Joan H. Parks

Randall’s plaque of patients with nephrolithiasis begins in basement membranes of thin loops of Henle

Our purpose here is to test the hypothesis that Randalls plaques, calcium phosphate deposits in kidneys of patients with calcium renal stones, arise in unique anatomical regions of the kidney, their formation conditioned by specific stone-forming pathophysiologies. To test this hypothesis, we performed intraoperative biopsies of plaques in kidneys of idiopathic-calcium-stone formers and patients with stones due to obesity-related bypass procedures and obtained papillary specimens from non-stone formers after nephrectomy. Plaque originates in the basement membranes of the thin loops of Henle and spreads from there through the interstitium to beneath the urothelium. Patients who have undergone bypass surgery do not produce such plaque but instead form intratubular hydroxyapatite crystals in collecting ducts. Non-stone formers also do not form plaque. Plaque is specific to certain kinds of stone-forming patients and is initiated specifically in thin-limb basement membranes by mechanisms that remain to be elucidated.

Familial Idiopathic Hypercalciuria

The frequency of hypercalciuria was determined in the families of nine hypercalciuric patients with idiopathic hypercaliuria who formed recurrent calcium oxalate renal stones. Idiopathic hypercalciuria occurred in 26 of 73 relatives, in three consecutive generations of two families and in two successive generations of four other families. Multiple siblings or children of the probands were affected in three families. Nineteen of 44 first-degree relatives (43 per cent) had idiopathic hypercalciuria, as compared to seven of 29 (29 per cent) other relatives; there was no relation to age or sex. Renal stones were formed by 19 of the 44 first-degree relatives but by none of the others; nine of the 19 were women. We conclude that there is a familial form of hypercalciuria, which appears to be transmitted as an autosomal dominant trait. Stone disease is frequent in first-degree relatives, and affects both sexes equally.

Urine glycoprotein crystal growth inhibitors. Evidence for a molecular abnormality in calcium oxalate nephrolithiasis.

One reason that some people are prone to calcium oxalate nephrolithiasis is that they produce urine that is subnormal in its ability to inhibit the growth of calcium oxalate crystals. We have identified in human urine a glycoprotein (GCI) that inhibits calcium oxalate crystal growth strongly, and at low concentrations (10(-7) M); in this study, we have isolated GCI molecules from the urine of normal people and patients with calcium oxalate stones. GCI from stone formers is abnormal in three ways: it contains no detectable gamma-carboxyglutamic acid (Gla), whereas normal GCI contains 2-3 residues of Gla per mole; about half of the GCI in urine of patients inhibits crystal growth 4-20 times less than normal GCI as judged by its performance in a kinetic growth assay, in vitro; at the air-water interface, patient GCI has a film collapse pressure approximately half of normal. GCI molecules from the urine of patients with calcium oxalate nephrolithiasis are intrinsically abnormal, and these abnormalities could play a role in the genesis of stones.

Factors that predict relapse of calcium nephrolithiasis during treatment: A prospective study

We evaluated 522 patients with idiopathic, recurrent calcium nephrolithiasis using a comprehensive clinical and laboratory protocol, and obtained additional laboratory measurements during their subsequent years of treatment in our program. In 57 patients, a new calcium stone ultimately formed during treatment (relapse), whereas 189 others have been free of recurrence during at least two years (average 4.3 +/- 2.2 [SD] years) of follow-up. Compared with the patients who remained stone-free, the patients with relapse (1) had a shorter interval between the time they entered our program and the time their last recurrent, pretreatment stone formed; (2) excreted more calcium *in mg/kg of body weight pr 24 hours) in their urine during treatment (2.79 +/- 1.08 versus 2.39 +/- 0.98 [SD] for relapse and stone-free); and (3) increased their urine volume less during treatment compared with pretreatment values (delta in liters per 24 hours was -0.02 +/- 0.48 versus 0.23 +/- 0.54 for relapse and stone-free). The two groups were otherwise the same. All comparisons used only data obtained prior to relapse. A discriminant function using only these three characteristics correctly identified 72 percent of patients with relapse and 67 percent of those who remained stone-free.

A Single 24-Hour Urine Collection Is Inadequate For The Medical Evaluation Of Nephrolithiasis

PURPOSE We determined the adequacy of a single 24-hour urine sample for evaluating patients for medical renal stone prevention. MATERIALS AND METHODS A total of 459 patients from a private urology practice specializing in the treatment of urolithiasis and 683 from a university stone research clinic provided 2 and 3, 24-hour urine samples, respectively. We used samples 1 and 2 from private practice patients, and 1 and 3 from university clinic patients for analysis, and compared each to the others by correlation coefficients and calculation of the mean difference plus or minus standard deviation (SD) of the difference. Urine risk factors were measured by standard methods. RESULTS Although the correlation of urine values 1 and 2 was excellent for all stone risk factors, SD values for the differences were large enough that within 1 SD on either side of 0, which included 68.8% of cases, by chance urine 1 would depart from urine 2 by clinically important amounts. These departures would be more than sufficient to misdiagnose common metabolic disorders. CONCLUSIONS A single 24-hour sample is not sufficient for evaluating patients before metabolic treatment for stone prevention because misdiagnosis is common, leading to inappropriate treatment.

Nephrolithiasis during pregnancy.

WOMEN who form renal stones may be concerned about the possible prejudicial effect of their disease upon pregnancy. Unfortunately, reports concerning renal stones in pregnancy are few in number.1 2...

CLINICAL USE OF CYSTINE SUPERSATURATION MEASUREMENTS

PURPOSE We measured the concentration and solubility of cystine in urine from patients with cystinuria or calcium stones and from normal subjects to determine whether urine cystine supersaturation can be calculated from a standard nomogram of solubility versus pH or needs to be measured directly. We also evaluated whether increasing pH of the 24-hour collection recovered enough crystallized cystine to increase cystine supersaturation. MATERIALS AND METHODS Cystine concentration, pH and usual stone risk factors were measured on 50 ml. aliquots of 24-hour collections from 24 patients with cystinuria, 22 calcium stone formers and 15 normal subjects. After 48 hours of incubation with sodium bicarbonate, a second aliquot was taken from the 24-hour collection for cystine concentration. The original urine at its ambient pH was incubated with an excess of cystine crystals for 24, 48, 72 or 96 hours at 37C to determine solubility and kinetics of equilibration. RESULTS Cystine solubility varied so widely at any pH range that no predictive nomogram could be relied on for calculating supersaturation. Addition of sodium bicarbonate to the 24-hour urine significantly increased cystine concentration. Urine from stone formers had higher cystine solubility than urine from normal subjects. CONCLUSIONS Clinical management of cystinuria can be improved by direct measurement of cystine solubility because it varies widely at any given pH. Increasing 24-hour collection pH with sodium bicarbonate additionally improves accuracy of supersaturation measurement by recovering crystallized cystine.

New Insights into the Pathophysiology and Treatment of Nephrolithiasis: New Research Venues

NEPHROLITHIASIS shares with mineralization of bone a requirement for supersaturation and for modulation of crystal formation by cells and cell secretion products. The needs of the body demand a considerable traffic of calcium, phosphate, oxalate, and uric acid, which create multiple supersaturations in the renal tubule and the final urine. The additional need for water conservation exaggerates these supersaturations, especially in the distal nephron. As a result, late tubule fluid and urine are almost always supersaturated with at least calcium oxalate monohydrate. Defenses against nephrocalcinosis and stones include regulation of urine pH into an optimal zone, control of urine calcium and citrate concentrations, the addition to tubule fluid of at least six protein and glycosaminoglycan modulators of crystallization, and cellular responses to crystals, which include attachment and internalization. In principle, stones may arise from abnormalities at any of these points of compromise between homeostatic needs and the dangers of crystallization. At the present time, medical stone prevention concerns only what might be called physical chemistry, the interactions of ions and small molecules, whereas the most exciting research directions concern the cell and molecular biology of the defenses.

Urinary Saturation Measurements in Calcium Nephrolithiasis

Urinary saturation with respect to calcium oxalate monohydrate was measured in 111 consecutive patients with calcium nephrolithiasis. Each patient also was evaluated by a detailed conventional metabolic protocol. Patients with idiopathic hypercalciuria produced abnormally oversaturated urine more frequently than normal subjects and normocalciuric patients, but normocalciuric patients had unexpectedly high levels of urine saturation. Measuring levels of calcium concentration, oxalate concentration, or the chemical concentration product of calcium and oxalate in urine did not predict oversaturation. During thiazide treatment, saturation level tended to fall if it was initially elevated, whether the patient was hypercalciuric or not. Patients whose urine was not remarkably oversaturated showed no tendency to elaborate even less saturated urine during thiazide treatment; instead, the average calcium oxalate saturation level remained constant. Direct urine saturation measurements can detect a small but significant number of normocalciuric patients who have marked oversaturation with respect to calcium oxalate and appear to benefit from treatment.

Urine pH in renal calcium stone formers who do and do not increase stone phosphate content with time

BACKGROUND Calcium phosphate (CaP) renal stones appear to be increasing in prevalence, and are caused by high urine CaP supersaturation, which arises from genetic hypercalciuria and high urine pH. Renal damage from stones or procedures, or treatments for stone could raise urine pH; alternatively pH may be intrinsically high in some people who are thereby predisposed to CaP stones. METHODS To distinguish these alternatives we sequenced changes in urine pH and stone CaP content asking which occurs first in patients whose stones showed progressive increase in CaP over time. From 4767 patients we found 62 in whom we could document transformation from calcium oxalate (CaOx) to CaP stones, and 134 CaOx controls who did not transform. Laboratory and clinical finding were contrasted between these groups. RESULTS Even when patients were forming relatively pure CaOx stones, those destined to increase stone CaP had higher urine pH than controls who never did so. Their higher pH was present before and during treatments to prevent new stone formation. Shock wave lithotripsy was strongly associated with increasing stone CaP but urine pH bore no relationship to number of procedures. CONCLUSION We conclude that high pH may not be acquired as a result of stones or their treatments but may precede transformation from CaOx to CaP stones and arise from diet or possibly heredity.