Gitelman syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Gitelman syndrome (GS) is a rare, salt-losing tubulopathy characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. The disease is recessively inherited, caused by inactivating mutations in the SLC12A3 gene that encodes the thiazide-sensitive sodium-chloride cotransporter (NCC). GS is usually detected during adolescence or adulthood, either fortuitously or in association with mild or nonspecific symptoms or both. The disease is characterized by high phenotypic variability and a significant reduction in the quality of life, and it may be associated with severe manifestations. GS is usually managed by a liberal salt intake together with oral magnesium and potassium supplements. A general problem in rare diseases is the lack of high quality evidence to inform diagnosis, prognosis, and management. We report here on the current state of knowledge related to the diagnostic evaluation, follow-up, management, and treatment of GS; identify knowledge gaps; and propose a research agenda to substantiate a number of issues related to GS. This expert consensus statement aims to establish an initial framework to enable clinical auditing and thus improve quality control of care.

Mineral and Bone Disorder in Chronic Kidney Disease: A Case Report from Vietnam.

We report a case of calcium pyrophosphate dihydrate deposition disease (CPDD) involving a patient on maintenance hemodialysis (MHD). The 32-year-old man presented in August 2016 with a complaint of left shoulder swelling of 8 months' duration with no trauma or fever. He was diagnosed with nephrotic syndrome in 1998, which progressed to ESRD. He commenced MHD in 2012. Examination at our hospital revealed a soft nontender swelling of the left shoulder. Blood biochemistry showed elevated serum urate, phosphate, ß2 microglobulin, and parathyroid hormone. Imaging revealed joint effusion and dense heterogenous deposition. Aspirate analysis showed urate crystals 3+, and culture yielded no growth. Following rheumatology review, the working diagnosis was periarticular tissue tuberculosis, after excluding pseudogout and amyloidosis. Following 1 month of colchicine and allopurinol, synovial fluid microscopy showed CPDD crystals. Symptoms gradually resolved over the course of 6 months. In this rare case, a diagnosis of CPDD was made with a multidisciplinary approach that included imaging and biochemical investigations.

Unilateral anterior crossbite induces aberrant mineral deposition in degenerative temporomandibular cartilage in rats.

OBJECTIVE: To investigate whether mechanical stress induces mineral deposits that contribute to matrix degradation at the onset of osteoarthritis (OA) in temporomandibular joint (TMJ) cartilage. DESIGN: Female Spraguee-Dawley rats were subjected to an unilateral anterior crossbite (UAC) procedure. Histology, electron microscopy, and energy dispersive spectrometer (EDS) were used to examine cartilage matrix structures and composition of mineral deposit in the affected TMJ cartilage. Protein and/or RNA expression of phenotypic markers and mineralization modulators and matrix degradation was analyzed by immunohistochemistry and/or real-time PCR. Synthetic basic calcium phosphate (BCP) and calcium pyrophosphate dehydrate (CPPD) crystals were used to stimulate ATDC5 cells for their impact on cell differentiation and gene expression. RESULTS: Fragmented and disorganized collagen fibers, expanded fibrous spaces, and enhancement of matrix vesicle production and mineral deposition were observed in matrices surrounding hypertrophic chondrocytes in cartilage as early as 2-weeks post-UAC and exacerbated with time. The mineral deposits in TMJ cartilage at 12- and 20-weeks post-UAC had Ca/P ratios of 1.42 and 1.44, which are similar to the ratios for BCP. The expression of mineralization inhibitors, NPP1, ANK, CD73, and Matrix gla protein (MGP) was decreased from 2 to 8 weeks post-UAC, so were the chondrogenic markers, Col-2, Col-X and aggrecan. In contrast, the expression of tissue-nonspecific alkaline phosphatase (TNAP) and MMP13 was increased 4-weeks post-UAC. Treating ADTC5 cells with BCP crystals increased MMPs and ADAMTS5 expression, but reduced matrix production in a time-dependent manner. CONCLUSION: UAC induces deposition of BCP-like minerals in osteoarthritic cartilage, which can stimulate matrix degradation by promoting the expression of cartilage-degrading enzymes to facilitate OA progression.

Alkaptonuria Presenting with Impressive Osteoarticular Changes and Severe Aortic Stenosis.

Alkaptonuria, or ochronosis, a rare autosomal recessive metabolic disorder, causes an excess of homogentisic acid that results in dark pigmentation, calcification, and inflammation of cartilaginous and other tissues. Cardiovascular complications are also typical of the disease. We report the case of a 78-year-old male who presented with impressive osteoarticular changes and aortic stenosis associated with alkaptonuria.

Gitelman syndrome disclosed by calcium pyrophosphate deposition disease: early diagnosis by ultrasonographic study.

Gitelman's syndrome is a rare autosomal-recessive tubular disorder characterized by hypomagnesemia and hypocalciuria associated to hypokalemia. The clinical spectrum is wide and usually characterized by chronic fatigue, cramps, muscle weakness and paresthesiae. We describe a case of a 43 year-old male patient with early onset of knee arthritis and no other symptoms. Ultrasound revealed diffuse and confluent hyperechoic deposits in cartilage, fibrocartilage of the menisci and synovium and calcium pyrophosphate crystals were observed in the synovial fluid of the knee. The concomitant presence of hypomagnesemia, hypocalciuria and hypokalemia made clear the diagnosis of Gitelman's syndrome associated with chondrocalcinosis.

[From chondrocalcinosis to rheumatism with calcium pyrophosphate dehydrate]. / De la chondrocalcinose au rhumatisme à cristaux de pyrophosphate de calcium.

Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease is a joint pathology that affects joints, fibrocartilages and periarticular structures. Chondrocalcinosis refers to CPPD deposits on the X-ray that does not summarize the disease. It willingly affects the knees and the wrists, but all the joints can be affected. There are primitive and secondary forms of the disease to particularly look for in patients less than 50 years. The diagnosis is usually easy with standard radiography, ultrasound and synovial fluid analysis that shows the microcrystals. The therapeutics of the acute attacks are nonspecific and close to those used for acute attacks of gout.

[Gout and and calcium pyrophosphate crystal arthropathies: pathophysiology]. / Physiopathologie des arthropathies microcristallines.

Microcrystalline arthropathies are consecutive to microcrystals formation and deposition within the joint. The formation of monosodium urate crystals depends on many physico-chemical factors: the concentration of uric acid, the temperature and pH. Beyond 60 mg/L (360 µmol/L), uric acid crystallizes in tissues. Chronic hyperuricemia is a necessary condition for the occurrence of gouty arthropathy. The mechanisms of hyperuricemia and inflammatory access and their therapeutic implications are described. Chondrocalcinosis is a radiographic entity characterized by deposits of calcium pyrophosphate crystals (CPP) within the fibrocartilage or hyalin cartilage. CPP arthropathies symptomatology is polymorphic and likely resemble in primary osteoarthritis, pseudo-gout acute attacks, or chronic mono-, oligo- or polyarthritis. Its pathophysiology remains uncompletely understood, although there is growing knowledge on the place of some actors involved in the pathogenesis of chondrocalcinosis, described in the article.

Clinical implications of pathogenic calcium crystals.

PURPOSE OF REVIEW: The role of intraarticular calcifications has been challenged over the past years, with respect to cartilage destruction, especially in osteoarthritis. RECENT FINDINGS: Main themes reviewed in this article will discuss prevalence of articular cartilage calcifications, mechanisms of cartilage calcifications, and mostly the pathogenic role of both calcium pyrophosphate and basic calcium phosphate crystals. SUMMARY: A direct pathogenic role of both calcium crystals has been depicted, in cartilage as a crystal-induced stress, or via acute or chronic crystal-induced synovitis.

Association between low cortical bone mineral density, soft-tissue calcification, vascular calcification and chondrocalcinosis: a case-control study.

OBJECTIVES: To examine the association between bone mineral density (BMD), soft-tissue calcification, vascular calcification and chondrocalcinosis (CC). METHODS: A case-control study within the Genetics of Osteoarthritis and Lifestyle (GOAL) database (n=3170). All GOAL participants completed a questionnaire self-reporting current and early adult life exposures. Radiographs of knees, hands and pelvis were scored for osteoarthritis (OA), CC, pelvic vascular calcification, peri-articular knee calcification and metacarpal index (MCI-measure of cortical BMD). Calcaneal dual-energy X-ray absorptiometry (DEXA) was performed. Cases had radiographic CC, while controls did not have CC at any radiographed site. OR, 95% CI were used to measure association between risk factors and CC. Logistic regression was used to adjust for confounding and to estimate the adjusted OR (aOR). RESULTS: Low MCI (aOR (95%) for CC in 1st tertile 1.41 (1.06 to 1.89), with 3rd tertile referent), soft-tissue calcification (aOR (95%) for CC 1.81 (1.36 to 2.42)), and vascular calcification (aOR (95%) for CC 1.76 (1.13 to 2.75)) independently associated with CC. There was a negative association between body mass index and CC (aOR (95%) for CC in 2nd and 3rd tertiles 0.68 (0.53 to 0.89), and 0.67 (0.51 to 0.88) respectively with 1st tertile referent). Age and OA associated with CC. However, only age and low MCI independently associated with CC at >1 joint. Self-reported meniscectomy, low cortical BMD, vascular calcification, and soft-tissue calcification independently associated with knee CC. CONCLUSIONS: This study identifies several novel associations of CC including low cortical BMD. The association between vascular calcification, soft-tissue calcification, and CC suggests a generalised constitutional predisposition to calcium crystal formation.

HFE-related hemochromatosis: an update for the rheumatologist.

Hereditary hemochromatosis is a frequent disease in Caucasian populations. It leads to progressive iron overload in a variety of organs. The most common cause is the C282Y homozygous mutation in the HFE gene. The classical triad of skin hyperpigmentation, diabetes, and liver cirrhosis is nowadays rare but musculoskeletal symptoms are common in HFE-related hemochromatosis. Typically the second and third metacarpophalangeal joints, and the wrist, hip, and ankle joints are affected. Clinical symptoms include osteoarthritis-like symptoms, pseudogout attacks, and synovitis sometimes resembling rheumatoid arthritis. Radiographs show degenerative changes with joint space narrowing, osteophytes, and subchondral cysts. Chondrocalcinosis in the wrist and knee joints is seen in up to 50 % of patients. Although most other organ manifestations regress during phlebotomy, musculoskeletal symptoms often persist or even become worse. Importantly, patients are at an increased risk of severe large-joint arthritis necessitating joint replacement surgery. Therefore, future research should focus on the pathogenesis and treatment options for HH arthropathy.

Gitelman's syndrome associated with chondrocalcinosis: a case report.

Gitelman's syndrome (GS) is a rare disease with autosomal recessive trait, characterized by hypokalemia, hypomagnesemia, metabolic alkalosis, hypocalciuria and hyperkinemic hyperaldosteronism. While muscle weakness, tetany, stomachache, nausea and fever are very common, it could sometimes be completely asymptomatic as is the case in our patient. It is generally benign, but some severe complications like growth retardation and, though rare, paralysis and cardiac arrest could also be seen. A 57-year-old male patient sent to our hospital for further examination because of hypokalemia was diagnosed with GS as a result of clinical and laboratory assessments. Potassium and magnesium replacement was started. We are presenting our case seeing that GS is not a syndrome to be overlooked as it bears a risk of severe complications, although it might be asymptomatic until advanced ages.

Pseudogout in the early postoperative period after total knee arthroplasty.

Postoperative pseudogout after total knee arthroplasty is rare. If pseudogout attacks are misdiagnosed as periprosthetic sepsis, patients may undergo unnecessary surgical procedures. We report a case of pseudogout in the early postoperative period. The attack ensued shortly after a nonsteroidal antiinflammatory drug was discontinued. The diagnosis was confirmed by aspiration, and the patient improved after readministration of the nonsteroidal antiinflammatory drug. Although rare, pseudogout should be considered in the differential when approaching a suspected infection after total knee arthroplasty.

Risk factors for pseudogout in the general population.

Objective. To evaluate the association between the purported risk factors for chondrocalcinosis and gout and the risk of pseudogout in the general population. Methods. We conducted a case-control study nested within a UK general practice database (The Health Improvement Network) by identifying incident cases of pseudogout between 1986 and 2007 and up to 10 control subjects matched to each case, based on age, sex and follow-up time. We evaluated the purported risk factors for chondrocalcinosis (i.e. OA, RA, hyperparathyroidism and diuretics) and established risk factors for gout (as comparison exposures) using conditional logistic regression analysis. Results. We identified 795 cases of pseudogout and 7770 matched control subjects. The risk of pseudogout was associated with hyperparathyroidism [odds ratio (OR) 4.87; 95% CI 2.10, 11.3], OA (OR 2.91; 95% CI 2.48, 3.43) and loop diuretic use (OR 1.35; 95% CI 1.09, 1.67). RA, thiazide diuretic use, BMI and other gout risk factors were not associated with the risk of pseudogout, except for chronic renal failure (OR 2.29; 95% CI 1.30, 4.01). Conclusion. This general population study based on physician-recorded pseudogout suggests that most of the previously observed associations with chondrocalcinosis are replicable with the risk of pseudogout, but there are notable differences, such as thiazide diuretics, RA and chronic renal failure, highlighting the need to study the clinical outcome, pseudogout. Avoiding loop diuretics may help individuals with recurrent pseudogout.

Cauda equina syndrome caused by pseudogout involving the lumbar intervertebral disc.

Calcium pyrophosphate dihydrate (CPPD) deposition disease, also known as pseudogout, is a disease that causes inflammatory arthropathy in peripheral joints, however, symptomatic involvement of the intervertebral disc is uncommon. Herein, we describe a 59-yr-old patient who presented with cauda equina syndrome. Magnetic resonance imaging of the patient showed an epidural mass-like lesion at the disc space of L4-L5, which was compressing the thecal sac. Biopsy of the intervertebral disc and epidural mass-like lesion was determined to be CPPD deposits. We reviewed previously reported cases of pseudogout involving the lumbar intervertebral disc and discuss the pathogenesis and treatment of the disease.

European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis.

OBJECTIVES: To agree terminology and to develop recommendations for the diagnosis of calcium pyrophosphate deposition (CPPD). METHODS: The European League Against Rheumatism (EULAR) CPPD Task Force, comprising 15 experts from 10 countries, agreed the terms and recommendations for diagnosis of CPPD using a Delphi consensus approach. Evidence was systematically reviewed and presented in terms of sensitivity, specificity and positive likelihood ratio (LR) to support diagnosis; ORs were used for association. Strength of recommendation (SOR) was assessed by the EULAR visual analogue scale. RESULTS: It was agreed that 'CPPD' should be the umbrella term that includes acute calcium pyrophosphate (CPP) crystal arthritis, osteoarthritis (OA) with CPPD and chronic CPP crystal inflammatory arthritis. Chondrocalcinosis (CC) defines cartilage calcification, most commonly due to CPPD and detected by imaging or histological examination. A total of 11 key recommendations were generated on the topics of clinical features, synovial fluid (SF) examination, imaging, comorbidities and risk factors. Definitive diagnosis of CPPD relies on identification of SF CPP crystals. Rapid onset inflammatory symptoms and signs are suggestive but not definitive for acute CPP crystal arthritis. Radiographic CC is not highly sensitive or specific, whereas ultrasonography appears more useful (LR=24.2, 95% CI 3.51 to 168.01) for peripheral joints. Recognised risk factors for CPPD include ageing, OA and metabolic conditions such as primary hyperparathyroidism, haemochromatosis and hypomagnesaemia; familial forms are rare. SORs varied from 53 to 99 (maximum 100). CONCLUSION: New terms for CPPD were agreed and 11 key recommendations for diagnosis of CPPD were developed using research evidence and expert consensus.

Pathogenesis of calcium pyrophosphate deposition disease.

Calcium pyrophosphate deposition disease is defined by the presence of calcium pyrophosphate (CPP) crystals in articular cartilage and is the fourth most common type of arthritis in adults. Despite its high prevalence, the etiology of CPPD disease remains unclear and no specific therapies currently exist. It has been known for several decades that abnormalities of cartilage pyrophosphate metabolism are common in patients with CPPD disease, and this classic work will be reviewed here. Recent studies of rare familial forms of CPPD disease have provided additional novel information about its pathophysiology. This work suggests that CPPD disease occurs through at least two unique and potentially intertwined biomolecular pathways. We are hopeful that a detailed understanding of the components and regulation of these pathways will lead to improved therapies for this common disease.

The role of calcium crystals and their effect on osteoarthritis pathogenesis.

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive degeneration of articular cartilage. Due to its high prevalence and limited treatment options, OA has become one of the most disabling diseases in developed countries. In recent years, OA has been recognized as a heterogenic disease with various phenotypes. Calcium crystal-related endotypes, which are defined by either a distinct functional or pathobiological mechanism, are present in approximately 60% of all OA patients. Two different calcium crystals can accumulate in the joint and thereby calcify the cartilage matrix, which are basic calcium phosphate (BCP) and calcium pyrophosphate (CPP) crystals. The formation of these crystals depends mainly on the balance of phosphate and pyrophosphate, which is regulated by specific proteins controlling the pyrophosphate metabolism. Dysregulation of these molecules subsequently leads to preferential formation of either BCP or CPP crystals. BCP crystals, on the one hand, are directly associated with OA severity and cartilage degradation. They are mostly located in the deeper cartilage layers and are associated with chondrocyte hypertrophy. CPP crystal deposition, on the other hand, is a hallmark of chondrocalcinosis and is associated with aging and chondrocyte senescence. Therefore, BCP and CPP crystals are associated with different chondrocyte phenotypes. However, BCP and CPP crystals are not mutually exclusive and can coexist in OA, creating a mixed endotype of OA. Both crystals clearly play a role in the pathogenesis of OA. However, the exact impact of each crystal type on either driving the disease progression or being a result of chondrocyte differentiation is still to be elucidated.