Functional tests to guide management in an adult with loss of function of type-1 angiotensin II receptor.

BACKGROUND: Genetic loss of function of AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), or AGTR1 (type-1 angiotensin II receptor) leads to renal tubular dysgenesis (RTD). This syndrome is almost invariably lethal. Most surviving patients reach stage 5 chronic kidney disease at a young age. METHODS: Here, we report a 28-year-old male with a homozygous truncating mutation in AGTR1 (p.Arg216*), who survived the perinatal period with a mildly impaired kidney function. In contrast to classic RTD, kidney biopsy showed proximal tubules that were mostly normal. During the subsequent three decades, we observed evidence of both tubular dysfunction (hyperkalemia, metabolic acidosis, salt-wasting and a urinary concentrating defect) and glomerular dysfunction (reduced glomerular filtration rate, currently ~30 mL/min/1.73 m2, accompanied by proteinuria). To investigate the recurrent and severe hyperkalemia, we performed a patient-tailored functional test and showed that high doses of fludrocortisone induced renal potassium excretion by 155%. Furthermore, fludrocortisone lowered renal sodium excretion by 39%, which would have a mitigating effect on salt-wasting. In addition, urinary pH decreased in response to fludrocortisone. Opposite effects on urinary potassium and pH occurred with administration of amiloride, further supporting the notion that a collecting duct is present and able to react to fludrocortisone. CONCLUSIONS: This report provides living proof that even truncating loss-of-function mutations in AGTR1 are compatible with life and relatively good GFR and provides evidence for the prescription of fludrocortisone to treat hyperkalemia and salt-wasting in such patients.

A Novel Hypokalemic-Alkalotic Salt-Losing Tubulopathy in Patients with CLDN10 Mutations.

Mice lacking distal tubular expression of CLDN10, the gene encoding the tight junction protein Claudin-10, show enhanced paracellular magnesium and calcium permeability and reduced sodium permeability in the thick ascending limb (TAL), leading to a urine concentrating defect. However, the function of renal Claudin-10 in humans remains undetermined. We identified and characterized CLDN10 mutations in two patients with a hypokalemic-alkalotic salt-losing nephropathy. The first patient was diagnosed with Bartter syndrome (BS) >30 years ago. At re-evaluation, we observed hypocalciuria and hypercalcemia, suggesting Gitelman syndrome (GS). However, serum magnesium was in the upper normal to hypermagnesemic range, thiazide responsiveness was not blunted, and genetic analyses did not show mutations in genes associated with GS or BS. Whole-exome sequencing revealed compound heterozygous CLDN10 sequence variants [c.446C>G (p.Pro149Arg) and c.465-1G>A (p.Glu157_Tyr192del)]. The patient had reduced urinary concentrating ability, with a preserved aquaporin-2 response to desmopressin and an intact response to furosemide. These findings were not in line with any other known salt-losing nephropathy. Subsequently, we identified a second unrelated patient showing a similar phenotype, in whom we detected compound heterozygous CLDN10 sequence variants [c.446C>G (p.(Pro149Arg) and c.217G>A (p.Asp73Asn)]. Cell surface biotinylation and immunofluorescence experiments in cells expressing the encoded mutants showed that only one mutation caused significant differences in Claudin-10 membrane localization and tight junction strand formation, indicating that these alterations do not fully explain the phenotype. These data suggest that pathogenic CLDN10 mutations affect TAL paracellular ion transport and cause a novel tight junction disease characterized by a non-BS, non-GS autosomal recessive hypokalemic-alkalotic salt-losing phenotype.

Hepatocyte Nuclear Factor 1ß-Associated Kidney Disease: More than Renal Cysts and Diabetes.

Hepatocyte nuclear factor 1ß (HNF1ß)-associated disease is a recently recognized clinical entity with a variable multisystem phenotype. Early reports described an association between HNF1B mutations and maturity-onset diabetes of the young. These patients often presented with renal cysts and renal function decline that preceded the diabetes, hence it was initially referred to as renal cysts and diabetes syndrome. However, it is now evident that many more symptoms occur, and diabetes and renal cysts are not always present. The multisystem phenotype is probably attributable to functional promiscuity of the HNF1ß transcription factor, involved in the development of the kidney, urogenital tract, pancreas, liver, brain, and parathyroid gland. Nephrologists might diagnose HNF1ß-associated kidney disease in patients referred with a suspected diagnosis of autosomal dominant polycystic kidney disease, medullary cystic kidney disease, diabetic nephropathy, or CKD of unknown cause. Associated renal or extrarenal symptoms should alert the nephrologist to HNF1ß-associated kidney disease. A considerable proportion of these patients display hypomagnesemia, which sometimes mimics Gitelman syndrome. Other signs include early onset diabetes, gout and hyperparathyroidism, elevated liver enzymes, and congenital anomalies of the urogenital tract. Because many cases of this disease are probably undiagnosed, this review emphasizes the clinical manifestations of HNF1ß-associated disease for the nephrologist.

NaCl 3% Bolus Therapy as Emergency Treatment for Severe Hyponatremia: Comparison of 100 mL vs 250 mL.

CONTEXT: The aim of initial treatment of severe hyponatremia is to rapidly increase serum sodium to reduce the complications of cerebral edema. The optimal strategy to achieve this goal safely is still under debate. OBJECTIVE: To compare the efficacy and safety of 100 and 250 mL NaCl 3% rapid bolus therapy as initial treatment of severe hypotonic hyponatremia. METHODS: Retrospective analysis of patients admitted to a teaching hospital in The Netherlands between 2017 and 2019. The patients were 130 adults with severe hypotonic hyponatremia, defined as serum sodium ≤ 120 mmol/L. A bolus of either 100 mL (n = 63) or 250 mL (n = 67) NaCl 3% was the initial treatment. Successful treatment was defined as a rise in serum sodium ≥ 5 mmol/L within the first 4 hours after bolus therapy. Overcorrection of serum sodium was defined as an increase of more than 10 mmol/L in the first 24 hours. RESULTS: The percentage of patients with a rise in serum sodium ≥5 mmol/L within 4 hours was 32% and 52% after a bolus of 100 and 250 mL, respectively (P = .018). Overcorrection of serum sodium was observed after a median of 13 hours (range 9-17 hours) in 21% of patients in both treatment groups (P = .971). Osmotic demyelination syndrome did not occur. CONCLUSION: Initial treatment of severe hypotonic hyponatremia is more effective with a NaCl 3% bolus of 250 mL than of 100 mL and does not increase the risk of overcorrection.

Effects of sildenafil, metformin, and simvastatin on ADH-independent urine concentration in healthy volunteers.

Nephrogenic diabetes insipidus (NDI) is a rare disorder characterized by resistance of the kidney to the action of antidiuretic hormone (ADH), resulting in a decrease in the capacity of the kidney to concentrate the urine. NDI can be inherited or acquired due to, for example, chronic lithium therapy. Current treatment options are limited to attempts to lower urine output by a low-solute diet and the use of diuretics or anti-inflammatory drugs. These measures are only partially effective. Recent reports suggested that sildenafil, metformin, and simvastatin might improve ADH-independent urine concentration. If confirmed, this would provide interesting additional therapeutic options for patients with NDI. We, therefore, tested the effect of these drugs on ADH-independent urine concentrating capacity in healthy volunteers. We included 36 healthy volunteers who received sildenafil 20 mg thrice daily, metformin 500 mg thrice daily or simvastatin 40 mg once daily during 1 week. At baseline and at the end of treatment, a water loading test was performed. No significant increase in lowest urine osmolality was seen after the use of metformin or sildenafil (P = 0.66 and P = 0.09 respectively). Lowest urine osmolality increased modestly but significantly after the use of simvastatin (70 mOsm/kg to 85 mOsm/kg, P = 0.05). Our data suggest that only simvastatin has an effect on urine osmolality in healthy volunteers. Validation studies are needed and, most importantly, these drugs should be tested in patients with NDI.

Reference values of renal tubular function tests are dependent on age and kidney function.

Electrolyte disorders due to tubular disorders are rare, and knowledge about validated clinical diagnostic tools such as tubular function tests is sparse. Reference values for tubular function tests are based on studies with small sample size in young healthy volunteers. Patients with tubular disorders, however, frequently are older and can have a compromised renal function. We therefore evaluated four tubular function tests in individuals with different ages and renal function. We performed furosemide, thiazide, furosemide-fludrocortisone, and desmopressin tests in healthy individuals aged 18-50 years, healthy individuals aged more than 50 years and individuals with compromised renal function. For each tubular function test we included 10 individuals per group. The responses in young healthy individuals were in line with previously reported values in literature. The maximal increase in fractional chloride excretion after furosemide was below the lower limit of young healthy individuals in 5/10 older subjects and in 2/10 patients with compromised renal function. The maximal increase in fractional chloride excretion after thiazide was below the lower limit of young healthy individuals in 6/10 older subjects and in 7/10 patients with compromised renal function. Median maximal urine osmolality after desmopressin was 1002 mosmol/kg H2O in young healthy individuals, 820 mosmol/kg H2O in older subjects and 624 mosmol/kg H2O in patients with compromised renal function. Reference values for tubular function tests obtained in young healthy adults thus cannot simply be extrapolated to older patients or patients with compromised kidney function. Larger validation studies are needed to define true reference values in these patient categories.

Impact of fractional phosphate excretion on the relation of FGF23 with outcome in CKD patients.

BACKGROUND: Cardiovascular risk is increased in patients with chronic kidney disease (CKD). Fibroblast growth factor 23 (FGF23) has emerged as an important, independent predictor of outcome in CKD patients. High FGF23 may, however, be a reflection of renal tissue resistance to its actions, reflected by low fractional excretion of phosphate (FePi). We evaluated the modifying effect of FePi on the association between FGF23 and outcome in patients with CKD stage 3-4. METHODS: An analysis was performed in a subset of 166 adult patients of two participating centers of the MASTERPLAN trial of whom urine samples at baseline were available to calculate FePi. Outcome was defined as a composite of death, renal failure (defined as need for renal replacement therapy or doubling of serum creatinine) and cardiovascular events (myocardial infarction, cerebrovascular accident, percutaneous transluminal coronary angioplasty or coronary artery bypass graft. Patients were categorized by FGF23 and FePi. A product term was added to Cox regression and RERIs were calculated. RESULTS: Patients had a median estimated glomerular filtration rate (eGFR) of 36 ml/min/1.73 m(2) [interquartile range (IQR) 27-44], serum phosphate 1.04 mmol/l (IQR 0.92-1.20), FGF23 140 RU/ml (IQR 81-236) and FePi 0.32 (IQR 0.25-0.44). A total of 96 events occurred during 5 years of follow up. LnFGF23 was a significant, independent predictor for the composite outcome [hazard ratio (HR) 2.13, 95% confidence interval (CI) 1.53-2.95]. FePi did not modify the relation between FGF23 and outcome in these patients with CKD. CONCLUSIONS: Our study shows that FGF23 itself, but not its renal tissue resistance as reflected by FePi, is an important risk factor for clinical events in subjects with CKD stage 3-4.

Association of anti-PLA2R antibodies with outcomes after immunosuppressive therapy in idiopathic membranous nephropathy.

BACKGROUND: The optimal timing and duration of immunosuppressive therapy for idiopathic membranous nephropathy (iMN) have been debated. This study aimed to evaluate whether measuring the antibody against the phospholipase A2 receptor (PLA2R-ab) at start and end of therapy predicts long-term outcome and therefore may inform this debate. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This observational study included all consecutive high-risk patients with progressive iMN observed from 1997 to 2005 and treated with oral cyclophosphamide (CP) or mycophenolate mofetil (MMF) in combination with corticosteroids for 12 months. Patients were prospectively followed, and outcome was ascertained up to 5 years after completion of immunosuppressive therapy. Serum samples were collected before and after completion of therapy. PLA2R antibodies were determined retrospectively in stored samples using ELISA. RESULTS: In total, 48 patients (37 men) were included. The median age was 55 years (range, 34-75), and the median serum creatinine level was 1.60 mg/dl (range, 0.98-3.37 mg/dl). Twenty-two patients received MMF and 26 received CP. At baseline, PLA2R-abs were present in 34 patients (71%). Baseline characteristics and outcome did not significantly differ between patients negative or positive for PLA2R-ab. In PLA2R-ab-positive patients, treatment resulted in a rapid decrease of antibodies: median anti-PLA2R-ab, 428 U/ml (range, 41-16,260 U/ml) at baseline and 24 U/ml (range, 0-505 U/ml) after 2 months. The PLA2R-ab levels at baseline did not predict initial response, but antibody status at end of therapy predicted long-term outcome: After 5 years, 14 of 24 (58%) antibody-negative patients were in persistent remission compared with 0 of 9 (0%) antibody-positive patients (P=0.003). CONCLUSIONS: These data suggest that in PLA2R-ab-positive patients, measuring PLA2R-abs at the end of therapy predicts the subsequent course.

[A woman with a disappearing breast]. / Een vrouw met een verdwenen borst.

A 76-year-old woman presented with dyspnea. She had received breast conserving therapy for cancer in her left breast 26 years earlier. During physical examination a redness of the skin on the left side of the torso and neck, as well as disappearance of the left breast and shift of the left nipple was noted. This proved to be a metastatic recurrence of the breast cancer. Despite over 20 years of follow-up consisting of mammography, the complete shrinkage of the breast as an expression of locally recurrent disease was missed because no physical examination was performed. This underlines the importance of physical examination in addition to mammography in the follow-up of breast cancer patients.

Isolation of the left subclavian artery from the pulmonary artery in a patient with CHARGE association.

A male infant diagnosed with CHARGE association presented with respiratory insufficiency and a cardiac murmur. Diagnostic evaluation showed a right sided aortic arch with an isolation of the left subclavian artery arising from the pulmonary artery through a left patent arterial duct. This is a rare cardiac disorder not previously described in patients with CHARGE association, detected with a 3D computed tomography scan, which emphasizes the importance of a thorough cardiac screening in patients with CHARGE association.