Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:Hypernatremia is a relatively frequent electrolyte disorder seen in critically ill patients. As many as 27% of patients in intensive care units (ICUs) develop hypernatremia of variable severity during an ICU stay. Debate among specialists often ensues as to whether to correct hypernatremia or not. Some practitioners, particularly intensivists, believe that correction of hypernatremia with fluids may cause expansion of the extracellular fluid volume (ECFV) thereby worsening ventilation and impeding extubation. Other practitioners, including many nephrologists, do not expect correction of hypernatremia to lead to clinically apparent ECFV expansion, and fear other deleterious effects of hypernatremia. In this review we address the controversy regarding appropriate practice. FINDINGS/RESULTS:There are no randomized, clinical trials (RCTs) to guide the administration of electrolyte-free fluid administration in hypernatremic patients. However, there are associations, demonstrated in the literature, suggesting that hypernatremia of any severity will increase the mortality and length of stay in these patients. These associations generally support the practice of correction of hypernatremia. In addition, our knowledge of the distribution of total body water influences us towards correcting hypernatremia as an appropriate therapy. We do not expect that adequate RCTs addressing this question will be performed. SUMMARY/CONCLUSIONS:Allowing persistence of any degree of hypernatremia is associated with increased mortality, length of stay (LOS) and postdischarge mortality. We expect that proper use of electrolyte-free water intake will avoid adverse outcomes.

Cystinuria is the most common genetic cause of nephrolithiasis in children. It is considered a heritable aminoaciduria as the genetic defect affects the reabsorption of cystine and three other amino acids (ornithine, lysine, and arginine) in the renal proximal tubule. Patients affected by this condition have elevated excretion of cystine in the urine, and because of this amino acid's low solubility at normal urine pH, patients tend to form cystine calculi. To date, two genes have been identified as disease-causative: SLC3A1 and SLC7A9, encoding for the two subunits of the heterodimeric transporter. The clinical features of this condition are solely related to nephrolithiasis. The diagnosis is usually made during infancy or adolescence, but cases of late diagnosis are common. The goal of therapy is to reduce excretion and increase the solubility of cystine, through both modifications of dietary habits and pharmacological treatment. However, therapeutic interventions are not always sufficient, and patients often have to undergo several surgical procedures during their lives to treat recurrent nephrolithiasis. The goal of this literature review is to synthesize the available evidence on diagnosis and management of patients affected by cystinuria in order to provide physicians with a practical tool that can be used in daily clinical practice. This review also aims to shed some light on new therapy directions with the aim of ameliorating kidney outcomes while improving adherence to treatment and quality of life of cystinuric patients.

OBJECTIVE:Patients with kidney stones are counseled to eat a diet low in animal protein, sodium, and oxalate and rich in fruits and vegetables, with a modest amount of calcium, usually from dairy products. Restriction of sodium, potassium, and oxalate may also be recommended in patients with chronic kidney disease. Recently, plant-based diets have gained popularity owing to health, environmental, and animal welfare considerations. Our objective was to compare concentrations of ingredients important for kidney stones and chronic kidney disease in popular brands of milk alternatives. DESIGN AND METHODS/METHODS:Sodium, calcium, and potassium contents were obtained from nutrition labels. The oxalate content was measured by ion chromatography coupled with mass spectrometry. RESULTS:The calcium content is highest in macadamia followed by soy, almond, rice, and dairy milk; it is lowest in cashew, hazelnut, and coconut milk. Almond milk has the highest oxalate concentration, followed by cashew, hazelnut, and soy. Coconut and flax milk have undetectable oxalate levels; coconut milk also has comparatively low sodium, calcium, and potassium, while flax milk has the most sodium. Overall, oat milk has the most similar parameters to dairy milk (moderate calcium, potassium and sodium with low oxalate). Rice, macadamia, and soy milk also have similar parameters to dairy milk. CONCLUSION/CONCLUSIONS:As consumption of plant-based dairy substitutes increases, it is important for healthcare providers and patients with renal conditions to be aware of their nutritional composition. Oat, macadamia, rice, and soy milk compare favorably in terms of kidney stone risk factors with dairy milk, whereas almond and cashew milk have more potential stone risk factors. Coconut milk may be a favorable dairy substitute for patients with chronic kidney disease based on low potassium, sodium, and oxalate. Further study is warranted to determine the effect of plant-based milk alternatives on urine chemistry.

BACKGROUND: Primary hyperoxaluria (PH) is a family of rare genetic disorders affecting 1-3 per 1 million persons globally. PH causes hepatic oxalate overproduction leading to increased urinary oxalate excretion, that can result in frequent kidney stone events, progression to end-stage kidney disease (ESKD) and then other systemic morbidities.
OBJECTIVE(S): To assess the burden of PH among patients and caregivers with respect to healthcare resource utilization (HRU), quality of life (QoL) and work productivity.
METHOD(S): An IRB-approved web survey was conducted among adults (>= 18 years) with PH, and caregivers of children (< 17 years) with PH in the US. Participants were asked about their or their child's medical care, HRU and QoL. The Kidney Disease Quality of Life (KDQOL-36TM: range 0-100, higher score = better QOL) and Work Productivity and Activity Impairment (WPAI: range 0-100%, higher score = more impairment) questionnaires were administered. Descriptive statistics summarized the responses.
RESULT(S): Patient sample (n = 21) comprised 7 adults (median age 42 years) and 14 children (median age 8 years). Patients' HRU consisted of visits to nephrologists (81%), urologists (67%) and ophthalmologists (10%). 33% visited the emergency room and 29% were hospitalized. Patients on dialysis (n = 5) spent a median of 24 hours per week receiving dialysis. PH complications included kidney stone events (95%), pain (71%, nearly all moderate-severe) and nephrocalcinosis (48%). 48% of all patients experienced PH-related anxiety. Adult patients' mean KDQOL-36TM domain scores (burden, symptoms/problems and effects of kidney disease) were 38 (SD = 23), 77 (SD = 23) and 65 (SD = 26), respectively. Employed adult patients (n = 4) reported 25% presenteeism (reduced productivity at work) on average based on the WPAI. Children missed a median of 15 hours/month of school due to their PH. Caregivers (n = 13) experienced moderate-severe anxiety about the possibility of future PH-related outcomes (i.e., kidney stones [54%], kidney disease progression [62%] and ESKD [62%]) for their child. Employed caregivers (n = 9) reported 28% presenteeism on average based on the WPAI.
CONCLUSION(S): This research quantifies the burden of PH in terms of HRU, QoL and productivity for patients and caregivers. Patients experienced considerable clinical sequalae associated with PH, such as kidney stones and pain, which appear to negatively affect these outcomes. Numerous clinician visits indicated an intensive level of care. Further, PH burden goes beyond the patient, as evidenced by caregiver burden, including anxiety and impact on work productivity

Background: Potassium citrate is a mainstay of treatment to prevent recurrent calcium-containing kidney stones. However, it can increase urine pH and calcium phosphate (CaP) supersaturation (SS). HCA, extracted from Garcinia cambogia, is a potent inhibitor of calcium oxalate crystal growth in vitro and should not provide "potential base", as citrate does. Urine excretion of HCA has not been well-studied.
Method(s): We enrolled 2 groups: calcium stone formers (SF; n = 9) and non-stone forming (NSF, n = 9) controls (after excluding 2 SF and 2 NSF whose urine creatinine excretion on the 2 collections differed by more than 20%). Mean age 49.3 years. Thiazides and citrate were held for 2 weeks prior to study. Participants recorded a self-selected diet for 2 days and performed 24-hour urine collection on day 2. HCA was purchased online from Amazon.com (Super CitriMax Garcinia Cambogia); 2 caps = 900 mg of HCA. Participants took 900 mg 3 times daily orally for 7 days. Diet from days 1 and 2 was replicated on day 6 and 7 of the HCA arm of the study. 24-hour urine was collected on day 7. Urine was sent to Litholink, Inc. (Chicago, IL) for analysis. Urinary excretion of hydroxycitrate and citrate were measured using LC/MS.
Result(s): According to label, 6 pills would provide 2700 mg (13.2 mmol) of HCA per day; we measured content as 3198 mg (15.6 mmol). Citrate content is supposed to be 0, but we found 126 mg (0.66 mmol) per day. Both NSF and SF had appearance of HCA in the urine: 1.86 +/- 0.80 and 2.07 +/- 0.67 mmol/day (p = 0.56). Urine chemistry seen in Table 1. In NSF, pH and citrate did not change. In SF, pH increased, citrate did not. K went up in both groups.
Conclusion(s): Administration of HCA, a potential inhibitor of Ca stone formation, leads to significant urinary HCA excretion. Citrate excretion was not affected. Urine pH increased, suggesting some alkalinizing effect. The difference in NSF and SF may be due to the lower starting pH in SF. The effect of HCA on stone formation remains to be determined. (Figure Presented)

Background: Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH) is a rare monogenic disorder caused by SLC34A3 pathogenic variants, characterized by renal phosphate wasting, hypophosphatemia, hypercalciuria (HC), elevated 1,25-dihydroxyvitamin D, nephrocalcinosis (NC), and urinary stone disease (USD). Previously we reported a high prevalence of kidney cysts in CYP24A1 deficiency. Thus, in the current study, we characterized cyst presence in HHRH, another monogenic cause of HC, NC, and USD.
Method(s): Medical records from Mayo Clinic and Rare Kidney Stone Consortium research results were queried for all patients with genetically confirmed HHRH diagnosis. Clinical characteristics and imaging data are summarized in table 1.
Result(s): Among 12 patients with SLC34A3 pathogenic variants (7 monoallelic, 5 biallelic), 42% (5/12) were males. Median age at clinical presentation was 17 yrs (range 8-46) and at genetic confirmation 42 yrs (range 9-66). None had a family history of cystic kidney disease. Kidney cysts (Figure 1) were present in 75% (9/12), among whom median age at first kidney imaging and first cyst detection was 41 yrs (range 9-64). Median number of cysts per patient was 3 (range 1-23). The number of cysts >=5 mm in size was above the 97.5th percentile of an age-and sex-matched control population in 6/9 (67%). At least 2 cysts >=5 mm in size were found in 100% of children.
Conclusion(s): We found a strong association between HHRH and kidney cysts. Similarities in the biochemical profiles of HHRH and CYP24A1 deficiency suggest elevated active vitamin D, and/or HC may be potential factors in cyst formation. Further studies are needed to evaluate the role of the SLC34A3 gene in cyst formation. (Figure Presented)

INTRODUCTION/BACKGROUND:The term "lactic acidosis" reinforces the misconception that lactate contributes to acidemia. Although it is common to discover an anion gap acidosis with a concomitant elevated lactate concentration, the two are not mutually dependent. CASE REPORT/METHODS:Here we describe two patients exhibiting high lactate concentrations in the setting of metabolic alkalemia. CONCLUSION/CONCLUSIONS:Lactate is not necessarily the direct cause of acid-base disturbances, and there is no fixed relationship between lactate and the anion gap or between lactate and pH. The term "metabolic acidosis with hyperlactatemia" is more specific than "lactic acidosis" and thus more appropriate.

Introduction/UNASSIGNED:Because of phenotypic overlap between monogenic urinary stone diseases (USD), gene-specific analyses can result in missed diagnoses. We used targeted next generation sequencing (tNGS), including known and candidate monogenic USD genes, to analyze suspected primary hyperoxaluria (PH) or Dent disease (DD) patients genetically unresolved (negative; N) after Sanger analysis of the known genes. Cohorts consisted of 285 PH (PHN) and 59 DD (DDN) families. Methods/UNASSIGNED:Variants were assessed using disease-specific and population databases plus variant assessment tools and categorized using the American College of Medical Genetics (ACMG) guidelines. Prior Sanger analysis identified 47 novel PH or DD gene pathogenic variants. Results/UNASSIGNED:accounted for 1 pedigree each. Of the 48 defined pathogenic variants, 27.1% were truncating and 39.6% were novel. Most patients were diagnosed before 18 years of age (76.1%), and 70.3% of biallelic patients were homozygous, mainly from consanguineous families. Conclusion/UNASSIGNED:Overall, in patients suspected of DD or PH, 23.9% and 7.3% of cases, respectively, were caused by pathogenic variants in other genes. This study shows the value of a tNGS screening approach to increase the diagnosis of monogenic USD, which can optimize therapies and facilitate enrollment in clinical trials.