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.

How useful is an oral calcium load test for diagnosing recurrent calcium stone formers?

Hypercalciuria is the main risk factor for recurrent calcium urolithiasis. The goal of our study is to determinate how useful an oral calcium load test is for stone formers to classify different forms of hypercalciuria in pathogenetic categories defined as renal or absorptive according to the current knowledge. Between June 2013 and February 2016, a prospective study was carried out on 117 documented recurrent hypercalciuric stone formers undergoing an oral calcium load test modified from the original description by Pak. After 2 days of calcium-restricted diet, urine and blood were analyzed at baseline and 120 min after receiving orally 1 g of calcium. Total and ionized calcium, parathyroid hormone from serum and urine calcium and creatinine were assessed in order to divide patients in three groups as previously described: resorptive, absorptive, and renal hypercalciuria. This allowed the identification of 19, 39, 34 and 33 patients with normocalcemic primary hyperparathyroidism (NPHPT), renal hypercalciuria aka renal calcium leak (RCL), absorptive hypercalciuria (AH) and unidentified cause, respectively. Patients with NPHPT (who required parathyroidectomy) experienced a lower PTH decrease (41.41 ± 12.82 vs. 54.06 ± 13.84% p < 0.01), higher beta-crosslaps, as well as lower TmP/GFR and distal third radius bone mineral density. RCL resulted in increased fasting urine calcium-to-creatinine ratio (Uca/Cr), i.e., > 0.37 mmol/mmol), without hyperparathyroidism. AH was diagnosed by the presence of ΔUCa/Cr > 0.60 mmol/mmol between baseline and 120 min without any other anomaly. For all remaining patients, results were inconclusive due to the lack of sufficient increase in serum calcium or because the cause of lithogenesis could not be clearly identified. The oral calcium load test is useful in nearly 80% of patients by identifying the different forms of hypercalciuria causing urolithiasis and by guiding treatment, including parathyroid surgery.

How the diagnosis and the management of genetic renal phosphate leak impact the life of kidney stone formers?

Genetic renal phosphate leak is one of the rare disorders in recurrent stone formers with absorptive hypercalciuria. Diagnosis and appropriate management may change the life of patients. To provide answers on how and when to make the diagnosis of genetic renal phosphate leak and how medical management prevents the recurrences and changes patients' life, we conducted a retrospective study including nine patients with recurrent nephrolithiasis and a confirmed genetic mutation of a phosphate transporter between 2008 and 2019 in our multidisciplinary center at the Pitié Salpetriere Hospital, Paris, France. We compared the number and the annual rate of urological intervention before and after the diagnosis and management using the Wilcoxon test. A qualitative survey was done to evaluate the quality of life of patients. A total of 9 patients were included in this study. Patient baseline characteristics and elements supporting the diagnosis are described. We showed an effective decrease in urological intervention number (p = 0.0078) and annual rate (p = 0.0117) after the diagnosis and the appropriate management, and an improvement in the patients' quality of life. The diagnosis and the appropriate management of genetic renal phosphate leak disorder improve the quality of life by preventing stone recurrence and decreasing the number of surgical intervention.

Long-term health-related quality of life outcomes of adults with pediatric onset of frequently relapsing or steroid-dependent nephrotic syndrome.

BACKGROUND: Long-term psychosocial outcomes and health-related quality of life (HRQOL) in adults with pediatric onset of frequently relapsing or steroid-dependent idiopathic nephrotic syndrome (FRNS or SDNS) remain to be determined. METHODS: In this prospective cohort study, 59 adults with pediatric onset of FRNS/SDNS and persistent active glomerular disease in adulthood completed the GEDEPAC-2 questionnaire exploring 11 well-being domains. Data were compared to the French general population (FGP) with standardized incidence ratio ([SIR]; adjusted for period, age, gender). Regression models were performed to identify predictive factors of psychosocial well-being. RESULTS: In 82% of cases, the questionnaire was completed while the participants (n = 59; 47 men; median age = 32 years; median number of relapses = 13) were in complete remission (under specific therapy in 76% of cases). Participants had higher educational degree than in the FGP (SIR = 6.3; p < 0.01) and more frequently a managerial occupation (SIR = 3.1; p < 0.01). Social integration was acceptable with regard to marital status and experience of sexual intercourse, but experiences of discrimination were far more frequent (SIR = 12.5; p < 0.01). The SF-12 mental component summary (MCS) score was altered (Z-score = - 0.6; p < 0.01) and mean multidimensional fatigue inventory (MFI-20) global fatigue score appeared high (12). Transfer from pediatric to adult healthcare was followed by a period of discontinued care for 33% of participants. Multivariate analysis revealed a close relationship between MFI-20, physical health, and MCS. CONCLUSIONS: This study shows that pediatric onset FRNS and SDNS may have a long-term negative impact on mental HRQOL and highlights the impact of fatigue, which is often not adequately considered in routine care.

Ciclosporin A in bilateral auto-immune chronic posterior uveitis associated with macular oedema: a Long-term Observational Safety and Efficacy Study.

OBJECTIVE: A non-interventional, longitudinal, retrospective follow-up study to assess CsA-induced nephrotoxicity (IN) and its reversibility after withdrawal in patients exhibiting a bilateral chronic posterior uveitis (CPU) associated with cystoid macular oedema (CMO) in at least one eye. Data from medical records between 1986 and 2013. METHODS: Primary outcome was the renal tolerance during and after CsA treatment assessed by plasma creatinine concentration and glomerular filtration rate (GFR) estimated by Chronic Kidney Disease Epidemiology (CKD-Epi) formula. Secondary outcomes were CsA through concentration, occurrence of cancers and ophthalmologic efficacy assessed by three parameters including CMO, vitreous inflammation, and best-corrected visual acuity BVCA changes. RESULTS: One hundred forty-three patients were followed for renal tolerance. Underlying diseases were Birdshot retinochoroiditis (n = 67), Behçet disease (n = 9), probable sarcoidosis (n = 23), sympathetic ophthalmia (n = 3), idiopathic (n = 41). After CsA discontinuation in 115 patients (mean treatment duration of 5.9 ± 3.8 years) mean plasma creatinine concentration was 82.2 ± 14.2 µmol/L versus 82.1 ± 14.1 µmol/L at baseline, mean GFR was 79.4 ± 13.9 mL/min versus 82.5 ± 14.3 mL/min at baseline, with no significant difference (respectively p = 0.91 and p = 0.09). Blood pressure did not significantly change during follow-up. CMO was completely resorbed in at least one eye, in 70.8% patients (n = 72) at 6 months, in 71.4% patients (n = 49) at 10 years and in 54.2% patients (n = 24) at 20 years. BCVA did not statistically change over time. CONCLUSION: Early and long-term monitoring of renal tolerance and dual adjustment of CsA doses in inflammatory stages of CPU were associated with reversible CsA IN. CsA could be effective in the treatment of CMO in CPU patients.

[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.

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.

Clinical and molecular characterization of cystinuria in a French cohort: relevance of assessing large-scale rearrangements and splicing variants.

BACKGROUND: Cystinuria is an autosomal recessive disorder of dibasic amino acid transport in the kidney and the intestine leading to increased urinary cystine excretion and nephrolithiasis. Two genes, SLC3A1 and SLC7A9, coding respectively for rBAT and b0,+AT, account for the genetic basis of cystinuria. METHODS: This study reports the clinical and molecular characterization of a French cohort including 112 cystinuria patients and 25 relatives from 99 families. Molecular screening was performed using sequencing and Quantitative Multiplex PCR of Short Fluorescent Fragments analyses. Functional minigene-based assays have been used to characterize splicing variants. RESULTS: Eighty-eight pathogenic nucleotide changes were identified in SLC3A1 (63) and SLC7A9 (25) genes, of which 42 were novel. Interestingly, 17% (15/88) and 11% (10/88) of the total number of variants correspond, respectively, to large-scale rearrangements and splicing mutations. Functional minigene-based assays were performed for six variants located outside the most conserved sequences of the splice sites; three variants affect splice sites, while three others modify exonic splicing regulatory elements (ESR), in good agreement with a new in silico prediction based on ΔtESRseq values. CONCLUSION: This report expands the spectrum of SLC3A1 and SLC7A9 variants and supports that digenic inheritance is unlikely. Furthermore, it highlights the relevance of assessing large-scale rearrangements and splicing mutations to fully characterize cystinuria patients at the molecular level.

Prevalence of alternative diagnoses in patients with suspected uncomplicated renal colic undergoing computed tomography: a prospective study.

OBJECTIVES: Unenhanced computed tomography (CT) has become a standard imaging technique for uncomplicated renal colic in many countries. The appropriate timing of CT imaging has not been established, and guidelines recommend that this imaging be performed between 1 and 7 days of presentation. The primary objective of this study was to determine the prevalence of alternative diagnosis identified with low-dose unenhanced CT in the emergency department (ED) in patients with suspected uncomplicated renal colic. METHODS: This prospective single-centre study was carried out in a large university hospital ED. Over a 6-month period, all patients with clinically diagnosed renal colic and a plan to be discharged underwent low-dose unenhanced CT in the ED. Pregnant women, women of childbearing age not willing to have a pregnancy test, and patients who had already undergone diagnostic imaging were excluded. The primary outcome was the number and nature of the alternative diagnosis. Univariate analyses were performed to assess factors associated with the primary outcome. RESULTS: A total of 178 patients were screened, and 155 underwent CT in the ED. The mean age was 42.2 years; 69% were male. The diagnosis of uncomplicated renal colic was confirmed in 118 participants (76%); 27 (17%) had an inconclusive CT scan. Overall, 10 patients (6%; 95% confidence interval [CI] 3-10) had an alternative diagnosis, 5 of whom were subsequently hospitalized. CONCLUSION: Low-dose unenhanced CT in the ED detects alternative diagnoses in 6% (95% CI 3-10) of patients with suspected uncomplicated renal colic, half of whom are subsequently hospitalized. Our prospective findings, which were similar to those reported in retrospective studies, are a potential argument for a systematic approach to ED imaging in suspected renal colic. Future research involving intervention and control groups would be helpful.

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.

[Urinary stone management at the time of its discovery]. / Conduite a tenir lors de la découverte d'un calcul urinaire.

Circumstances of diagnosis of urinary stones vary. Medical management is performed either in emergency for acute or serious symptoms, or delayed. Renal colic is the most typical clinical form. The emergency analgesic treatment is well established. After sedation of the pain, radiological study (plain film and ultrasound of the abdomen) may be supplemented by abdominal computerized tomography which is the best exam for the diagnosis of urinary stone and its impact. In complicated cases urological drainage is performed in emergency. If needed the urological treatment of the urinary stone is performed secondarily according to the French recommendations. A metabolic evaluation and dietary survey are required for each patient to identify and avoid the risk of recurrence. Some stone formers or complex patients must be followed in nephrology.

[Kidney diseases in HIV-infected patients]. / Néphropathies rencontrées au cours de l'infection par le virus de l'immunodéficience humaine (VIH).

HIV infection has become a global disease, both in geographic terms, since it has spread worldwide, and at the individual level since it affects every organ of the human body. Antiretroviral treatments, in countries where they are easily available, have modified HIV infection into a systemic chronic disease, the life expectancy of which is yet to be determined precisely. Treatments have dramatically changed the pattern of the disease and clinicians now have to face a number of new challenges. Kidneys, like all the other organs, can be involved in a great number of diseases in HIV-infected patients. We have voluntarily chosen to present "kidney diseases in HIV-infected patients" in their wider meaning, with a discussion of renal diseases that are directly caused by the virus, nephropathies due to frequent viral co-infections in HIV-infected patients such as HCV and HBV, nephropathies induced by anti-HIV, HBV and HCV therapies. Physicians in charge of HIV-infected patients should be aware of the key role they have to play in the screening for kidney abnormalities. This participates not only in improving patients' kidney prognosis but also their long-term general outcome. Renal screening strategies must refer to simple routine laboratory tests. Enclosed at the end of this article are a few suggestions for the renal management of situations that frequently occur in HIV infected patients (kidney dysfunction screening, serum creatinine increase and discovery of a proteinuria).

[New ethical issues around dialysis. To dialyze or not to dialyze, that is not the question]. / Nouveaux enjeux éthiques autour de la dialyse. Dialyser ou non, telle n'est pas la question essentielle.

Although a physician's first ethical duty is to master the relevant techniques, it is not enough for kidney specialists to know the major principles of dialysis and apply them to all patients with kidney failure. Historically a truly ethical promise, dialysis revolutionized the management of chronic kidney disease by sparing life for the time needed to wait for renal transplantation. Constrained by a supply considerably lower than demand, the nephrologists of that time selected patients, treating only the young and relatively healthy. These decisions were probably made jointly with others. Ethical reflections about patient selection at that time thus took place in a different setting, where the supply of dialysis was limited. Today, in a different context, dialysis has not always kept its ethical promises. It is widely available, and its practical contraindications are rare. Nonetheless, we can sometimes doubt its pertinence, as the population on chronic dialysis becomes increasingly elderly and increasingly ill, with comorbidities that contraindicate transplantation. Might dialysis become harmful? Used ill-advisedly, it can hinder the quality of life. There are increasingly more situations in which we may doubt its salutary effects and conclude that it is not always adequate to fulfill the real objective of medicine: providing care, without necessarily curing. We must avoid ethical blindness about this technique. Let us use it well by looking for different types of use for it. To dialyze or not to dialyze, that is not the question. What matters is our mission of care - beyond the quantity of life we must improve its quality, especially at its end. To succeed in providing this care is not to know to how begin, limit, space out or shorten sessions. It requires instead that professionals working in nephrology be trained in palliative care for it is their job to provide care to the very end to these very sick patients, outside of palliative care units, which do not seem to have been created for them or adapted to their needs.

Antiretroviral drug dosing errors in HIV-infected patients undergoing hemodialysis.

BACKGROUND: Several studies have revealed the frequency of antiretroviral (ARV) drug prescription errors. We analyzed highly active antiretroviral therapy (HAART) prescribing practices for human immunodeficiency virus (HIV)-infected patients undergoing hemodialysis in France. METHODS: Prescribed ARV drug doses in our cohort (consisting of all HIV-infected patients who underwent hemodialysis from 1 January 2002 and were prospectively followed up until 1 January 2004) were compared with the recommended doses for patients undergoing hemodialysis. The log-rank test was used to compare the outcomes among different groups of treated patients. RESULTS: One hundred seven of the 129 patients in our cohort received a total of 317 ARV drugs, 59% of which were improperly prescribed. The dosing was too low for 18% of the patients and too high for 39% of the patients. Twenty-eight patients (26%) did not receive any of their ARV drugs at the recommended dose. The lowest prescribed dose (8% of the daily recommended dose) was observed with indinavir and zidovudine, and the highest prescribed dose (1000% of the recommended dose) was observed with stavudine. Among patients who received HAART, those who were prescribed an insufficient dose of a protease inhibitor had more-severe HIV disease and worse 2-year survival than did the other patients (mean rate of survival+/-standard deviation, 79.5%+/-7.5% vs. 95.4%+/-2.6%, respectively; P<.02). For dialyzable ARV drugs, the delay between ARV drug receipt by the patients and dialysis sessions was not respected in 9% of cases, and in 73% of cases, it was not known whether the patients took the ARV drugs before or after dialysis sessions. CONCLUSION: This is, to our knowledge, the first study to show a significant association between ARV drug prescription errors and survival in patients undergoing dialysis.

Renal outcome after ciclosporin-induced nephrotoxicity.

BACKGROUND: Renal outcome after ciclosporin (CsA) is not clear in most studies involving patients with many renal comorbid conditions. We first report on renal function recovery after CsA in previously healthy kidney patients. METHODS: Uveitis patients, enroled in a unique single centre cohort follow-up study initiated in 1987, were prospectively evaluated for plasma creatinine and glomerular filtration rate (GFR) before, during (>2 years) and after (>6 months) CsA therapy. We hypothesized that CsA alters renal function progressively over time according to two additive exponential components (irreversible and reversible) and used a mixed linear model with exponential speed parameters maximizing the likelihood. RESULTS: Twenty-seven patients treated for 60+/-34 months (CsA 5.1+/-2.5 mg/kg/day) were followed up for 56+/-42 months after CsA withdrawal. Baseline creatinine was 0.92+/-0.15 mg/dl. The reversible effect of CsA was quantified as a 0.11+/-0.07 mg/dl increase in creatinine/100 mg CsA/day (P<0.001) and a 6.0+/-3.7 ml/min/1.73 m(2) decrease in GFR/100 mg CsA/day (P<0.0001). The irreversible effect was quantified as a 0.03+/-0.05 mg/dl increase in creatinine/100 g cumulative CsA received (P<0.007) and a decrease of 3.3+/-3.9 ml/min/1.73 m(2) GFR/100 g CsA. CONCLUSIONS: Although significant decrease in GFR is induced by low-dose CsA therapy in previously healthy kidney patients, renal function recovery is possible after CsA withdrawal and best predicted by CsA daily dosage. Irreversible loss in GFR is correlated to cumulated CsA exposure. The lowest CsA dosage and shortest exposure time effect as well as unlimited renal monitoring are required in order to provide the best long-term renal outcome.

Outcome and prognosis factors in HIV-infected hemodialysis patients.

HIV-infected patients who are on hemodialysis have a worse prognosis than noninfected patients who are on hemodialysis. Their outcome in the highly active antiretroviral therapy (HAART) era remains unclear. Outcomes in patients who were enrolled in the French Dialysis in HIV/AIDS (DIVA) cohort were determined in a 2-yr prospective follow-up. All HIV-infected patients who were on hemodialysis in France on January 1, 2002, were included and followed prospectively until January 1, 2004. Patients' survival was examined by Kaplan-Meier method, and mortality risk factors were examined using uni- and multicovariate analyses. Survival was compared with that of 584 hemodialysis patients who did not have HIV or diabetes and were enrolled in the French Dialysis Outcomes and Practice Patterns Study II (DOPPS II) in the same period (after standardization for the average age, gender, and ethnicity of the DIVA cohort). A total of 27,577 patients were receiving hemodialysis in France at the beginning of the study; 164 (0.59%) were infected with HIV, 72% were male, mean age was 44.8 +/- 10.9 yr, and 65% were black. The 2-yr survival rate was 89 +/- 2% and statistically indistinguishable from the survival of the French cohort extracted from the DOPPS II study. Significant mortality risk factors were low CD4 cell count (hazard ratio [HR] 1.4/100 CD4 cells per mm(3) lower), high viral load (HR 2.5/1 Log per ml), absence of HAART (HR 2.7), and a history of opportunistic infection (HR 3.7), the last two being independent (HR 2.6 and 3.6, respectively). Survival of HIV-infected patients who are hemodialysis has greatly improved. A prospective cohort of paired hemodialysis patients with and without HIV is required to compare better their mortality in the HAART era.