Faculty Bibliography

A twin study of genetic and dietary influences on nephrolithiasis: A report from the Vietnam Era Twin (VET) Registry. Background. Nephrolithiasis is a complex phenotype that is influenced by both genetic and environmental factors. We conducted a large twin study to examine genetic and nongenetic factors associated with stones. Methods. The VET Registry includes approximately 7500 male-male twin pairs born between 1939 to 1955 with both twins having served in the military from 1965 to 1975. In 1990, a mail and telephone health survey was sent to 11,959 VET Registry members; 8870 (74.2%) provided responses. The survey included a question asking if the individual had ever been told of having a kidney stone by a physician. Detailed dietary habits were elicited. In a classic twin study analysis, we compared concordance rates in monozygotic (MZ) and dizygotic (DZ) twins. We also conducted a cotwin control study of dietary risk factors in twins discordant for stones. Results. Among dizygotic twins, there were 17 concordant pairs and 162 discordant pairs for kidney stones. Among monozygotic twins, there were 39 concordant pairs and 163 discordant pairs. The proband concordance rate in MZ twins (32.4%) was significantly greater than the rate in DZ twins (17.3%) (chi(2)= 12.8; P < 0.001), consistent with a genetic influence. The heritability of the risk for stones was 56%. In the multivariate analysis of twin pairs discordant for kidney stones, we found a protective dose-response pattern of coffee drinking (P= 0.03); those who drank 5 or more cups of coffee were half as likely to develop kidney stones as those who did not drink coffee (OR = 0.4, 95% CI 0.2, 0.9). Those who drank at least 1 cup of milk per day were half as likely to report kidney stones (OR = 0.5, 95% CI 0.3, 0.8). There were also marginally significant protective effects of increasing numbers of cups of tea per day and frequent consumption of fruits and vegetables. Other factors such as the use of calcium supplements, alcohol drinking, consumption of solid dairy products, and the amount of animal protein consumed were not significantly related to kidney stones in the multivariate model. Conclusion. These results confirm that nephrolithiasis is at least in part a heritable disease. Coffee, and perhaps tea, fruits, and vegetables were found to be protective for stone disease. This is the first twin study of kidney stones, and represents a new approach to elucidating the relative roles of genetic and environmental factors associated with stone formation

Purpose: To determine the effect of cystine-binding thiol drugs (CBTD) on urinary cystine capacity in patients with cystinuria. Patients and Methods: Seven cystinuric patients performed two sets of urine collections while on and off CBTD while controlling for all other variables: diet and fluid and alkali intake. They monitored and recorded their diet for 3 days and performed urine collections on days 2 and 3. They then stopped the CBTD for 7 days. On days 8, 9, and 10, they replicated their diets of days 1 through 3 and performed two more urine collections on days 9 and 10. Two patients took D-penicillamine, four took tiopronin, and one took tiopronin and captopril. The cystine capacity was determined, and the values obtained when the patient was on and off the CBTD were compared to determine whether CBTDs affect urinary cystine capacity. To measure the cystine capacity, we used a solid-phase assay in which cystine crystals are added to the urine and incubated for 48 hours. The crystals are spun down and resolubilized in high-pH buffer, and the amount of cystine in the crystals is calculated. The solid phase will take up cystine from urine (negative cystine capacity) that is supersaturated and give up cystine to an undersaturated urine (positive cystine capacity). Results: All seven patients had significant improvement in urinary cystine capacity on CBTDs. The mean cystine capacity off CBTD was -130.6 +/- 280.8, while the value during CBTD use was 43.1 +/- 131.2 (P < 0.05). On CBTDs, two patients still had negative values, but both had important improvements. The mean urinary volumes were similar on and off CBTD, indicating adequate and similar fluid intake. Urine pH values and urinary excretion of sodium and urea also were comparable, indicating consistency of citrate intake and diet. Conclusions: Our results demonstrate that CBTDs lower the urinary supersaturation of cystine, as shown by a less-negative or more-positive cystine capacity. Cystine capacity can be measured directly, even in the presence of CBTDs. The value of this measurement lies in the potential to monitor the response to the drug, prescribe the minimum effective dose, and potentially decrease the adverse effects often associated with CBTDs

A decrease in urine volume is considered the therapeutic goal of the treatment of central diabetes insipidus (DI) with desmopressin (dDAVP). A low urine volume is a risk factor for kidney stone formation. This is the first report of nephrolithiasis in association with DI. It is likely that successful therapy with dDAVP and the patient's own purposeful decreased fluid intake contributed to calcium oxalate stone formation. Prevention of stone recurrence requires an increase in urine volume. The patient's compliance with this recommendation led to an episode of acute hyponatremia, a well-known complication of dDAVP therapy. The challenge of the management of stones in the setting of DI requires balancing the conflicting goals of both decreasing and increasing urine volume

BACKGROUND: Patients with inflammatory bowel disease have a 10- to 100-fold increased risk of nephrolithiasis, with enteric hyperoxaluria being the major risk factor for these and other patients with fat malabsorptive states. Endogenous components of the intestinal microflora can potentially limit dietary oxalate absorption. METHODS: Ten patients were studied with chronic fat malabsorption, calcium oxalate stones, and hyperoxaluria thought to be caused by jejunoileal bypass (1) and Roux-en-Y gastric bypass surgery for obesity (4), dumping syndrome secondary to gastrectomy (2), celiac sprue (1), chronic pancreatitis (1), and ulcerative colitis in remission (1). For 3 months, patients received increasing doses of a lactic acid bacteria mixture (Oxadrop), VSL Pharmaceuticals), followed by a washout month. Twenty-four-hour urine collections were performed at baseline and after each month. RESULTS: Mean urinary oxalate excretion fell by 19% after 1 month (1 dose per day, P < 0.05), and oxalate excretion remained reduced by 24% during the second month (2 doses per day, P < 0.05). During the third month on 3 doses per day oxalate excretion increased slightly, so that the mean was close to the baseline established off treatment. Urinary oxalate again fell 20% from baseline during the washout period. Calcium oxalate supersaturation was reduced while on Oxadrop, largely due to the decrease in oxalate excretion, although mean changes did not reach statistical significance. CONCLUSION: Manipulation of gastrointestinal (GI) flora can influence urinary oxalate excretion to reduce urinary supersaturation levels. These changes could have a salutary effect on stone formation rates. Further studies will be needed to establish the optimal dosing regimen

Microorganisms may have a role in the pathogenesis and prevention of kidney stones. The subjects of this review include nanobacteria, Oxalobacter formigenes, and lactic acid bacteria. Not reviewed here is the well-described role of infections of the urinary tract with Proteus species and other urease-producing organisms associated with struvite stone formation. Nanobacteria have been proposed to be very small (0.08-0.5 nm), ubiquitous organisms that could play a role in stone formation. The theory is that nanobacteria can nucleate carbonate apatite on their surfaces and thereby provide the nidus for stone formation. However, their existence remains uncertain and many investigators are openly skeptical. Recent investigations suggest that they are artifacts, and not actually living organisms, but their proponents continue to study them. O. formigenes is an obligate anaerobe which may be important in the prevention of stone formation. Its sole substrate for generation of ATP is oxalate. It may thereby metabolize its human host's dietary oxalate and diminish intestinal absorption and subsequent urinary excretion of oxalate. There is evidence that the organism's absence, perhaps sometimes due to courses of antibiotics, may be a cause of hyperoxaluria and stone formation. In early investigations, patients not colonized with the organism can be recolonized. Urinary oxalate can be diminished by accompanying an oxalate-containing meal with the organism. One study demonstrated that a preparation of lactic acid bacteria successfully reduced urinary oxalate excretion in 6 patients with calcium oxalate stones and hyperoxaluria. The mechanism of this effect is uncertain since these bacteria lacked the gene possessed by O. formigenes which codes for that organism's oxalate uptake mechanism. The author is currently completing a small randomized controlled clinical trial with this preparation in calcium stone-forming patients with idiopathic hyperoxaluria

The occupational risks for nephrolithiasis have not been widely studied. The published literature focuses on exposure to heat stress and toxic substances, not on the equally important behavioral risk factor of limited water consumption over many years. Urologic morbidity has been associated with suppressing the need to drink or void under restrictive work environments; however, no such studies link work related behavioral change with the development of kidney stones. This case report is the first to associate a restrictive work environment with limited fluid consumption, resulting in the development of nephrolithiasis