Hydrochlorothiazide and Prevention of Kidney-Stone Recurrence.

BACKGROUND: Nephrolithiasis is one of the most common conditions affecting the kidney and is characterized by a high risk of recurrence. Thiazide diuretic agents are widely used for prevention of the recurrence of kidney stones, but data regarding the efficacy of such agents as compared with placebo are limited. Furthermore, dose-response data are also limited. METHODS: In this double-blind trial, we randomly assigned patients with recurrent calcium-containing kidney stones to receive hydrochlorothiazide at a dose of 12.5 mg, 25 mg, or 50 mg once daily or placebo once daily. The main objective was to investigate the dose-response effect for the primary end point, a composite of symptomatic or radiologic recurrence of kidney stones. Radiologic recurrence was defined as the appearance of new stones on imaging or the enlargement of preexisting stones that had been observed on the baseline image. Safety was also assessed. RESULTS: In all, 416 patients underwent randomization and were followed for a median of 2.9 years. A primary end-point event occurred in 60 of 102 patients (59%) in the placebo group, in 62 of 105 patients (59%) in the 12.5-mg hydrochlorothiazide group (rate ratio vs. placebo, 1.33; 95% confidence interval [CI], 0.92 to 1.93), in 61 of 108 patients (56%) in the 25-mg group (rate ratio, 1.24; 95% CI, 0.86 to 1.79), and in 49 of 101 patients (49%) in the 50-mg group (rate ratio, 0.92; 95% CI, 0.63 to 1.36). There was no relation between the hydrochlorothiazide dose and the occurrence of a primary end-point event (P = 0.66). Hypokalemia, gout, new-onset diabetes mellitus, skin allergy, and a plasma creatinine level exceeding 150% of the baseline level were more common among patients who received hydrochlorothiazide than among those who received placebo. CONCLUSIONS: Among patients with recurrent kidney stones, the incidence of recurrence did not appear to differ substantially among patients receiving hydrochlorothiazide once daily at a dose of 12.5 mg, 25 mg, or 50 mg or placebo once daily. (Funded by the Swiss National Science Foundation and Inselspital; NOSTONE ClinicalTrials.gov number, NCT03057431.).

Dominant PAX2 mutations may cause steroid-resistant nephrotic syndrome and FSGS in children.

BACKGROUND: Heterozygous PAX2 mutations cause renal coloboma syndrome (RCS) [OMIM no. 120330]. RCS is a renal syndromic disease encompassing retinal coloboma and sensorineural hearing loss. Recently, a causative role for PAX2 was reported in adult-onset nephrotic syndrome secondary to focal segmental glomerulosclerosis (FSGS). However, the prevalence of PAX2 mutations among large cohort of children with steroid-resistant nephrotic syndrome (SRNS) and FSGS has not been systematically studied. METHODS: We employed whole-exome sequencing (WES) to identify the percentage of SRNS cases explained by monogenic mutations in known genes of SRNS/FSGS. As PAX2 mutations are not an established cause of childhood FSGS, we evaluated a cohort of 215 unrelated families with SRNS, in whom no underlying genetic etiology had been previously established. RESULTS: Using WES, we identified 3 novel causative heterozygous PAX2 mutations in 3 out of the 215 unrelated index cases studied (1.3%). All three cases were detected in individuals from families with more than one affected and compatible with an autosomal dominant mode of inheritance (3/57 familial cases studied (5.2%)). The clinical diagnosis in three out of four pediatric index patients was done during routine medical evaluation. CONCLUSIONS: Our findings demonstrate high frequency of PAX2 mutations in familial form of SRNS (5.2%) and further expand the phenotypic spectrum of PAX2 heterozygous mutations to include autosomal dominant childhood-onset FSGS. These results highlight the importance of including PAX2 in the list of genes known to cause FSGS in children.

Efficacy of standard and low dose hydrochlorothiazide in the recurrence prevention of calcium nephrolithiasis (NOSTONE trial): protocol for a randomized double-blind placebo-controlled trial.

BACKGROUND: Nephrolithiasis is a global healthcare problem with a current lifetime risk of 18.8% in men and 9.4% in women. Given the high cost of medical treatments and surgical interventions as well as the morbidity related to symptomatic stone disease, medical prophylaxis for stone recurrence is an attractive approach. Thiazide diuretics have been the cornerstone of pharmacologic metaphylaxis for more than 40 years. However, evidence for benefits and harms of thiazides in the prevention of calcium containing kidney stones in general remains unclear. In addition, the efficacy of the currently employed low dose thiazide regimens to prevent stone recurrence is not known. METHODS: The NOSTONE trial is an investigator-initiated 3-year prospective, multicenter, double-blind, placebo-controlled trial to assess the efficacy of standard and low dose hydrochlorothiazide treatment in the recurrence prevention of calcium containing kidney stones. We plan to include 416 adult (≥ 18 years) patients with recurrent (≥ 2 stone episodes in the last 10 years) calcium containing kidney stones (containing ≥50% of calcium oxalate, calcium phosphate or a mixture of both). Patients will be randomly allocated to 50 mg or 25 mg or 12.5 mg hydrochlorothiazide or placebo. The primary outcome will be incidence of stone recurrence (a composite of symptomatic or radiologic recurrence). Secondary outcomes will be individual components of the composite primary outcome, safety and tolerability of hydrochlorothiazide treatment, changes in urinary biochemistry elicited by hydrochlorothiazide treatment and impact of baseline disease severity, biochemical abnormalities and stone composition on treatment response. DISCUSSION: The NOSTONE study will provide long-sought information on the efficacy of hydrochlorothiazide in the recurrence prevention of calcium containing kidney stones. Strengths of the study include the randomized, double-blind and placebo-controlled design, the large amount of patients studied, the employment of high sensitivity and high specificity imaging and the exclusive public funding support. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03057431 . Registered on February 20 2017.

[The renal transplant patient in primary care: do´s and don´ts]. / Der nierentransplantierte Patient in der Hausarztpraxis: dos and don'ts.

The renal transplant patient in primary care: do's and don'ts Abstract. Kidney transplantation is the best therapeutic option for patients with end-stage renal disease regarding mortality, quality of life and cost efficiency. In the medium to long term patients may be seen primarily by the general nephrologist and family physician. In this article we give a rough overview about care of the adult renal transplant recipient combined with practical advice for family doctors.

Pembrolizumab-associated minimal change disease in a patient with malignant pleural mesothelioma.

BACKGROUND: Pembrolizumab is an anti- Programmed Death 1 (PD-1) antibody approved in melanoma, non-small cell lung cancer and investigated in malignant pleural mesothelioma. The most frequent immunotherapy related autoimmune reactions include dermatitis, pneumonitis, colitis, hypophysitis, uveitis, hypothyreodism, hepatitis and interstitial nephritis. CASE PRESENTATION: We describe a 62-year old patient diagnosed with malignant pleural mesothelioma who experienced ten days after the second dose of third line therapy with pembrolizumab sudden onset of generalized edema including legs and eyelids and weight gain of 15 kg resulting from nephrotic syndrome and acute renal failure. Pembrolizumab was discontinued and prednisone, diuretics and angiotensin II receptor blocker were initiated with full recovery of symptoms and renal function. Pembrolizumab-associated minimal change disease (MCD) was confirmed by electron microscopy in the renal biopsy. CONCLUSION: We are the first to describe pembrolizumab-related minimal change disease (MCD). Physicians should be aware of this side effect in patients presenting with edema and weight gain and initiate prompt renal function testing, serum albumin and urinalysis followed by steroid treatment if pembrolizumab-related MCD is suspected.

Pauciimmune Glomerulonephritis, ANCA-Vaskulitis.

Pauci-immune glomerulonephritis and ANCA associated vasculitides (AAV) are chronic autoimmune diseases with necrotizing inflammation of the small vessels, affecting several organ systems with a variety of symptoms, in rarer cases isolated renal manifestation without extrarenal vasculitis. The term "pauci-immune" defines the characteristic absence of immune complexes in the tissues. Circulating antineutrophil cytoplasmic antibodies (ANCA) are of pathogenic and diagnostic relevance. The typical renal manifestation is rapidly progressive glomerulonephritis, progressing to dialysis within weeks without treatment. To prevent diagnostic delay practitioners should measure ANCA promptly in case of acute kidney injury with hematuria. Current immunosuppressive regimens have impressively improved patient and kidney survival, but are far away from being optimal due to a high rate of adverse events and relapses.

A pulmonary mass caused by Rhodococcus equi infection in a renal transplant recipient.

BACKGROUND: A 62-year-old male kidney transplant recipient was admitted to hospital with a 14-day history of fever, hemoptysis and left-sided pleuritic chest pain. He had suffered malaise, weight loss, night sweats and exertional dyspnea over the previous 3 months. Imaging studies of the patient's chest revealed a noncavitated mass measuring 5 x 8 cm in the anterior segment of the left upper lobe of the lung and a left-sided pleural effusion with septa, and bacterial cultures revealed the presence of Rhodococcus equi. INVESTIGATIONS: Physical examination, laboratory tests, chest X-ray, CT scan of the chest, bronchoscopy, and bacterial culture of blood, sputum, bronchoalveolar lavage fluid and pleural fluid. DIAGNOSIS: R. equi infection with bacteremic pleuropneumonia and pseudotumor. A secondary myopathy occurred 6 months after diagnosis of the infection as a result of a drug interaction between clarithromycin and simvastatin. MANAGEMENT: Long-term combination antibiotic therapy (ciprofloxacin plus vancomycin or clarithromycin), resection of the inflammatory pseudotumor, and reduction of immunosuppressive therapy. Following the diagnosis of myopathy, simvastatin was discontinued.