Effect of urine alkalization on urinary inflammatory markers in cystinuric patients.

Background: Cystinuria is associated with a high prevalence of chronic kidney disease (CKD). We previously described a urinary inflammatory-protein signature (UIS), including 38 upregulated proteins, in cystinuric patients (Cys-patients), compared with healthy controls (HC). This UIS was higher in Cys-patients with CKD. In the present observational study, we aimed to investigate the UIS in Cys-patients without CKD and patients with calcium nephrolithiasis (Lith-patients), versus HC and the effect of urine alkalization on the UIS of Cys-patients. Methods: UIS was evaluated by nano-liquid chromatography coupled to high-resolution mass spectrometry in adult HC, Lith-patients and non-treated Cys-patients with an estimated glomerular filtration rate >60 mL/min/1.73 m2, and after a 3-month conventional alkalizing treatment in Cys-patients. Results: Twenty-one Cys-patients [12 men, median age (interquartile range) 30.0 (25.0-44.0) years], 12 Lith-patients [8 men, 46.2 (39.5-54.2) years] and 7 HC [2 men, 43.1 (31.0-53.9) years] were included. Among the 38 proteins upregulated in our previous work, 11 proteins were also upregulated in Cys-patients compared with HC in this study (5 circulating inflammatory proteins and 6 neutrophil-derived proteins). This UIS was also found in some Lith-patients. Using this UIS, we identified two subclusters of Cys-patients (5 with a very high/high UIS and 16 with a moderate/low UIS). In the Cys-patients with very high/high UIS, urine alkalization induced a significant decrease in urinary neutrophil-derived proteins. Conclusion: A high UIS is present in some Cys-patients without CKD and decreases under alkalizing treatment. This UIS could be a prognostic marker to predict the evolution towards CKD in cystinuria.

Hydration for Adult Patients with Nephrolithiasis: Specificities and Current Recommendations.

Nephrolithiasis affects around 10% of the population and is frequently associated with impaired dietary factors. The first one is insufficient fluid intake inducing reduced urine volume, urine supersaturation, and subsequently urinary lithiasis. Kidneys regulate 24 h urine volume, which, under physiological conditions, approximately reflects daily fluid intake. The aim of this study is to synthesize and highlight the role of hydration in the treatment of nephrolithiasis. Increasing fluid intake has a preventive effect on the risk of developing a first kidney stone (primary prevention) and also decreases the risk of stone recurrence (secondary prevention). Current guidelines recommend increasing fluid intake to at least at 2.5 L/day to prevent stone formation, and even to 3.5-4 L in some severe forms of nephrolithiasis (primary or enteric hyperoxaluria or cystinuria). Fluid intake must also be balanced between day and night, to avoid urinary supersaturation during the night. Patients should be informed and supported in this difficult process of increasing urine dilution, with practical ways and daily routines to increase their fluid intake. The liquid of choice is water, which should be chosen depending on its composition (such as calcium, bicarbonate, or magnesium content). Finally, some additional advice has to be given to avoid certain beverages such as those containing fructose or phosphoric acid, which are susceptible to increase the risk of nephrolithiasis.

Fibroblast growth factor 23 but not copeptin is independently associated with kidney failure and mortality in patients with chronic kidney disease.

Background: Copeptin and intact fibroblast growth factor 23 (iFGF23) increase early during chronic kidney disease (CKD) and may be predictive of unfavourable outcomes. The aim of this study was to evaluate their respective associations with renal and vital outcomes in CKD patients. Methods: We included CKD patients from the NephroTest cohort with concomitant measurements of plasma copeptin and iFGF23 concentrations and isotopic glomerular filtration rate measurement (mGFR). The primary endpoint was a composite outcome including kidney failure (KF) (dialysis initiation, pre-emptive transplantation or a 57% decrease of mGFR, corresponding to doubling of serum creatinine) or death before KF. Hazard ratios (HRs) of the primary endpoint associated with log-transformed copeptin and iFGF23 concentrations were estimated by Cox models. The slope of mGFR over time was analysed using a linear mixed model. Results: A total of 329 CKD patients (243 men, mean age 60.3 ± 14.6 years) were included. Among them, 301 with an mGFR >15 ml/min/1.73 m2 were included in survival and mGFR slope analyses. During a median follow-up of 4.61 years (quartile 1-quartile 3: 3.72-6.07), 61 KFs and 32 deaths occurred. Baseline iFGF23 concentrations were associated with the composite outcome after multiple adjustments {HR 2.72 [95% confidence interval (CI) 1.85-3.99]}, whereas copeptin concentrations were not [HR 1.01 (95% CI 0.74-1.39)]. Neither copeptin nor iFGF23 were associated with mGFR slope over time. Conclusion: Our study shows for the first time in population of CKD patients an independent association between iFGF23 and unfavourable renal and vital outcomes and shows no such association regarding copeptin, encouraging the integration of iFGF23 measurement into the follow-up of CKD.

Comparison of 99mTc-DTPA and 51Cr-EDTA for glomerular filtration rate measurement with the continuous infusion method.

BACKGROUND: In late 2018, the production of 51Chromium-labelled ethylenediamine tetra-acetic acid (51Cr-EDTA), a validated and widely used radio-isotopic tracer for measuring glomerular filtration rate, was halted. Technetium-99m-diethylenetriaminepentaacetic acid (99mTc-DTPA) has been validated for GFR measurement with a single bolus injection, a procedure not suitable in patients with extracellular compartment hyperhydration. In such cases, a bolus followed by continuous infusion of the tracer is required. The aim of this study was to evaluate whether 99mTc-DTPA with the infusion protocol can replace 51Cr-EDTA for GFR measurement. METHODS: We conducted a prospective single centre study during February and March 2019. All patients referred for GFR measurement received both radiotracers simultaneously: 51Cr-EDTA and 99mTc-DTPA bolus and continuous infusion were administered concomitantly through the same intravenous route. Over four and a half hours, plasma and urine samples were collected to calculate urinary and plasma clearance. RESULTS: Twenty-two patients were included (mean age 63.4 ± 17.5 years; 68% men). Mean urinary clearance of 51Cr-EDTA and 99mTc-DTPA was 52.4 ± 22.5 mL/min and 52.8 ± 22.6 mL/min, respectively (p = 0.47), with a mean bias of 0.39 ± 2.50 mL/min, an accuracy within 10% of 100% (95% CI 100; 100) and a Pearson correlation coefficient of 0.994. Mean plasma clearance of 51Cr-EDTA and 99mTc-DTPA was 54.8 ± 20.9 mL/min and 54.4 ± 20.9 mL/min, respectively (p = 0.61), with a mean bias of - 0.43 ± 3.89 mL/min, an accuracy within 10% of 77% (95% CI 59; 91) and a Pearson correlation coefficient of 0.983. CONCLUSIONS: Urinary and plasma clearance of 99mTc-DTPA can be used with the infusion protocol to measure GFR.

Hypomagnesemia, Hypocalcemia, and Tubulointerstitial Nephropathy Caused by Claudin-16 Autoantibodies.

BACKGROUND: Chronic hypomagnesemia is commonly due to diarrhea, alcoholism, and drugs. More rarely, it is caused by genetic defects in the effectors of renal magnesium reabsorption. METHODS: In an adult patient with acquired severe hypomagnesemia, hypocalcemia, tubulointerstitial nephropathy, and rapidly progressing kidney injury, similarities between the patient's presentation and features of genetic disorders of renal magnesium transport prompted us to investigate whether the patient had an acquired autoimmune cause of renal magnesium wasting. To determine if the patient's condition might be explained by autoantibodies directed against claudin-16 or claudin-19, transmembrane paracellular proteins involved in renal magnesium absorption, we conducted experiments with claudin knockout mice and transfected mouse kidney cells expressing human claudin-16 or claudin-19. We also examined effects on renal magnesium handling in rats given intravenous injections of IgG purified from sera from the patient or controls. RESULTS: Experiments with the knockout mice and in vitro transfected cells demonstrated that hypomagnesemia in the patient was causally linked to autoantibodies directed against claudin-16, which controls paracellular magnesium reabsorption in the thick ascending limb of Henle's loop. Intravenous injection of IgG purified from the patient's serum induced a marked urinary waste of magnesium in rats. Immunosuppressive treatment combining plasma exchange and rituximab was associated with improvement in the patient's GFR, but hypomagnesemia persisted. The patient was subsequently diagnosed with a renal carcinoma that expressed a high level of claudin-16 mRNA. CONCLUSIONS: Pathogenic claudin-16 autoantibodies represent a novel autoimmune cause of specific renal tubular transport disturbances and tubulointerstitial nephropathy. Screening for autoantibodies targeting claudin-16, and potentially other magnesium transporters or channels in the kidney, may be warranted in patients with acquired unexplained hypomagnesemia.

[Cystinuria]. / Cystinurie.

Cystinuria is the most common monogenic nephrolithiasis disorder. Because of its poor solubility at a typical urine pH of less than 7, cystine excretion results in recurrent urinary cystine stone formation. A high prevalence of high blood pressure and of chronic kidney disease has been reported in these patients. Alkaline hyperdiuresis remains the cornerstone of the preventive medical treatment. To reach a urine pH between 7.5 and 8 and a urine specific gravity less than or equal to 1.005 should be the goal of medical treatment. D-penicillamine and tiopronin, two cysteine-binding thiol agents, should be considered as second line treatments with frequent adverse events that should be closely monitored.

[Nephrolithiasis: From mechanisms to preventive medical treatment]. / Lithiase rénale : des mécanismes au traitement médical préventif.

Renal lithiasis is a frequent pathology (prevalence ranging from 10 to 12% in France) and a recurrent condition. It is associated with chronic kidney disease and is responsible for 2 to 3% of cases of end-stage renal disease, especially if it is associated with nephrocalcinosis and/or is part of a monogenic disease (1.6% of lithiasis in adults, including 1% of cystinuria). In order to understand the pathophysiology of the nephrolithiasis, the analysis of stones (morphological and by infrared spectrophotometry) as well as a minimal biological evaluation including crystalluria must be carried out. Calcium nephrolithiasis is the most common form (more than 80%). Its preventive medical treatment relies on simple hygienic dietetics: non-alkaline hyperdiuresis greater than 2liters/day, normalization of calcium intakes (1g/day to be distributed over the three meals), restriction of sodium intakes (6g/day) and of protein intakes (0.8-1g/kg of theoretical weight/day), and avoidance of foods rich in oxalate. If there is a hypercalciuria (greater than 0.1mmol/kg of theoretical weight/day with normal calcium intakes), its mechanism should be explored with an oral calcium load test. In the absence of primary hyperparathyroidism, thiazide diuretics can be prescribed, taking care to prevent hypokalemia and iatrogenic hypocitraturia. The treatment of uric acid lithiasis includes alkaline hyperdiuresis (urinary pH 6.2 to 6.8). Allopurinol is only justified if the urinary excretion of uric acid exceeds 4mmol/day. With a well-managed medical treatment, more than 80% of recurrent lithiasis can be stopped, making nephrolithiasis one of the kidney diseases the more accessible to the preventive medical treatment.

Adverse events associated with currently used medical treatments for cystinuria and treatment goals: results from a series of 442 patients in France.

OBJECTIVE: To evaluate medical treatments, in terms of adverse events (AEs) and therapeutic goals, in a large series of patients with cystinuria. PATIENTS AND METHODS: Data from 442 patients with cystinuria were recorded retrospectively. Crystalluria was studied in 89 patients. A mixed-effects logistic regression model was used to estimate how urine pH, specific gravity and cysteine-binding thiols (CBT) correlate with risk of cystine crystalluria. RESULTS: Alkalizing agents and CBT agents were given to 88.8% (n = 381) and 55.3% (n = 238) of patients, respectively. Gastrointestinal AEs were reported in 12.3%, 10.4% and 2.6% of patients treated with potassium bicarbonate, potassium citrate and sodium bicarbonate, respectively (P = 0.008). The percentages of patients who experienced at least one AE with tiopronin (24.6%) and with D-penicillamine (29.5%) were similar (P = 0.45). Increasing urine pH and decreasing urine specific gravity significantly reduced the risk of cystine crystalluria, whereas D-penicillamine and tiopronin treatments did not reduce this risk (odds ratio [OR] 1 for pH ≤6.5; OR 0.52 [95% confidence interval {95% CI} 0.28-0.95] for 7.0 8.0, P <0.001). CONCLUSION: Adverse events were frequent with D-penicillamine and tiopronin. Alkaline hyperdiuresis was well tolerated and reduced cystine crystalluria. Urine specific gravity ≤1.005 and urine pH >7.5, while warning about calcium-phosphate crystallization, should be the goals of medical therapy.

Extreme hypomagnesemia: characteristics of 119 consecutive inpatients.

Extreme hypomagnesemia (hypoMg) can be encountered in many situations, but little data currently exist. Our aim is to describe the epidemiological, clinical, etiological characteristics, and the biological abnormalities of consecutive inpatients with extreme hypomagnesemia. In our observational monocentric study, between 1st July 2000 and April 2015, all inpatients with extreme hypomagnesemia, defined by at least one plasma magnesium concentration (PMg) below 0.3 mmol/L, were included. Demographic, clinical, biological characteristics and the drugs prescribed before the qualifying PMg measurement were retrospectively collected. 41,069 patients had at least one PMg assessment. The prevalence of extreme hypomagnesemia is 0.3% (119 inpatients). The median age is 70 years, 52% are women. The patients were mainly hospitalized in intensive care (n = 37, 31.1%), oncology (n = 21, 17.6%), gastroenterology (n = 18, 15.1%) and internal medicine (n = 16, 13.4%) departments. One hundred patients (84%) had a medical history of gastrointestinal disease (39% with bowel resections, 24% with stoma), and 50 (42%) had a cancer history. The drugs most commonly prescribed (known to induce hypoMg) are proton pump inhibitors (PPI) (n = 77, 70%), immunosuppressive regimens (n = 25, 22.5%), platinum salt-based chemotherapies (n = 19, 17.1%), and diuretics (n = 22, 19.8%). The suspected causes of hypomagnesemia are often multiple, but drugs (46%, including PPI in 19%) and chronic gastrointestinal disorders (37%) are prominent. Associated electrolyte disturbances include hypocalcemia (77%) and mild hypokalemia (51%). The 1-month mortality from all causes is 16%. Extreme hypomagnesemia is rare in inpatients, and is frequently associated with severe hypocalcemia. Digestive disorders and drugs are the main contributory causes.

Pro-FHH: A Risk Equation to Facilitate the Diagnosis of Parathyroid-Related Hypercalcemia.

Context: Parathyroid-related hypercalcemia is due to primary hyperparathyroidism (PHPT) or to familial hypocalciuric hypercalcemia (FHH). PHPT can lead to complications that necessitate parathyroidectomy. FHH is a rare genetic disease resembling PHPT; surgery is ineffective. A reliable method for distinguishing FHH from PHPT is needed. Objective: To develop an easy-to-use tool to predict if a patient has PHPT. Design: Retrospective analysis of two prospective cohorts. Development of an unsupervised risk equation (Pro-FHH). Setting: University hospitals in Paris, France, and Aarhus, Denmark. Participants: Patients (Paris: 65 with FHH, 85 with PHPT; Aarhus: 38 with FHH, 55 with PHPT) were adults with hypercalcemia and PTH concentration within normal range. Main Outcome Measures: Performance of Pro-FHH to predict PHPT. Results: Pro-FHH takes into account plasma calcium, PTH, and serum osteocalcin concentrations, and calcium-to-creatinine clearance ratio calculated from 24-hour urine collection (24h-CCCR). In the Paris cohort, area under the receiver operating characteristic curve (AUROC) of Pro-FHH was 0.961, higher than that of 24h-CCCR. With a cutoff value of 0.928, Pro-FHH had 100% specificity and 100% positive predictive value for the diagnosis of PHPT; it correctly categorized 51 of 85 patients with PHPT; the remaining 34 were recommended to undergo genetic testing. No patients with FHH were wrongly categorized. In an independent cohort from Aarhus, AUROC of Pro-FHH was 0.951, higher than that of 24h-CCCR. Conclusion: Pro-FHH effectively predicted whether a patient has PHPT. A prospective trial is necessary to assess its usefulness in a larger population and in patients with elevated PTH concentration.

What is the significance of end-stage renal disease risk estimation in living kidney donors?

Two end-stage renal disease (ESRD) risk calculators were recently developed by Grams et al., and Ibrahim et al. to calculate ESRD risk before donation among living kidney donors. However, those calculators have never been studied among potential donors for whom donation was refused due to medical contraindications and compared to a group of donors. We compared 15-year and lifetime ESRD risk of donors and nondonors due to medical cause as estimated by those two calculators. Nondonors due to medical cause (n = 27) had a significantly higher 15-year ESRD risk compared to donors (n = 288) with both calculators (0.25 vs. 0.14, P < 0.001 for that developed by Grams et al. and 2.21 vs. 1.43, P = 0.002 for that developed by Ibrahim et al.). On the contrary, lifetime ESRD risk was not significantly different between the two groups. At both times (15 years and lifetime), we observed a significant overlap of ESRD risk between the two groups. ESRD risk calculators could be complementary to standard screening strategy but cannot be used alone to accept or decline donation.

CKD and Its Risk Factors among Patients with Cystinuria.

BACKGROUND AND OBJECTIVES: Cystinuria is an autosomal recessive disorder affecting renal cystine reabsorption; it causes 1% and 8% of stones in adults and children, respectively. This study aimed to determine epidemiologic and clinical characteristics as well as comorbidities among cystinuric patients, focusing on CKD and high BP. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective study was conducted in France, and involved 47 adult and pediatric nephrology and urology centers from April 2010 to January 2012. Data were collected from 442 cystinuric patients. RESULTS: Median age at onset of symptoms was 16.7 (minimum to maximum, 0.3-72.1) years and median diagnosis delay was 1.3 (0-45.7) years. Urinary alkalinization and cystine-binding thiol were prescribed for 88.8% and 52.2% of patients, respectively, and 81.8% had at least one urological procedure. Five patients (1.1%, n=4 men) had to be treated by dialysis at a median age of 35.0 years (11.8-70.7). Among the 314 patients aged ≥16 years, using the last available plasma creatinine, 22.5% had an eGFR≥90 ml/min per 1.73 m(2) (calculated by the Modification of Diet in Renal Disease equation), whereas 50.6%, 15.6%, 7.6%, 2.9%, and 0.6% had an eGFR of 60-89, 45-59, 30-44, 15-29, and <15, respectively. Among these 314 patients, 28.6% had high BP. In multivariate analysis, CKD was associated with age (odds ratio, 1.05 [95% confidence interval, 1.03 to 1.07]; P<0.001), hypertension (3.30 [1.54 to 7.10]; P=0.002), and severe damage of renal parenchyma defined as a past history of partial or total nephrectomy, a solitary congenital kidney, or at least one kidney with a size <10 cm in patients aged ≥16 years (4.39 [2.00 to 9.62]; P<0.001), whereas hypertension was associated with age (1.06 [1.04 to 1.08]; P<0.001), male sex (2.3 [1.3 to 4.1]; P=0.003), and an eGFR<60 ml/min per 1.73 m(2) (2.7 [1.5 to 5.1]; P=0.001). CONCLUSIONS: CKD and high BP occur frequently in patients with cystinuria and should be routinely screened.