Improvement of secondary hyperparathyroidism and reduction of the set point of calcium after intravenous calcitriol.

In this study we evaluated the effect of intravenous calcitriol on parathyroid function and ionized calcium/PTH sigmoidal curve obtained during low and high calcium hemodialysis in 10 patients with osteitis fibrosa whose secondary hyperparathyroidism was refractory to conventional therapy. After four months of intravenous calcitriol, serum ionized calcium increased from 1.28 +/- 0.08 to 1.37 +/- 0.11 mmol/liter (P < 0.001), serum phosphate from 1.54 +/- 0.18 to 1.79 +/- 0.4 mmol/liter (P = NS), serum calcitriol from 16.7 +/- 9.9 to 34.3 +/- 6.4 pg/ml (P < 0.001), while alkaline phosphatase decreased from 366 +/- 340 to 226 +/- 180 IU/liter (P < 0.05), osteocalcin from 46.4 +/- 20 to 34.5 +/- 15.3 ng/ml (P < 0.05) and basal intact PTH from 1069 +/- 700 to 305 +/- 270 (P < 0.01). Basal PTH started to decrease after one month of treatment prior to the increase in the ionized calcium. Because of hypercalcemia, the dialysate calcium was decreased from 1.75 to 1.5 mmol/liter in three of five patients on hemodialysis and calcium-containing solutions were substituted by calcium-free replacement fluids in four of five patients on hemodiafiltration. Calcitriol dose at the first month of therapy was 5.6 +/- 0.8 micrograms/week, but successively it was decreased because of hypercalcemia to a final dose of 3.6 +/- 1.3 micrograms/week. After intravenous calcitriol the ionized calcium/PTH sigmoidal curve shifted to the left and downward. Maximally stimulated PTH and maximally inhibited PTH obtained during low and high calcium dialysis significantly decreased as did the ratio of basal PTH/PTHmax and the set point of calcium.(ABSTRACT TRUNCATED AT 250 WORDS)

[Acute renal failure and thrombotic microangiopathy (TM)]. / Insufficienza renale acuta e microangiopatia trombotica.

BACKGROUND: Thrombotic microangiopathy (TM) is a disorder characterized by fibrin formation and platelet aggregation in the small arteries and capillaries. Two main clinical settings are reported in association with this disorder: hemolitic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Both conditions share common findings such as microangiopathic anemia and thrombocytopenia. HUS is more frequent in children and is mainly characterized by renal symptoms, whereas PTT is dominated by neurologic abnormalities. However, in many patients, the clinical distinction between HUS and PTT is not clear; therefore, some authors consider the two syndromes as manifestations of the same entity. In children, the most common cause of HUS is an enteric infection caused by cytotoxin-producing bacteria (mainly Escherichia coli with serotype O157:H7). This toxin--the Shiga toxin--can bind to glomerular endothelial cells and stimulate the production of cytokines and the secretion of von Willebrand factor (vWf). TM may be caused by drugs such as cyclosporin, tacrolimus, mytomicin C, ticlopidine, quinine, and oral contraceptives. It may be associated with disorders of pregnancy (severe pre-eclampsia and postpartum HUS) or with systemic disorders such as systemic lupus erythematosus (SLE), antiphospholipid syndrome, systemic sclerosis, and human immunodeficiency virus (HIV) infection. Abnormalities of the gene of complement factor H have been found in familial HUS and in some sporadic cases of HUS not associated with diarrhea. Factor H abnormalities induce an uncontrolled complement activation that can activate the coagulation cascade. In familial PTT, genetic abnormalities of the cleaving metalloproteinase of fWf ADAMTS 13 have been identified. In other patients with TTP, antibodies inhibiting this enzyme have been found. As a consequence of plasma ADAMTS 13 deficiency, unusually large vWf multimers are produced. This abnormality, in the presence of an increased shear stress, stimulates platelet adhesion and aggregation. CONCLUSIONS: Knowledge of the type of causative abnormality is relevant to a therapeutic approach. Children with diarrheal HUS usually do not benefit from plasma infusion or exchange, whereas in patients with factor H or ADAMTS 13 deficiency procedures that include the administration of the lacking product and removal of the inhibiting or toxic factors, such as ultralarge vWfs, are mandatory. Potentially renal transplantation candidates should be screened for genetic defects to avoid the recurrence of TM in the graft.

Effect of chronic intravenous calcitriol on parathyroid function and set point of calcium in dialysis patients with refractory secondary hyperparathyroidism.

This study evaluates the effect of intravenous calcitriol on parathyroid function and ionized calcium-PTH sigmoidal curve obtained during low- and high-calcium haemodialysis in 10 patients with osteitis fibrosa whose secondary hyperparathyroidism was refractory to conventional therapy. After 4 months of intravenous calcitriol, serum ionized calcium increased from 1.28 +/- 0.08 to 1.37 +/- 0.11 mmol/l (P less than 0.001), serum phosphate from 1.54 +/- 0.18 to 1.79 +/- 0.4 mmol/l (P NS), serum calcitriol from 16.7 +/- 9.9 to 34.3 +/- 6.4 pg/ml (P less than 0.001), while alkaline phosphatase decreased from 366 +/- 340 to 226 +/- 180 IU/l (P less than 0.05), osteocalcin from 46.4 +/- 20 to 34.5 +/- 15.3 ng/ml (P less than 0.05), and basal intact PTH from 1069 +/- 700 to 305 +/- 270 (P less than 0.01). Basal PTH started to decrease after 1 month of treatment prior to the increase in the ionized calcium. Because of hypercalcaemia the dialysate calcium was decreased from 1.75 to 1.5 mmol/l in three of five patients on haemodialysis, and calcium-containing solutions were replaced by calcium-free fluids in four of five patients on haemodiafiltration. Calcitriol dose, at the first month of therapy was 5.6 +/- 0.8 micrograms/week, but it was successively decreased because of hypercalcaemia to a final dose of 3.6 +/- 1.3 micrograms/week. After intravenous calcitriol the ionized calcium-PTH sigmoidal curve shifted to the left and downward. Maximally stimulated PTH and maximally inhibited PTH obtained during low- and high-calcium dialysis significantly decreased, as well as the ratio of basal PTH/PTHmax and the set point of calcium.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term effects of intravenous calcitriol therapy on the control of secondary hyperparathyroidism.

Although high-dose intravenous calcitriol has been shown to be effective in suppressing parathyroid hormone (PTH) secretion in dialysis patients with secondary hyperparathyroidism, an increasing number of patients is refractory to treatment. Only a few studies have evaluated the factors that can predict a favorable response to calcitriol, but contrasting results have been reported. This study was performed to evaluate the effect of high-dose intravenous calcitriol on parathyroid function and to investigate the factors that can predict a favorable response to treatment. Thirty-five dialysis patients were selected for intravenous calcitriol treatment (2 microg after dialysis for 12 months) because of increased PTH levels (>325 pg/mL). Before starting the treatment, the set point of calcium and the PTH-ionized calcium (ICa) curve was evaluated in each patient by inducing hypocalcemia and, 1 week later, hypercalcemia to maximally stimulate or inhibit PTH secretion. Parathyroid glands were assessed by high-resolution color Doppler ultrasonography. Throughout the study, calcium carbonate or acetate dosage was modified to maintain serum phosphate less than 5.5 mg/dL. Hypercalcemia was managed by reducing dialysate calcium to 5 mg/dL and, if necessary, calcitriol dose. The therapeutic goal was to reduce PTH levels below 260 pg/mL while maintaining normocalcemia. The patients who achieved the therapeutic goal were considered responders. Taking the data from the 35 patients together, we observed a significant decrease (P < 0.01) in alkaline phosphatase (from 252 +/- 106 IU/L to 194 +/- 81 IU/L) and PTH (from 578 +/- 231 pg/mL to 408 +/- 291 pg/mL), and a significant increase in serum ICa (from 5.1 +/- 0.2 mg/dL to 5.3 +/- 0.2 mg/dL; P < 0.001) after calcitriol therapy. PTH changes after therapy were not correlated to serum ICa changes, serum phosphate levels during treatment, and calcitriol dose. The response to therapy was heterogeneous because PTH levels markedly decreased over the treatment period in 18 responsive patients, whereas they increased or remained unchanged in 14 of 17 nonresponders. In three additional refractory patients, there was a decline in PTH of 20% to 35%, but this decline was associated with hypercalcemia. Pretreatment parathyroid gland size, serum ICa, PTH, maximal PTH induced by hypocalcemia, minimal PTH induced by hypercalcemia, the set point of ICa, and the ICa levels at which maximal PTH secretion and inhibition occurred were higher in the 17 refractory patients than in the 18 responsive patients. However, logistic regression analysis showed that among these parathyroid function parameters, the only significant predictors of a favorable response to calcitriol therapy were the parathyroid gland size and the set point of ICa. Throughout the study, serum phosphate and calcitriol dose were comparable in the two groups. In conclusion, the response to intravenous calcitriol therapy in dialysis patients with secondary hyperparathyroidism is heterogeneous, consisting of patients who are either responsive or refractory to treatment; refractoriness can be predicted by parathyroid volume and calcium set point.

Different effects of calcitriol and parathyroidectomy on the PTH-calcium curve in dialysis patients with severe hyperparathyroidism.

BACKGROUND: The PTH-calcium sigmoidal curve is shifted to the right, the slope of the curve is steeper, and the set point of calcium is increased in dialysis patients with secondary hyperparathyroidism, compared to patients with low-turnover bone disease. These findings could be related to increased parathyroid cell mass and increased sensitivity of parathyroid cells to serum calcium variations in these patients. Calcitriol therapy has been documented to reduce PTH levels by shifting the curve to the left and downward. The effect of a surgical reduction of parathyroid gland mass on the PTH-calcium curve has not yet been investigated. In this study we compared the effects of calcitriol and subtotal parathyroidectomy (PTH) on the dynamics of PTH secretion in response to acute changes of serum calcium in two groups of dialysis patients with severe hyperparathyroidism. METHODS: Fourteen dialysis patients treated for 6 months with high-dose i.v. calcitriol (1-2 micrograms thrice weekly, and 10 dialysis patients who underwent subtotal PTx were studied. The PTH-calcium relationship obtained by inducing hypo- and hypercalcaemia means of low and high calcium dialysis was evaluated before and 2-6 months after treatment. RESULTS: Both calcitriol and subtotal PTx significantly decreased PTH (respectively from 797 +/- 595 to 380 +/- 244 and from 1036 +/- 250 to 70 +/- 34 pg/ml), as well as maximal PTH response to hypocalcaemia (PTHmax), and maximal PTH suppression during hypercalcaemia ( PTHmin). When the PTH-calcium curves were constructed using PTHmax as 100% to factor for differences in absolute PTH levels and to provide an assessment of individual parathyroid cell function, a shift of the sigmoidal curve to the left and downward, and a significant decrease in the set point of ionized calcium (from 1.31 +/- 0.05 to 1.26 +/- 0.05 and from 1.36 +/- 0.09 to 1.22 +/- 0.07 mmol/l) was documented with both treatments. However, the slope of the PTH-calcium curve increased after subtotal PTx indicating that the sensitivity of the parathyroid cell to serum calcium changes increased with PTx, while on the contrary it decreased with calcitriol. CONCLUSIONS: PTH secretion decreases proportionally more with calcitriol than with surgery for a given decrease in the functional mass of parathyroid cells. The change in the PTH-ICa sigmoidal curve induced by subtotal PTx is due to the removal of a large mass of parathyroid tissue with advanced hyperplasia.

Glomerular disease and pregnancy. A study of 123 pregnancies in patients with primary and secondary glomerular diseases.

The clinical course of 123 pregnancies in 86 patients with biopsy-proven glomerular diseases have been studied. In 35 women the onset of nephropathy occurred during pregnancy. No complications were observed in more than half of the pregnancies. In the others, one third of the complications were obstetrical or fetal accidents, one third were renal manifestations (hypertension or deterioration of renal function) and one third were both causes. The lowest incidence of complications was observed in patients with membranous nephropathy and the highest in membranoproliferative glomerulonephritis patients. There were 6 spontaneous late abortion, 6 stillbirths and 5 neonatal deaths. 17 deliveries were preterm and 7 fetuses were small for gestational age. Hypertension appeared in 24 pregnancies, in 13 of which it was reversible and related to superimposed preeclampsia and in 11 it persisted after delivery (5 of these 11 pregnancies were in patients with IgA nephropathy). Renal function deteriorated in 10 cases during pregnancy. The deterioration was reversible in 6 and progressive in 4 (2 of whom had membranoproliferative glomerulonephritis). It is suggested that in most patients pregnancy does not change the natural history of glomerular disease.

Small frameshift deletions within the COL4A5 gene in juvenile-onset Alport syndrome.

Small frameshift deletions within the COL4A5 gene were identified in three Alport syndrome Italian families by non-isotopic single-strand conformation polymorphism (SSCP) screening: in family RMA, a 7-bp deletion (GGGTGAA) in exon 39; in family DGR, a 4-bp deletion (TGGA) in exon 41; in family MIB, deletion of a G in exon 50. The phenotype was characterized by juvenile-onset renal failure with sensorineural hearing loss in males, and a milder clinical pattern in heterozygous females.

Relationship between sodium intake, proximal tubular function and calcium excretion in normal subjects and in idiopathic hypercalciuria.

Proximal tubular function was studied with maximal water clearance studies in 15 controls (C), 22 Ca stone formers with idiopathic hypercalciuria (IH) and 10 normocalciuric Ca stone formers (NC). Distal delivery of glomerular filtrate (ClDD) and Na excretion were higher in IH and NC than in C; NaCl loading (6 g/day) for seven days in C increased Na excretion and ClDD to similar levels as in IH and NC; the distribution of ClDD for any level of Na excretion was similar in C, NC and IH. NaCl loading in C slightly reduced renal phosphate threshold, which still remained higher than in IH on a free diet. It appears that reduced tubular reabsorption of glomerular filtrate in Ca stone formers is related to habitual high Na intake and is not peculiar to hypercalciuric patients. Habitual high Na intake is unlikely to be responsible for all the metabolic spectrum of idiopathic hypercalciuria.

Lupus nephropathy and pregnancy. A study of 26 pregnancies in patients with systemic lupus erythematosus and nephritis.

We describe 26 pregnancies in 19 patients with lupus nephritis. There were 4 spontaneous abortions, 2 therapeutic abortions, 4 stillbirths and 1 neonatal death. 10 deliveries were preterm and 2 fetuses were small for gestational age. 8 pregnancies were not accompanied by change of renal symptoms. Mild signs of renal involvement appeared during pregnancy in 4 patients. 6 patients showed an increase in proteinuria already present before pregnancy without renal function deterioration. A moderate worsening of renal function was observed in 3 patients. 4 patients, 3 of whom had an apparent onset of systemic lupus erythematosus during pregnancy, developed anuric acute renal failure after delivery or after late spontaneous abortion. 2 of them died from sepsis and disseminated intravascular coagulation while 2 had complete recovery of renal function. A high rate of complications was observed in patients not adequately treated during pregnancy. Renal biopsy before gestation was not predictive of the outcome of nephropathy during pregnancy, and change of histology in repeated biopsies was frequently observed.