Phenotype-genotype correlation and follow-up in adult patients with hypokalaemia of renal origin suggesting Gitelman syndrome.

INTRODUCTION: Gitelman syndrome (GS) is a tubulopathy caused by SLC12A3 gene mutations, which lead to hypokalaemic alkalosis, secondary hyperaldosteronism, hypomagnesaemia and hypocalciuria. AIM: The aim of this study was to assess the prevalence of SLC12A3 gene mutations in adult hypokalaemic patients; to compare the phenotype of homozygous, heterozygous and non-mutated patients; and to determine the efficiency of treatment. METHODS: Clinical, biological and genetic data were recorded in 26 patients. RESULTS: Screening for the SLC12A3 gene detected two mutations in 15 patients (six homozygous and nine compound heterozygous), one mutation in six patients and no mutation in five patients. There was no statistical difference in clinical symptoms at diagnosis between the three groups. Systolic blood pressure tended to be lower in patients with two mutations (P=0.16). Hypertension was unexpectedly detected in four patients. Five patients with two mutated alleles and two with heterozygosity had severe manifestations of GS. Significant differences were observed between the three groups in blood potassium, chloride, magnesium, supine aldosterone, 24 h urine chloride and magnesium levels and in modification of the diet in renal disease. Mean blood potassium levels increased from 2.8 ± 0.3, 3.5 ± 0.5 and 3.2 ± 0.3 before treatment to 3.2 ± 0.5, 3.7 ± 0.6 and 3.7 ± 0.3 mmol/l with treatment in groups with two (P=0.003), one and no mutated alleles respectively. CONCLUSION: In adult patients referred for renal hypokalaemia, we confirmed the presence of mutations of the SLC12A3 gene in 80% of cases. GS was more severe in patients with two mutated alleles than in those with one or no mutated alleles. High blood pressure should not rule out the diagnosis, especially in older patients.

[Sarcoidosis associated with hypothyroidism due to thyrotropin-receptor blocking antibodies]. / Syndrome de Löfgren associé à une hypothyroïdie par anticorps bloquant les récepteurs de la TSH.

The association of sarcoidosis and auto-immune thyroid disease has been reported. We report a 29-year-old woman, treated for hypothyroidism caused by thyrotropin-receptor blocking antibodies, who developed a sarcoidosis (Löfgren's syndrome). Auto-immune thyroid diseases and sarcoidosis could share common pathogenic mechanisms.

[Urinary ammonium: validation of an enzymatic method and reliability with an indirect urine ammonium estimation]. / Ammoniuries: validation d'une technique de dosage enzymatique et évaluation par rapport à une estimation par le calcul.

Urinary ammonium excretion is the best parameter to quantify net acid excretion by the kidney. As measurement of ammonium excretion is not routinely available, clinicians use formulas to estimate NH(4)+ excretion. However, the measurement of urinary NH(4)+ concentration can be performed by an automatically method, which is suitable for clinical practice. The aim of this study is to evaluate the validity of the enzymatic method of ammonium determination with Ammonia SL Elitech Diagnostics reagent on an Olympus AU 2700 analyzer, which use 1/100 diluted urine samples. A clinico-biological study allowed us to compare measurements obtained during a 30 months' period with the above enzymatic method with results obtained by a formula of calculation. Variations coefficients (CV%) of repeatability were less than 2.4% and, those of reproducibility tests less than 2,6%. Linearity was verified from 0.62 mmol/L to 158 mmol/L. Analytical sensitivity was 0.52 mmol/L and the correlation obtained with the assay used to date in the laboratory was excellent (y = 1.11 x - 1.72 ; r = 0.98). There is a significant positive correlation between measured concentrations obtained with this enzymatic method and urinary ammonium concentration estimates using the modified urine osmolal gap in two groups of patients, with and without mild chronic renal failure. As urine ammonium estimation is not reliable for detecting small changes in ammonium excretion, it must be absolutely measured when renal functional tests are performed. The assay described in this paper is simple, automatic and offers for the clinician accurate matter for the measurement of NH(4)+ excretion.

[Digital ischemia related to bromocriptin]. / Ischémie digitale sous bromocriptine.

INTRODUCTION: Bromocriptin has been associated with stroke and myocardial infarction in the postpartum period. We report on the case of a patient who developed digital ischemia while receiving this drug. EXEGESIS: Mrs D, 28 years old presented with digital ischemia occurring five days after the introduction of bromocriptin. Magnetic resonance imaging also displayed stroke in the area of the right posterior cerebellar artery. The course was favourable after discontinuation of the drug. DISCUSSION: Bromocriptin is an ergot derivative with dopaminergic agonist properties. A paradoxical vasoconstriction is rarely associated with vascular ischemic complications, including digital ischemia.

[Results of systematic subtotal parathyroidectomy with thymectomy for tertiary hyperparathyroidism after renal transplantation - 70 patients]. / Résultats de la parathyroïdectomie subtotale de principe associée à une thymectomie systématique pour le traitement de l'hyperparathyroïdisme tertiaire après transplantation rénale chez 70 patients.

BACKGROUND: Due to the relatively small number of patients involved, there is currently no consensus on what operation should be performed in patients with tertiary hyperparathyroidism after renal transplantation. METHOD: Retrospective analysis of the 70 patients with tertiary hyperparathyroidism who all underwent subtotal parathyroidectomy with transcervical thymectomy in the same institution between 1978 and 2003. RESULTS: The delay between transplantation and parathyroidectomy was 4,1+/-4,3 years. Follow up was available for all patients. Mean follow-up was 5,6+/-5 years. Glomerular filtration rate (GFR) was 53+/-21 ml/min at parathyroidectomy and 42+/-29 ml/min at follow-up [<30 ml/min in 26 patients (37%), 30 - 60 ml/min in 25 patients (36%) et>60 ml/min in 19 patients (27%)]. One patient was successfully reoperated for persistent tertiary hyperparathyroidism during follow-up. No patient was hypercalcemic at follow-up. Four patients with a GFR<30 ml/min had a PTH level>fourfold normal values (6%) without signs or symptoms of hyperparathyroidism. One patient was hypocalcemic (1,5%) and two patients were normocalcemic with undetectable or infranormal PTH level (3%) under oral vitamin D and calcium medication. CONCLUSION: This approach permits not only to cure the majority of patients with tertiary hyperparathyroidism but also to avoid recurrence when the renal function declines. When medical management has failed, we recommend systematic subtotal parathyroidectomy with thymectomy for patients with tertiary hyperparathyroidism and this should usually be performed during the second year after transplantation.

[Calcific arteriolopathy (Calciphylaxis)]. / Artériolopathie calcique (Calciphylaxie).

PURPOSE: Calcific arteriolopathy (CA), also known as " Calciphylaxis " describes a phenomenon of necrosis, mainly cutaneous and sometimes systemic, due to the obliteration of the arteriole's lumen. Initially there are under-intimal calcium deposits, and then the thrombosis occurs leading to the necrosis. CA affects mainly the renal insufficient hemodialysed patient, but not exclusively. We present 4 cases which illustrate well the etiologic spectrum of CA: terminal renal insufficiency, neoplasia, primary hyperparathyroidism, proteinuria, vitamin K inhibitors. We describe the AC's epidemiology, its cutaneous and systemic clinical presentations, its treatment. We make the hypothesis that CA is a strong risk marker in matter of cardiac mortality and we discuss this point. CURRENT KNOWLEDGE AND KEY POINTS: In this article we describe the numerous breakthroughs that have been made in matter of research about calcification over the past few years: inhibitors of calcium phosphate deposition, vitamin D and PTH1R, protein-calcium complexes, cell death, induction of bone formation. These data are analysed from a clinical point of view with practical purposes. We present CA not only as a cutaneous disease but as a systemic pathology. FUTURE PROSPECTS AND PROJECTS: The CA epidemiology is an incentive to more diagnosis suspicion in front of organ infarct involving a patient likely to be concerned by CA. The scientific and therapeutic breakthroughs in matter of calcification enable a better prevention of the disease. Nevertheless it remains very difficult to cure when installed.

Thrombotic microangiopathy in adult Still's disease.

Adult Still's disease (ASD) is a rare systemic disorder characterized by fever, arthralgia, cutaneous rash, and lymphadenopathy, with high polymorphonuclear leucocytosis and low glycosylated ferritinaemia. Kidney involvement has been reported rarely. We present a patient with ASD who developed haemolytic uraemic syndrome (HUS). The 42-year-old patient was admitted for unexplained fever related to ASD according to Yamaguchi's classification criteria. As Still's disease was resistant to prednisone, high-dose intravenous immunoglobulins (IV Ig) were administered. During the follow-up the patient developed acute renal failure and non-immune haemolytic anaemia with high levels of antiphospholipid antibodies (IgG anticardiolipin antibodies and anti-beta2 glycoprotein 1 antibodies). Renal biopsy disclosed thrombotic microangiopathy (TMA) with arteriolar and glomerular involvement. Treatment with steroids and intravenous IV Ig was reinitiated but renal function worsened towards end-stage renal failure. In this case, we suggest that antiphospholipid antibodies could have promoted arteriolar and glomerular TMA. HUS may be the cause of acute renal failure in Still's disease.

[Familial small-vessel vasculitis of the kidney]. / Vascularite familiale des vaisseaux de petit calibre des reins.

INTRODUCTION: Familial forms of small-vessel vasculitis has been reported in 14 families (including this one). CASES: A father and son were both diagnosed with renal vasculitis (pauci-immune crescentic glomerulonephritis). Both had antimyeloperoxidase autoantibodies, and there was no evidence of a common environmental factor. DISCUSSION: These cases suggest the role of constitutional factors in the pathogenesis of antineutrophil cytoplasmic antibody-associated vasculitis.

Subtotal parathyroidectomy with thymectomy for autonomous hyperparathyroidism after renal transplantation.

BACKGROUND: There is currently no consensus on the operation that should be performed in patients with tertiary hyperparathyroidism (HPT) after renal transplantation. METHODS: : A retrospective analysis of 70 patients with tertiary HPT who underwent subtotal parathyroidectomy with transcervical thymectomy was performed. RESULTS: Mean (s.d.) follow-up was 5.6(5.0) years. Mean (s.d.) glomerular filtration rate (GFR) at follow-up was 42(29) ml/min and was less than 30 ml/min in 26 patients (37 per cent), 30-60 ml/min in 25 (36 per cent) and more than 60 ml/min in 19 (27 per cent). One patient had persistent disease and was cured after reoperation. No patient was hypercalcaemic. Four patients (6 per cent) with a GFR below 30 ml/min had a parathyroid hormone (PTH) level more than four times the normal value without any signs or symptoms of secondary HPT. One patient (1 per cent) was hypocalcaemic and two (3 per cent) were normocalcaemic, with undetectable or below-normal PTH levels while receiving oral vitamin D and calcium medication. CONCLUSION: Systematic subtotal parathyroidectomy associated with thymectomy is effective in treating most renal transplant recipients with tertiary HPT and also minimizes the recurrence of HPT in patients with declining renal function.

Proximal tubular dysfunction in primary Sjögren's syndrome: a clinicopathological study of 2 cases.

Tubulointerstitial nephritis is the most common renal complication in primary Sjögren's syndrome (SS). It is usually associated with symptoms of distal tubular dysfunction, type I (distal) renal tubular acidosis (RTA) and nephrogenic diabetes insipidus. Proximal tubular abnormalities are considered to be less frequent, and Fanconi's syndrome has been only exceptionally reported in patients with SS. We describe 2 patients with primary SS, characterized by xerostomia, dry eyes, extensive lymphocytic infiltrate on salivary gland biopsy, positive tests for anti-SSA/SSB antibodies and/or antinuclear antibodies, who presented in renal failure with proteinuria, microscopic hematuria and type I RTA. Further studies revealed proximal tubular dysfunction, including renal glucosuria, generalized aminoaciduria, phosphaturia, uricosuria, together with proximal (type II) RTA in 1 case. Neither of these patients had Bence Jones proteinuria or monoclonal gammopathy. Kidney biopsy showed focal proximal tubulitis, associated with proximal tubular cell atrophy and dedifferentiation, and diffuse interstitial nephritis with fibrosis. No significant glomerular or peritubular deposits of immunoglobulin light or heavy chain were observed. These findings demonstrate that diffuse, distal and proximal, tubular dysfunction may occur in patients with SS and interstitial nephritis. Lymphocytic infiltration of proximal tubular cells is probably involved in the pathogenesis of Fanconi's syndrome in SS. However, the mechanisms involved in the alteration of sodium-dependent apical transports remain to be elucidated.

[Polymyositis induced or associated with lipid-lowering drugs: five cases]. / Polymyosites induites ou associées aux traitements hypolipémiants? A propos de cinq cas.

PURPOSE: Rhabdomyolysis and myositis are rare, dose-related complications of statins and fenofibrates. The outcome is favorable as a rule with rapid regression after stopping the responsible drug. Recently, various auto-immune disease with evidence of hypersensitivity to HMG-CoA reductase inhibitors or fibrates drugs have been reported. Less than ten cases of dermatomyositis and polymyositis due to cholesterol-lowering drugs (CLD) have been previously reported. Five more cases polymyositis associated with CLD are reported. METHODS: Symptoms were compatible with diagnosis of polymyositis according to Bohan and Peter and with previous reported criteria for drug-induced myopathy in all cases. None of these patients had previous other connective tissue disorders. RESULTS: Five patients (median age 68 [54-78], female N =4) with CLD treatment (statin N =4, fenofibrates N =1) have developed iatrogenic polymyositis. All of them presented both proximal muscular weakness and increased muscle enzyme levels. One patient had iatrogenic antisynthetase syndrome characterized by mechanic's hand, Raynaud's phenomenon and anti JO1 antibodies. One other had sclerodermic hand oedema. Antinuclear antibodies were positive in 4 cases and muscle biopsy revealed polymyositis infiltrate in 4 cases. CLD treatment was discontinued with partial clinical improvement in 3 cases. Clinical remission was obtained with corticosteroid (N =5) in association with immunosuppresive agents in 3 cases. CONCLUSION: Muscular symptoms in patient with CLD treatment could be the first symptom of a polymyositis revealed or increased by this treatment and must encourage physician with antinuclear antibodies screening especially in case of proximal muscular weakness and increased muscle enzyme levels.

[Camptocormia: a sign of axial myopathy. Report of 7 cases]. / La camptocormie: un signe de myopathie axiale. A propos de sept observations.

PURPOSE: Camptocormia or progressive lumbar kyphosis is an anterior bend of the trunk. It appears in orthostatism or while walking and is reducible in the decubitus position. It concerns patients older than 60 years of age. It is due to a fatty degeneration of the paravertebral muscles, although the physiopathology remains unclear. METHODS: We report seven cases of camptocormia revealing authentic myopathies. RESULTS: Our observations concern five women and two men of 55 to 72 years of age. All patients present lumbar kyphosis and had a fatty involution of the paraspinal muscles on the muscular MRI. Four patients fulfilled the Bohan and Peter criteria of polymyositis and dermatomyositis. In the other cases paravertebral muscular biopsies led to the diagnosis of a congenital myopathy, a mitochondrial myopathy and an amyloid myopathy. Four patients received a corticosteroid-immunoglobulins or cyclosporin regimen. An improvement in the camptocormia was observed in three cases. In the other cases the treatment consisted of chemotherapy on account of severe nephrotic syndrome, a coenzyme-Q treatment for the patient with mitochondrial myopathy and only physiotherapy in the case of congenital myopathy, but without positive effect on camptocormia. CONCLUSION: Camptocormia appears as a muscular symptom that may reveal an axial myopathy due to multiple and varied pathologies. Thus, the discovery of camptocormia requires an aetiological investigation in order to propose an adequate treatment, which should be associated with physiotherapy.

[Hemorrhagic fever with renal syndrome]. / Fièvre hémorragique avec syndrome rénal.

Puumala hantavirus is the most common hantavirus infection in Western Europe. The causative agent, Puumala virus, is a member of the Hantavirus genus in the Bunyaviridae family. The natural hosts of hantaviruses are chronically, but asymptomatic infected rodents, which transmit the virus to human in their excretions. Puumala virus is carried by the bank vole, clethrionomys glareolus. Hemorrhagic fever with renal syndrome (HFRS) caused by Puumala virus in France or Belgium is very similar to the previously described Nephropathia epidemica in Scandinavia. In most severe cases, the disease is clinically characterized by high fever of abrupt onset, headache, loin or abdominal pains, nausea and vomiting, and occasionally acute and transient myopia. Renal involvement results in transient proteinuria and hematuria and acute renal failure. Except for interstitial hemorrhage in the outer medulla, the renal histopathologic findings are unspecific and include prominent changes in the interstitium with interstitial oedema and inflammatory infiltrates. Thrombocytopenia, mild elevation of liver enzymes, and leukocytosis are typical laboratory findings. Spontaneous complete recovery is the rule. Laboratory diagnosis is primarily based on serology such as indirect immunofluorescence or capture enzyme--linked immunosorbent assays which detect IgM antibodies and an increased level of IgG antibodies against Puumala virus. Viral antigen may be demonstrated in the cytoplasm of renal tubular epithelial cells.

Intraoperative decay profile of intact (1-84) parathyroid hormone in surgery for renal hyperparathyroidism--a consecutive series of 80 patients.

BACKGROUND: The utility of intraoperative parathyroid hormone (PTH) monitoring is unclear in the surgical management of renal hyperparathyroidism. Our goal was to define the normal pattern of decay during operation for renal hyperparathyroidism by using the rapid intact (1-84) parathyroid hormone (PTH) assay. METHODS: Eighty consecutive patients underwent neck exploration for renal hyperparathyroidism. Intact PTH levels were monitored with a rapid immunochemiluminometric assay. Samples were assayed at the induction of anesthesia, after dissection before resection, and 20 and 40 minutes after resection. Follow-up ranged from 3 to 24 months. RESULTS: Twenty minutes after resection, PTH levels remained many-fold supranormal. Seventy-seven patients (96%) were cured. Of these, 75 patients (94%) had PTH decay of more than 50% from the preoperative level; 74 (99%) were cured. Only 1 of 3 patients (33%) in whom the PTH level decreased less than 40% from the preoperative level was cured. Two patients had intermediate values and both were cured. CONCLUSIONS: The intraoperative decay of PTH during operation for renal hyperparathyroidism is slower than for patients with normal renal function. However, 20 minutes after resection, a decline to less than 50% of the preoperative level predicts cure, while a level greater than 60% predicts failure.

The diabetic patient with renal insufficiency.

Diabetic mellitus is often complicated by nephropathy with progression to renal failure. Most patients with clinical diabetes who present with renal insufficiency have diabetic glomerulosclerosis, although some (particularly in Type 2 diabetes) present with other glomerular diseases. The purpose of this study was to provide practical recommendations for the management of patients with diabetes and renal failure and evaluate the prevalence of non-diabetic glomerulopathies in Type 2 diabetic patients. Various forms of glomerulonephritis have been associated with diabetes, occasionally leading to alternative management of these patients in attempts to reverse or contain renal failure.

Adult Fanconi syndrome secondary to light chain gammopathy. Clinicopathologic heterogeneity and unusual features in 11 patients.

Fifty-seven cases of Ig light chain-associated Fanconi syndrome (FS) have been reported so far, mostly as isolated reports. The pioneering work by Maldonado and associates (35), who reviewed the first 17 cases in 1975, led to the unifying concept that patients with FS and Bence Jones proteinuria have a special form of plasma cell dyscrasia characterized by slow progression of the tumor and by prominent crystal formation in proximal tubule cells, in the absence of myeloma casts in the distal tubule. We carefully reappraised these characteristics in a series of 11 patients. Ten renal biopsy specimens were available for electron microscopy, adding to the 15 previously reported cases with ultrastructural studies. Moreover, 10 of the kappa light chains could be entirely or partially sequenced and tested for their resistance to cathepsin B, a lysosomal protease present in proximal tubule cells. Our series showed an unexpected clinicopathologic heterogeneity. Seven patients presented with the typical clinical and pathologic features of FS and low-mass myeloma or monoclonal gammopathy of undetermined significance (MGUS), in keeping with Maldonado et al's description. Crystals in bone marrow cells were detected in patients of this group, only. Three patients who presented with full-blown FS exhibited, however, the characteristic features of myeloma cast nephropathy in the setting of high-mass myeloma. One patient of this group also had numerous crystals in proximal tubule cells. The eleventh patient had complete FS with MGUS, but no crystals in proximal tubule cells even after electron microscopy. Contrasting with the clinicopathologic heterogeneity, genetic and biochemical analyses of the light chains showed a striking homogeneity. First, they all were of the kappa type. Second, 8 of 9 belonged to the V kappa I variability subgroup, which indicates that FS light chains are related by the sequence of their variable regions. Third, the 8 V kappa I light chain sequences most likely originated from only 2 germline genes, LCO2/012 and LCO8/018. Fourth, all 5 LCO2/012-derived sequences presented an unusual hydrophobic or nonpolar residue at position 30. These sequence peculiarities may account for unusual physicochemical properties of the light chains including the resistance of their variable domain V kappa to proteolysis by cathepsin B, observed in 7 of 9 patients in our series, while light chains isolated from patients with myeloma cast nephropathy are completely digested. Resistance of V kappa to proteolysis in FS patients can explain the accumulation of the light chain in the endocytotic compartment of the proximal tubule cells, leading to impairment of proximal tubule functions.

[Heterogeneity of nephropathies in type 2 diabetes]. / Hétérogénéité de la néphropathie chez les diabétiques de type 2.

DIVERSE KIDNEY DISORDERS: Patients with type 2 diabetes mellitus who develop nephropathy can have various types of disorders capable of progressively destroying the kidneys. It is now clear that the same type of diffuse or nodular glomerulosclerosis develops irrespective of the type of diabetes, i.e. the pathophysiology of hyperglycemia. HETEROGENEITY: There is however a certain degree of heterogeneity in terms of clinical presentation, clinical course and response to treatment. Heterogeneity is due to age, the number of different accumulated risk factors and disease states, genetic factors that are in the process of being identified, and finally, lesions to the urologic apparatus, the arteries, and the renal parenchyma itself that are not directly caused by diabetes. PRACTICAL IMPACT: Mixed lesions, due to both diabetic and non-diabetic causes, may therefore exist in the same kidney. These different possibilities should be systematically considered in order to adopt an individualized investigative and therapeutic attitude for each new patient.

Serial measurements of antineutrophil cytoplasmic autoantibodies in patients with systemic vasculitis.

PURPOSE: To assess the value of serial determinations of antineutrophil cytoplasmic autoantibodies (ANCA) for monitoring disease activity in patients with systemic vasculitis. PATIENTS AND METHODS: Forty-three patients with histologically proven vasculitis (21 with Wegener's granulomatosis, 17 with microscopic polyangiitis, and 5 with renal-limited vasculitis) were studied for a median follow-up of 22 months. Disease activity was prospectively assessed and quantified by the Birmingham Vasculitis Activity Score. A total of 347 sera were analyzed for ANCA determination. RESULTS: Relapses occurred in 23 (54%) of 43 patients. Diagnostic category (Wegener's granulomatosis vs micropolyangiitis and renal-limited vasculitis), severity of initial symptoms (mean vasculitis activity score, mean number of organs involved), and ANCA pattern [cytoplasmic-ANCA (c-ANCA) vs perinuclear-ANCA (p-ANCA)] did not significantly differ between relapsers and nonrelapsers. Lung involvement was more frequent at onset among relapsers [16 of 23 (70%) vs 6 of 20 (30%); P = 0.02]. Relapses were slightly, but not significantly, more frequent in patients with Wegener's granulomatosis or a c-ANCA pattern. The percentage of relapsers was greater in patients with persistently positive ANCA than in patients with negative or decreasing ANCA titers (86% vs 20%, P = 0.0001). However, the predictive value of an increase in ANCA titers for the occurrence of a subsequent relapse was only 28% (4 of 14) for c-ANCA, 12% (2 of 17) for anti-proteinase 3-ANCA, and 43% (6 of 14) for anti-myeloperoxidase-ANCA. An increase in ANCA occurred before or during relapse in 33% (10 of 30) of cases for c-ANCA/anti-proteinase 3 antibodies, and 73% (11 of 15) of cases for anti-myeloperoxidase antibodies. CONCLUSION: The persistence of ANCA positivity is strongly associated with relapses. However, an increase in ANCA titers has a poor value for the early prediction of a subsequent relapse and should not be used as a sole parameter for therapeutic intervention. In addition, our results suggest that serial anti-myeloperoxidase determination may be useful as a prognostic marker in patients who are p-ANCA positive.