Chronic Acidosis Research Articles

Adaptation of intercalated cells along the collecting duct to systemic acid/base changes

Collecting duct intercalated cells respond to short-term acid/base perturbations by rapidly shuttling H(+)-ATPase to and from the plasma membrane. Purkerson et al. provide information on the regulation of the anion transporters during chronic acidosis and acute recovery (alkalosis). They found that the major mechanism for both acute and chronic states is regulation of both the H(+)-ATPase and the anion exchangers plus changes in the overall expression level of these anion transporters in chronic adaptation.

Comparison of Hamm and Zhoushousheng's formulae for expected compensation in acid-base imbalance

Objective To compare the difference and rationalities between Harmm and Zhou' s formulae for expected acid-base compensation in acid-base imbalance. Methods 745 cases of arterial blood gas analysis results of acid-base disorder were evaluated respectively by Hamm and Zhou' s formulae, and the concordance was judged. Results For metabolic acidosis ( 108 cases), the concordance rate was 70. 4% between Hamm and Zhou's( Kappa value =0. 41 ,P ＜0. 01 ) ;for metabolic alkalosis ( 132 cases) ,the concordance rate was 59. 1% ( Kappa value =0. 18 ,P ＜0. 05) ;for acute respiratory acidosis(81 cases) ,the concordance rate was 65.43% ( Kappa value = 0. 31, P ＜ 0. 01 ) ;for acute respiratory alkalosis ( 168 cases), the concordance rate was 54. 8% ( Kappa value = 0. 24%, P ＜ 0. 01 ); for chronic respiratory acidosis ( 119 cases ), the concordance rate was 67.2% ( Kappa value = 0. 41, P ＜ 0. 01 ) ;for chronic respiratory alkalosis( 137 cases), the concordance rate was 66. 6% ( Kappa value = 0. 43, P ＜ 0. 01 ). Conclusion The difference between Hamm and Zhou' s formulae for expected acid-base compensation in acid-base imbalance was obvious. The Zhou' s expected max compensation coefficient were slightly higher than the primary adopted compensation coefficient. Key words: Acid-base imbalance; Expected compensation range

The caudal solitary complex is a site of central CO2 chemoreception and integration of multiple systems that regulate expired CO2

The solitary complex is comprised of the nucleus tractus solitarius (NTS, sensory) and dorsal motor nucleus of the vagus (DMV, motor), which functions as an integrative center for neural control of multiple systems including the respiratory, cardiovascular and gastroesophageal systems. The caudal NTS-DMV is one of the several sites of central CO(2) chemoreception in the brain stem. CO(2) chemosensitive neurons are fully responsive to CO(2) at birth and their responsiveness seems to depend on pH-sensitive K(+) channels. In addition, chemosensitive neurons are highly sensitive to conditions such as hypoxia (e.g., neural plasticity) and hyperoxia (e.g., stimulation), suggesting they employ redox and nitrosative signaling mechanisms. Here we review the cellular and systems physiological evidence supporting our hypothesis that the caudal NTS-DMV is a site for integration of respiratory, cardiovascular and gastroesophageal systems that work together to eliminate CO(2) during acute and chronic respiratory acidosis to restore pH homeostasis.

Glucose stimulated insulin secretion: Effect of chronic acidosis and alkalosis in MIN6 cells

In addition to exacerbating insulin resistance, obesity has been associated with obstructive sleep apnea and hypercapnia. To explore the underlying mechanisms of these latter phenomena on glucose‐stimulated insulin secretion, we explored the effect of CO2/HCO3−/pH alterations in mouse secretagogue‐responsive insulinoma cells MIN6 exposed to different extracellular pHs ([pH]o) for 6 days, and measured glucose‐stimulated insulin secretion (GSIS), and passive and active electrophysiological membrane properties. We found that 1) when the extracellular [pH]o was alkaline (7.9) (fixing CO2 concentration at 5% and increasing NaHCO3 concentrations from 18 to 50 mM) GSIS decreased significantly and this was accompanied by a significantly hyperpolarized Vm, decreased Ri and increase in rheobase; 2) by fixing NaHCO3 at 18 mM and increasing the CO2 concentration from 5% to 15%, there was no effect on GSIS, resting membrane potential (Vm), and input resistance (Ri); 3) a decrease in extracellular pH (a pH of 6.5 or below with 5% CO2 and 0 mM NaHCO3) inhibited GSIS, and this was accompanied by a significantly depolarized Vm, decreased Ri and increase in rheobase. We conclude that 1) although GSIS does not depend on extracellular pH when extracellular pH is between 7.1 and 7.7, GSIS decreased when pH was outside this range; 2) uncompensated extracellular pH by eliminating NaHCO3 reduces GSIS, and this may involve a chloride‐dependent mechanism. These findings have important implications for the management of insulin resistance and diabetes in obese patients.

Blood gas changes in Duchenne type muscular dystrophy

We studied changes in blood gas data from 32 patients with Duchenne type muscular dystrophy (DMD), who were followed for more than 5 years. Regression lines for each blood gas variable were obtained by the least square regression method, from 276 observations. The mean change per year was calculated by averaging the individual slopes. All blood gas variables (PaO2, PaCO2, pH, and [HCO3-]) correlated significantly with age the regression lines were: PaO2 = 95.6-0.45x Age, PaCO2 = 34.7 + 0.70x Age, pH = 7.397-0.0023x Age, [HCO3-] = 20.7 + 0.28x Age. The rates of change were -0.74 Torr/year for PaO2, 1.07 Torr/year for PaCO2, -0.0028 per year for pH and 0.55 mEq/l/year for [HCO3-]. The slope of each regression line was within the average individual yearly change +/- one standard deviation. AaDO2 did not change significantly with age, but chronic respiratory acidosis worsened because of alveolar hypoventilation. As an index of the severity of DMD, PaCO2 was better than PaO2, because the former was more strongly correlated with age and the values of PaCO2 deviated less from the the regression line.

A novel mitochondrial MTND5 frameshift mutation causing isolated complex I deficiency, renal failure and myopathy

Isolated complex I deficiency is the most commonly reported enzyme defect in paediatric mitochondrial disorders, and may arise due to mutations in nuclear-encoded structural or assembly genes, or the mitochondrial genome. We present the clinical, biochemical and molecular genetic data in a young girl whose clinical picture is dominated by chronic renal failure, myopathy and persistent lactic acidosis. An isolated complex I deficiency in muscle was identified due to a novel mutation (m.12425delA) in the MTND5 gene. This single nucleotide deletion is heteroplasmic and detectable in several tissues from the proband but not her mother, suggesting a de novo mutation event. The description of the first frameshift mutation in a mitochondrial complex I gene affirms mitochondrial DNA mutations as an important cause of isolated complex I deficiency in children and the importance of whole mitochondrial genome sequencing in the diagnostic work-up to elucidate the underlying molecular genetic abnormality and provide important genetic advice.

G.P.3.05 A novel heteroplasmic mitochondrial MT-ND5 frameshift mutation causing isolated paediatric complex I deficiency

Defects of the mitochondrial respiratory chain are associated with a diverse and ever-growing spectrum of clinical phenotypes in both adults and children, and may be caused by mutations in either the nuclear or mitochondrial genome (mtDNA). We report the molecular genetic investigations of a young girl who presented to our service at age 9 years with myopathy, chronic renal failure, learning difficulties and persistent lactic acidosis. Muscle biopsy revealed evidence of cytochrome c oxidase (COX)-positive, ragged red fibres which were associated with an isolated biochemical defect involving respiratory chain complex I.

Metabolic bone disease in HIV infection

HIV mainly replicates in CD4þ T lymphocytes andmonocyte/macrophages causing severe immunologicalimpairment. In addition to the immune system, HIVinfection affects tissues and organs such as kidney, liver,the central nervous system, heart and bone showing acomplex pathogenesis [1].The advent and widespread use of highly activeantiretroviral therapy (HAART) in the last two decadeshasled toa markedimprovementinthe treatmentofHIVdisease even though viral infection cannot be eradicatedbecause HAART does not completely eliminate the viralreservoirs [2]. HAART has dramatically changed thecourseofHIVinfection froma fatalinfectiontoachronicand relatively manageable disease. The increased lifeexpectancyofHIVpatientsandtheeffectsofHAARThavechanged the management of HIV infection. Nowadaysmedical treatment is no longer focused solely on HIVinfection, opportunistic diseases and monitoring immunederangement, but also includes the control of metabolic,cardiovascular, liver, bone and kidney complications. Inparticular, bone alterations have been observed in thecourse of HIV disease representing a pivotal clinicalprobleminthemanagementofHIVpatientsespeciallyforapossible development of bone fractures [3]. The majorbonelesionsdetectableinHIVpatientsarerelatedtobonedemineralization (osteopenia/osteoporosis and osteoma-lacia) and osteonecrosis ([4] for a review).This report will discuss the pathogenesis, diagnosis andtreatment of major bone complications represented bybone demineralization diseases during HIV infection andHAART treatment.

Structural insights on pathogenic effects of novel mutations causing pyruvate carboxylase deficiency

Pyruvate carboxylase (PC), a key enzyme for gluconeogenesis and anaplerotic pathways, consists of four domains, namely, biotin carboxylase (BC), carboxyltransferase (CT), pyruvate carboxylase tetramerization (PT), and biotin carboxyl carrier protein (BCCP). PC deficiency is a rare metabolic disorder inherited in an autosomal recessive way. The most severe form (form B) is characterized by neonatal lethal lactic acidosis, whereas patients with form A suffer chronic lactic acidosis with psychomotor retardation. Diagnosis of PC deficiency relies on enzymatic assay and identification of the PC gene mutations. To date, six mutations of the PC gene have been identified. We report nine novel mutations of the PC gene, in five unrelated patients: three being affected with form B, and the others with form A. Three of them were frameshift mutations predicted to introduce a premature termination codon, the remaining ones being five nucleotide substitutions and one in frame deletion. Impact of these mutations on mRNA was assessed by RT-PCR. Evidence for a deleterious effect of the missense mutations was achieved using protein alignments and three-dimensional structural prediction, thanks to our modeling of the human PC structure. Altogether, our data and those previously reported indicate that form B is consistently associated with at least one truncating mutation, mostly lying in CT (C-terminal part) or BCCP domains, whereas form A always results from association of two missense mutations located in BC or CT (N-terminal part) domains. Finally, although most PC mutations are suggested to interfere with biotin metabolism, none of the PC-deficient patients was biotin-responsive.

Inhibition of osteoclast formation and function by bicarbonate: Role of soluble adenylyl cyclase

High [HCO(3)(-)] inhibits and low [HCO(3)(-)] stimulates bone resorption, which mediates part of the effect of chronic acidosis or acid feeding on bone. Soluble adenylyl cyclase (sAC) is a bicarbonate sensor that can potentially mediate the effect of bicarbonate on osteoclasts. Osteoclasts were incubated in 0, 12, and 24 mM HCO(3)(-) at pH 7.4 for 7-8 days and assayed for tartrate-resistant acid phosphatase (TRAP) and vacuolar-ATPase expression, and H+ accumulation. Total number and area of TRAP (+) multinucleated osteoclasts was decreased by HCO(3)(-) in a dose-dependent manner. V-ATPase expression and H+ accumulation normalized to cell cross-sectional area or protein were not significantly changed. The HCO(3)(-) -induced inhibition of osteoclast growth and differentiation was blocked by either 2-hydroxyestradiol, an inhibitor of sAC or sAC knockdown by sAC specific siRNA. The model of HCO(3)(-) inhibiting osteoclast via sAC was further supported by the fact that the HCO(3)(-) dose-response on osteoclasts is flat when cells were saturated with 8-bromo-cAMP, a permeant cAMP analog downstream from sAC thus simulating sAC activation. To confirm our in vitro findings in intact bone, we developed a 1-week mouse calvaria culture system where osteoclasts were shown to be viable. Bone volume density (BV/TV) determined by micro-computed tomography (microCT), was higher in 24 mM HCO(3)(-) compared to 12 mM HCO(3)(-) treated calvaria. This HCO(3)(-) effect on BV/TV was blocked by 2-hydroxyestradiol. In summary, sAC mediates the inhibition of osteoclast function by HCO(3)(-), by acting as a HCO(3)(-) sensor.

An unusual presentation of pulmonary artery dissection

A morbidly obese woman presented with exertional dyspnoea and leg swelling. Past medical history included deep venous thrombosis and atrial fibrillation. Arterial blood gases demonstrated chronic respiratory acidosis and type...

Insulin Resistance in Chronic Uremia

Insulin resistance often characterizes chronic uremia, and is associated with enhanced morbidity and mortality, because it may contribute to protein-energy wasting (in turn, an independent predictor of reduced survival), atherosclerosis, and cardiovascular death. Causes of insulin resistance in chronic uremia are complex and multifactorial. Obesity is emerging as an independent risk factor for chronic kidney disease, and an expected rise in number of obese uremic patients because of the ongoing worldwide obesity epidemic is likely to increase the prevalence of insulin resistance in chronic uremia in the near future. Similar to the general population, reported associations between obesity and insulin resistance in chronic uremia support a role of adipose tissue and altered adipokine profiles in insulin resistance in obese chronic kidney disease patients. Hormonal imbalances, chronic acidosis, and systemic inflammation and oxidative stress are uremia-associated relevant causes of insulin resistance in nonobese individuals. A further understanding of the causes of insulin resistance in chronic uremia represents a potential important tool in the design of more effective therapeutic strategies to reduce uremia-associated morbidity and mortality.

ELECTROLYTE IMBALANCE FOLLOWING ILEAL URINARY DIVERSION

SUMMARY Measurements of serum electrolytes were made in 38 patients in whom ileum was used in the urinary tract. A high incidence (61 per cent.) of transient early hyperchlorzmic acidosis due to reabsorption was found but most patients were able to compensate for it. However, 27 per cent. of patients were unable to compensate because of permanent renal damage and they developed chronic hyperchlorzmic acidosis. Normal levels of serum uric acid, calcium and inorganic phosphorus were found in all of the patients. For monitoring renal function in patients with ileal urinary diversion measurements of serum creatinine were found to be more useful than estimation of blood urea.

Chronic binge ethanol-mediated acidemia reduces availability of glutamine and related amino acids in maternal plasma of pregnant sheep

Heavy drinking during pregnancy can result in fetal alcohol syndrome (FAS), of which, fetal and postnatal growth retardation and central nervous system deficits are cardinal features. Although a number of mechanisms have been proposed, none fully account for these deficiencies. We have previously reported that maternal ethanol exposure (1.75 g/kg) results in transient acidemia in the mother and fetus. Alterations in pH are known to regulate glutamine homeostasis. Therefore, we hypothesized that chronic binge ethanol-mediated acidosis reduces glutamine concentrations in maternal plasma that result in decreases in the circulating levels of amino acids related to glutamine metabolism. Pregnant ewes were divided into three groups: ethanol (1.75 g/kg), saline control, and acidemia (inspired fractional carbon dioxide [CO 2] was manipulated to mimic the maternal arterial pH pattern created by ethanol). The experiment was conducted on three consecutive days followed by four days without treatment beginning on gestational day (GD) 109, continuing to GD 132. Plasma samples were analyzed for nutrients and metabolites using HPLC and spectrophotometric methods. Maternal plasma concentrations of glutamate increased (58%), whereas glutamine, citrulline, and arginine decreased (between 14 and 53%) in response to an acute challenge after the chronic exposure in ethanol-treated ewes. No differences in these amino acid concentrations were noted between the ethanol and acidemic group subjects. Maternal plasma lactate levels increased by ∼100% in response to ethanol, whereas glucose and urea levels did not change in any group. We conclude that maternal chronic binge ethanol consumption results in acidosis-mediated reductions in circulating levels of glutamine and related amino acids that could be responsible for neuronal deficits, altered fetal growth, development, and programming. We also speculate that the consequent increase in fetal glutamate during critical periods of brain development may contribute to the pathogenesis of FAS.

Blocking acid-sensing ion channel 1 alleviates Huntington's disease pathology via an ubiquitin-proteasome system-dependent mechanism

Huntington's disease (HD) is a fatal neurodegenerative disorder. Despite a tremendous effort to develop therapeutic tools in several HD models, there is no effective cure at present. Acidosis has been observed previously in cellular and in in vivo models as well as in the brains of HD patients. Here we challenged HD models with amiloride (Ami) derivative benzamil (Ben), a chemical agent used to rescue acid-sensing ion channel (ASIC)-dependent acidotoxicity, to examine whether chronic acidosis is an important part of the HD pathomechanism and whether these drugs could be used as novel therapeutic agents. Ben markedly reduced the huntingtin-polyglutamine (htt-polyQ) aggregation in an inducible cellular system, and the therapeutic value of Ben was successfully recapitulated in the R6/2 animal model of HD. To reveal the mechanism of action, Ben was found to be able to alleviate the inhibition of the ubiquitin-proteasome system (UPS) activity, resulting in enhanced degradation of soluble htt-polyQ specifically in its pathological range. More importantly, we were able to demonstrate that blocking the expression of a specific isoform of ASIC (asic1a), one of the many molecular targets of Ben, led to an enhancement of UPS activity and this blockade also decreased htt-polyQ aggregation in the striatum of R6/2 mice. In conclusion, we believe that chemical compounds that target ASIC1a or pharmacological alleviation of UPS inhibition would be an effective and promising approach to combat HD and other polyQ-related disorders.

Determinants and mechanisms of enamel fluorosis.

Enamel fluorosis occurs when fluoride concentrations in or in the vicinity of the forming enamel are excessive during its pre-eruptive development. Fluoride concentrations in plasma, enamel and other tissues reflect the difference between intake and excretion, i.e. fluoride balance. In addition to the diet, modern sources of ingested fluoride include a variety of dental products, some of which have been identified as risk factors for fluorosis. Fluoride absorption is inversely related to dietary calcium which, at high concentrations, may cause net fluoride secretion into the gastrointestinal tract. The excretion of absorbed fluoride occurs almost exclusively via the kidneys, a process which is directly related to urinary pH. Thus, fluoride balance and tissue concentrations and the risk of fluorosis are increased by factors such as high protein diets, residence at high altitude, and certain metabolic and respiratory disorders that decrease pH. Factors that increase urinary pH and decrease the balance of fluoride include vegetarian diets, certain drugs and some other medical conditions. Although several other fluoride-induced effects might be involved in the aetiology of fluorosis, it now appears that inhibition of enzymatic degradation of amelogenins, which may delay their removal from the developing enamel and impair crystal growth, may be of critical importance. In addition to the effects of fluoride, disturbances in enamel formation that can be confused with fluorosis are caused by chronic acidosis and hypoxia independently of the level of fluoride exposure.

Adaptive redistribution of NBCe1-A and NBCe1-B in rat kidney proximal tubule and striated ducts of salivary glands during acid-base disturbances

The cellular distribution of the NH2-terminal electrogenic Na+-HCO3(-) cotransporter (NBCe1) variants NBCe1-A and NBCe1-B has been investigated in rat kidney and submandibular gland (SMG) under physiological conditions and after systemic acid-base perturbations. Moreover, the in vivo data were complemented in vitro by using an immortalized cell line derived from the S1 segment of the proximal tubule (PT) of normotensive Wistar-Kyoto rats (WKPT-0293 Cl.2). NBCe1-A was basolaterally localized in PT cells, whereas NBCe1-B exhibited intracellular and basolateral distribution. SMG showed transcript and protein expression for NBCe1-A and NBCe1-B. NBCe1-B was basolaterally localized in duct cells; NBCe1-A was found intracellularly in salivary striated ducts and apically in main duct cells. Acute metabolic acidosis significantly increased cells that showed basolateral NBCe1-A in the PT, indicating increased HCO3(-) reabsorption, and significantly decreased cells that exhibited basolateral NBCe1-B in the salivary ducts, suggesting decreased HCO3(-) secretion. Chronic acidosis had no effect on NBCe1 distribution in PT but significantly increased the percentage of cells with basolateral NBCe1-A in salivary striated duct cells, suggesting increased HCO3(-) reabsorption. In contrast, chronic alkalosis caused adaptive redistribution of NBCe1-A and NBCe1-B in renal PT, favoring decreased HCO3(-) reabsorption. In vitro, WKPT-0293 Cl.2 cells expressed key acid-base transporters. Extracellular alkalosis downregulated NBCe1-A protein. WKPT-0293 Cl.2 cells are therefore a useful model to study renal acid-base regulation in vitro. The results propose redistribution of the transporters as a potential posttranslational regulation modus during acid-base disturbances. Moreover, the data demonstrate that renal PT and salivary duct epithelia respond to acid-base disturbances by an opposite redistribution pattern for NBCe1-A and NBCe1-B, reflecting specialized functions as the HCO3(-)-reabsorbing and HCO3(-)-secreting epithelium, respectively.

Effects of NH4Cl-induced systemic metabolic acidosis on kidney mitochondrial coupling and calcium transport in rats

We have previously shown that chronic metabolic acidosis, induced in rats by NH(4)Cl feeding, leads to nephron hypertrophy and to a decreased water-salt reabsorption by the kidneys. Since mitochondria are the main source of metabolic energy that drives ion transport in kidney tubules, we examined energy-linked functions (respiration, electrochemical membrane potential and coupling between respiration and ADP phosphorylation) in mitochondria isolated from rat kidney and liver at 48 h after metabolic acidosis induced by NH(4)Cl. Mitochondria isolated from the kidneys and liver of metabolic acidotic rats, induced by NH(4)Cl, was used to study of the oxygen consumption by Clark-type electrode, mitochondrial electrical transmembrane potential estimated by the safranine O method and the variations in free medium Ca(2+) concentrations examined by absorbance spectrum of Arsenazo III set at the 675-685 nm wavelength pair. Whole kidney and liver mitochondria isolated from 48 h acidotic rats presented higher resting respiration, lower respiratory control and a lower ADP/O ratio than controls. These differences in mitochondrial coupling, between respiration and oxidative phosphorylation (ATP synthesis), were totally corrected when experiments were carried out in the presence of carboxyatractyloside, GDP and BSA, indicating that mitochondrial uncoupling proteins are more active in acidotic rat kidneys. Interestingly, determination of Ca(2+) transport demonstrated a faster rate of initial Ca(2+) uptake by acidotic kidney mitochondria, which resulted in a lower concentration of extra-mitochondrial Ca(2+) under steady-state conditions (Ca(2+) set point) when compared with control mitochondria. In contrast, there were no significant differences in the rates of Na(+) or ruthenium red induced Ca(2+) efflux. We suggest that the mild uncoupling and higher Ca(2+) accumulation represents an adaptation of the mitochondria to cope with conditions of oxidative stress and high cytosolic Ca(2+), which are associated with a decreased efficiency of oxidative phosphorylation that may explain, at least in part, the striking natriuresis observed under chronic acidosis. Finally, there were no changes in Ca(2+) transport or coupling in liver mitochondria isolated from the acidotic rats.

Renal compensation to chronic hypoxic hypercapnia: downregulation of pendrin and adaptation of the proximal tubule

The molecular basis for the renal compensation to respiratory acidosis and specifically the role of pendrin in this condition are unclear. Therefore, we studied the adaptation of the proximal tubule and the collecting duct to respiratory acidosis. Male Wistar-Hannover rats were exposed to either hypercapnia and hypoxia [8% CO(2) and 13% O(2) (hypercapnic, n = 6) or normal air (controls, n = 6)] in an environmental chamber for 10 days and were killed under the same atmosphere. In hypercapnic rats, arterial pH was lower than controls (7.31 +/- 0.01 vs. 7.39 +/- 0.01, P = 0.03), blood HCO(3)(-) concentration was increased (42 +/- 0.9 vs. 32 +/- 0.24 mM, P < 0.001), arterial Pco(2) was increased (10.76 +/- 0.4 vs. 7.20 +/- 0.4 kPa, P < 0.001), and plasma chloride concentration was decreased (92.2 +/- 0.7 vs. 97.2 +/- 0.5 mM, P < 0.001). Plasma aldosterone levels were unchanged. In the proximal tubule, immunoblotting showed an increased expression of sodium/bicarbonate exchanger protein (188 +/- 22 vs. 100 +/- 11%, P = 0.005), confirmed by immunohistochemistry. Total Na/H exchanger protein expression in the cortex was unchanged by immunoblotting (119 +/- 10 vs. 100 +/- 11%, P = 0.27) and immunohistochemistry. In the cortex, the abundance of pendrin was decreased (51 +/- 9 vs. 100 +/- 7%, P = 0.003) by immunoblotting. Immunohistochemistry revealed that this decrease was clear in both cortical collecting ducts (CCDs) and connecting tubules (CNTs). This demonstrates that pendrin expression can be regulated in acidotic animals with no changes in aldosterone levels and no external chloride load. This reduction of pendrin expression may help in redirecting the CNT and CCD toward chloride excretion and bicarbonate reabsorption, contributing to the increased plasma bicarbonate and decreased plasma chloride of chronic respiratory acidosis.

Metastatic pulmonary calcification in a dialysis patient: Case report and a review

A 19-year-old male presented with chest pain and dyspnea. He was anephric following nephrectomy for focal segmental glomerulosclerosis, had a subsequent failed transplant, and had been dialysis dependent for 3 years. Workup revealed hyperparathyroidism and an abnormal chest X-ray and computed tomography scan, significant for massive extra-skeletal pulmonary calcification. A markedly abnormal Technitium99 methylene diphosphonate (Tc99m-MDP) bone scan confirmed the clinical suspicion of metastatic pulmonary calcification. Metastatic pulmonary calcification (MPC) is common, occurring in 60% to 80% of dialysis patients on autopsy and bone scan series. It may lead to impaired oxygenation and restrictive lung disease. Typically, the calcium crystal is whitlockite rather than hydroxyapatite, which occurs in vascular calcification. Four major predisposing factors may contribute to MPC in dialysis patients. First, chronic acidosis leaches calcium from bone. Second, intermittent alkalosis favors deposition of calcium salts. Third, hyperparathyroidism tends to cause bone resorption and intracellular hypercalcemia. Finally, low glomerular filtration rate can cause hyperphosphatemia and an elevated calcium-phosphorus product. There may be other factors. Some authors suggest that the incidence of MPC in recent years may be lower due to improved dialysis techniques. The diagnosis is confirmed by biopsy, but can be suspected by typical findings on a Tc99m-MDP bone scan. Therapy is limited to ensuring adequate dialysis, correcting calcium-phosphorus product, and hyperparathyroidism; discontinuing vitamin D analogues may help. Conflicting reports show that transplantation may either improve or worsen the situation. MPC should be considered in dialysis patients who have characteristic abnormal chest radiography and/or pulmonary symptoms.