology.

This Moving Points in Nephrology series highlights the state-of-the-art presentations at a symposium on nephrolithiasis held at the 2010 Annual Meeting of the American Society of Nephrology in Denver and focuses on recent advances in this area.

The first article, by Dr. David Sas, confirms and underscores the nearly universal documentation of a substantial increase in the incidence of nephrolithiasis in pediatric patients. Dr. Sas reviews the potential causes of this problem and concludes that it is likely to be related to alterations in urine composition, especially calcium concentration. Even though he may not be able to account for why the problem is occurring, his findings indicate that the clinical spectrum of kidney stone disease can no longer be confined to the adult population. It needs to be considered as a clinical possibility in children and adolescents who present with unexplained abdominal pain or suggestive abnormalities in the urinalysis.

Dr. Andrew Rule follows up on Dr. Sas's presentation and provides cumulative data from a large patient cohort followed at the Mayo Clinic in Minnesota about the numerous long-term health ramifications of kidney stone disease (including myocardial infarction). Dr. Rule highlights that kidney stone disease is more than just a short-term, self-limited health problem of acute pain and a few days of missed work. His epidemiologic studies verify that nephrolithiasis is associated with substantial health problems, including chronic kidney disease and end-stage kidney disease, that can be counted on to catch the attention of all nephrologists. Once again, this would put kidney stone disease squarely in the sights of any clinical nephrologist worth his or her credentials.

Moving on to an understanding of the cause of kidney stones, Dr. Kirsten Renkema uses an ingenious mouse model of hypercalciuric disease to demonstrate that increased calcium excretion in the urine has profound effects on renal concentrating capacity, tubular expression of aquaporin 2, and urinary acidification. These secondary changes have substantial impact on the severity of nephrocalcinosis and stone disease in an experimental in vivo model of nephrolithiasis. Although it is unclear whether her findings in knockout mice have direct relevance to the pathophysiology of kidney stone disease as it occurs in human beings, her elegant work indicates that the mechanisms underlying the onset and perpetuation of kidney stone disease is likely to be complicated. Close investigation into the tight web of the functional causes and consequences of kidney stones are likely to reveal new therapeutic targets and alternative strategies to reduce the likelihood of kidney stone formation.

The next article is by Dr. Fredric Coe, an investigator with a long history of monumental contributions to the field of kidney stone disease. His article focuses on the value of close attention to kidney anatomy and detailed assessment of segmental renal function in the pathogenesis of kidney stones. He demonstrates the importance of plaque formation and brushite plugs and indicates how close attention to the precise steps in the initiation of crystal formation and stone accretion can provide greater sense of order and reason to the standard treatments of kidney stones. This includes alterations in diet and fluid intake. It was recently demonstrated that calcium oxalate monohydrate crystals reduce the expression of the tight junction proteins occludin and zonula occludens 1 in polarized MDCK cells and interfere with the barrier and fence function of the renal epithelium (⁴). These findings, which help explain how intratubular changes in the luminal fluid could affect the renal interstitium, highlight the importance of Dr. Coe's approach to the treatment of kidney stones. Whether widespread implementation of the Dietary Approaches to Stop Hypertension (DASH) diet will accomplish the therapeutic goals outlined by Dr. Coe is a topic worthy of further study (^5,6).

The last article in this series is by Dr. David Goldfarb, who presents novel insights from studies of cystinuria that have led to the development of a targeted treatment that works at the molecular level to prevent the formation of kidney stones on a disease-specific basis. He describes how investigations of cystine crystal formation in vitro led to the selection of a molecule that successfully inhibited crystal growth. He discusses how this approach can serve as a paradigm for the development of disease-specific therapeutic molecules in vitro, progressing to preclinical animal models of urolithiasis and then application to clinical trials in patients. He also reviews the possible use of febuxostat, a nonpurine inhibitor of xanthine oxidase that could prevent calcium stones. Dr. Goldfarb reviews the sparse literature suggesting that hyperuricosuria is an important risk factor for calcium stones and describes a trial to determine whether urate-lowering therapy will prevent recurrent calcium stones.

Overall, this series of articles proves that nephrolithiasis is a disease that should have the self-confidence to attract the best and the brightest in nephrology who would dedicate their research efforts to the basic science understanding and clinical research management of kidney stones. I think it is a mark of the success in this field that the new Editor-In-Chief of CJASN, Dr. Gary Curhan, is an expert in this field. His ascendancy has probably been greeted favorably by his colleagues in the field. I think that this series of articles will demonstrate the vitality of kidney stone research and hopefully will spur more work in this vibrant area that will ultimately translate into improvements in the clinical care of the growing number of patients of all ages who experience kidney stone disease.

• David J. Sas, Medical University of South Carolina: “An Update on the Changing Epidemiology and Metabolic Risk Factors in Pediatric Kidney Stone Disease”
• Andrew D. Rule, Mayo Clinic: “Chronic Kidney Disease in Kidney Stone Formers”
• Kirsten Y. Renkema, University Nijmegen Medical Centre: Role of the Calcium-Sensing Receptor in Reducing the Rish for Calcium Stones”
• Fredrick L. Coe, University of Chicago: “Pathophysiology-Based Treatment of Idiopathic Calcium Kidney Stones”
• David S. Goldfarb, New York University School of Medicine: “Potential Pharmacologic Treatments for Cystinuria and for Calcium Stones Associated with Hyperuricosuria”