We came across a somewhat peculiar case of terminal renal insufficiency in an elderly lady. We believe this case illustrates well the difficulties that a clinician faces on daily basis regarding the evaluation of glomerular filtration rate building on serum Creatinine level measurement alone. We have witnessed a creatinine clearance plunging till less than 2 ml/min without real need for renal replacement therapy. We have performed a Cystatine c serum level measurement for comparison.

Renal toxicity constitutes a dose-limiting side effect of anticancer therapies targeting vascular endothelial growth factor (VEGF). In order to study this further, we followed up 29 patients receiving this treatment, who experienced proteinuria, hypertension, and/or renal insufficiency. Eight developed minimal change nephropathy/focal segmental glomerulopathy (MCN/FSG)-like lesions and 13 developed thrombotic microangiopathy (TMA). Patients receiving receptor tyrosine kinase inhibitors (RTKIs) mainly developed MCN/FSG-like lesions, whereas TMA complicated anti-VEGF therapy. There were no mutations in factor H, factor I, or membrane cofactor protein of the complement alternative pathway, while plasma ADAMTS13 activity persisted and anti-ADAMTS13 antibodies were undetectable in patients with TMA. Glomerular VEGF expression was undetectable in TMA and decreased in MCN/FSG. Glomeruli from patients with TMA displayed a high abundance of RelA in endothelial cells and in the podocyte nuclei, but c-mip was not detected. Conversely, MCN/FSG-like lesions exhibited a high abundance of c-mip, whereas RelA was scarcely detected. RelA binds in vivo to the c-mip promoter and prevents its transcriptional activation, whereas RelA knockdown releases c-mip activation. The RTKI sorafenib inhibited RelA activity, which then promoted c-mip expression. Thus, our results suggest that c-mip and RelA define two distinct types of renal damage associated with VEGF-targeted therapies.

We would like to confirm the finding described recently by Dr Post1Post J.B. Thrombocytopenia associated with use of a biocompatible hemodialysis membrane: a case report.Am J Kidney Dis. 2010; 55: e25-e28Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar by reporting another case in which switching to a polysulfone dialysis membrane from another manufacturer was sufficient to reverse thrombocytopenia in a pregnant dialyzed patient. In May 2010, we started a 28-year-old gravida 5 para 2 pregnant woman on a daily program (6 days a week) of 4 hours postdilution online hemodiafiltration (HDF)2Haase M. Morgera S. Bamberg C. et al.A systematic approach to managing pregnant dialysis patients—the importance of an intensified haemodiafiltration protocol.Nephrol Dial Transplant. 2005; 20 (2537–2444)Crossref Scopus (74) Google Scholar using a polyethersulfone membrane (SureLyzer; a biocompatible polysulfone membrane supplied by Nipro Europe [www.nipro-europe.com]). Our objective was a predialysis serum urea level <14 mmol/L. Chronic kidney disease had been diagnosed nearly 2 years prior, without renal histology available before the preterminal stage. She was 13 weeks pregnant when we started HDF. Two weeks after the start of treatment, the platelet count started to decrease (Fig 1). Pre-eclampsia and HELLP (hemolysis, elevated liver enzymes, and low platelet count occurring in association with preeclampsia) syndrome were excluded because of the absence of hypertension, edema, proteinuria, and abnormal liver enzyme levels and because of the onset early in pregnancy. Antiphospholipid and antiplatelet antibodies were undetectable. Changing to a different biocompatible polysulfone membrane, FX100 (Fresenius [www.fresenius.com]), was followed by an increasing platelet count without a change in other HDF parameters. The patient completed her pregnancy successfully and gave birth at 36 weeks of gestation without complications. Platelet count remained within the reference range, ∼160 × 103/μL, until delivery. Although there is limited experience with the use of HDF in pregnant women,2Haase M. Morgera S. Bamberg C. et al.A systematic approach to managing pregnant dialysis patients—the importance of an intensified haemodiafiltration protocol.Nephrol Dial Transplant. 2005; 20 (2537–2444)Crossref Scopus (74) Google Scholar more efficient urea clearance and more frequent weekly sessions may be beneficial. We would like to confirm the finding described recently by Dr Post1Post J.B. Thrombocytopenia associated with use of a biocompatible hemodialysis membrane: a case report.Am J Kidney Dis. 2010; 55: e25-e28Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar by reporting another case in which switching to a polysulfone dialysis membrane from another manufacturer was sufficient to reverse thrombocytopenia in a pregnant dialyzed patient. In May 2010, we started a 28-year-old gravida 5 para 2 pregnant woman on a daily program (6 days a week) of 4 hours postdilution online hemodiafiltration (HDF)2Haase M. Morgera S. Bamberg C. et al.A systematic approach to managing pregnant dialysis patients—the importance of an intensified haemodiafiltration protocol.Nephrol Dial Transplant. 2005; 20 (2537–2444)Crossref Scopus (74) Google Scholar using a polyethersulfone membrane (SureLyzer; a biocompatible polysulfone membrane supplied by Nipro Europe [www.nipro-europe.com]). Our objective was a predialysis serum urea level <14 mmol/L. Chronic kidney disease had been diagnosed nearly 2 years prior, without renal histology available before the preterminal stage. She was 13 weeks pregnant when we started HDF. Two weeks after the start of treatment, the platelet count started to decrease (Fig 1). Pre-eclampsia and HELLP (hemolysis, elevated liver enzymes, and low platelet count occurring in association with preeclampsia) syndrome were excluded because of the absence of hypertension, edema, proteinuria, and abnormal liver enzyme levels and because of the onset early in pregnancy. Antiphospholipid and antiplatelet antibodies were undetectable. Changing to a different biocompatible polysulfone membrane, FX100 (Fresenius [www.fresenius.com]), was followed by an increasing platelet count without a change in other HDF parameters. The patient completed her pregnancy successfully and gave birth at 36 weeks of gestation without complications. Platelet count remained within the reference range, ∼160 × 103/μL, until delivery. Although there is limited experience with the use of HDF in pregnant women,2Haase M. Morgera S. Bamberg C. et al.A systematic approach to managing pregnant dialysis patients—the importance of an intensified haemodiafiltration protocol.Nephrol Dial Transplant. 2005; 20 (2537–2444)Crossref Scopus (74) Google Scholar more efficient urea clearance and more frequent weekly sessions may be beneficial. The corresponding author, Dr Bourry, may be contacted at [email protected] . Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests. Thrombocytopenia Associated With Use of a Biocompatible Hemodialysis Membrane: A Case ReportAmerican Journal of Kidney DiseasesVol. 55Issue 6PreviewBiocompatibility of a dialyzer membrane has been defined largely by the degree to which it activates complement. Modifications of the cellulose membrane and the development of synthetic membranes have minimized the activation of complement and its associated complications. However, less is known about the blood–dialyzer membrane interactions that may occur in membranes made of the same synthetic polymer. A patient is described who developed dialysis-associated thrombocytopenia using a Fresenius Medical Care Optiflux polysulfone membrane (F-160) that significantly improved when switched to the polysulfone Asahi REXEED 25S membrane (AR-25S). Full-Text PDF

En dehors de la greffe, les deux methodes de substitution de la fonction renale au stade d’insuffisance terminale sont l’hemodialyse et la dialyse peritoneale. Ces deux methodes comprennent plusieurs techniques : l’hemofiltration et l’hemodiafiltration rattachees a l’hemodialyse et la dialyse peritoneale automatisee avec ses multiples variantes rattachees a la dialyse peritoneale. Le but est le meme pour ces deux grandes lignes de traitement ; il s’agit de soustraire du plasma du patient un maximum des toxines dites uremiques qui ont tendance a s’accumuler avec la progression de l’insuffisance renale. La prise en charge de l’insuffisance renale terminale, la transplantation renale comprise, est un probleme de sante publique qui touche plus de 1 000 personnes par million d’habitants avec un coUt total pour la societe qui depasse les quatre milliards d’euros par an. Les modalites de dialyse varient par souci d’efficacite d’epuration, de confort du patient ou d’efficacite d’epuration pour telle ou telle famille de toxines uremiques. Le principe physico-chimique de base reste le meme pour les deux methodes : il s’agit de creer un contact entre deux milieux aqueux, le sang du patient d’une part et un liquide de constitution pharmacologique controlee dit le dialysat d’autre part, a travers une membrane selective et semi-permeable. Ce contact favorise un transfert des molecules dans les deux sens afin de retablir l’equilibre du milieu interne. La membrane est naturelle (le peritoine) dans le cas de la dialyse peritoneale et elle est synthetique dans le cas de l’hemodialyse. Globalement, les deux grandes lignes d’epurations extrarenales ont une efficacite comparable en terme de morbi-mortalite des patients. La dialyse peritoneale reste neanmoins une methode qui depend de la viabilite du peritoine en tant que membrane d’echange qui a tendance a se deteriorer, ce qui limite sa duree de vie. Les deux methodes, avec la transplantation renale, sont plus complementaires qu’exclusives d’autant plus que la duree de survie des patients ainsi que l’âge de mise en dialyse ne cessent d’augmenter avec le vieillissement general de la population. Autrement dit on envisage de plus en plus une prise en charge sur plusieurs annees voire sur plusieurs decennies ou se succederaient les trois methodes de remplacement de la fonction renale.

Although uncommon, thrombotic microangiopathy (TMA) is one of the most serious complications in patients with systemic lupus erythematosus. A 30-year-old black woman admitted to our hospital because of fever, fatigue, ‘dark’ urine and rapidly progressive renal failure was found to have systemic lupus erythematous and atypical hemolytic uremic syndrome. Kidney biopsy showed WHO class IV lupus nephritis with crescents and TMA. Hemodialysis was initiated for worsening renal failure. The patient was treated with corticosteroids, monthly pulse intravenous Cyclophosphamide, plasmapheresis and Rituximab on a weekly basis for 4 weeks. The patient’s blood pressure was aggressively controlled using antihypertensive agents. Despite this extensive therapy, she remained dialysis dependent although hematological parameters returned to normal values.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a devastating consequence of allogeneic haematopoietic stem cell transplantation (HSCT) with a mortality rate of 60–90%. None of the interventions used, as used up till now in idiopathic thrombotic thrombocytopaenic purpura (TTP) (fresh frozen plasma transfusion, plasma exchange and steroids), were effective to treat TA-TMA [1,2]. We report a dramatic improvement of TA-TMA in two HSCT patients [conditioning, cyclophosphamide, total body irradiation, graft-versus-host disease (GVHD) prophylaxis] using doxycycline. A 36-year-old woman with Hodgkin's lymphoma received an allogeneic HSCT in December 2002. Twelve months later, she developed a biopsy-proven TMA (proteinuria, 3 g/day, microscopic haematuria, oliguric acute renal failure with creatinine level at 680 µmol/L; haemoglobin Hb, 6.3 g/dL; schistocytes; platelet count, 35 × 109/L; LDH, 1754 IU/L). The serum complement proteins were at normal levels, no mutations of the membrane cofactor protein were found and a plasma ADAMTS13 activity was found at 40%. Steroids, plasma exchange, fresh frozen plasma transfusion, vincristine and haemodialysis were tried with a partial response (haemoglobin, 7.3 g/dL, platelet 70 000/mm3 both after treatment). Doxycycline 200 mg daily was added for a suspected gastrointestinal Bartonella infection. Within two months, haemoglobin and platelet count rose without transfusion to 10.8 g/dL and 234 000/mm3, respectively. Despite improvement of haematological parameters, the patient remained dialysis-dependent. The second patient had a similar haematologic disease and course under doxycycline prescribed for a bartholinitis. Five patients with TTP and Bartonella-like erythrocyte inclusions, successfully treated with doxycycline, experienced recurrence of their TTP following cessation of treatment [3]. TA-TMA has a multi-factorial aetiology of endothelial damage. Doxycycline targeting the adherens junction on endothelial cells prevents vascular hyperpermeability [4]. Doxycycline as a potential treatment of TA-TMA warrants further studies. Conflict of interest statement. None declared.

Background: Hepatitis C virus (HCV) co-infection occurs in 25% of HIV-infected persons. The impact of HIV/HCV coinfection on renal and patient outcomes is unclear.Methods: The main objective of the study is the comparison of outcomes (progression to advanced renal failure, initiation of dialysis, and death) in patients with HIV (n = 40), HCV (n = 30) or coinfection (n = 30) during the period between January 1999 and December 2007.Results: Patients were predominantly white men with a mean creatinine clearance of 2 50.6 +/- 32.2 ml per min per 1.73 m. Membranoproliferative glomerulonephritis (MPGN) and HIV-associated nephropathy were found in 34 and 9%, respectively. Seventeen patients needed transitory or definitive hemodialysis after 2, 2.5, and 12 months in HIV/HCV (n = 5), HIV (n = 6) and HCV (n = 6) infections, respectively. In multivariate analysis, variables found to independently predict outcome in HIV/HCV coinfected patients were younger age, a longer delay to kidney biopsy, cryoglobulinemia and MPGN. Twenty-one patients died, mostly in the HCV (n = 8) and/or HIV/HCV coinfected (n = 12) groups. The relative risk of death for HIV/HCV co-infected patients was 2.1 times more than for HCV-infected patients and 7.5 times more than for HIV-infected patients. HIV/HCV co-infection [odds ratio (OR),= 4; 95% confidence interval (CI), 1.3-12.9; P = 0.015] and MPGN (OR, 6; 95% CI, 2-18.8; P = 0.0018) were independently associated with death.Conclusion: Kidney disease is a relatively frequent complication in HIV or HCV monoinfected individuals. The impact of kidney disease on survival of HIV/HCV coinfected patients seems deleterious but remains largely unknown. (c) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

Priapism is defined as a prolonged penile erection of more than 6 h in the absence of sexual stimulation, which persists despite orgasm. The classification into two broad subtypes, low-flow and high-flow priapism, is universal. Stuttering priapism refers to a distinct condition whereby patients develop short-lived self-limiting episodes of prolonged and painful erections [1,2]. We report a rare case of stuttering priapism in a HIV positive patient. A 60-year-old white male with a long-standing HIV/HBV coinfection was admitted with an orthostatic stuttering painful penile erection. His current illness started 2 days earlier, when he developed a painful swelling of the lower limbs. There was no history of trauma, recent sexual activity, bicycle riding, alcohol consumption, and no previous priapism. His treatment included lamivudine, ritonavir, darunavir, etravirine, enfuvirtide, and tenofovir. Past medical history revealed left calf deep vein thrombosis and pulmonary embolism related to protein S deficiency 14 years earlier. Treatment at that time was cava filter implantation because of cerebral cavernoma hemorrhage under anticoagulation therapy. Physical examination in supine position was unremarkable with the penis at rest. When the patient stood up, examination showed a man distressed with pain, exhibiting swollen warm, tender lower limbs with tense shiny skin. The penis was markedly engorged and extremely tender. Angiographic computed tomography confirmed the diagnosis of extensive deep vein thrombosis extending into the deep pelvic veins and cava vein with cava filter thrombosis. Other investigations including full blood count, kidney, and liver function tests were all normal. The patient received analgesia and unfractionated heparin intravenously followed by a subcutaneous low-molecular weight heparin (enoxaparin sodium) 80 mg twice daily. On the sixth day of hospitalization, there was a 2 cm decrease in the circumference of both lower limbs, and the penis remained at rest in the supine position. After 26 days in hospital, the patient was discharged in a stable condition. He was maintained on warfarin 12.5 mg/day, achieving an international normalized ratio (INR) of 3. The majority of our understanding of stuttering priapism is derived from observations in patients with sickle cell disease. These episodes are commonly short lived (<3 h) and are self-limiting, although some are prolonged and require acute medical intervention [2]. Physicians should be aware of this possible complication.

A 48-year-old obese male (body mass index, 33), who was an active smoker, was admitted to our department to undergo percutaneous angioplasty of a markedly stenosed left renal artery. Six months earlier, severe hypertension (blood pressure, 200/100 mm Hg) associated with hypokalemia of renal origin (serum potassium level, 3.1 mmol/l; urinary potassium, 75 mmol/day) and stage III chronic kidney disease (serum creatinine level, 146 μmol/l; estimated glomerular filtration rate, 48 ml/min per 1.73 m2) were discovered. Doppler ultrasound showed 90% stenosis of the ostium and the first segment of the left renal artery. The right renal artery was normal. Both kidneys were 100 mm in length. Magnetic resonance angiography confirmed the Doppler results and the decision to perform a percutaneous renal angioplasty was made. On admission, the patient's blood pressure was 135/75 mm Hg on three medications including nebivolol (5 mg/day), amlodipine (5 mg/day), and spironolactone (50 mg/day). Physical examination was unremarkable. Laboratory findings were as follows: hypertriglyceridemia at 7.5 mmol/l, hypercholesterolemia (HDL cholesterol at 0.61 mmol/l and LDL cholesterol level at 4.97 mmol/l), serum potassium at 3.5 mmol/l, and serum creatinine at 147 μmol/l. Urine analysis was normal. A renal angiography was performed (Figure 1). An unusual finding led us to perform a computed tomography scan angiography (Figure 2).Figure 2Computed tomography scan: coronal curved multiplanar reconstruction image of the left RA (black arrow), which shows arterial entrapment between the aorta (black star) and the left diaphragmatic crus (white arrowheads).View Large Image Figure ViewerDownload Hi-res image Download (PPT) What abnormality do you see in the left renal artery and in the CT angiography? What is the cause of this patient's hypertension? Conventional renal angiography findings (Figure 1) supported the diagnosis of extrinsic renal artery compression. Multidetector computed tomography (MDCT) angiography (Figure 2) was performed and revealed that diaphragm muscle fibers caused a verticalization of the root of the left renal artery and lead to a stenosis at its origin. The artery follows an unusual course at an acute angle, which gives it a sigmoid course. MDCT showed compression of the left renal artery by the diaphragmatic crus. This is known as renal artery entrapment (RAE) syndrome. Renovascular hypertension is the cause of hypertension in 5% of cases. The most common causes of renovascular hypertension are atherosclerotic stenosis (65% of cases) and fibromuscular dysplasia (16% of cases).1.Textor S.C. Renovascular hypertension and ischemic nephropathy.in: Brenner B.M. Rector F.C. The Kidney.7th edn. WB Saunders, Philadelphia, USA2004: 2065-2108Google Scholar Renal artery aneurysm, arteriovenous fistula, and extrinsic compression are rather rare causes of renovascular hypertension.1.Textor S.C. Renovascular hypertension and ischemic nephropathy.in: Brenner B.M. Rector F.C. The Kidney.7th edn. WB Saunders, Philadelphia, USA2004: 2065-2108Google Scholar Renal artery compression leading to hypertension has been attributed to abdominal aortic aneurysm, tumor, hypertrophic adrenal tissue, psoas muscle band, sympathetic nerve fibers, and compression by a diaphragmatic crus.2.Thony F. Baguet J.P. Rodiere M. et al.Renal artery entrapment by the diaphragmatic crus.Eur Radiol. 2005; 15: 1841-1849Crossref PubMed Scopus (26) Google Scholar Since the first case reported by D’Abrieu, several cases of RAE by the diaphragmatic crus have been reported in the literature.2.Thony F. Baguet J.P. Rodiere M. et al.Renal artery entrapment by the diaphragmatic crus.Eur Radiol. 2005; 15: 1841-1849Crossref PubMed Scopus (26) Google Scholar Abnormalities such as abnormal musculotendinous fibers, high ectopic renal artery origin, and hypertrophic diaphragmatic crus were found to be responsible for these entrapments.2.Thony F. Baguet J.P. Rodiere M. et al.Renal artery entrapment by the diaphragmatic crus.Eur Radiol. 2005; 15: 1841-1849Crossref PubMed Scopus (26) Google Scholar They occur because of the compression of the renal artery by fibers from the crus of the diaphragm and can be easily diagnosed by helical or MDCT angiography.2.Thony F. Baguet J.P. Rodiere M. et al.Renal artery entrapment by the diaphragmatic crus.Eur Radiol. 2005; 15: 1841-1849Crossref PubMed Scopus (26) Google Scholar The diaphragmatic crura arise from the anterior surface of the L1 to L4 vertebral bodies on the right and from the first L2 or L3 vertebral bodies on the left. These muscle fibers can, in some cases, cause a verticalization of the root of the renal artery and lead to a stenosis, usually at the origin of the artery. Subsequently, the artery follows an unusual course at an acute angle, which gives it a sigmoid course.2.Thony F. Baguet J.P. Rodiere M. et al.Renal artery entrapment by the diaphragmatic crus.Eur Radiol. 2005; 15: 1841-1849Crossref PubMed Scopus (26) Google Scholar, 3.Baguet J.P. Thony F. Sessa C. et al.Stenting of a renal artery compressed by the diaphragm.J Hum Hypertens. 2003; 17: 213-214Crossref PubMed Scopus (29) Google Scholar Doppler ultrasound permits the visualization of renal blood flow during a complete respiratory cycle. Doppler ultrasound evaluating the blood renal flow during both inspiration and expiration could help in the diagnosis. Flow demodulation over the arterial ostia and increase of flow velocities during expiration and normalization in inspiration provided hemodynamic information highly suggestive of RAE, which could confirm the diagnosis. These findings must be corroborated by CT angiography.4.Déglise S. Corpataux J.M. Haller C. et al.Bilateral renal artery entrapment by diaphragmatic crura: a rare cause of renovascular hypertension with a specific management.J Comput Assist Tomogr. 2007; 31: 481-484Crossref PubMed Scopus (11) Google Scholar CT angiography, especially one using high spatial resolution, permits visualization of the vascular anatomy (aorta and its branches) and diaphragm relationship. There is no established protocol for the treatment of the RAE syndrome. Although surgery and stenting have been used, both were associated with surgical morbidity and stent-related complications such as stenosis and occlusion. Botulinum toxin type A injection has shown to be useful in one human case5.Bilici A. Karcaaltincaba M. Ilica A.T. et al.Treatment of hypertension from renal artery entrapment by percutaneous CT-guided botulinum toxin injection into diaphragmatic crus as alternative to surgery and stenting.AJR Am J Roentgenol. 2007; 189: W143-W145Crossref PubMed Scopus (7) Google Scholar and in several rabbit studies. Treatment options were discussed between the nephrology, vascular interventional radiology, and surgery teams and were presented to our patient. Options discussed included medical treatment, stent placement, and aortorenal bypass. The decision made was to continue medical treatment and monitor the patient's blood pressure closely. If the case had involved prolonged uncontrolled hypertension, more invasive treatment would have been considered. In summary, renal artery may be entrapped by diaphragmatic crus and cause renovascular hypertension. RAE should be suspected if angiography shows a renal artery parallel to the aorta in the proximal part of its course. Thin fibrous bands from the diaphragm insertion are well shown by the non-invasive MDCT angiography. This pathology, unlike common renal artery stenosis, requires specific therapeutic management, including renal artery decompression and/or aortorenal bypass.

Waldenström's macroglobulinemia (WM) is a low-grade lymphoplasmacytic lymphoma characterized by a circulating monoclonal IgM. Renal involvement in classical cases of WM is rare, and the pathological hallmark finding in the renal biopsy specimen is a thrombotic microangiopathy. We report the case of a 69-year-old man with the diagnosis of WM for 3 months before he presented with acute renal failure (ARF). A renal biopsy performed suggested the diagnosis of acute tubular necrosis. The diagnosis of ARF related to IgM flare after Rituximab therapy was made.

A 69-year-old man was admitted to hospital for the evaluation of refractory hypokalemia and metabolic alkalosis. The patient had a 1-year history of a stage pT4N0M1 non-small cell squamous lung carcinoma (NSCLC) that was managed by Pemetrexed (Alimta 500mg/m(2) every 21 days) for the last 6 months. The patient had a 45-pack/y history of smoking without history of alcohol abuse, hypertension, or diabetes mellitus. He was married, had 2 children without health problems and used to work as a truck driver. He had no family history of cancer or metabolic problems. He was in his usual state of health until 1 month before admission. His medication list contained only paracetamol every 6 h.

A 42-year-old African man was admitted to our Nephrology Department for the management of a severe hyponatraemia (117mmol/l). The patient had been hospitalized 1 month earlier for generalized weakness, weight loss (30 kg in the past 3 months), abdominal pain, cough, dyspnoea, haemoptysis and confusion. His clinical examination was unremarkable except for severe malnutrition. His Glasgow coma scale was 15, with no focal neurological signs. Blood pressure was 100/70mmHg with orthostatic hypotension and tachycardia (120 pulse/min). Routine blood tests revealed hyponatraemia at 117mmol/l, plasma osmolarity of 250mOsm/l, serum glucose level 5.5mmol/l and normal serum potassium level (4.5mmol/l). Chest X-ray showed an excavated shadow of the right superior lobe. Head CT scan was normal. CSF examination revealed a lymphocytic reaction (130 cells/cm) with a protein of 1.9 g/l and glucose of 2.3mmol/l. Meanwhile, the patient was found to be HIV-1 positive with disseminated tuberculosis (i.e. pulmonary and meningitis). Based on the clinical and biological findings, the patient was treated for adrenal insufficiency with glucoand mineralocorticoid substitution and normal saline perfusion with an improvement in plasma sodium level (from 117 to 123mmol/l). However, since Synacthen test remained normal, steroid substitution was stopped and the serum sodium decreased to 118mmol/l. Urine output increased (5 l in 24 h). Biochemistrical parameters are summarized in Table 1.

BACKGROUND:A 58-year-old African American man with an uncontrolled HIV infection presented to hospital with nephrotic syndrome and diffuse lymphadenopathy. The patient had been taking highly active antiretroviral therapy (HAART; lamivudine, abacavir, fosamprenavir and ritonavir) for 10 years. A renal biopsy showed acute granulomatous interstitial nephritis. Despite a negative tuberculin skin test, he was treated with antituberculosis drugs for 12 months without improvement of his renal profile. Two months after antituberculosis treatment was discontinued, the patient was readmitted to hospital because of acute renal failure. Corticosteroid therapy (prednisone) was started and resulted in a marked improvement in renal function. However, 18 months after steroids were discontinued, renal function declined dramatically. Furthermore, the patient had CD8+ lymphocytosis as well as interstitial tissue infiltration by CD8+ T lymphocytes.INVESTIGATIONS:Physical examination, plasma HIV viral load, lymphocyte counts, urinalysis, tuberculin skin test, liver function tests, renal ultrasonography, human leukocyte antigen (HLA) typing, renal and minor salivary gland biopsies, ophthalmological examination, chest radiography and culture of bronchoalveolar lavage fluid.DIAGNOSIS:Acute granulomatous interstitial nephritis secondary to diffuse infiltrative lymphocytosis syndrome.MANAGEMENT:HAART and prednisone.

Plasma cell leukemia (PCL) is a rare plasma cell disorder, defined by more than 26 10/L (20%) circulating plasma cells. Primary disease (pPCL) presents as de novo leukemia, whereas secondary PCL (sPCL) arises on top of a pre-existing multiple myeloma (MM). pPCL and sPCL represent two distinct clinico-pathological entities. 14p32 (IgH) translocations involve 11q13 chromosomic region (CCND1) in pPCL, contrary to sPCL in which IgH translocations partners are similar to those detected in MM [1]. However, both share a high incidence of p53 loss and a high rate of Ras mutations [1]. PCL and MM express different membrane molecules, such as CD56 (NCAM), which is absent in PCL cells. This molecule facilitates plasma cell interactions with the bone marrow (BM) microenvironment and prevents their circulation from the BM to the blood [2]. The prognosis of PCL patients treated with standard chemotherapy remains poor (median survival: 7–14 months) [3,4]. Bortezomib, widely used in MM, may be of great therapeutic value in PCL [5,6]. We present four case reports of patients with PCL treated with the bortezomib, adriamycin and dexamethasone combination (PAD). Three achieved a very good partial response (VGPR) and one a complete response (CR), all persisting with a median follow-up of 10.5 months (8–22). We also review the recently published data concerning bortezomib use in PCL. Clinical and biological data concerning our patients are detailed in Table I. Median age was 65 (57–75 years). There were three women and one man. PAD chemotherapy, as first described by Oakervee et al., consisted of bortezomib 1.3 mg/m at days 1, 4, 8, 11; adriamycin 9 mg/m at days 1–4 (continuous injection) and dexamethasone 40 mg at days 1–4, 8–11 and 15–18 during the first course, and then, from days 1–4 every 21 days, for a median of six cycles (4–6). The response was assessed according to the International Myeloma Working Group (IMWG) response criteria [7]. The first patient was a 57-year-old woman, diagnosed with a stage III IgG l MM in 1996. She was treated with three cycles of vincristine, adriamycin and dexamethasone (VAD), followed by autologous stem-cell transplantation (ASCT) (melphalan 200 mg/m conditioning). A partial remission (PR) was obtained and she remained stable until 2002, when a first relapse was successfully treated with dexamethasone. She relapsed again in July 2007, and was treated with thalidomide and dexamethasone (Thal/Dex). Patient’s general condition got worse despite Thal/Dex and 156 10/L (64%) of circulating dystrophic plasmocytes were noted, with pancytopenia (hemoglobin 7.7 g/L and platelet 206 10/ L). Serum creatinine and calcium rose to 130 mmol/ L and 2.82 mmol/L, respectively. The M-protein was 12.2 g/L, Bence–Jones proteinuria (BJ) was 3 g/24 h,

A 42-year-old white man was admitted to hospital with a 3-day history of progressive muscle weakness, myalgias and dark urines. He was HIV/hepatitis C virus (HCV) coinfected, with an absolute CD4+ T lymphocyte count of 393 cells/mm3, a serum HIV-1 RNA load of <40 copies/mm3 and an HCV RNA load of 6 log10 before admission to the hospital. His antiretroviral treatment consisted of lamivudine (150 mg bd), abacavir (300 mg bd), indinavir (400 mg bd) and ritonavir (100 mg bd) at the time of admission. This regimen had not been changed in the past 2 years. The patient also had a history of hyperlipidaemia, coronary artery disease and a cerebral stroke in 2004. Because of severe hyperlipidaemia (LDL cholesterol, 175 mg/dL; triglyceride level, 191 mg/dL) that was refractory to dietary therapy and a 6-month trial of pravastatin (40 mg/day), a combination of ezetimibe (10 mg/day) and simvastatin (40 mg/day) was introduced 3 weeks prior to admission. The patient was also taking aspirin (75 mg/day), bisoprolol (5 mg/day) and perindopril (2 mg/day). He took no herbal or over-the-counter medications, and he did not use alcohol or illicit drugs. His basal serum creatinine level was 65 μmol/L (0.81 mg/dL). Calculated creatinine clearance using the modified diet in renal disease formula (MDRD) was 98 mL/min. Ten days after the initiation of treatment with ezetimibe– simvastatin combination, the patient noted the development of new generalized and progressive muscle weakness and dark urines. He denied having recently exercised strenuously or having sustained a trauma, and he had no prior history of HIV myopathy. He was well nourished (weight 66 kg). Laboratory evaluation revealed findings that were consistent with rhabdomyolysis [creatine kinase (CK),

A 40-year-old man of North-African Arab origin was referred for pretransplantation evaluation along with his 38-year-old brother, who volunteered for kidney donation. The patient’s history was remarkable for renal insufficiency caused by recurrent nephrolithiasis, and he had been on regular hemodialysis therapy for approximately 4 years. The patient experienced nephrolithiasis at the age of 15 years. Afterward, recurrent passages of oxalate stones and urinary tract infections occurred. According to his referring physician, the patient had well-documented hypercalciuria and hypomagnesemia. Past values for urinary calcium and serum electrolytes were not available. No stigmata of a proximal tubulopathy (hypokalemia, metabolic acidosis, low serum phosphorus level, low uric acid level, normoglycemic glycosuria, or aminoaciduria) or proteinuria was present. We suspected an inherited disease because the patient’s mother and father are first-degree cousins, but there was no family history of kidney stones. On admission, the patient’s physical examination findings were unremarkable. Weight and height were 51 kg and 165 cm, respectively. Laboratory investigations showed normal red and white blood cell counts. Urinalysis was not performed because the patient was anuric. Albumin-corrected serum calcium level (8.84 mg/dL [2.21 mmol/L]; normal range, 8.80 to 10.40 mg/dL [2.20 to 2.59 mmol/L]) and serum magnesium levels were normal (2.79 mg/dL [1.15 mmol/L]; normal range, 1.94 to 2.33 mg/dL [0.80 to 0.96 mmol/L]), parathormone level was increased (111 pg/mL; normal range, 12 to 65 pg/mL), and serum 25 hydroxy vitamin D level was 99 ng/mL (normal range, 23 to 113 ng/mL). Bone density was within normal range despite end-stage renal failure. After informed consent was obtained, genetic analysis was performed on the index case and the brother who had volunteered for kidney donation. Physical examination of the donor was unremarkable, and his biochemical test results also were within normal limits (serum magnesium, 1.82 mg/dL [0.75 mmol/L], and serum creatinine, 1.22 mg/dL [108 μmol/L]). Renal ultrasonography and osteodensitometry showed no abnormalities. We first considered heritable causes of renal failure with calcium oxalate nephrolithiasis. Primary hyperoxaluria (PH) type 1 is associated with multiple bilateral renal calculi on ultrasonography and is more common in people of Maghrebian origin. However, neither soft-tissue nor vascular calcifications were found, and bone density measurements did not show areas of bone hyperdensity. Moreover, hypomagnesemia is not seen in patients with PH type I. Finally, there was no evidence of a mutation in the AGXT gene that would cause an isoleucine-to-threonine substitution at amino acid 244, thus definitively excluding the common Maghrebian form of PH type 1. Hypercalciuria with nephrocalcinosis and renal failure association might also suggest Dent disease, but the absence of other signs of a proximal tubular defect argued against this possibility. Neither PH type 1 nor Dent disease cause hypomagnesemia, the critical clinical observation in this case. Hypomagnesemia, defined as serum magnesium level less than 1.7 mg/dL (<0.7 mmol/L), has many possible causes. Table 1 lists the major causes of inherited hypomagnesemia (including some not discussed because of space constraints). However, of these, only a few are associated with recurrent urinary stones leading to total renal failure. Such disorders comprise a set of rare tubular disorders with different modes of inheritance including isolated renal magnesium loss (Online Mendelian Inheritance in Man [OMIM] 154020 and OMIM 248250),1Geven W.B. Monnens L.A. Willems H.L. Buijs W.C. ter Haar B.G. Renal magnesium wasting in two families with autosomal dominant inheritance.Kidney Int. 1987; 31: 1140-1144Crossref PubMed Scopus (66) Google Scholar Gitelman syndrome (OMIM 263800),2Gitelman H.J. Graham J.B. Welt L.G. A new familial disorder characterized by hypokalemia and hypomagnesemia.Trans Assoc Am Physicians. 1966; 79: 221-235PubMed Google Scholar and autosomal recessive familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC; OMIM 248250 and OMIM 603959).3Weber S. Schneider L. Peters M. et al.Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.J Am Soc Nephrol. 2001; 12: 1872-1881PubMed Google Scholar The combination of hypercalciuria and hypomagnesemia seen in our patient helps eliminate isolated renal magnesium loss and Gitelman syndrome because urinary calcium excretion is usually low or normal in these conditions. However, this combination of abnormalities is observed in patients with FHHNC.Table 1Major Causes of Inherited HypomagnesemiaDiseasesFeaturesInheritance/OMIM No./ChromosomeUrinary MagnesiumUrinary CalciumRenal Stone/NephrocalcinosisFHHNCAR/603959/3q27HighHighYes/yesIsolated dominant hypomagnesemiaAD/154020/11q23HighLowNo/noIsolated recessive hypomagnesemiaAR/248250/?High?No/noHypomagnesemia and secondary hypocalcemiaAR/602014/9q22Normal or highNormal or highAD hypoparathyroidismAD/601198/3q13.3-21HighHighYes/yesGitelman syndromeAR/263800/16q13HighLowNo/noClassic Bartter syndromeAR/602023/1p36Normal or highVariableNo/rareAbbreviations: OMIM, Online Mendelian Inheritance in Man; FHHNC, familial hypomagnesemia, hypercalciuria, and nephrocalcinosis; AR, autosomal recessive; AD, autosomal dominant. Open table in a new tab Abbreviations: OMIM, Online Mendelian Inheritance in Man; FHHNC, familial hypomagnesemia, hypercalciuria, and nephrocalcinosis; AR, autosomal recessive; AD, autosomal dominant. The diagnosis of FHHNC was confirmed by means of mutational analysis of the CLDN16 (claudin 16) gene, which encodes paracellin 1. Sequencing showed a mutation in CLDN16 that would cause an alanine-to-valine substitution at amino acid 139; this mutation was homozygous in the patient and heterozygous in the donor. FHHNC, first described by Michelis et al4Michelis M.F. Drash A.L. Linarelli L.G. De Rubertis F.R. Davis B.B. Decreased bicarbonate threshold and renal magnesium wasting in a sibship with distal renal tubular acidosis: Evaluation of the pathophysiological role of parathyroid hormone.Metabolism. 1972; 21: 905-920Abstract Full Text PDF PubMed Scopus (91) Google Scholar in 1972, is an autosomal recessive tubulopathy characterized by excessive renal magnesium and calcium wasting, bilateral nephrocalcinosis, and progressive renal failure. The condition results from CLDN16 mutations,5Simon D.B. Lu Y. Choate K.A. et al.Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption.Science. 1999; 285: 103-106Crossref PubMed Scopus (941) Google Scholar making it the first identified human disease associated with a tight-junction protein defect. Magnesium is one of the most abundant divalent cations in the intracellular fluid. It has a critical role in a wide variety of metabolic and cellular processes, including cellular energy storage, DNA/RNA processing, ion transport, membrane stabilization, and nerve conduction.6Romani A. Scarpa A. Regulation of cell magnesium.Arch Biochem Biophys. 1992; 298: 1-12Crossref PubMed Scopus (320) Google Scholar In the kidney, approximately 80% of total serum magnesium is filtered at the glomeruli, and more than 95% of filtered magnesium is reabsorbed along the nephron (15% to 20% in the proximal tubule, 65% to 75% in the thick ascending limbs of the loops of Henle, and 5% to 10% in distal convoluted tubules).7de Rouffignac C. Quamme G. Renal magnesium handling and its hormonal control.Physiol Rev. 1994; 74: 305-322PubMed Google Scholar, 8Dai L.J. Ritchie G. Kerstan D. Kang H.S. Cole D.E. Quamme G.A. Magnesium transport in the renal distal convoluted tubule.Physiol Rev. 2001; 81: 51-84Crossref PubMed Scopus (258) Google Scholar Thus, less than 5% of filtered magnesium should be finally excreted in urine. In thick ascending limbs of the loops of Henle, magnesium is passively reabsorbed with calcium through paracellular tight junctions; the driving force of this reabsorption is a lumen-positive electrochemical gradient. Conversely, magnesium reabsorption in the distal convoluted tubule is an active transcellular process.7de Rouffignac C. Quamme G. Renal magnesium handling and its hormonal control.Physiol Rev. 1994; 74: 305-322PubMed Google Scholar, 8Dai L.J. Ritchie G. Kerstan D. Kang H.S. Cole D.E. Quamme G.A. Magnesium transport in the renal distal convoluted tubule.Physiol Rev. 2001; 81: 51-84Crossref PubMed Scopus (258) Google Scholar Paracellin 1 is expressed predominantly in medullary thick ascending limb, the nephron site where active control of magnesium and calcium takes place. Recently, Efrati et al9Efrati E. Arsentiev-Rozenfeld J. Zelikovic I. The human paracellin-1 gene (hPCLN-1): Renal epithelial cell-specific expression and regulation.Am J Physiol Renal Physiol. 2005; 288: F272-F283Crossref PubMed Scopus (32) Google Scholar showed that paracellin 1–mediated magnesium transport may be regulated at the transcriptional level by hypermagnesemia or hypomagnesemia, hypercalcemia, and 1,25-vitamin D, as well as by cyclosporine A therapy, which causes hypomagnesemia as a side effect. Incidences of hypercalciuria and nephrolithiasis are exceptionally high in family members heterozygous for CLDN16 mutations, which indicates that CLDN16 is a candidate gene for idiopathic hypercalciuria.3Weber S. Schneider L. Peters M. et al.Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.J Am Soc Nephrol. 2001; 12: 1872-1881PubMed Google Scholar, 10Tajima T. Nakae J. Fujieda K. Two heterozygous mutations of CLDN16 in a Japanese patient with FHHNC.Pediatr Nephrol. 2003; 18: 1280-1282Crossref PubMed Scopus (30) Google Scholar, 11Praga M. Vara J. Gonzalez-Parra E. et al.Familial hypomagnesemia with hypercalciuria and nephrocalcinosis.Kidney Int. 1995; 47: 1419-1425Crossref PubMed Scopus (179) Google Scholar Clinical manifestations of FHHNC are variable; the majority of patients present early in childhood with recurrent urinary tract infections, polyuria/polydipsia, isosthenuria, or renal stones. Progression to chronic renal failure was considered to result from chronic progressive tubulointerstitial nephropathy associated with nephrocalcinosis.11Praga M. Vara J. Gonzalez-Parra E. et al.Familial hypomagnesemia with hypercalciuria and nephrocalcinosis.Kidney Int. 1995; 47: 1419-1425Crossref PubMed Scopus (179) Google Scholar, 12Rodriguez-Soriano J. Vallo A. Garcia-Fuentes M. Hypomagnesaemia of hereditary renal origin.Pediatr Nephrol. 1987; 1: 465-472Crossref PubMed Scopus (137) Google Scholar According to Weber et al,3Weber S. Schneider L. Peters M. et al.Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.J Am Soc Nephrol. 2001; 12: 1872-1881PubMed Google Scholar the median age of end-stage renal failure is 14.5 years (range, 5.5 to 37.5 years). Similarly, nephrocalcinosis associated with other diseases does not always correlate with chronic renal failure, as shown in patients with distal renal tubular acidosis or antenatal Bartter syndrome.3Weber S. Schneider L. Peters M. et al.Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.J Am Soc Nephrol. 2001; 12: 1872-1881PubMed Google Scholar, 13Köckerling A. Reinalter S.C. Seyberth H.W. Impaired response to furosemide in hyperprostaglandin E syndrome: Evidence for a tubular defect in the loop of Henle.J Pediatr. 1996; 129: 519-528Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar Other findings in patients with FHHNC are unexplained. Hyperuricemia is present in the majority of patients with this syndrome,11Praga M. Vara J. Gonzalez-Parra E. et al.Familial hypomagnesemia with hypercalciuria and nephrocalcinosis.Kidney Int. 1995; 47: 1419-1425Crossref PubMed Scopus (179) Google Scholar, 12Rodriguez-Soriano J. Vallo A. Garcia-Fuentes M. Hypomagnesaemia of hereditary renal origin.Pediatr Nephrol. 1987; 1: 465-472Crossref PubMed Scopus (137) Google Scholar, 14Ulmann A. Hadj S. Lacour B. Bourdeau A. Bader C. Renal magnesium and phosphate wastage in a patient with hypercalciuria and nephrocalcinosis: Effect of oral phosphorus and magnesium supplements.Nephron. 1985; 40: 83-87Crossref PubMed Scopus (28) Google Scholar but the mechanism is not known. No paracellular secretory process for uric acid was described or even proposed. Ocular abnormalities, such as severe myopia, nystagmus, coloboma, bilateral keratoconus, corneal calcifications, tapetoretinal degeneration or chorioretinitis,3Weber S. Schneider L. Peters M. et al.Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.J Am Soc Nephrol. 2001; 12: 1872-1881PubMed Google Scholar, 11Praga M. Vara J. Gonzalez-Parra E. et al.Familial hypomagnesemia with hypercalciuria and nephrocalcinosis.Kidney Int. 1995; 47: 1419-1425Crossref PubMed Scopus (179) Google Scholar, 15Benigno V. Canonica C.S. Bettinelli A. von Vigier R.O. Truttmann A.C. Bianchetti M.G. Hypomagnesaemia-hypercalciurianephrocalcinosis: A report of nine cases and a review.Nephrol Dial Transplant. 2000; 15: 605-610Crossref PubMed Scopus (82) Google Scholar and hearing impairment were reported.15Benigno V. Canonica C.S. Bettinelli A. von Vigier R.O. Truttmann A.C. Bianchetti M.G. Hypomagnesaemia-hypercalciurianephrocalcinosis: A report of nine cases and a review.Nephrol Dial Transplant. 2000; 15: 605-610Crossref PubMed Scopus (82) Google Scholar These abnormalities were not apparent in the index case or family members. There is no specific treatment; magnesium supplements, citrate, and thiazide diuretics are not effective in preventing the progression of nephrocalcinosis.11Praga M. Vara J. Gonzalez-Parra E. et al.Familial hypomagnesemia with hypercalciuria and nephrocalcinosis.Kidney Int. 1995; 47: 1419-1425Crossref PubMed Scopus (179) Google Scholar However, kidney transplantation corrects the tubular disorder. Twelve kidney recipients with FHHNC were reported in the literature, all with cadaveric donors. No recurrence of tubular dysfunction has been noticed.3Weber S. Schneider L. Peters M. et al.Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.J Am Soc Nephrol. 2001; 12: 1872-1881PubMed Google Scholar Living related kidney transplantation can be performed with a family member lacking the mutation. Furthermore, it is reasonable to consider heterozygous subjects as potential living related kidney donors if they are asymptomatic in adulthood, given the incomplete heterozygous mutation penetrance.3Weber S. Schneider L. Peters M. et al.Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.J Am Soc Nephrol. 2001; 12: 1872-1881PubMed Google Scholar In our patient, renal transplantation was performed in late 2006. The postoperative course was uneventful. After 2 months of follow-up, results of laboratory tests of the recipient (treated with a calcineurin inhibitor) were as follows: serum creatinine, 0.98 mg/dL (87 μmol/L); serum calcium, 10.0 mg/dL (2.50 mmol/L); serum magnesium, 1.21 mg/dL (0.5 mmol/L); and urinary calcium excretion, 0.06 mmol/kg/d.

f m w r b c m d i e w t i H f e t 40-year-old man of North-African Arab origin was referred for pretransplantation valuation along with his 38-year-old brother, ho volunteered for kidney donation. The paient’s history was remarkable for renal insuffiiency caused by recurrent nephrolithiasis, and e had been on regular hemodialysis therapy for pproximately 4 years. The patient experienced ephrolithiasis at the age of 15 years. Afterward, ecurrent passages of oxalate stones and urinary ract infections occurred. According to his refering physician, the patient had well-documented ypercalciuria and hypomagnesemia. Past vales for urinary calcium and serum electrolytes ere not available. No stigmata of a proximal ubulopathy (hypokalemia, metabolic acidosis, ow serum phosphorus level, low uric acid level, ormoglycemic glycosuria, or aminoaciduria) or roteinuria was present. We suspected an inherted disease because the patient’s mother and ather are first-degree cousins, but there was no amily history of kidney stones. On admission, the patient’s physical examinaion findings were unremarkable. Weight and height ere 51 kg and 165 cm, respectively. Laboratory nvestigations showed normal red and white blood ell counts. Urinalysis was not performed because