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High dialysate flow rate continuous arteriovenous hemodialysis: a new approach for the treatment of acute renal failure and tumor lysis syndrome.

A continuous dialysis technique such as continuous arteriovenous hemodialysis (CAVHD) could be an interesting alternative to frequent intermittent hemodialysis to treat acute renal failure (ARF) secondary to tumor lysis syndrome (TLS). However, because of massive release of intracellular solutes in TLS, CAVHD clearances need to be increased to treat this syndrome. Continuous arteriovenous hemodialysis using a high dialysate flow rate at 4 L/hr was assessed in TLS and ARF associated with severe hyperphosphatemia. A 0.6-m2 hollow-fiber polyacrylonitrile dialyzer (Multiflow 60; Hospal, St-Léonard, Québec, Canada) was used. Blood urea nitrogen and serum creatinine levels decreased, respectively, from 102.5 to 27.2 mg/dL and from 3.1 to 1.8 mg/dL during the 36 hours of treatment. Serum urate concentration was normal at the beginning of treatment (4.5 mg/dL) and decreased to 2.1 mg/dL by the end of CAVHD. Serum phosphorus decreased from 16.7 to 4.4 mg/dL after the 36 hours of treatment. The calcium x phosphorus product decreased from 111.1 to 42.1 by 28 hours and remained under 50 thereafter. Serum potassium was easily controlled with the addition of 2.5 mEq/L of KCl in dialysate and replacement solutions. No rebound increases in phosphorus or potassium were noted after cessation of therapy. Continuous arteriovenous hemodialysis clearances of urea, creatinine, phosphorus, and urate were measured at 2-hour intervals for the first 24 hours and at 4-hour intervals for the remaining 12 hours. They were 53.0 +/- 2.3 mL/min, 43.7 +/- 2.2 mL/min, 40.4 +/- 1.9 mL/min, and 39.3 +/- 1.9 mL/min (n = 15), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗

Bilateral vocal cord paralysis secondary to treatment of severe hypophosphatemia in a continuous ambulatory peritoneal dialysis patient.

Neuromuscular complications, including tetany and laryngeal spasm, are recognized complications of hypocalcemia and hypomagnesemia. We present a continuous ambulatory peritoneal dialysis patient with hypomagnesemia who developed hyperphosphatemia and profound hypocalcemia after oral phosphate replacement for severe hypophosphatemia. The combination of hypocalcemia and hypomagnesemia resulted in life-threatening bilateral vocal cord paralysis. Phosphate replacement should be determined and given cautiously, particularly in patients with renal failure and concomitant electrolyte disturbances.

Female↗

Safety and efficacy of long-term treatment of secondary hyperparathyroidism by low-dose intravenous calcitriol.

To assess the safety and efficacy of low-dose intravenous (IV) calcitriol therapy for the treatment of secondary hyperparathyroidism, 21 hemodialysis patients with amino-terminal parathyroid hormone (N-PTH) levels greater than 4 times normal were treated for 12 to 24 months in a prospective trial. The initial dose was 0.50 microgram, which was titrated every 3 months thereafter, as dictated by predialysis calcium, phosphorus, and N-PTH concentration. Dialysate calcium concentration was 1.5 mmol/L. Low-dose IV calcitriol decreased the N-PTH concentration to 48 +/- 6% and 29 +/- 5% of baseline following 12 and 24 months of therapy, respectively. The maximum dose of calcitriol was 0.92 +/- 0.11 microgram (0.50 to 2.25 micrograms). After 12 months of therapy, serum calcium increased from 2.22 +/- 0.04 to 2.41 +/- 0.03 mmol/L (8.9 +/- 0.2 to 9.7 +/- 0.1 mg/dL) without change thereafter. Baseline serum phosphorus was 1.44 +/- 0.09 mmol/L (4.5 +/- 0.3 mg/dL), and was unaltered by calcitriol therapy. Control of serum phosphorus was achieved with calcium-containing phosphate binders, except in three patients who were subsequently withdrawn from the study after 12 months because of persistent hyperphosphatemia due to noncompliance. We conclude that long-term, low-dose IV calcitriol is a safe and effective therapy for most hemodialysis patients with secondary hyperparathyroidism. In contrast to conventional dosing regimens, low-dose IV therapy does not necessitate the use of aluminum-containing phosphate binders and/or a low-calcium dialysate bath.

Calcitriol↗

Hypocalcemia in end-stage renal disease: a consequence of spontaneous parathyroid gland infarction.

Advances over the last several years have led to a better understanding of the etiology of hyperparathyroidism in renal disease and to more effective means of medical prevention and therapy. Thus, in most dialysis populations, many of the serious complications, such as bone fractures, refractory hypercalcemia, and hyperphosphatemia with vascular and other extraskeletal calcifications, have diminished. Furthermore, more aggressive medical management has decreased the requirement for parathyroidectomy. Unfortunately, not all patients respond to medical management and few still develop refractory hyperparathyroidism with associated morbidity. Of the many complications of refractory hyperparathyroidism in dialysis patients, the development of life-threatening hypocalcemia has not been described. We describe a patient with severe secondary hyperparathyroidism who presented with the acute development of hypocalcemia. To our knowledge, this represents the fourth case, the first reported in a patient with end-stage renal disease, of parathyroid autoinfarction presenting as acute hypocalcemia.

Adult↗

Reduced risk of hypercalcemia for hemodialysis patients by administering calcitriol at night.

Renal osteodystrophy therapy in dialysis patients with calcitriol and intestinal phosphate binders containing calcium entails the risk of hypercalcemia. A study was performed using 35 hemodialysis patients to see whether the time of day when calcitriol is administered influences the incidence of hypercalcemia. It was shown that simply by administering at night (11:00 PM), the occurrence of hypercalcemia was significantly reduced. While greater than 80% of patients developed hypercalcemia when calcitriol was administered in the morning, when administered at night, this figure was only 50% (P less than 0.013). At the same time, the extent of hypercalcemia when calcitriol was administered at night was significantly lower than when it was administered in the morning. The incidence of hypercalcemia occurred regardless of the type of phosphate binder containing calcium used, whether it was calcium acetate or calcium carbonate. In addition, hypercalcemic episodes were always associated with hyperphosphatemia. On the basis of the above information, it would be expedient to administer calcitriol at night to dialysis patients, in order to reduce the risk of hypercalcemia and to preserve the hypophosphatemic effect of the applied intestinal phosphate binders.

Acetates↗

A search for nephrotoxic factors within the uremic milieu.

The purpose of this study was to ascertain whether selected components of the uremic milieu adversely affected glomerular filtration rate (GFR), the glomerular protein filtration barrier, or the integrity of the proximal renal tubular brush border membrane. To achieve these goals, GFR and the excretion rates of albumin and of brush border derived-renal tubular epithelial antigens (RTE) were measured in normal rats and in rats with experimental nephropathies before and after the intravenous infusion of concentrated urine. This experimental protocol uniformly produced severe biochemical manifestations of uremia (for example 10-50-fold increases in BUN and creatinine, hyperphosphatemia, hyperkalemia, metabolic acidosis). However, despite these perturbations, GFR, albuminuria, and RTE excretion remained constant. To assess the influence of uremic hormonal derangements on renal function, GFR, albuminuria, and RTE excretion were measured in normal rats before and after inducing acute serum elevations of seven hormones whose concentrations are known to be increased in uremia (parathyroid hormone, growth hormone, insulin, glucagon, gastrin, prolactin, gastric inhibitory peptide). Again, GFR, albuminuria, and RTE excretion were not adversely affected. These results suggest that glomerular capillary function and proximal tubular brush border membranes are acutely resistant to many of the solute and hormonal derangements which are characteristic of uremia.

Albuminuria↗

Pulmonary calcinosis after renal transplantation in pediatric patients.

Pulmonary calcinosis is a recognized complication of renal failure. The resulting pulmonary compromise may be severe or even fatal. The potential contribution of hypercalcemia, hyperphosphatemia, and increased calcium-phosphorus product to the development of pulmonary calcinosis has been controversial. We describe four patients (ages 2 1/4 to 18 years) who had severe pulmonary calcinosis and respiratory failure within three to five days after renal transplantation. Initial clinical and roentgenographic findings suggested noncardiogenic pulmonary edema. Marked pulmonary hypertension was present in the two patients in whom pulmonary artery pressure data were available. Other clinical features in common included poor allograft function with persistent uremia requiring dialysis and evidence of moderate to severe secondary hyperparathyroidism. In three of the patients, the calcium-phosphorus product increased markedly after transplantation, to peak values of 122 to 147. This increase occurred at the same time as the onset of respiratory failure. Peak serum calcium levels were 10.0 to 11.0 mg/dL and peak serum phosphorus levels were 9.2 to 13.5 mg/dL. All patients died of respiratory failure five to 58 days after transplantation. The posttransplantation period may be a time of increased risk of potentially fatal pulmonary calcinosis in pediatric renal transplant recipients. The diagnosis should be considered in any patient with respiratory failure of unknown cause following renal transplantation.

Adolescent↗

Renal osteodystrophy: some new questions on an old disorder.

The two major lesions of renal osteodystrophy are osteitis fibrosa cystica (OFC) and osteomalacia (OM). OFC is the characteristic bone lesion of uremic hyperparathyroidism. Although renal failure causes predictable parathyroid hyperplasia, the precise pathogenetic mechanism is still not defined. The "hyperphosphatemia-hypocalcemia-parathyroid hormone (PTH) hypersecretion" sequence of events is no longer an adequate model for the pathogenesis of uremic hyperparathyroidism. Other abnormalities associated with uremia include reduced 1,25-dihydroxyvitamin D (1,25D) synthesis, changes in intracellular phosphorus content or transcellular phosphate fluxes, or alteration in PTH metabolism, eg, change in set-point for PTH secretion. Each abnormality interacts with others and contributes to PTH hypersecretion, but none can completely account for the development and persistence of hyperparathyroidism in renal failure. The possibility that uremia may directly cause parathyroid hyperplasia remains open. It is also possible that factor(s) that initiate hyperparathyroidism may turn out to be quite different from that which sustains the hyperparathyroid state. Although both vitamin D-deficient and vitamin D-resistant OM may develop in patients with renal failure, the majority of uremic OM seen currently is "vitamin D-refractory." Although now there is persuasive evidence implicating aluminum (Al) accumulation as the major pathogenetic cause for the mineralization defect seen in this disorder, additional disturbances may play important contributory roles. Such factors would include extraskeletal effects of Al, differences in host-susceptibility to this element, the localization of Al within bone, uremia per se, and the participation of other metals and toxins. Finally, possible interactions between hyperparathyroidism and OM of uremia are speculated on.

Aluminum↗

Biochemical parameters in chronic renal failure.

We analyzed biochemical data derived from 911 patients with renal insufficiency observed at our institution for periods up to 7 years. During early renal failure (RF) (creatinine less than 5 mg/dL), the rate of change of hematocrit, total CO2 (tCO2) and urea per unit change of creatinine was significantly higher than during moderate (creatinine between 5 and 10 mg/dL) or advanced (creatinine greater than 10 mg/dL) RF. For example, the rate of change of hematocrit (%, volume/volume [v/v]) was (mean +/- SEM) -2.15 +/- 0.15% for each 1 mg/dL increase in creatinine in the range of creatinine less than 5 mg/dL, whereas for the range of creatinine greater than 10 mg/dL, the rate of change was only -0.48 +/- 0.06% (P less than 0.001). Similarly, the rate of change of tCO2 was -1.68 +/- 0.09 mEq/L for each 1 mg/dL increment in creatinine concentration during early RF, and -0.19 +/- 0.09 mEq/L per unit increase in creatinine during advanced RF (P less than 0.001). Chloride concentration initially increased as a function of creatinine in early RF, but decreased in advanced RF, whereas the anion gap increased throughout the course of RF. Mean serum phosphate concentration also increased steadily, but remained below the upper range of normal (4.7 mg/dL) during early RF without the use of phosphate binders. These data suggest that different biochemical parameters change at different rates as a function of the severity of renal dysfunction, and that although phosphate retention may occur, hyperphosphatemia is not a hallmark of early RF.

Acid-Base Equilibrium↗

Reversal of aluminum-related bone disease after substituting calcium carbonate for aluminum hydroxide.

Aluminum-related osteodystrophy, a crippling disease in patients with renal failure, can develop from the long-term ingestion of aluminum hydroxide gels. We present a diabetic patient treated with continuous ambulatory peritoneal dialysis (CAPD) who developed markedly elevated plasma aluminum levels but no musculoskeletal symptoms. Bone biopsy revealed features of the aplastic form of aluminum-related disease with significant aluminum staining, decreased osteoblastic osteoid, and decreased bone formation by double tetracycline labeling, but no excess accumulation of unmineralized osteoid. Aluminum hydroxide gels were discontinued and the patient received calcium carbonate to control hyperphosphatemia; 9 months later, a bone biopsy showed marked improvement of the aluminum-related bone disease, and at 2 to 10 months, plasma aluminum had decreased from 208.7 +/- 10.3 (SE) to 55.7 +/- 3.9 micrograms/L.

Aged↗

A new analog of 1,25-(OH)2D3, 19-NOR-1,25-(OH)2D2, suppresses serum PTH and parathyroid gland growth in uremic rats without elevation of intestinal vitamin D receptor content.

We have previously reported that 19-nor-1,25-(OH)2D2, a new analog of 1,25-(OH)2D3, suppresses parathyroid hormone (PTH) secretion in uremic rats in the absence of hypercalcemia or hyperphosphatemia. In the current study, we examined the effect of 19-nor-1,25-(OH)2D2 on parathyroid gland growth and intestinal vitamin D receptor (VDR) content. After induction of uremia by 5/6 nephrectomy, rats were divided into five experimental groups and received intraperitoneal injections of vehicle, 1,25-(OH)2D3 (2 or 6 ng/rat), or 19-nor-1,25-(OH)2D2 (25 or 100 ng/rat) three times a week for 8 weeks. Twelve normal rats received vehicle and served as the normal control group. During the course of the study, rats were maintained on a 1.0% calcium and 0.8% phosphorus diet. The higher dose of 1,25-(OH)2D3, 6 ng, significantly decreased PTH from 52.7 +/- 10.2 pg/mL in the uremic control group to 25.7 +/- 6.7 pg/mL (P < 0.01). This dose of 1,25-(OH)2D3, however, increased serum levels of both ionized calcium (4.71 +/- 0.05 to 4.85 +/- 0.06 mg/dL; P < 0.05) and phosphorus (4.34 +/- 0.30 to 6.67 +/- 0.63 mg/dL; P < 0.01). Both doses of 19-nor-1,25-(OH)2D2 decreased serum PTH as effectively as 1,25-(OH)2D3 without changes in serum calcium or phosphorus. The 100-ng dose of 19-nor-1,25-(OH)2D2 decreased PTH to 20.7 +/- 3.1 pg/mL (P < 0.01) and suppressed parathyroid gland growth by more than 50%. Both doses of 19-nor-1,25-(OH)2D2 also decreased endogenous 1,25-(OH)2D3 levels compared with uremic control rats (25 ng:30.4 +/- 2.0, P < 0.05, and 100 ng:27.9 +/- 3.2, P < 0.01, v 48.4 +/- 6.6 pg/mL). The 6-ng dose of 1,25-(OH)2D3 elevated intestinal VDR content (138.5 +/- 20.0 fmol/mg protein) compared with animals receiving both doses of 19-nor-1,25-(OH)2D2 (25 ng:84.0 +/- 11.9, P < 0.05, and 100 ng:78.4 +/- 10.9, P < 0.01). This was probably attributable to the marked decrease in endogenous 1,25-(OH)2D3 levels caused by both doses of 19-nor-1,25-(OH)2D2 because intestinal VDR correlated directly with serum 1,25-(OH)2D3 (r = 0.963; P = 0.008). Thus, 19-nor-1,25-(OH)2D2 appears to exert a selective action on the parathyroid glands compared with the intestine. Its low calcemic and phosphatemic properties may result from the decreased endogenous 1,25-(OH)2D3 levels that lead to a reduction in intestinal VDR. This selectivity makes this analog ideal for the treatment of secondary hyperparathyroidism.

Animals↗

Influence of pH on in vitro disintegration of phosphate binders.

Hyperphosphatemia, a common complication in patients with end-stage renal disease, is treated with oral phosphate-binding medications that restrict phosphorus absorption from the gastrointestinal (GI) tract. Impaired product performance, such as failure to disintegrate and/or dissolve in the GI tract, could limit the efficacy of the phosphate binder. Disintegration may be as important as dissolution for predicting in vitro product performance for medications that act locally on the GI tract, such as phosphate binders. Furthermore, patients with end-stage renal disease have a wide range in GI pH, and pH can influence a product's performance. The purpose of this study was to determine the effect of pH on in vitro disintegration of phosphate binders. Fifteen different commercially available phosphate binders (seven calcium carbonate tablet formulations, two calcium acetate tablet formulations, three aluminum hydroxide capsule formulations, and three aluminum hydroxide tablet formulations) were studied using the United States Pharmacopeia (USP) standard disintegration apparatus. Phosphate binders were tested in simulated gastric fluid (pH 1.5), distilled water (pH 5.1), and simulated intestinal fluid (pH 7.5). Product failure was defined as two or more individual tablets or capsules failing to disintegrate completely within 30 minutes. Results indicate that 9 of the 15 phosphate binders tested showed statistically significant differences in disintegration time (DT) based on pH. The percentage of binders that passed the disintegration study test in distilled water, gastric fluid, and intestinal fluid were 80%, 80%, and 73%, respectively. The findings of this study show that the disintegration of commercially available phosphate binders is highly variable. The pH significantly affected in vitro disintegration in the majority of phosphate binders tested; how significantly this affects in vivo performance has yet to be studied.

Absorption↗

In search of ideal hemodialysis: is prolonged frequent dialysis the answer?

Advances in technology have made it possible to deliver a high Kt/V in a shorter time. The realization that duration of dialysis may be an important predictor of survival independent of dialysis dose has resulted in the popularity of prolonged slow dialysis (PHD). The longer duration and increased frequency of dialysis achieve excellent small- and middle-molecular weight solute clearance and also attenuate the peak concentration of uremic toxins. The slow dialysis process enables the equilibration of tissue and vascular compartments, resulting in better clearance and decreased postdialysis rebound increase in solutes. Gentle, persistent ultrafiltration allows the control of hypertension with minimal antihypertensive use. The intense and more frequent dialysis improves appetite and permits liberalization of diet. This greater dietary protein intake results in a progressive increase in serum albumin level and dry weight. Nocturnal hemodialysis achieves control of hyperphosphatemia without phosphate binders and a significant reduction in serum beta(2)-microglobulin levels. Normalization of extracellular volume, better clearance of uremic toxins, and improved nutrition result in a significant improvement in survival. The flexible time schedule with home hemodialysis and improvement of sleep and neurocognitive function allow better rehabilitation. The available evidence indicates PHD may be closer to the concept of an ideal dialysis, but there is lingering uncertainty about the consequence of prolonged immune stimulation, catabolism, and loss of essential solutes with these therapies.

Blood Urea Nitrogen↗

[Community-acquired pneumonia requiring hospitalization in immunocompetent elderly patients: clinical features, prognostic factors and treatment].

BACKGROUND: Community-acquired pneumonia (CAP) is the leading cause of death from infectious disease among the elderly. This study was carried out to examine the clinical manifestations, etiology, prognostic factors and treatment of CAP in immunocompetent elderly patients requiring hospitalization. RESULTS: A total of 306 elderly (80 +/- 7 years) patients were evaluated: 54% were male, 89% had concurrent diseases (principally cardiovascular and neurological disease, chronic obstructive lung disease and diabetes), and 97% were treated with second-or third-generation cephalosporins. Mean hospital stay was 10 days, and mortality was approximately 10% in hospital and around 13% on follow up at 30 days. As compared to younger CAP patients, multiple comorbidity, altered mental status, hypoxemia, high serum urea nitrogen on hospital admission were more frequent in the elderly. Intermediate care and intensive care unit admissions were also more frequent in the elderly. Hospital length of stay as well as mortality in the hospital and at 30 days were higher in elderly patients. The pathogen was identified as part of routine care in around 25% of cases. The most frequent pathogens were Streptococcus pneumoniae (10.5%), enteric Gram negative bacilli (5.2%), Staphylococcus aureus (4.2%) and Haemophilus influenzae (3.9%). In multivariate analysis the prognostic factors on admission associated with in-hospital mortality were advanced age (> 83 years), absence of cough, low blood pressure and hyperphosphatemia. CONCLUSION: CAP in elderly patients is a prevalent disease with specific clinical and epidemiological characteristics, clinical course and prognosis.

Adult↗

Asystole during combination chemotherapy for non-Hodgkin's lymphoma: the acute tumor lysis syndrome.

The acute tumor lysis syndrome is a rare condition that has most frequently been documented in patients with rapidly dividing myeloproliferative and lymphoproliferative malignancies. It is characterized by the development of hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, acute renal failure and metabolic acidosis, as a result of massive tumor cell destruction, usually secondary to effective cytotoxic treatment. We want to present the case history of a 62-year-old woman who died from cardiorespiratory arrest during combination chemotherapy for non-Hodgkin's lymphoma due to acute tumor lysis syndrome. Despite general preventive measures, severe electrolyte abnormalities developed within 18 h of the start of chemotherapy. The general guidelines for the management of this potentially fatal oncologic emergency are discussed, with special emphasis on the pathogenetic mechanisms and risk factors in our patient.

Antineoplastic Combined Chemotherapy Protocols↗

Dementia associated with hyperphosphatemic tumoral calcinosis.

Hyperphosphatemic tumoral calcinosis (HTC) is a rare inherited metabolic disorder manifested by pararticular calcification and hyperphosphatemia, caused by an elevated renal phosphate reabsorption threshold and elevated serum 1,25-dihydroxyvitamin D levels. The disorder usually affects African-American subjects, but has also been described in Caucasians and Hispanics. Vascular calcifications and angioid streaks have been reported to be associated with the disorder; however, dementia has not been previously reported. Our medical center has followed two African-American siblings, with HTC for over 30 years, who have developed dementia at 56 years and 67 years of age. Neither man has been hypertensive, however, magnetic resonance imaging (MRI) scans in both cases revealed multiple periventricular infarcts, suggestive of infarcts caused by vascular calcification in the central nervous system. These two brothers with HTC suggest that periventricular infarcts with dementia may be a long term complication of this disorder.

Aged↗

A randomised, blinded, placebo-controlled clinical trial with allopurinol in canine leishmaniosis.

A total of 45 non-uremic dogs, with clinical signs indicating leishmaniosis, entered the study. Diagnosis was confirmed by indirect immunofluorescence assay (IFA) on serum and polymerase chain reaction (PCR) on bone marrow samples. The dogs were randomly allocated into Group A (n=37) that received allopurinol (10mg/kg B.W., per os, twice daily) for 4 consecutive months, and Group B (n=8) that were placebo-treated. Clinical signs were scored just before and at monthly intervals throughout the study period, in a blinded and independent fashion. Complete blood count, serum biochemistry profile, urinalysis, lymph node and bone marrow parasitology, IFA and enzyme-linked immunosorbent assay (ELISA) serology and bone marrow PCR were carried out at the beginning and at the end of the trial. A total of three Group A and one Group B dogs died of end stage kidney disease that developed during the trial. In Group A animals that endured the trial there was a significant improvement in the general body condition, conjunctivitis, peripheral lymphadenopathy, splenomegaly, masticatory muscle atrophy, ulcerative stomatitis, epistaxis, exfoliative dermatitis, cutaneous ulcerations, blepharitis and nasodigital hyperkeratosis. The same observation was made for anemia, lymphopenia, hyperproteinemia, hyperglobulinemia, hyperphosphatemia, increased alkaline phosphatase activity and the low albumin/globulin ratio. By contrast, no improvement of any kind was seen in Group B dogs. Lymph node and bone marrow parasite numbers were significantly decreased in Group A animals. In Group B, that occurred only in the lymph nodes. Apart from remission of clinical signs and restoration to normal of clinicopathological abnormalities, allopurinol did not eliminate Leishmania organisms, as the PCR result on bone marrow was still positive in all the dogs that finished the trial.

Allopurinol↗

Tumoral calcinosis: a case report and review of the literature.

Tumoral calcinosis rarely occurs in the hand. It is an uncommon familial disease suggesting an autosomal recessive gene pattern, often with laboratory findings of hyperphosphatemia and normocalcemia. Our patient had bilateral hand involvement, including local calcinosis cutis of the skin and bone changes not previously reported in the literature. At a 2-year follow-up after two lesions were excised from her left hand, one lesion had completely resolved and the other recurred. Two large symptomatic lesions and one area of local calcinosis cutis in her right hand have recently been excised.

Adolescent↗