Comparison of Class-Specific Side Effects Across Preventative Pharmacologic Therapies for Kidney Stone Disease.

INTRODUCTION: Clinical guidelines recommend monitoring for metabolic derangements while on preventive pharmacologic therapy for kidney stone disease. The study objective was to compare the frequency of side effects among patients receiving alkali citrate, thiazides, and allopurinol. METHODS: Using claims data from working-age adults with kidney stone disease (2008-2019), we identified those with a new prescription for alkali citrate, thiazide, or allopurinol within 12 months after their index stone-related diagnosis or procedure. We fit multivariable logistic regression models, adjusting for cohort characteristics like comorbid illness and medication adherence, to estimate 2-year measured frequencies of claims-based outcomes of acute kidney injury, falls/hip fracture, gastritis, abnormal liver function tests/hepatitis, hypercalcemia, hyperglycemia/diabetes, hyperkalemia, hypokalemia, hyponatremia, and hypotension. RESULTS: Our cohort consisted of 1776 (34%), 2767 (53%), and 677 (13%) patients prescribed alkali citrate, thiazides, or allopurinol, respectively. Comparing unadjusted rates of incident diagnoses, thiazides compared to alkali citrate and allopurinol were associated with the highest rates of hypercalcemia (2.3% vs 1.5% and 1.0%, respectively, P = .04), hypokalemia (6% vs 3% and 2%, respectively, P < .01), and hyperglycemia/diabetes (17% vs 11% and 16%, respectively, P < .01). No other differences with the other outcomes were significant. In adjusted analyses, compared to alkali citrate, thiazides were associated with a higher odds of hypokalemia (OR=2.01, 95% CI 1.44-2.81) and hyperglycemia/diabetes (OR=1.52, 95% CI 1.26-1.83), while allopurinol was associated with a higher odds of hyperglycemia/diabetes (OR=1.34, 95% CI 1.02-1.75). CONCLUSIONS: These data provide evidence to support clinical guidelines that recommend periodic serum testing to assess for adverse effects from preventive pharmacologic therapy.

Subconjunctival Administration of Mesenchymal Stem Cells Alleviates Ocular Inflammation in a Murine Model of Corneal Alkali Burn.

Corneal alkali burns cause extensive damage not only to the cornea but also to the intraocular tissues. As an anti-inflammatory therapy, subconjunctival administration of mesenchymal stem cells (MSCs) for corneal protection after corneal alkali burn has been explored. Little evidence demonstrates the potential of subconjunctival MSCs delivery in protecting the post-burn intraocular tissues. This study aimed to evaluate the therapeutic efficacy of subconjunctival injection of human placental (hP)-MSCs in protecting against ocular destruction after the burn. hP-MSCs were subconjunctivally administered to C57/BL mice after corneal alkali burn. Western blot of iNOS and CD206 was performed to determine the M1 and M2 macrophage infiltration in the cornea. Infiltration of inflammatory cells in the anterior uvea and retina was analyzed by flow cytometry. The TUNEL assay or Western blot of Bax and Bcl2 was used to evaluate the anti-apoptotic effects of MSCs. MSCs could effectively facilitate cornea repair by suppressing inflammatory cytokines IL-1ß, MCP-1, and MMP9, and polarizing CD206 positive M2 macrophages. Anterior uveal and retinal inflammatory cytokines expression and inflammatory cell infiltration were inhibited in the MSC-treated group. Reduced TUNEL positive staining and Bax/Bcl2 ratio indicated the anti-apoptosis of MSCs. MSC-conditioned medium promoted human corneal epithelial cell proliferation and regulated LPS-stimulated inflammation in RAW 264.7 macrophages, confirming the trophic and immunoregulatory effects of MSCs. Our findings demonstrate that subconjunctival administration of MSCs exerted anti-inflammatory and anti-apoptotic effects in the cornea, anterior uvea, and retina after corneal alkali burn. This strategy may provide a new direction for preventing post-event complications after corneal alkali burn.

Comparison of Empiric Preventative Pharmacologic Therapies on Stone Recurrence Among Patients with Kidney Stone Disease.

OBJECTIVE: To compare the frequency of stone-related events among patients receiving thiazides, alkali citrate, and allopurinol without prior 24 h urine testing.  It is unknown whether 1 preventative pharmacological therapy (PPT) medication class is more beneficial for reducing kidney stone recurrence when prescribed empirically. MATERIALS AND METHODS: Using medical claims data from working-age adults with kidney stone disease diagnoses (2008-2018), we identified those prescribed thiazides, alkali citrate, or allopurinol. We excluded those who received 24 h urine testing prior to initiating PPT and those with less than 3 years of follow-up. We fit multivariable regression models to estimate the association between the occurrence of a stone-related event (emergency department visit, hospitalization, or surgery for stones) and PPT medication class. RESULTS: Our cohort consisted of 1834 (60%), 654 (21%), and 558 (18%) patients empirically prescribed thiazides, alkali citrate, or allopurinol, respectively. After controlling for patient factors including medication adherence and concomitant conditions that increase recurrence risk, the adjusted rate of any stone event was lowest for the thiazide group (14.8%) compared to alkali citrate (20.4%) or allopurinol (20.4%) (each P < .001). Thiazides, compared to allopurinol, were associated with 32% lower odds of a subsequent stone event by 3 years (OR 0.68, 95% CI 0.53-0.88). No such association was observed when comparing alkali citrate to allopurinol (OR 1.00, 95% CI 0.75-1.34). CONCLUSION: Empiric PPT with thiazides is associated with significantly lower odds of subsequent stone-related events. When 24 h urine testing is unavailable, thiazides may be preferred over alkali citrate or allopurinol for empiric PPT.

Cordycepin prevents the esophageal stricture formation in the alkali-burn rat model by exerting anti-inflammatory and antifibrotic effects.

PURPOSE: To investigate the efficacy of cordycepin, an adenosine analogue, on prevention of esophageal damage and stricture formation due to esophageal caustic burns in rat model comparing with prednisolone. METHODS: Caustic esophageal burn was introduced by 37.5% of NaOH to distal esophagus. Thirty-two Wistar albino rats were divided in four groups: sham rats undergone laparotomy, treated with 0.9% NaCl; control rats injured with NaOH without cordycepin treatment; cordycepin group injured with NaOH, treated with 20 mg/kg cordycepin; prednisolone group injured with NaOH, treated with 1 mg/kg prednisolone for 28 days. Efficacy was assessed by histopathological and immunohistochemical analysis of esophageal tissues. RESULTS: Cordycepin treatment significantly decreased inflammation, granulation tissue and fibrous tissue formation and prevented formation of esophageal strictures shown by histopathological damage score and stenosis indexes compared to control group (p < 0.01). These effects are relatively more substantial than prednisolone, probably based on attenuation of elevation of proinflammatory cytokines hypoxia-inducible factor 1-alpha (HIF-1?), tumor necrosis factor alpha (TNF-?), proliferative and fibrotic factor fibroblast growth factor 2 (FGF2) and angiogenic factor vascular endothelial growth factor A (VEGFA) (p < 0.05). CONCLUSIONS: The findings suggest that cordycepin has a complex multifactorial healing process in alkali-burned tissue, more successful than prednisolone in preventing the formation of esophageal strictures and may be used as a therapeutic agent in the acute phase of esophageal alkali-burn.

Malignancy-induced lactic acidosis in adult lymphoma.

Malignancy-induced lactic acidosis (MILA), a rare paraneoplastic phenomenon, is mostly described with hematologic malignancies (lymphomas and leukemias) but has also been reported with solid tumors. It is a subset of type B lactic acidosis being mediated without evidence of tissue hypoperfusion. Lymphoma-induced lactic acidosis is often considered an oncologic emergency and is associated with an increased risk of mortality and poor prognosis. It has a complex pathophysiology centered in the "Warburg effect," i.e., the programming of cancer cells to depend on aerobic glycolysis for promotion of their proliferation and anabolic growth. The treatment of lymphoma-induced lactic acidosis is focused on prompt administration of chemotherapy. The role of alkali therapy in this setting is controversial and has limited proven benefit with a potential for worsening the lactic acidosis. If alkali therapy is used in the presence of severe acidemia to optimize cardiovascular status, it should be administered judiciously.

Cordycepin prevents the esophageal stricture formation in the alkali-burn rat model by exerting anti-inflammatory and antifibrotic effects

ABSTRACT Purpose To investigate the efficacy of cordycepin, an adenosine analogue, on prevention of esophageal damage and stricture formation due to esophageal caustic burns in rat model comparing with prednisolone. Methods Caustic esophageal burn was introduced by 37.5% of NaOH to distal esophagus. Thirty-two Wistar albino rats were divided in four groups: sham rats undergone laparotomy, treated with 0.9% NaCl; control rats injured with NaOH without cordycepin treatment; cordycepin group injured with NaOH, treated with 20 mg/kg cordycepin; prednisolone group injured with NaOH, treated with 1 mg/kg prednisolone for 28 days. Efficacy was assessed by histopathological and immunohistochemical analysis of esophageal tissues. Results Cordycepin treatment significantly decreased inflammation, granulation tissue and fibrous tissue formation and prevented formation of esophageal strictures shown by histopathological damage score and stenosis indexes compared to control group (p < 0.01). These effects are relatively more substantial than prednisolone, probably based on attenuation of elevation of proinflammatory cytokines hypoxia-inducible factor 1-alpha (HIF-1?), tumor necrosis factor alpha (TNF-?), proliferative and fibrotic factor fibroblast growth factor 2 (FGF2) and angiogenic factor vascular endothelial growth factor A (VEGFA) (p < 0.05). Conclusions The findings suggest that cordycepin has a complex multifactorial healing process in alkali-burned tissue, more successful than prednisolone in preventing the formation of esophageal strictures and may be used as a therapeutic agent in the acute phase of esophageal alkali-burn.

A Basic Therapy Gone Awry.

Baking soda (sodium bicarbonate) is a common household item that has gained popularity as an alternative cancer treatment. Some have speculated that alkali therapy neutralizes the extracellular acidity of tumor cells that promotes metastases. Internet blogs have touted alkali as a safe and natural alternative to chemotherapy that targets cancer cells without systemic effects. Sodium bicarbonate overdose is uncommon, with few reports of toxic effects in humans. The case described here is the first reported case of severe metabolic alkalosis related to topical use of sodium bicarbonate as a treatment for cancer. This case highlights how a seemingly benign and readily available product can have potentially lethal consequences.

Clinical and molecular aspects of distal renal tubular acidosis in children.

BACKGROUND: Distal renal tubular acidosis (dRTA) is characterized by hyperchloraemic metabolic acidosis, hypokalaemia, hypercalciuria and nephrocalcinosis. It is due to reduced urinary acidification by the α-intercalated cells in the collecting duct and can be caused by mutations in genes that encode subunits of the vacuolar H+-ATPase (ATP6V1B1, ATP6V0A4) or the anion exchanger 1 (SLC4A1). Treatment with alkali is the mainstay of therapy. METHODS: This study is an analysis of clinical data from a long-term follow-up of 24 children with dRTA in a single centre, including a genetic analysis. RESULTS: Of the 24 children included in the study, genetic diagnosis was confirmed in 19 patients, with six children having mutations in ATP6V1B1, ten in ATP6V0A4 and three in SLC4A1; molecular diagnosis was not available for five children. Five novel mutations were detected (2 in ATP6V1B1 and 3 in ATP6V0A4). Two-thirds of patients presented with features of proximal tubular dysfunction leading to an erroneous diagnosis of renal Fanconi syndrome. The proximal tubulopathy disappeared after resolution of acidosis, indicating the importance of following proximal tubular function to establish the correct diagnosis. Growth retardation with a height below -2 standard deviation score was found in ten patients at presentation, but persisted in only three of these children once established on alkali treatment. Sensorineural hearing loss was found in five of the six patients with an ATP6V1B1 mutation. Only one patient with an ATP6V0A4 mutation had sensorineural hearing loss during childhood. Nine children developed medullary cysts, but without apparent clinical consequences. Cyst development in this cohort was not correlated with age at therapy onset, molecular diagnosis, growth parameters or renal function. CONCLUSION: In general, the prognosis of dRTA is good in children treated with alkali.

[Cystinuria]. / Cistinuria.

Cystinuria is an autosomal recessive disorder characterized by impairment of the proximal renal tubules which are unable to reabsorb cystine and dibasic amino acids, leading to the formation of recurrent kidney stones. According to the most recent genetic knowledge, there are two types of cystinuria. The disease is more severe in men than in women in terms of early appearance and number of produced stones. Renal function is generally maintained even after long-lasting disease. Type A heterozygotes are generally asymptomatic while type B heterozygotes usually have a three-fold increased incidence of kidney stones compared to the general population. Medical treatment of cystinuria with cystine-binding drugs and alkali is feasible and effective but requires continuous monitoring of free-cystine urine levels and urine pH and careful surveillance of side effects, with particular attention to the onset of proteinuria.

Pharmacology of stone disease.

Kidney stone disease remains a major health and economic burden on the nation. It has been increasingly recognized that nephrolithiasis can be both a chronic or systemic illness. There have been major limitations in the development of new drugs for the prevention and management of this disease, largely due to our lack of understanding of the complex pathophysiologic mechanisms involving the interaction of three major target organs: the kidney, bone, and intestine. We also do not yet understand the molecular genetic basis of this polygenic disorder. These limitations are coupled with the incorrect perception that kidney stone disease is solely an acute illness, and the lack of reliable tests to assess outcome measures. All of these factors combined have diminished the willingness of the pharmaceutical industry to engage in the development of novel drugs.

Alkaline mineral water lowers bone resorption even in calcium sufficiency: alkaline mineral water and bone metabolism.

BACKGROUND: Dietary acid charge enhances bone loss. Bicarbonate or alkali diet decreases bone resorption in humans. We compared the effect of an alkaline mineral water, rich in bicarbonate, with that of an acid one, rich in calcium only, on bone markers, in young women with a normal calcium intake. METHODS: This study compared water A (per litre: 520 mg Ca, 291 mg HCO(3)(-), 1160 mg SO(4)(-), Potential Renal Acid load (PRAL) +9.2 mEq) with water B (per litre: 547 mg Ca, 2172 mg HCO(3)(-), 9 mg SO(4)(-), PRAL -11.2 mEq). 30 female dieticians aged 26.3 yrs (SD 7.3) were randomized into two groups, followed an identical weighed, balanced diet (965 mg Ca) and drank 1.5 l/d of the assigned water. Changes in blood and urine electrolytes, C-telopeptides (CTX), urinary pH and bicarbonate, and serum PTH were measured after 2 and 4 weeks. RESULTS: The two groups were not different at baseline, and showed a similar increase in urinary calcium excretion. Urinary pH and bicarbonate excretion increased with water B, but not with water A. PTH (p=0.022) and S-CTX (p=0.023) decreased with water B but not with water A. CONCLUSION: In calcium sufficiency, the acid calcium-rich water had no effect on bone resorption, while the alkaline water rich in bicarbonate led to a significant decrease of PTH and of S-CTX.

Urinary citrate levels do not correlate with urinary pH in patients with urinary stone formation.

OBJECTIVES: Urinary excretion of citrate is dependent on glomerular filtration, tubular reabsorption, and excretion. Acid base status is thought to play a significant role in urinary citrate excretion. It has been assumed that increased urinary citrate will increase urinary pH. The aim of this study was to confirm the association of increased urinary citrate levels with increased urinary pH. METHODS: The 24-hour urine collections of all patients with stones referred to our clinic in the past 4 years were reviewed. The samples were collected and analyzed for routine stone risk profiles by a commercial laboratory (Litholink, Chicago, Ill). The Student t test and analysis of variance were used to compare the mean values as applicable. Pearson's correlations were also calculated for each variable. RESULTS: A total of 572 patients had at least one 24-hour urine sample from the past 4 years. The mean urinary citrate was 305 mg/day. The mean urinary pH of all patients was 6.14. Statistical evaluation of all patients showed no correlation between urinary citrate and pH (r = -0.04, P = 0.36). In a subset of patients with urinary potassium greater than 100 mEq/day (n = 100), urinary citrate and urinary pH were both increased; however, there was still no correlation between the two (r = 0.011, P = 0.806). CONCLUSIONS: Despite the current dogma that increasing urinary citrate increases urinary pH, in a cohort of patients with urinary stone formation who provided 24-hour urine specimens, no correlation was found between urinary citrate and urinary pH levels.

[Cystinuria: from diagnosis to follow-up]. / Cystinurie : du diagnostic à la surveillance thérapeutique.

Cystinuria is an autosomal recessive disorder characterized by an impaired transport of cystine and dibasic aminoacids, lysine, arginine and ornithine in the proximal renal tubule and in the epithelial cells of the gastrointestinal tract. Recurrent cystine nephrolithiasis is the main clinical feature. Mutations in SLC3A1 and/or SLC7A9 genes, which are encoding respectively the rBAT and the b(0,+)AT proteins of the amino acid transport system, are responsible of this disorder thus inducing a high dibasic amino acid excretion. Diagnostic is based on stone analysis by infrared spectroscopy or microscopic examination of urine which may reveal typical cystine crystals. Quantitative cystine excretion, which may be assessed by aminoacid chromatography, is higher in cystinic patients. Molecular approach can identify mutations which are responsible of this pathology. Medical treatment is mainly based on hydratation and urine alkalinisation, with the addition of thiol derivative only in refractory cases. Follow-up based on pH and specific gravity determination in urine samples and cystine crystal volume measurement are used to optimally monitor the medical treatment of cystinuric patients. Even with medical management, long-term outcome is poor due to insufficient efficacy and low patient compliance. Many patients suffer from renal insufficiency as a result of recurrent stone formation and repeated surgical procedures.

Acquired fanconi syndrome with osteomalacia secondary to monoclonal gammopathy of undetermined significance.

A 60-year-old woman was admitted because of multiple bone pain. Examination revealed hypophosphatemic osteomalacia and acquired Fanconi syndrome. Further exploration revealed monoclonal gammopathy of undetermined significance (MGUS) excreting urinary Bence Jones protein (kappa light chain). Renal biopsy showed non-specific tubulointerstitial nephritis, yet neither crystalline inclusions in the cytoplasm of the tubular epithelium nor myeloma casts nor amyloid deposits were found. She was treated with supplementation by phosphate, alkali agents, and vitamin D, and responded well to the treatment symptomatically and biochemically. MGUS was observed without chemotherapy. Myeloma had not developed after 10 months follow-up.

[Alkaline citrates in urology. A status report]. / Alkalizitrate in der Urologie. Eine Standortbestimmung.

Alkaline citrates have been used as an efficient therapy in hypocitraturic calcium nephrolithiasis, uric acid lithiasis, cystinuria, and renal tubular acidosis. Furthermore, alkaline citrates are very effective in treating and preventing hyperchloremic metabolic acidosis in patients with urinary diversion. The main physiological effects during urolithiasis therapy have been significant increases in urinary pH, in citrate and potassium, and a decrease in calcium excretion. This paper reviews current indications, therapy modalities, and metaphylactic use reported in the literature and/or recommended by the Deutsche Gesellschaft für Urologie (DGU) and the European Association of Urology (EAU). It is intended to give useful advice for the urologist's daily practice.

Cystine crystal volume determination: a useful tool in the management of cystinuric patients.

We prospectively determined cystine crystal volume (Vcys) in urine specimens from all consecutive patients with cystine urolithiasis followed at our institution over the past decade, in order to assess its predictive value as to the risk of recurrent cystine stone formation. A total of 57 patients (29 males, 28 females) with homozygous cystinuria entered in the study between January 1990 and December 2000, including 15 children aged less than 15 years and 42 patients aged 15 years or more. The clinical and radiological course was followed until December 2001, for a total of 243 patient-years of follow-up. From study entry until the end of follow-up, we serially examined first voided morning urine specimens in all patients, with determination of the number of cystine crystals per mm3, and the average size of crystals, thus allowing us to calculate Vcys using a simple formula based on crystal geometry. Recurrence was diagnosed on the basis of serial radiographic examinations using X-rays and echography. Overall, cystine crystals were present in 179 (39%) of the 460 examined urine specimens. Cystine crystalluria was significantly more frequent among the 27 patients who developed new cystine stones (SF) than in the other 30 who remained stone-free (63.3 vs 25.5% of samples, P<0.001). The presence of crystals in > or =50% of serially examined urine samples was more frequently found in patients with recurrent stone formation than in non-recurrent patients (24/27 vs 2/30, P<0.001). The average Vcys value was significantly higher in recurrent SF than in stone-free patients (8,173 +/- 1,544 vs 233 +/- 150 micro3/mm3, P<0.001) and there was no overlap in the individual values of recurrent vs stone-free patients. A Vcys value > or =3,000 micro3/mm3 was observed at least once prior to each of the 63 stone recurrences observed in 27 patients (2.3 per patient on the average). In addition, Vcys reflected the efficacy of treatment, with Vcys mean values of 12,097 +/- 3,214 micro3/mm3 at baseline, falling to 2,648 +/- 658 micro3/mm3 on basic therapy (hyperdiuresis plus alkalinization) alone, 1,141 +/- 522 micro3/mm3 on tiopronin therapy (median dose 1,000 mg/day) and 791 +/- 390 micro3/mm3 on D-penicillamine therapy (median dose 900 mg/day) whereas captopril had no effect (5,114 +/- 2,128 micro3/mm3). Based on the results of the present study, cystine crystalluria appears to accurately reflect active stone formation in cystinuric patients. Determination of total Vcys provides a simple, cheap and accurate means of predicting the risk of cystine stone recurrence with a Vcys value > or =3000 micro3/mm3 as the threshold risk value. We propose that serial Vcys determination be performed simultaneously with the measurement of urine pH and specific gravity to optimally monitor the medical treatment of cystine patients.

Lidocaine in ultrasound-assisted lipoplasty.

The doses of lidocaine used for lipoplasty often exceed what is commonly recommended for other surgical procedures. When using these high volumes of lidocaine and wetting solutions, a variety of safety issues must be considered. The author knows of no other plastic surgery operation in which the safety of the procedure is so influenced by the medications administered. Each component of the wetting solution--the alkalized fluid, the epinephrine, and the lidocaine--has an individual and interrelated role. The absorption of lidocaine with epinephrine after subcutaneous installation for lipoplasty probably represents a unique situation, and the concepts presented should not necessarily be extrapolated to other types of procedures.

Contemporary urological intervention for cystinuric patients: immediate and long-term impact and implications.

PURPOSE: We determined the immediate efficacy of contemporary urological intervention for cystine stones and the impact of such intervention on the subsequent rate of recurrent stone formation. MATERIALS AND METHODS: A total of 31 cystinuric patients underwent selected intervention for 61 stone events. Patients were subsequently followed at 6 to 12-month intervals while being treated with standard medical therapy. Logistic regression models were used to correlate potential risk factors with the efficacy of the intervention in achieving a stone-free status. Kaplan-Meier estimates of the probability of recurrence-free survivals at 1 and 5 years were generated, and risk factors for stone recurrence were analyzed using the log rank test. RESULTS: Overall stone-free rate was 86.9%, which was not significantly influenced by the initial stone burden or type of intervention selected. The probability of recurrence-free survival at 1 and 5 years was 0.73 and 0.27, respectively, and again this probability was independent of initial stone burden or type of intervention selected. Urinary cystine levels before intervention and post-procedure residual stone status also failed to impact significantly on the risk of recurrence. However, a stone-free result, in contrast to residual stones, prolonged the mean time to stone recurrence from 346 to 1,208 days. CONCLUSIONS: While cystine stones are not amenable to all currently available minimally invasive therapeutic modalities, high stone-free rates can be achieved without the need for open surgery and as such cystinuric patients clearly benefit from contemporary intervention. When such intervention is used selectively, with consideration given primarily to stone burden and location, rates of recurrence will relate primarily to the natural history of the medically treated cystinuric patient, and not the type of intervention applied.