Do kidney stone formers have a kidney disease?
Authors: Anna L. Zisman, Andrew P. Evan, Fredric L. Coe, Elaine M. Worcester
Journal: Kidney International (2015)

Nephrolithiasis is a highly prevalent disorder affecting approximately one in eleven people and is associated with multiple complications including hypertension, cardiovascular disease, and chronic kidney disease. Significant epidemiologic associations with chronic kidney disease and ESRD have been noted and are reviewed herein, but debate persists in the literature as to whether kidney stone formation is a pathogenic process contributing to kidney disease. Corroborating evidence supporting the presence of kidney disease in stone formers includes the variability of renal function by stone type, the positive association of stone size with renal dysfunction, the presence of markers of renal injury in the urine of even asymptomatic stone formers, and direct evidence of renal tissue injury on histopathology. Proposed pathogenic mechanisms include recurrent obstruction and comorbid conditions such as recurrent urinary tract infections and structural abnormalities. Recent work evaluating the renal histopathology of different groups of stone formers adds further granularity, suggesting variability in mechanisms of renal injury by stone type and confirming the pathogenic effects of crystal formation. Genetic abnormalities leading to stone formation including cystinuria and primary hyperoxaluria, among others, contribute to the burden of disease in the stone-forming population. Nephrolithiasis is a highly prevalent disorder affecting approximately one in eleven people and is associated with multiple complications including hypertension, cardiovascular disease, and chronic kidney disease. Significant epidemiologic associations with chronic kidney disease and ESRD have been noted and are reviewed herein, but debate persists in the literature as to whether kidney stone formation is a pathogenic process contributing to kidney disease. Corroborating evidence supporting the presence of kidney disease in stone formers includes the variability of renal function by stone type, the positive association of stone size with renal dysfunction, the presence of markers of renal injury in the urine of even asymptomatic stone formers, and direct evidence of renal tissue injury on histopathology. Proposed pathogenic mechanisms include recurrent obstruction and comorbid conditions such as recurrent urinary tract infections and structural abnormalities. Recent work evaluating the renal histopathology of different groups of stone formers adds further granularity, suggesting variability in mechanisms of renal injury by stone type and confirming the pathogenic effects of crystal formation. Genetic abnormalities leading to stone formation including cystinuria and primary hyperoxaluria, among others, contribute to the burden of disease in the stone-forming population. For many years, nephrolithiasis has been viewed as a highly unpleasant nuisance by patients and doctors alike, but there had been little concern regarding long-term ramifications. Over the last several decades, however, there has been an increasing appreciation for the association of nephrolithiasis with negative long-term outcomes including cardiovascular morbidity,1.Ferraro P.M. Taylor E.N. Eisner B.H. et al.History of kidney stones and the risk of coronary heart disease.JAMA. 2013; 310: 408-415Crossref PubMed Scopus (143) Google Scholar,2.Liu Y. Li S. Zeng Z. et al.Kidney stones and cardiovascular risk: a meta-analysis of cohort studies.Am J Kidney Dis. 2014; 64: 402-410Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar metabolic disturbances,3.Domingos F. Serra A. Metabolic syndrome: a multifaceted risk factor for kidney stones.Scand J Urol. 2014; 48: 414-419Crossref PubMed Scopus (31) Google Scholar and renal complications including chronic kidney disease (CKD) and end-stage renal disease (ESRD).4.Sarnak M.J. Levey A.S. Schoolwerth A.C. et al.Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research.Clinical Cardiology, and Epidemiology and Prevention. Hypertension. 2003; 42: 1050-1065Google Scholar, 5.Schiffrin E.L. Lipman M.L. Mann J.F. Chronic kidney disease: effects on the cardiovascular system.Circulation. 2007; 116: 85-97Crossref PubMed Scopus (1192) Google Scholar, 6.Shavit L. Girfoglio D. Vijay V. et al.Vascular calcification and bone mineral density in recurrent kidney stone formers.Clin J Am Soc Nephrol. 2015; 10: 278-285Crossref PubMed Scopus (47) Google Scholar, 7.Tonelli M. Wiebe N. Culleton B. et al.Chronic kidney disease and mortality risk: a systematic review.J Am Soc Nephrol. 2006; 17: 2034-2047Crossref PubMed Scopus (1204) Google Scholar Guilt by association, however, places nephrolithiasis in a nebulous category—is it simply a bother, a risk factor for other disease states, or is kidney stone formation itself a disease? In the ensuing pages, we will consider these issues through the panoramic lens of epidemiology, reviewing data supporting the relationship between nephrolithiasis and impaired kidney function, as well as through the microscopic lens of histopathology, potentially shedding light on the mechanisms leading to kidney injury and dysfunction. Although classically renal dysfunction has been thought of as a decrement in the glomerular filtration rate (GFR), renal disease states may present with normal GFR but an abnormality in one of its other functions such as maintenance of blood pressure (through salt and water handling and hormonal regulation) or maintenance of acid/base homeostasis. For example, patients with a renal tubular acidosis may have a normal GFR but have an inability to maintain acid/base homeostasis. Halperin et al.8.Halperin M.L. Cheema D.S. Kamel K.S. Physiology of acid-base balance: links with kidney stone prevention.Semin Nephrol. 2006; 26: 441-446Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar have proposed that the human kidney is designed to maintain systemic acid–base balance while maintaining the ‘ideal’ urine pH of 6 to prevent crystallization within the kidney. Within this framework, any stone former has failed the test of normal renal function, as stone formation has resulted from a failure of the kidney to prevent crystallization. More recently, international guidelines9.Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD).Kidney Int Suppl. 2009; 113: S1-130PubMed Google Scholar,10.Levey A.S. Coresh J. Chronic kidney disease.Lancet. 2012; 379: 165-180Abstract Full Text Full Text PDF PubMed Scopus (1293) Google Scholar have expanded the definition of CKD from simply a decreased GFR to the presence of any of the following for more than 3 months: estimated GFR (eGFR)<60 ml/min per 1.73 m2, albuminuria, urine sediment abnormalities, electrolyte abnormalities due to tubular disorders, structural abnormalities detected by imaging, or history of kidney transplantation, as these have been shown to be predictive of downstream complications. For the purposes of our discussion, we will focus on kidney stone formation as a parenchymal disease of the kidney that may be associated with decrements in GFR, rather than simply a nuisance within the urological tract. The aforementioned guidelines specifically include abnormal histopathological findings in the renal parenchyma as its own category defining CKD, which, as we will demonstrate, is not an uncommon finding in stone-forming patients.11.Evan A.E. Lingeman J.E. Coe F.L. et al.Histopathology and surgical anatomy of patients with primary hyperparathyroidism and calcium phosphate stones.Kidney Int. 2008; 74: 223-229Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 12.Evan A.P. Coe F.L. Rittling S.R. et al.Apatite plaque particles in inner medulla of kidneys of calcium oxalate stone formers: osteopontin localization.Kidney Int. 2005; 68: 145-154Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 13.Evan A.P. Lingeman J.E. Coe F.L. et al.Crystal-associated nephropathy in patients with brushite nephrolithiasis.Kidney Int. 2005; 67: 576-591Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar, 14.Evan A.P. Coe F.L. Lingeman J.E. et al.Renal crystal deposits and histopathology in patients with cystine stones.Kidney Int. 2006; 69: 2227-2235Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 15.Evan A.P. Coe F.L. Lingeman J.E. et al.Mechanism of formation of human calcium oxalate renal stones on Randall's plaque.Anat Rec (Hoboken). 2007; 290: 1315-1323Crossref PubMed Scopus (155) Google Scholar, 16.Evan A.P. Lingeman J. Coe F. et al.Renal histopathology of stone-forming patients with distal renal tubular acidosis.Kidney Int. 2007; 71: 795-801Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 17.Evan A.P. Lingeman J.E. Coe F.L. et al.Role of interstitial apatite plaque in the pathogenesis of the common calcium oxalate stone.Semin Nephrol. 2008; 28: 111-119Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 18.Evan A.P. Coe F.L. Gillen D. et al.Worcester EM. Renal intratubular crystals and hyaluronan staining occur in stone formers with bypass surgery but not with idiopathic calcium oxalate stones.Anat Rec (Hoboken). 2008; 291: 325-334Crossref PubMed Scopus (47) Google Scholar, 19.Evan A.P. Lingeman J.E. Coe F.L. et al.Intra-tubular deposits, urine and stone composition are divergent in patients with ileostomy.Kidney Int. 2009; 76: 1081-1088Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 20.Evan A.P. Weinman E.J. Wu X.R. et al.Comparison of the pathology of interstitial plaque in human ICSF stone patients to NHERF-1 and THP-null mice.Urol Res. 2010; 38: 439-452Crossref PubMed Scopus (19) Google Scholar, 21.Evan A.P. Lingeman J.E. Worcester E.M. et al.Renal histopathology and crystal deposits in patients with small bowel resection and calcium oxalate stone disease.Kidney Int. 2010; 78: 310-317Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 22.Evan A.P. Lingeman J.E. Worcester E.M. et al.Contrasting histopathology and crystal deposits in kidneys of idiopathic stone formers who produce hydroxy apatite, brushite, or calcium oxalate stones.Anat Rec (Hoboken). 2014; 297: 731-748Crossref PubMed Scopus (39) Google Scholar, 23.Evan A.P. Worcester E.M. Williams Jr, J.C. et al.Biopsy proven medullary sponge kidney: clinical findings, histopathology, and role of osteogenesis in stone and plaque formation.Anat Rec (Hoboken). 2015; 298: 865-877Crossref PubMed Scopus (30) Google Scholar, 24.Evan A.P. Worcester E.M. Coe F.L. et al.Mechanisms of human kidney stone formation.Urolithiasis. 2015; 43: 19-32Crossref PubMed Scopus (109) Google Scholar Furthermore, recent data highlight the increased prevalence of albuminuria and renal scarring even in asymptomatic stone formers—both considered diagnostic for CKD.25.Lorenz E.C. Lieske J.C. Vrtiska T.J. et al.Clinical characteristics of potential kidney donors with asymptomatic kidney stones.Nephrol Dial Transplant. 2011; 26: 2695-2700Crossref PubMed Scopus (48) Google Scholar In healthy subjects being evaluated for kidney donation at the Mayo clinic, subjects noted to have asymptomatic kidney stones on computerized tomography imaging were significantly more likely than donors without a stone to have renal parenchymal thinning and focal scarring.25.Lorenz E.C. Lieske J.C. Vrtiska T.J. et al.Clinical characteristics of potential kidney donors with asymptomatic kidney stones.Nephrol Dial Transplant. 2011; 26: 2695-2700Crossref PubMed Scopus (48) Google Scholar Furthermore, among subjects who had previously had a symptomatic stone event, 13% had evidence of albuminuria of >30 mg/24 h, compared with 3.5% and 3.6% of subjects with no stone disease and asymptomatic stone disease, respectively. Although albuminuria is suggestive of glomerular injury, markers of tubular injury are also elevated in patients in nephrolithiasis. Sun et al.26.Sun W. Feng Y. Yao X.D. et al.Urinary angiotensinogen is elevated in patients with nephrolithiasis.Biomed Res Int. 2014; 2014: 349602PubMed Google Scholar have shown that in a series of 60 stone formers, urinary angiotensinogen is significantly higher than in control subjects and is negatively correlated with eGFR. Urinary angiotensinogen concentrations are a marker of intrarenal angiotensin II levels, a critical modulator of renal injury via its role in potentiating glomerular capillary hypertension27.Siragy H.M. Carey R.M. Role of the intrarenal renin-angiotensin-aldosterone system in chronic kidney disease.Am J Nephrol. 2010; 31: 541-550Crossref PubMed Scopus (172) Google Scholar and in activation of signaling pathways associated with inflammation, generation of reactive oxygen species, and endothelial dysfunction.28.Hsu T.W. Liu J.S. Hung S.C. et al.Renoprotective effect of renin-angiotensin-aldosterone system blockade in patients with predialysis advanced chronic kidney disease, hypertension, and anemia.JAMA Intern Med. 2014; 174: 347-354Crossref PubMed Scopus (150) Google Scholar Urinary angiotensinogen levels were also significantly correlated with urinary α1-microglobulin, a marker of proximal tubular injury that is believed to be one of the earliest markers of tubular dysfunction.29.Devarajan P. Krawczeski C.D. Nguyen M.T. et al.Proteomic identification of early biomarkers of acute kidney injury after cardiac surgery in children.Am J Kidney Dis. 2010; 56: 632-642Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar Urinary excretion of 8-hydroxydeoxyguanosine, a marker of oxidative DNA damage associated with glomerular and interstitial fibrosis,30.Tsai J.P. Liou J.H. Yeh K.T. et al.Intensity of cytosol expression of 8-OHdG in normal renal tubules is associated with the severity of renal fibrosis.Swiss Med Wkly. 2011; 141: w13268PubMed Google Scholar is also increased in stone formers.31.Boonla C. Wunsuwan R. Tungsanga K. et al.Urinary 8-hydroxydeoxyguanosine is elevated in patients with nephrolithiasis.Urol Res. 2007; 35: 185-191Crossref PubMed Scopus (68) Google Scholar Furthermore, immunohistochemical analysis demonstrates increased 8-hydroxydeoxyguanosine expression in the renal tissue adjacent to stone in subjects with nephrolithiasis.32.Kittikowit W. Waiwijit U. Boonla C. et al.Increased oxidative DNA damage seen in renal biopsies adjacent stones in patients with nephrolithiasis.Urolithiasis. 2014; 42: 387-394Crossref PubMed Scopus (14) Google Scholar The earliest study to note the relationship between nephrolithiasis and CKD in the general population was performed by Vupputuri et al.33.Vupputuri S. Soucie J.M. McClellan W. et al.History of kidney stones as a possible risk factor for chronic kidney disease.Ann Epidemiol. 2004; 14: 222-228Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar In their case–control study performed in North Carolina, the authors analyzed 548 patients with newly diagnosed CKD (defined as a creatinine greater than 1.5 mg/dl) and 514 age-, sex-, and race-matched community dwelling adults without kidney disease regarding history of nephrolithiasis. Among patients, 16.8% of subjects reported a diagnosis of a kidney stone, compared with 6.4% of controls. After adjustment for comorbidities, CKD was nearly twice as likely (odds ratio (OR)=1.9) in those with a history of nephrolithiasis. The following year Gillen et al.34.Gillen D.L. Worcester E.M. Coe F.L. Decreased renal function among adults with a history of nephrolithiasis: a study of NHANES III.Kidney Int. 2005; 67: 685-690Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar demonstrated that the relationship between estimated GFR and kidney stone history in more than 15,000 subjects (6% stone formers) from the Third National Health and Nutrition Examination Survey (NHANES III) was dependent on weight. Generally, those with a history of kidney stones were more likely to be older, non-African-American, male, and have a history of coronary artery disease. After adjustment for potential confounders, overweight stone formers (body mass index>27) had a mean eGFR of 3.4 ml/min per 1.73 m2 lower than their non-stone-forming counterparts. This difference was not noted in those with a body mass index<27. More recent data by Shoag et al. using the NHANES 2007–2010 database confirm the association between kidney stones and CKD.35.Shoag J. Halpern J. Goldfarb D.S. et al.Risk of chronic and end stage kidney disease in patients with nephrolithiasis.J Urol. 2014; 192: 1440-1445Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar Among 5971 NHANES participants with data on stones and kidney function, 521 subjects admitted to a history of nephrolithiasis. In a multivariate analysis, history of stone disease was strongly associated with CKD (OR=1.5) and dialysis requirement (OR=2.37) in the cohort. Notably, this association appeared driven by women (OR=1.76 for CKD, OR=3.26 for dialysis), as it was not noted in men. Stankus et al.36.Stankus N. Hammes M. Gillen D. et al.African American ESRD patients have a high pre-dialysis prevalence of kidney stones compared to NHANES III.Urol Res. 2007; 35: 83-87Crossref PubMed Scopus (22) Google Scholar compared the incidence of pre-ESRD kidney stones in a cohort of African-American hemodialysis patients. In the sample of 300 subjects, 8.2% had a history of nephrolithiasis before initiating dialysis, compared with 2.8% of patients matched for age, sex, and race in the NHANES III cohort. Generally, patients of African descent are at a lower risk for kidney stone disease37.Stamatelou K.K. Francis M.E. Jones C.A. et al.Time trends in reported prevalence of kidney stones in the United States: 1976-1994.Kidney Int. 2003; 63: 1817-1823Abstract Full Text Full Text PDF PubMed Scopus (1142) Google Scholar but at a higher risk for ESRD.38.Hsu C.Y. Lin F. Vittinghoff E. et al.Racial differences in the progression from chronic renal insufficiency to end-stage renal disease in the United States.J Am Soc Nephrol. 2003; 14: 2902-2907Crossref PubMed Scopus (355) Google Scholar These data suggest that those already at risk for CKD may have an additive burden in the face of nephrolithiasis. Several studies out of the Mayo clinic shed further light on the association between stone disease and CKD. In a nested case–control study in residents of Olmstead County, Saucier et al.39.Saucier N.A. Sinha M.K. Liang K.V. et al.Risk factors for CKD in persons with kidney stones: a case-control study in Olmsted County, Minnesota.Am J Kidney Dis. 2010; 55: 61-68Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar compared the characteristics of stone formers with CKD (n=53) and those without CKD (n=106). Predictably, subjects with CKD were more likely to have diabetes (OR=4.27) and hypertension (OR=3.57), as well as recurrent urinary tract infections (OR=5.81). CKD sufferers were also more likely to have had an ileal conduit (OR=7.69) and to have had a documented struvite stone (OR=15.61). Obesity and smoking were also more frequent in the CKD group, but this did not reach statistical significance. Concurrently, the Mayo group also reported on a much larger population-based cohort study, identifying all incident stone formers (n=4066) in Olmstead County diagnosed between 1986 and 2003 and matched to control subjects (n=10,150) from the local area.40.Rule A.D. Bergstralh E.J. Melton III, L.J. et al.Kidney stones and the risk for chronic kidney disease.Clin J Am Soc Nephrol. 2009; 4: 804-811Crossref PubMed Scopus (258) Google Scholar Incidence of CKD was determined using both diagnostic codes and lab confirmation of decreased GFR (eGFR<60 ml/min per 1.73 m2) sustained ≥3 months. Stone formers were more likely to have underlying hypertension, gout, diabetes, obesity, and coronary artery disease, but even in analyses adjusted for these CKD risk factors, risk of clinical CKD was 50–67% higher in stone formers than in controls. Most recently, the Mayo group focused on the association of urolithiasis with ESRD.41.El-Zoghby Z.M. Lieske J.C. Foley R.N. et al.Urolithiasis and the risk of ESRD.Clin J Am Soc Nephrol. 2012; 7: 1409-1415Crossref PubMed Scopus (93) Google Scholar The authors identified newly diagnosed stone formers in Olmstead County between 1984 and 2008 and matched each individual by age and sex to up to four controls without stone disease. After adjusting for classic cardiovascular risk factors, such as diabetes, gout, obesity, hyperlipidemia, and, notably, CKD, stone formers had more than twice the risk of developing ESRD compared with controls (HR=2.09). The findings were similar (HR=1.95) in a subset of patients who were validated to be symptomatic stone formers by chart review. The association between stone disease and renal dysfunction does not appear to be limited to the United States. In a registry cohort study of adults living in Alberta, Canada, between 1997 and 2009 encompassing nearly two million subjects, a significant association between one or more episodes of kidney stones and development of new stage 3b-5 CKD (HR=1.74), ESRD (HR=2.16), or a sustained doubling of serum creatinine from baseline (HR=1.94) was noted over a median follow-up of 4 years.42.Alexander R.T. Hemmelgarn B.R. Wiebe N. et al.Kidney stones and kidney function loss: a cohort study.BMJ. 2012; 345: e5287Crossref PubMed Scopus (186) Google Scholar Across the Atlantic, in a large British population–based cohort study of over 1.5 million designed to develop a prediction model for risk of moderate-to-severe CKD,43.Hippisley-Cox J. Coupland C. Predicting the risk of chronic Kidney Disease in men and women in England and Wales: prospective derivation and external validation of the QKidney Scores. BMC.Fam Pract. 2010; 11: 49Crossref Scopus (137) Google Scholar the adjusted risk for moderate-to-severe CKD was 1.27 in females, but not males, with a history of nephrolithiasis. The adjusted risk for ESRD was double in females with a history of stone disease (HR=2.1), but the association was not present in males. Despite these strong associations, however, it is important to note that only 0.2% of incident ESRD patients from 2004 to 2008 had nephrolithiasis listed as a primary etiology on the CMS ESRD Medical Evidence Form.44.Collins A.J. Foley R.N. Herzog C. et al.US Renal Data System 2010 Annual Data Report.Am J Kidney Dis. 2011; 57: e1-e526PubMed Google Scholar The complications of CKD should not be discounted, however, as the associations between CKD and cardiovascular disease and mortality are well described.4.Sarnak M.J. Levey A.S. Schoolwerth A.C. et al.Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research.Clinical Cardiology, and Epidemiology and Prevention. Hypertension. 2003; 42: 1050-1065Google Scholar, 5.Schiffrin E.L. Lipman M.L. Mann J.F. Chronic kidney disease: effects on the cardiovascular system.Circulation. 2007; 116: 85-97Crossref PubMed Scopus (1192) Google Scholar, 6.Shavit L. Girfoglio D. Vijay V. et al.Vascular calcification and bone mineral density in recurrent kidney stone formers.Clin J Am Soc Nephrol. 2015; 10: 278-285Crossref PubMed Scopus (47) Google Scholar, 7.Tonelli M. Wiebe N. Culleton B. et al.Chronic kidney disease and mortality risk: a systematic review.J Am Soc Nephrol. 2006; 17: 2034-2047Crossref PubMed Scopus (1204) Google Scholar Furthermore, although nephrolithiasis may not be the primary reason for an individual’s ESRD, evidence of distorted renal architecture in stone formers11.Evan A.E. Lingeman J.E. Coe F.L. et al.Histopathology and surgical anatomy of patients with primary hyperparathyroidism and calcium phosphate stones.Kidney Int. 2008; 74: 223-229Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 12.Evan A.P. Coe F.L. Rittling S.R. et al.Apatite plaque particles in inner medulla of kidneys of calcium oxalate stone formers: osteopontin localization.Kidney Int. 2005; 68: 145-154Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 13.Evan A.P. Lingeman J.E. Coe F.L. et al.Crystal-associated nephropathy in patients with brushite nephrolithiasis.Kidney Int. 2005; 67: 576-591Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar, 14.Evan A.P. Coe F.L. Lingeman J.E. et al.Renal crystal deposits and histopathology in patients with cystine stones.Kidney Int. 2006; 69: 2227-2235Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 15.Evan A.P. Coe F.L. Lingeman J.E. et al.Mechanism of formation of human calcium oxalate renal stones on Randall's plaque.Anat Rec (Hoboken). 2007; 290: 1315-1323Crossref PubMed Scopus (155) Google Scholar, 16.Evan A.P. Lingeman J. Coe F. et al.Renal histopathology of stone-forming patients with distal renal tubular acidosis.Kidney Int. 2007; 71: 795-801Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 17.Evan A.P. Lingeman J.E. Coe F.L. et al.Role of interstitial apatite plaque in the pathogenesis of the common calcium oxalate stone.Semin Nephrol. 2008; 28: 111-119Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 18.Evan A.P. Coe F.L. Gillen D. et al.Worcester EM. Renal intratubular crystals and hyaluronan staining occur in stone formers with bypass surgery but not with idiopathic calcium oxalate stones.Anat Rec (Hoboken). 2008; 291: 325-334Crossref PubMed Scopus (47) Google Scholar, 19.Evan A.P. Lingeman J.E. Coe F.L. et al.Intra-tubular deposits, urine and stone composition are divergent in patients with ileostomy.Kidney Int. 2009; 76: 1081-1088Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 20.Evan A.P. Weinman E.J. Wu X.R. et al.Comparison of the pathology of interstitial plaque in human ICSF stone patients to NHERF-1 and THP-null mice.Urol Res. 2010; 38: 439-452Crossref PubMed Scopus (19) Google Scholar, 21.Evan A.P. Lingeman J.E. Worcester E.M. et al.Renal histopathology and crystal deposits in patients with small bowel resection and calcium oxalate stone disease.Kidney Int. 2010; 78: 310-317Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 22.Evan A.P. Lingeman J.E. Worcester E.M. et al.Contrasting histopathology and crystal deposits in kidneys of idiopathic stone formers who produce hydroxy apatite, brushite, or calcium oxalate stones.Anat Rec (Hoboken). 2014; 297: 731-748Crossref PubMed Scopus (39) Google Scholar, 23.Evan A.P. Worcester E.M. Williams Jr, J.C. et al.Biopsy proven medullary sponge kidney: clinical findings, histopathology, and role of osteogenesis in stone and plaque formation.Anat Rec (Hoboken). 2015; 298: 865-877Crossref PubMed Scopus (30) Google Scholar, 24.Evan A.P. Worcester E.M. Coe F.L. et al.Mechanisms of human kidney stone formation.Urolithiasis. 2015; 43: 19-32Crossref PubMed Scopus (109) Google Scholar could be conceived to predispose to injury from other causes. If kidney stones are to be linked to a decrement in kidney function, one might expect that greater stone burden would be inversely associated with renal function. This is indeed what Ahmadi et al.45.Ahmadi F. Etemadi S.M. Lessan-Pezeshki M. et al.Contribution of stone size to chronic kidney disease in kidney stone formers.Int J Urol. 2015; 22: 104-108Crossref PubMed Scopus (15) Google Scholar noted in their study of 97 kidney stone formers presenting for extracorporeal shock wave lithotripsy. In patients with a total stone burden of <20 mm, each 1 mm increment in cumulative stone size (as determined by the sum of diameters of all stones present) was associated with a 20% increased risk of having CKD in a multivariate model. This is particularly striking as urine calcium levels markedly decline with even a small decline in renal function.46.Craver L. Marco M.P. Martinez I. et al.Mineral metabolism parameters throughout chronic kidney disease stages 1-5—achievement of K/DOQI target ranges.Nephrol Dial Transplant. 2007; 22: 1171-1176Crossref PubMed Scopus (219) Google Scholar Thus, in the case of calcium stones, it would be likely that the stone formation preceded the decline in GFR, although certainly causality cannot be established by these data. Historically, much of the ESRD ascribed to stone disease has been attributed to patients with solitary kidneys. In an elegant study by Jungers et al.,47.Jungers P. Joly D. Barbey F. et al.ESRD caused by nephrolithiasis: prevalence, mechanisms, and prevention.Am J Kidney Dis. 2004; 44: 799-805Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar the authors reviewed the histories of 1391 consecutive patients with ESRD, of which 45 patients (3.2%) were attributed to nephrolithiasis. Struvite stones were noted in 19 patients, calcium stones were noted in 12 patients, and uric acid stones in 8 patients, with the remainder attributed to hereditary stone disease (4 with primary hyperoxaluria (PH) and 2 with cystinuria). Interestingly, 40% of subjects in this study had a solitary kidney before the development of ESRD. Worcester et al.48.Worcester E. Parks J.H. Josephson M.A. et al.Causes and consequences of kidney loss in patients with nephrolithiasis.Kidney Int. 2003; 64: 2204-2213Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar characterized the etiology for presentation with a solitary kidney in a cohort of 115 patients with nephrolithiasis and a single kidney evaluated at the University of Chicago. The most common cause for loss of a kidney in this group of stone formers was a staghorn calculus or a high stone burden (29%), followed by infection (23%), ureteral obstruction (21%), and surgical removal (8%). It should be no