The role of Randall's plaques in the pathogenesis of calcium stones

PURPOSE: Knowledge of the inciting lesion in kidney stone formation has remained rudimentary until quite recently. Randall theorized that areas of apatite plaque on the renal papillae would be an ideal site for an overgrowth of calcium oxalate to develop into a calculus. We reviewed in vivo data that have further defined the role of Randall's plaques in stone disease. MATERIALS AND METHODS: We examined a set of literature that tested 2 hypotheses, that is 1) Randall's plaques are a specialized disease that begins as apatite in a unique region of the kidney due to local driving forces and anatomy, and 2) stones that arise from causes different from common calcium oxalate stones do not necessarily arise on plaque. RESULTS: Intraoperative papillary and cortical biopsy specimens obtained during percutaneous nephrolithotomy from the kidneys of 3 types of stone formers (idiopathic calcium stone formers, patients with stones due to bariatric procedures and brushite stone formers) showed unique histopathological findings. CONCLUSIONS: The metabolic and surgical pathological findings in 3 distinct groups of stone formers demonstrate that the histology of the renal papillae from a stone former is particular to the clinical setting.     

草酸钙结石患者肾乳头Randall斑的超微结构特点

目的 探讨草酸钙结石患者肾乳头Randall斑与草酸钙结石形成的关系. 方法经结石化学成分分析确诊为草酸钙肾结石患者12例.于经皮肾镜取石术中直视卜获取肾乳头Randall斑活检标本,分别行HE染色和锇酸固定,光镜和透射电镜下观察其组织病理和超微结构特点.结果 12例患者共检查肾乳头72处,肾乳头表面有Randall斑形成63处(87.5%),7例部分肾乳头表面有小结石附着.12例Randall斑活检标本光镜下肾乳头组织内见成团钙盐样沉积.2例电镜下肾乳头结缔组织中散在分布大小不均簇状草酸盐团聚体,典型结晶体呈针状,晶体轮廓周边电子密度高,晶体中央呈电子透亮区. 结论草酸钙结石患者肾乳头Randall斑主要是草酸盐结晶沉积,在Randall斑基础上草酸盐结晶进一步沉积可能促使草酸钙结石的形成.     

Histopathology and surgical anatomy of patients with primary hyperparathyroidism and calcium phosphate stones

Using a combination of intra-operative digital photography and micro-biopsy we measured renal cortical and papillary changes in five patients with primary hyperparathyroidism and abundant calcium phosphate kidney stones. Major tissue changes were variable papillary flattening and retraction, dilation of the ducts of Bellini, and plugging with apatite deposits of the inner medullary collecting ducts and ducts of Bellini. Some of the papillae in two of the patients contained plentiful large interstitial deposits of Randall's plaque and where the deposits were most plentiful we found overgrowth of the attached stones. Hence, this disease combines features previously described in brushite stone formers--dilation, plugging of ducts and papillary deformity--with the interstitial plaque and stone overgrowth characteristic of routine idiopathic calcium oxalate stone formers, suggesting that these two patterns can coexist in a single patient.     

Crystal-associated nephropathy in patients with brushite nephrolithiasis

BACKGROUND: We have biopsied the renal cortex and papillae of patients who form brushite renal stones asking if this unusual stone type is associated with specific tissue changes. We contrasted these with biopsies of 15 calcium oxalate stone formers, three stone formers with intestinal bypass, and four normal subjects. METHODS: We studied all ten brushite stone formers treated with percutaneous nephrolithotomy (PNL) during the past 3 years using digital video imaging of renal papillae, and obtained cortical and papillary biopsies. Biopsies were analyzed by light and electron microscopy, microinfrared spectroscopy, and electron diffraction. RESULTS: Apatite crystals plugged scattered terminal collecting ducts whose cells were injured or dead, and surrounding interstitium inflamed and fibrotic. White papillary deposits of interstitial apatite particles, so called Randall's plaque, were also present. Glomerular changes and cortical tubular atrophy and interstitial fibrosis were moderate to severe. CONCLUSION: Brushite stone formers combine the interstitial plaque of calcium oxalate stone formers with the collecting duct apatite plugs found in stone formers with intestinal bypass. Collecting duct injury and interstitial fibrosis are severe. Prominent cortical fibrosis, tubule atrophy, and glomerular pathology seem secondary to the collecting duct plugging. We believe crystallization obstructs and destroys terminal collecting duct segments thereby damaging nephrons, perhaps via intranephronal obstruction, and producing a hitherto unrecognized renal disease.     

Stone formation is proportional to papillary surface coverage by Randall's plaque

PURPOSE: Randall's plaques are common in calcium oxalate (CaOx) stone formers (SF). Plaque coverage correlates directly with urine calcium excretion and inversely with urine volume. We hypothesize that plaque coverage should increase proportionally with increasing stone number. We measured plaque areas in idiopathic CaOx stone formers and nonstone formers (NSF), and identified significant relationships with quantified stone histories. MATERIALS AND METHODS: A total of 13 SFs and 4 control NSFs underwent nephroscopic papillary mapping with representative still images and MPEG (Moving Pictures Experts Group) movies used to identify plaque and papillary borders. Stone histories were obtained through patient interviews, and from medical records and radiographs. The relationship of plaque coverage to clinical stone events was assessed by general multivariate linear modeling. Log transformation normalized the distribution of percent plaque coverage and stone number. RESULTS: Plaque surface area in SFs differed significantly from that in NSFs (p <0.0001). The duration of stone disease and the log transformed percent plaque coverage correlated significantly with the number of stones (0.677 and 0.620, p = 0.003 and 0.008, respectively). On multivariate analysis and correcting for the duration of stone disease total percent plaque coverage correlated significantly with the number of stones (R = 0.496, p = 0.05). Disease duration and plaque coverage did not correlate significantly (p = 0.257). CONCLUSIONS: Percent plaque coverage directly correlates with the number of stones formed even when corrected for the duration of stone disease. However, plaque coverage does not correlate with the duration of stone disease. These results support the hypothesis that the pathogenesis of CaOx stones begins with Randall's plaques.     

A formal test of the hypothesis that idiopathic calcium oxalate stones grow on Randall’s plaque

OBJECTIVE

To confirm that more than half of all idiopathic calcium oxalate (CaOx) stones grow on interstitial plaque, as CaOx stones can grow attached to interstitial apatite plaque but whether this is the usual mechanism of stone formation is uncertain.

PATIENTS AND METHODS

In nine idiopathic CaOx stone formers (ICSF) undergoing percutaneous nephrolithotomy or ureteroscopy all accessible renal papillae were endoscopically imaged using a digital endoscope. All stones were removed intact, and recorded by the operating surgeon as being attached or unattached; for all attached stones the surgeon determined if the site of attachment was to plaque. This determination was further verified by reviewing the intraoperative video record, and only instances where plaque was reliably seen on video were used for analysis. Surgical observations were further validated by a combination of microcomputed tomographic analysis and papillary biopsy. The results were analysed statistically using fixed‐sample testing and group sequential sampling.

RESULTS

The nine patients had a total of 115 stones, primarily CaOx; 90 stones were attached. Of these, 81 were attached to plaque; surgeons could not visualize the site of attachment with sufficient clarity to judge in the other nine cases. Based on these data, the final point estimate for the number of stones attached to plaque was 0.754 (95% confidence interval 0.575–0.933; P = 0.013).

CONCLUSIONS

In ICSF most stones grow attached to papillae, on plaque, so growth on plaque is the main mechanism for stone formation in this very common group of patients.     

In idiopathic calcium oxalate stone‐formers,unattached stones show evidence of having originated as attached stones on Randall’s plaque

Study Type – Diagnostic (exploratory cohort)
Level of Evidence 2b

OBJECTIVE

To analyse the structure and composition of unattached stones in idiopathic calcium oxalate (CaOx) stone‐formers (ICSF) and compare them to attached stones from the same cohort, to investigate whether there is more than one pathogenic mechanism for stone formation in ICSF.

PATIENTS AND METHODS

ICSF undergoing percutaneous nephrolithotomy or ureteroscopy for the treatment of nephrolithiasis gave consent to participate in this study. All accessible renal papillae were endoscopically imaged using a digital endoscope. All stones were removed and determined by the operating surgeon to be attached or unattached to the underlying papilla. Micro‐computed tomography (micro‐CT), which provides three‐dimensional analysis of entire stones, was used to compare the structure and composition of attached and unattached stones.

RESULTS

Of 115 stones collected from nine patients (12 renal units), only 25 stones were found not to be attached to renal papillae. Of these 25 stones, four were lost and 12 showed definite morphological evidence of having been attached to tissue, probably having been displaced from papillae during access. For the remaining nine stones, micro‐CT analysis showed at least one internal region of calcium phosphate within each of these unattached CaOx stones, i.e. the internal structure of the unattached stones is consistent with their having originated attached to Randall’s plaque, and then having become detached but retained in the kidney, with new layers of CaOx eventually covering the original attachment site.

CONCLUSIONS

Micro‐CT analysis supports the hypothesis that in ICSF, both attached and unattached stones occur as a result of a common pathogenic mechanism, i.e. in this type of stone former, CaOx stones, even those not showing morphology that betrays attachment, all originate attached to interstitial plaque on the renal papilla.     

Role of interstitial apatite plaque in the pathogenesis of the common calcium oxalate stone

By using intraoperative papillary biopsy material from kidneys of idiopathic calcium oxalate, intestinal bypass for obesity, brushite, cystine, and distal renal tubular acidosis stone formers during percutaneous nephrolithotomy, we have determined that idiopathic calcium oxalate stone formers appear to be the special case, although the most commonly encountered one, in which stones form external to the kidney and by processes that do not involve the epithelial compartments. It is in this one group of patients that we find not only abundant interstitial plaque, but also strong evidence that the plaque is essential to stone formation. The initial site of plaque formation is always in the papillary tip, and must be in the basement membrane of the thin loop of Henle. With time, plaque spreads throughout the papilla tip to the urothelium, which under conditions we do not understand is denuded and thereby exposes the apatite deposits to the urine. It is on this exposed apatite that a stone forms as an overgrowth, first of amorphous apatite and then layers of calcium oxalate. This process generates an attached stone fixed to the side of a papilla, allowing the ever-changing urine to dictate stone growth and composition.     

Metabolic and urinary risk factors associated with Randall's papillary plaques

BACKGROUND AND PURPOSE: Increasing evidence suggests that Randall's plaques contribute to the pathogenesis of urinary stone formation. The purpose of our study was to evaluate the urinary risk factors of stone patients who underwent endoscopic mapping of their calices for Randall's plaques. PATIENTS AND MATERIALS: Patients (N = 143) having endoscopic procedures to remove upper tract calculi or for other purposes underwent mapping of their calices for Randall's plaques. Plaque incidence and pattern were correlated with the stone composition and urinary risk factors found on subsequent metabolic evaluation. RESULTS: Papillary plaques were found more commonly in patients having calcium oxalate stones than in patients with other stone types and patients without a history of stones. Papillary plaque incidence and pattern did not correlate with any specific urinary risk factor; however, patients with plaques tended to exhibit a higher incidence of all risk factors. Plaque severity tended to be greater in patients exhibiting hypercalciuria. CONCLUSIONS: Randall's plaques are found most frequently in patients with calcium oxalate stones and are most important in the pathogenesis of calcium oxalate nephrolithiasis. Stone patients with papillary plaques are more likely to exhibit abnormalities in their urinary milieu than are patients without papillary plaques.     

The riddle of Randall's plaques.

Randall described a pre-calculus lesion of the renal papilla in the 1930s and this was substantiated by others during the next decade and then largely ignored. This insignificant subepithelial calcification of the renal papilla. Randall's plaque type I, becomes the nucleus of at least 15% of calcium oxalate calculi, as demonstrated by apatite nuclei existing in papillary depression on the external stone surface. Cross section study of the stone demonstrates the peripheral nucleus with eccentric lamination postulating a mural origin. Contrariwise, study of the stone developing upon a nucleus originating in the papillary ducts (without producing obstruction) or out in the calix demonstrates a central nucleus surrounded by concentric laminations or lack of a mural origin, the more common type of calcium oxalate stone structure. Obstruction of the papillary ducts by hyperexcretion of stone salt may result in anemic infarction and sloughing of the apex of the papilla. Data concerning the prevalence of Randall's plaques in the population have been reviewed. Evidence of the incidence of calcium oxalate calculi that have developed upon Randall's plaques has been presented. A plea for further study of the pathology of the renal papilla has been voiced.     

Physiopathology and etiology of stone formation in the kidney and the urinary tract

All stones share similar presenting symptoms, and urine supersaturation with respect to the mineral phase of the stone is essential for stone formation. However, recent studies using papillary biopsies of stone formers have provided a view of the histology of renal crystal deposition which suggests that the early sequence of events leading to stone formation differs greatly, depending on the type of stone and on the urine chemistry leading to supersaturation. Three general pathways for kidney stone formation are seen: (1) stones fixed to the surface of a renal papilla at sites of interstitial apatite plaque (termed Randall’s plaque), as seen in idiopathic calcium oxalate stone formers; (2) stones attached to plugs protruding from the openings of ducts of Bellini, as seen in hyperoxaluria and distal tubular acidosis; and (3) stones forming in free solution in the renal collection system, as in cystinuria. The presence of hydroxyapatite crystals in either the interstitial or tubule compartment (and sometimes both) of the renal medulla in stone formers is the rule and has implications for the initial steps of stone formation and the potential for renal injury.     

Calcium oxalate calculi found attached to the renal papilla: Preliminary evidence for early mechanisms in stone formation

BACKGROUND: Calculi are commonly found attached to the renal papilla in calcium oxalate (CaOx) stone formers, but the mechanisms by which stones form in this manner are not well established. MATERIALS AND METHODS: Data are presented from three attached stones collected from different patients. Stone morphology and composition were determined using micro computed tomography (CT) and infrared microspectrometry. RESULTS: One of the stones was composed of CaOx with a peripheral region of apatite, such as might have come from a Randall's plaque. Another stone was covered with large CaOx crystals but contained at least two layers of apatite, with no apatite regions exposed at the surface. The third stone contained CaOx with inclusions of apatite and more apatite on its surface, along with a substantial volume of poorly mineralized material that could not be identified. CONCLUSIONS: The complexity of these stones and their differing morphologies do not by themselves allow inference of the mechanism of stone formation. Future work will require the careful documentation of attached stones on the papilla, as well as study of the papilla after the stone has been removed, before it can be determined whether such diverse CaOx stones originate from the same or different underlying etiologies.     

Revisiting Randall's plaque

Kidney stones have probably affected mankind for ages with early reports in an Egyptian mummy. While prevalence of stone disease is increasing, its pathogenesis remains elusive. Randall, after his study on more than 1100 cadaver kidneys, gave hypothesis of subepithelial plaque acting as a nucleation site for kidney stones. His plaque hypothesis met with criticism because he proposed a unified theory for all types of stones. However, recently Randall's plaque has been reinvestigated. This review discusses their role in stone formation and current understanding about their pathogenesis.Randall's plaques begin in the basement membrane of thin segment of loop of Henle. Low urine volume, hypercalciuria, low urine pH are now implicated as important urinary risk factors. Plaque–stone association is best described in the idiopathic calcium oxalate stone formers. Pathogenesis of plaque itself involves interaction of multiple factors including gene polymorphism, oxidative stress, inflammatory mediators, matrix proteins, and urinary solute supersaturation.     

Epidemiology of nephrolithiasis in France

Nephrolithiasis is a frequent disease that affects about 10% of people in western countries. The prevalence of calcium oxalate stones has been constantly increasing during the past fifty years in France as well as in other industrialized countries. Stone composition varies depending to gender and age of patients and also underlines the role of other risk factors and associated pathologies such as body mass index and diabetes mellitus. The decrease in struvite frequency in female patients is the result of a significantly improved diagnostic and treatment of urinary tract infections by urea-splitting bacteria. In contrast, the increasing occurrence of weddellite calculi in stone forming women aged more than 50 years could be the consequence of post-menopausal therapy. A high prevalence of uric acid was found in overweight and obese stone formers and in diabetic ones as well. Another important finding was the increased occurrence with time of calcium oxalate stones formed from papillary Randall's plaques, especially in young patients. Nutritional risk factors for stone disease are well known: they include excessive consumption of animal proteins, sodium chloride and rapidly absorbed glucides, and insufficient dietary intake of fruits and potassium-rich vegetables, which provide an alkaline load. As a consequence, an excessive production of hydrogen ions may induce several urinary disorders including low urine pH, high urine calcium and uric acid excretion and low urine citrate excretion. Excess in calorie intake, high chocolate consumption inducing hyperoxaluria and low water intake are other factors, which favour excessive urine concentration of solutes. Restoring the dietary balance is the first advice to prevent stone recurrence. However, the striking increase of some types of calculi, such as calcium oxalate stones developed from Randall's plaque, should alert to peculiar lithogenetic risk factors and suggests that specific advices should be given to prevent stone formation.     

ENDOSCOPIC MAPPING OF RENAL PAPILLAE FOR RANDALL''S PLAQUES IN PATIENTS WITH URINARY STONE DISEASE

Purpose

Papillary "Randall's plaques" are theorized to act as nidi for urinary stone formation. The aim of this study was to document the presence, pattern and distribution of Randall's plaques in patients undergoing endoscopic procedures for urinary stone disease.

Materials and Methods

Patients undergoing either ureteroscopy or percutaneous nephroscopy for removal of urinary stones underwent endoscopic mapping of accessible calices. These patients were compared to a smaller group of patients undergoing endoscopic procedures for conditions unrelated to urinary stone disease. In patients found to have papillary plaques the presence, location and pattern of plaques were recorded. Plaque formation was correlated with patient age and sex, and primary composition of extricated stone.

Results

Endoscopic evidence of papillary Randall's plaques was found in 74% of 57 patients having ureteroscopic (21) or percutaneous (36) stone removal. Of 7 patients having endoscopic procedures for conditions unrelated to urinary stone disease 3 (43%) had evidence of papillary plaques. Plaques were found uniformly throughout all calices and most commonly diffusely scattered over the papillary surface. There was no correlation between patient age or sex and the presence of plaques. The incidence of plaques varied with the primary composition of extracted stones, and was 100% for calcium phosphate and uric acid, 88% for calcium oxalate, 33% for cystine and 20% for struvite. The incidence of papillary plaques was significantly more common in patients with calcium oxalate (88 versus 43%, p = 0.023) and calcium phosphate stones (100 versus 43%, p = 0.009) than patients without a history of urinary stone disease.

Conclusions

The endoscopic incidence of papillary Randall's plaques in patients with urolithiasis varies with the primary composition of formed urinary stones. Randall's plaques are found in the majority of patients with calcium urinary stone disease. Our findings suggest that the presence of papillary plaques is associated with calcium nephrolithiasis and may contribute to the pathogenesis of calcium urinary stones.     

Randall's plaque: pathogenesis and role in calcium oxalate nephrolithiasis

The purpose of these studies was to test the hypothesis that Randall's plaque develops in unique anatomical sites of the kidney and their formation is conditioned by specific stone-forming pathophysiologies. We performed intraoperative papillary biopsies from kidneys of idiopathic-calcium oxalate (CaOx), intestinal bypass for obesity, brushite (BR) and cystine stone formers (SF) during percutaneous nephrolithotomy. Tissues were examined by infrared analysis and light and electron microscopy. Our analysis revealed a distinct pattern of mineral deposition and papillary pathology for each type of SF. CaOx SF had interstitial apatite crystals beginning at thin loops of Henle. These deposits termed Randall's plaque are thought to serve as sites for stone attachment. No tubular injury was noted. Intestinal bypass patients possessed intraluminal apatite deposits in inner medullary collecting ducts (IMCD) with associated cell injury. BR SF showed the most severe form of cortical and medullary changes with sites of Randall's plaque, and yellowish intraluminal deposits of apatite in IMCD. Cystine SF had plugging of ducts of Bellini with cystine crystals and apatite deposits in IMCD and loops of Henle. Intratubular sites of crystalline deposits were always associated to adjacent regions of interstitial fibrosis. The metabolic, anatomic, and surgical pathologic findings in four distinct groups of SF clearly show that 'the histology of the renal papilla from a stone former, is particular to the clinical setting'. We believe our approach to studying stone disease will provide insights into the pathogenesis of stone formation for each type of SF that will lead to improved clinical treatment.     

Role of the renal collecting system in initial kidney stone formation

BACKGROUND: The anatomic site where the initial kidney stone grows to a clinically significant size is unknown. METHODS AND MATERIALS: We studied human forniceal anatomy by microdissection and correlated the anatomic findings with the clinical presentation of kidney stones. In addition, we examined crystal attachment sites within the collecting system by direct infusion of calcium oxalate crystals into the renal pelvis of rabbits. RESULTS: Secondary urinary dead spaces were found in the fornices of compound papillae only, which were located at the poles of the kidneys. This feature correlated with a higher incidence of stones in these areas at the time of lithotripsy. Calcium oxalate crystals tended not to attach to either the renal papilla nor the pelvic sidewall unless these epithelia were previously injured with hydrochloric acid. CONCLUSION: The renal collecting system may serve as an anatomic site for crystal retention and growth but is unlikely to be the principal site for crystal attachment, unless prior cellular injury occurs.     

The role of Randall plaques on kidney stone formation

Randall’s plaque is microscopically a plaque of calcium deposited in the interstitial tissue of the renal papilla. These plaques are thought to serve as a nidus for urinary stone formation. Large amounts of Randall’s plaque are unique to idiopathic calcium oxalate stone formers. Although Randall’s plaques can be found in other stone formers, only in idiopathic calcium oxalate stone formers, the detailed mechanism of stone overgrow on plaque was thoroughly studied. Calcification is invariably located in the basement membrane of the loops of Henle and from there plaques spread through the interstitium toward urothelium. Within the basement membrane, mineral deposits are individual laminated particles in which zones of crystal and organic matrix overlay each other. In the interstitium, the particles appear to fuse on the collagen bundles to form a syncytium of crystal islands in an organic sea. By loss of integrity of urothelium, regions of plaque are exposed to urine. The exposed surface will touch and be covered by molecules of urine origin, including osteopontin, Tamm Horsfall protein, and crystals formed under urine supersaturations, resulting in a ribbon of alternating matrix and crystal. Eventually crystallization escapes from matrix modulation and crystals extend outward into the space of urine and begin to form a calcium oxalate stone proper. Randall’s plaque plays an important role and is prerequisite of kidney stone formation in idiopathic calcium oxalate stone formers.     

Comparison of the pathology of interstitial plaque in human ICSF stone patients to NHERF-1 and THP-null mice

Extensive evidence now supports the role of papillary interstitial deposits—Randall’s plaques—in the formation of stones in the idiopathic, calcium oxalate stone former. These plaques begin as deposits of apatite in the basement membranes of the thin limbs of Henle’s loop, but can grow to become extensive deposits beneath the epithelium covering the papillary surface. Erosion of this covering epithelium allows deposition of calcium oxalate onto this plaque material, and the transition of mineral type and organic material from plaque to stone has been investigated. The fraction of the papilla surface that is covered with Randall’s plaque correlates with stone number in these patients, as well as with urine calcium excretion, and plaque coverage also correlates inversely with urine volume and pH. Two animal models—the NHERF-1 and THP-null mice—have been shown to develop sites of interstitial apatite plaque in the renal papilla. In these animal models, the sites of interstitial plaque in the inner medulla are similar to that found in human idiopathic calcium oxalate stone formers, except that the deposits in the mouse models are not localized solely to the basement membrane of the thin limbs of Henle’s loop, as in humans. This may be due to the different morphology of the human versus mouse papillary region. Both mouse models appear to be important to characterize further in order to determine how well they mimic human kidney stone disease.     

Nephrocalcinosis: re-defined in the era of endourology

Nephrocalcinosis generally refers to the presence of calcium salts within renal tissue, but this term is also used radiologically in diagnostic imaging in disease states that also produce renal stones, so that it is not always clear whether it is tissue calcifications or urinary calculi that give rise to the characteristic appearance of the kidney on x-ray or computed tomography (CT). Recent advances in endoscopic imaging now allow the visual distinction between stones and papillary nephrocalcinosis, and intrarenal endoscopy can also verify the complete removal of urinary stones, so that subsequent radiographic appearance can be confidently attributed to nephrocalcinosis. This report shows exemplary cases of primary hyperparathyroidism, type I distal renal tubular acidosis, medullary sponge kidney, and common calcium oxalate stone formation. In the first three cases—all being conditions commonly associated with nephrocalcinosis—it is shown that the majority of calcifications seen by radiograph may actually be stones. In common calcium oxalate stones formers, it is shown that Randall’s plaque can appear as a small calculus on CT scan, even when calyces are known to be completely clear of stones. In the current era with the use of non-contrast CT for the diagnosis of nephrolithiasis, the finding of calcifications in close association with the renal papillae is common. Distinguishing nephrolithiasis from nephrocalcinosis requires direct visual inspection of the papillae and so the diagnosis of nephrocalcinosis is essentially an endoscopic, not radiologic, diagnosis.