Faculty Bibliography

Introduction & Objectives: Genetic disorders are among the causes of the most severe stone disease. Among them, primary hyperoxaluria (PH), cystinuria, APRT deficiency, and Dent disease can also be associated with loss of kidney function. Due to their rarity, however, understanding of the impact of these stone diseases on kidney function over time is limited. We performed a cross-sectional study of kidney function in patients with each of these disorders over a range of ages. Material & Methods: Voluntary observational registries of the Rare Kidney Stone Consortium were queried. 155 patients with PH, 53 with cystinuria, 34 with APRT deficiency, and 78 with Dent disease had serum creatinine values available prior to development of end stage kidney failure. Serum creatinine at first presentation was used for calculation of eGFR. Kidney function was calculated by MDRD equation in adults and Schwartz equation in children. Spline curve was used to check linearity of plots. Results were compared with normal eGFR of 116 at 20 years of age with decline of 7.5 ml/min/1.73m2BSA per decade after age 30 years (Lindeman J Am Ger Soc, 1985). Results: Age at eGFR was 16.1+/-17.4, 39.8+/-16.7, 25.9+/-19.1, and 12.4+/-10.0 years (mean+/- SD) and the number of stones at presentation was 4.2+/-10.0, 1.9+/-1.8, 1.7+/-4.8, and 3.1+/-3.9 (mean+/-SD) in PH, cystinuria, APRT deficiency, and Dent patients, respectively. eGFR was 91.5, 80.2, 69.8, and 91.5 ml/min/1.73m2BSA in PH, cystinuria, APRT deficiency, and Dent disease patients, respectively. The change in eGFR per decade was -15 (2.1) ml/min/1.73m2 BSA (SE) in PH, -12 (2.2) in cystinuria, -16 (3.9) in APRT deficiency, and -26 (7.9) in Dent disease. Conclusions: Cross sectional data in patients with PH, cystinuria, APRT deficiency and Dent disease shows more rapid decline in kidney function by decade than observed in healthy subjects. Whether kidney damage is related to stone burden or to other factors remains to be determined. The distinction will be of importanc!

PURPOSE OF REVIEW: Cystinuria is a rare genetic disease with increased urinary excretion of the poorly soluble amino acid cystine. It can lead to significant morbidity in affected patients due to the often large and recurrent resulting kidney stones. Treatment is focused on the prevention of stone formation. There have been few advances in the available therapeutic options for the disorder in the last 15-20 years. RECENT FINDINGS: Although no new treatments have emerged in the prevention of cystinuria in recent years, several developments hold promise for advancing the field of caring for affected patients. A new method of measuring urinary cystine and estimating potential for stone formation, called cystine capacity, may prove to be a useful tool in monitoring the disease. The discoveries of the mutations that cause cystinuria have led to a new classification system based on genotype that is more accurate than the prior phenotypic one. The finding of new compounds that inhibit cystine crystal growth in vitro, now being tested in animal models, may lead to new potential therapies in years to come. The Rare Kidney Stone Consortium has developed a registry and hopes to lead further efforts in dealing with cystinuria. SUMMARY: With several recent advances in the monitoring and treatment of cystinuria, and the gathering of clinical patient data, there are now opportunities for new management protocols and therapies.

PURPOSE: The combination of sepsis and ureteral calculus is a urological emergency. Traditional teaching advocates urgent decompression with nephrostomy tube or ureteral stent placement, although published outcomes validating this treatment are lacking. National practice patterns for such scenarios are currently undefined. Using a retrospective study design, we defined the surgical decompression rate in patients admitted to the hospital with severe infection and ureteral calculi. We determined whether a mortality benefit is associated with this intervention. MATERIALS AND METHODS: Patient demographics and hospital characteristics were extracted from the 2007 to 2009 Nationwide Inpatient Sample. We identified 1,712 patients with ureteral calculi and sepsis. Multivariate logistic regression was performed to determine the association between mortality and surgical decompression. RESULTS: Of the patients 78% underwent surgical decompression. Mortality was higher in those not treated with surgical decompression (19.2% vs 8.82%, p <0.001). Lack of surgical decompression was independently associated with an increased OR of mortality even when adjusting for patient demographics, comorbidities and geographic region of treatment (OR 2.6, 95% CI 1.9-3.7). CONCLUSIONS: Absent surgical decompression is associated with higher odds of mortality in patients with sepsis and ureteral calculi. Further research to determine predictors of surgical decompression is necessary to ensure that all patients have access to this life saving therapy.

We summarize the data regarding the associations of individual dietary components with kidney stones and the effects on 24-hour urinary profiles. The therapeutic recommendations for stone prevention that result from these studies are applied where possible to stones of specific composition. Idiopathic calcium oxalate stone-formers are advised to reduce ingestion of animal protein, oxalate, and sodium while maintaining intake of 800 to 1200 mg of calcium and increasing consumption of citrate and potassium. There are few data regarding dietary therapy of calcium phosphate stones. Whether the inhibitory effect of citrate sufficiently counteracts increasing urine pH to justify more intake of potassium and citrate is not clear. Reduction of sodium intake to decrease urinary calcium excretion would also be expected to decrease calcium phosphate stone recurrence. Conversely, the most important urine variable in the causation of uric acid stones is low urine pH, linked to insulin resistance as a component of obesity and the metabolic syndrome. The mainstay of therapy is weight loss and urinary alkalinization provided by a more vegetarian diet. Reduction in animal protein intake will reduce purine ingestion and uric acid excretion. For cystine stones, restriction of animal protein is associated with reduction in intake of the cystine precursor methionine as well as cystine. Reduction of urine sodium results in less urine cystine. Ingestion of vegetables high in organic anion content, such as citrate and malate, should be associated with higher urine pH and fewer stones because the amino acid cystine is soluble in more alkaline urine. Because of their infectious origin, diet has no definitive role for struvite stones except for avoiding urinary alkalinization, which may worsen their development.

Evaluation of stone formers should include careful attention to medications, past medical history, social history, family history, dietary evaluation, occupation, and laboratory evaluation. Laboratory evaluation requires at least serum chemistries and urinalysis. Twenty-four-hour urine collections are most appropriate for patients with recurrent stones or complex medical histories. However, these collections may be appropriate for some first-time stone formers, including those with comorbidities or large stones. Although twin studies demonstrate that heritability accounts for at least 50% of the kidney stone phenotype, the responsible genes are not clearly identified, and so genetic testing is rarely indicated.

This article reviews the data on pharmacologic treatment of kidney stone disease, with a focus on prophylaxis against stone recurrence. One of the most effective and important therapies for stone prevention, an increase in urine volume, is not discussed because this is a dietary and not a pharmacologic intervention. Also reviewed are medical expulsive therapy used to improve the spontaneous passage of ureteral stones and pharmacologic treatment of symptoms associated with ureteral stents. The goal is to review the literature with a focus on the highest level of evidence (ie, randomized controlled trials).

Medullary sponge kidney (MSK) is associated with recurrent calcium stones. Gambaro's group evaluated the relatives of probands with MSK. When prior imaging was not available, they performed renal ultrasounds. They demonstrated familial clustering, providing the best evidence yet that MSK is a heritable disorder. Although a small proportion of MSK cases are associated with variants of glial cell-derived neurotrophic factor (GDNF), the genetic basis for most instances of MSK is not known.