Comparison of normocalcemic versus hypercalcemic primary hyperparathyroidism in a hypercalciuric renal stone population.

CONTEXT: Primary hyperparathyroidism (PHPT) is commonly diagnosed in the setting of hypercalcemia, whereas normocalcemic primary hyperparathyroidism (NHPT) may be misdiagnosed. OBJECTIVE: Our objective was to compare hypercalcemic hyperparathyroidism (HPHPT) versus NHPT hypercalciuric renal stone patients. DESIGN AND SETTING: We took advantage of a routine calcium load test performed in hypercalciuric renal stone patients to assess retrospectively among PHPT patients, prevalence and characteristics of NHPT and HPHPT under a calcium restricted diet. RESULTS: Among 1671 hypercalciuric patients included, 91 patients have a final diagnosis of PHPT(post load ionized calcium (iCa)>1.31 mmol/L and PTH>30 pg/ml). Prevalence of NHPT is 40% of all PHPT, however according to total serum calcium 4/35 NHPT and 7/56 HPHPT would have been misclassified in the other group. 18/35 NHPT and 40/56 HPHPT underwent parathyroidectomy. No significant characteristics related to parathyroid weight, stone composition or bone remodeling biomarkers is detected between groups. Whereas iCa is higher in HPHPT in fasting state and after calcium load, we found no difference for calcium diet, 24-hour calciuria, or calcitriol. Of notice, renal calcium excretion (FECa) post load increases by 303% in NHPT but only 176% in HPHPT (p=0.01) likely explained by a lesser PTH decrease (p=0.02). However, a strong negative association (p<0.0001) detected between pooled pre and post load iCa and PTH only in NHPT group suggests a persistent efficient PTH-CaSR control within parathyroid glands in this group. CONCLUSION: Our data show the relevance of dynamic tests to unmask NHPT in hypercalciuric renal stone patients.

Urine concentration impairment in sickle cell anemia: genuine nephrogenic diabetes insipidus or osmotic diuresis?

The urine concentration impairment responsible for hyposthenuria in sickle cell nephropathy is currently thought to be a consequence of renal medulla lesions, which lead to nephrogenic diabetes insipidus. The objective of the present study was to investigate the mechanism of hyposthenuria in patients with sickle cell anemia. We performed an observational study of patients with homozygous SS sickle cell anemia and data available on the fasting plasma antidiuretic hormone (ADH) concentration. A total of 55 patients were analyzed. The fasting plasma ADH values ranged from 1.2 to 15.4 pg/mL, and 82% of the patients had elevated ADH values and low fasting urine osmolality (<505 mosmol/kgH2O). Plasma ADH was positively associated with plasma tonicity and natremia (P < 0.001). None of the patients experienced polyuria and fasting free water clearance was negative in all cases, thus, ruling out nephrogenic diabetes insipidus. The tertile groups did not differ with regard to fasting urine osmolality, plasma renin level, mGFR, or several hemolysis biomarkers. The negative fasting free water clearance in all cases and the strong association between 24-h osmolal clearance and 24-h diuresis favors the diagnosis of osmotic diuresis due to an impaired medullary gradient, rather than lesions to collecting tubule.NEW & NOTEWORTHY The urine concentration impairment in sickle cell anemia is an osmotic diuresis related to an impaired renal medullary gradient leading to an ADH plateau effect. The fasting plasma ADH was high in the context of a basic state of close-to-maximal urine concentration probably driven by short nephrons maintaining a cortex-outer medullary gradient (about 400 milliosmoles). The patients had a low daily osmoles intake without evidence of thirst dysregulation so no one experienced polyuria.

Primary Hyperparathyroidism in Homozygous Sickle Cell Patients: A Hemolysis-Mediated Hypocalciuric Hypercalcemia Phenotype?

Primary hyperparathyroidism (pHPT) has been reported to have a higher prevalence in sickle cell disease (SCD) patients, including a high rate of recurrence following surgery. However, most patients are asymptomatic at the time of diagnosis, with surprisingly infrequent hypercalciuria, raising the issue of renal calcium handling in SCD patients. We conducted a retrospective study including (1) 64 hypercalcemic pHPT non-SCD patients; (2) 177 SCD patients, divided into two groups of 12 hypercalcemic pHPT and 165 non-pHPT; (3) eight patients with a diagnosis of familial hypocalciuric hypercalcemia (FHH). Demographic and biological parameters at the time of diagnosis were collected and compared between the different groups. Determinants of fasting fractional excretion of calcium (FeCa2+) were also analyzed in non-pHPT SCD patients. Compared to non-SCD pHPT patients, our data show a similar ionized calcium and PTH concentration, with a lower plasmatic calcitriol concentration and a lower daily urinary calcium excretion in pHPT SCD patients (p < 0.0001 in both cases). Fasting FeCa2+ is also surprisingly low in pHPT SCD patients, and thus inadequate to be considered hypercalcemia, recalling the FHH phenotype. FeCa2+ is also low in the non-pHPT SCD control group, and negatively associated with PTH and hemolytic biomarkers such as LDH and low hemoglobin. Our data suggest that the pHPT biochemical phenotype in SCD patients resembles the FHH phenotype, and the fasting FeCa2+ association with chronic hemolysis biomarkers strengthens the view of a potential pharmacological link between hemolytic by-products and calcium reabsorption, potentially through a decreased calcium-sensing receptor (CaSR) activity.