Diagnosis of rare entity CD138 negative plasma cell multiple myeloma: the synergy between laboratory and clinician makes the difference.

Plasma cell multiple myeloma (MM) is a multiform clinical entity characterized by different laboratory hallmarks. This case shows a rare entity of plasma cell myeloma: the entire plasma cell population lack the CD138 expression. In this case, a careful analysis of laboratory finding, particular flow cytometry gating strategies and the use of other ancillary laboratory tests, guide the clinicians to correct diagnosis. The correct evaluation of pre-analytical phase and the correct gating strategy are the necessary conditions to produce robust and solid flow cytometric results. The diagnostic implications of CD138-negative plasma cell are strictly linked to stem cell-like clonogenic features, such as possible more aggressive clinical behaviour and increasing probability of chemotherapy resistance. At this time, clinical laboratory remains the main reference point to MM diagnosis.

[Donor and recipient selection in living donor kidney transplantation: eligibility]. / La selezione del donatore e del ricevente nel trapianto di rene da donatore vivente: iter di idoneità.

This review is intended to be a guide for the physician to evaluate and prepare a donor / recipient couple for living kidney transplantation. Although it is intended to be exhaustive, it will not be able to respond at all possible and different cases, but it may apply at most of them. Renal transplantation is considered the choice treatment for patients with chronic renal failure and if the kidney transplant is performed pre-emptive it is associated with better organ and patient survival. The main aim of the program is to evaluate the risks of donor and recipient and to ensure the donor safety and well-being. Eligibility for living transplant can only be granted when the risks are acceptable, well defined and the couple is adequately informed. The review includes clinical and legal procedures needed to transplantation. Early conditions that contraindicate the transplant must be removed, to avoid unnecessary exams, excessive waste of time, money. The sequence of the exams has been ordered so that costly and invasive surveys are carried out only after other simple and essential investigations have confirmed the transplant suitability. Special attention should be paid to the renal function measurement, proteinuria, hematuria, hypertension, obesity, pre diabetes, renal calculus, and cancers. To give eligibility for living transplant is often not easy, but a careful study can avoid many complications and improve the transplant outcome.

Costimulatory pathways in kidney transplantation: pathogenetic role, clinical significance and new therapeutic opportunities.

Costimulatory pathways play a key role in immunity, providing the second signal required for a full activation of adaptive immune response. Different costimulatory families (CD28, TNF-related, adhesion and TIM molecules), characterized by structural and functional analogies, have been described. Costimulatory molecules modulate T cell activation, B cell function, Ig production, cytokine release and many other processes, including atherosclerosis. Patients suffering from renal diseases present significant alterations of the costimulatory pathways, which might make them particularly liable to infections. These alterations are further pronounced in patients undergoing kidney transplantation. In these patients, different costimulatory patterns have been related to distinct clinical features. The importance that costimulation has gained during the last years has led to development of several pharmacological approaches to modulate this critical step in the immune activation. Different drugs, mainly monoclonal antibodies targeting various costimulatory molecules (i.e. anti-CD80, CTLA-4 fusion proteins, anti-CD154, anti-CD40, etc.) were designed and tested in both experimental and clinical studies. The results of these studies highlighted some criticisms, but also some promising findings and now costimulatory blockade is considered a suitable strategy, with belatacept (a CTLA-4 fusion protein) being approved as the first costimulatory blocker for use in renal transplantation. In this review, we summarize the current knowledge on costimulatory pathways in the setting of kidney transplantation. We describe the principal costimulatory molecule families, their role and clinical significance in patients undergoing renal transplantation and the new therapeutic approaches that have been developed to modulate the costimulatory pathways.

Renal diseases in haemophilic patients: pathogenesis and clinical management.

Haemophilia A and B are genetic X-linked bleeding disorders, caused by mutations in genes encoding factors VIII and IX, respectively. Clinical manifestations of haemophilia are spontaneous haemorrhage or acute bleeding caused by minor trauma, resulting in severe functional consequences that can culminate in a debilitating arthropathy. Life expectancy and quality of life of patients with haemophilia have dramatically improved over the last years, mainly for new therapeutic options and the awareness to the risk of HCV and HIV infections. Different clinical problems arise from this important change in history of patients with haemophilia. In particular, ageing-related diseases, such as diabetes, hypertension and cancer, and chronic viral infections are emerging as new challenges in this patient population. Among the different types of chronic illnesses, renal diseases are of special interest as they involve some difficult management issues. In fact, decisions regarding adequate preventive strategies and viral infection treatment, the choice of the dialytic modality, placement of vascular access and prescription of dialytic treatments are particularly complicated, because only few data are available. In this review, we discuss the pathogenesis of renal damage in patients with haemophilia, especially in those with blood-transmitted viral infections, and the major issues about the management of renal diseases, including problems related to dialytic treatment and kidney transplantation, providing practical algorithms to guide the clinical decision-making process.

Renal function and functional reserve in healthy elderly individuals.

BACKGROUND: Aging is characterized by a decline in renal function and by a susceptibility to renal diseases. However it is not clear whether the observed changes are solely hemodynamic, structural or both. We evaluated renal function, functional reserve (RFR) and morphology in healthy elderly individuals. METHODS: Healthy participants (n=19) were divided into young (n=6, age range 25-37 years), middle-aged (n=6, 44-74 years) and elderly (n=7, 81-96 years). Nitric oxide (NO), plasma renin activity (PRA) and aldosterone, renal plasma flow (RPF) by p-aminohippurate clearance (CPAH) and glomerular filtration rate (GFR) by inulin clearance (CIN) were determined before and during maximal vasodilating stimuli, induced with the infusion of dopamine and amino acids. Glomerular sclerosis, lumen area and wall thickness of afferent arterioles were determined by kidney biopsy from 36 healthy kidney donors and from 6 nephrectomies for renal carcinoma. RESULTS: GFR and RPF were slightly reduced in elderly individuals whereas filtration fraction (FF) was increased. GFR and RPF did not increase in the elderly after maximal vasodilating stimuli as in young and middle-aged subjects suggesting a reduction of RFR. NO, increased at baseline, did not increase further after vasodilating stimuli; while on the contrary, PRA, similar in the 3 groups at baseline, was not reduced by vasodilating stimuli in the elderly. Sclerotic glomeruli but not glomerular volume were significantly increased by aging. Afferent arteriole lumens were reduced by aging whereas wall thickness was unchanged. CONCLUSIONS: Renal function is preserved with aging in healthy subjects at the expense of a complete reduction of RFR. RFR may be wasted to compensate for the increased number of sclerotic glomeruli. Vascular changes, suggested by reduced arteriolar lumen, may be so advanced that even in the presence of high levels of vasodilatory molecules, kidneys are not responsive anymore to maximal vasoactive stimuli.

Uremic serum induces proatherogenic changes in human endothelial cells.

BACKGROUND: Cardiovascular complications are the main cause of death in uremic patients. Uremic angiopathy has been regarded as an accelerated form of atherosclerosis. However the mechanism leading to vessel wall injury is still unknown. We hypothesized that uremic serum affects endothelium inducing a proatherogenic state. METHODS: We studied the effects of uremic serum on human endothelial cells (HECs). Cell proliferation and adhesion of mononuclear cells to HEC monolayers were evaluated by cell counting, apoptosis and collagen production by ELISA, and nitric oxide (NO) by measuring the concentration of nitrite/nitrate in the cell supernatant. (alfa2)IV collagen, tissue inhibitor of metalloproteases-1 (TIMP-1) and transforming growth factor-beta (TGF-beta) mRNA levels were measured by reverse transcriptase polymerase chain reaction (RT-PCR). In some experiments cells were preincubated with anti-receptor for advanced glycation end product (anti-RAGE) blocking antibodies. RESULTS: Uremic serum did not modify HEC proliferation but induced apoptosis after 72 hours of incubation. Adhesion of mononuclear cells to HEC monolayers was significantly increased by uremic serum. In addition, uremic serum increased (alfa2)IV collagen, TIMP-1 and TGF-beta mRNA levels. There was no increase in nitric oxide concentration in ure-mic serum-treated endothelial cells, and the expression of TGF-beta was neither modified by L-NAME nor by anti-RAGE antibodies. CONCLUSIONS: Our results indicate that uremic serum affects HEC inducing a proatherogenic state that may be responsible for the accelerated atherosclerosis of uremic patients. Apparently uremic serum effect is not mediated by NO or by AGEs.

Hepatocyte growth factor (HGF) modulates matrix turnover in human glomeruli.

BACKGROUND: The imbalance between synthesis and degradation of mesangial matrix causes glomerulosclerosis and leads to renal failure. Hepatocyte growth factor (HGF) has been shown to reduce the progression in murine models of chronic renal failure. The present study evaluated the effect of HGF on the extracellular matrix turnover and on c-met receptor in human glomeruli. METHODS: Human glomeruli microdissected from donor kidney biopsies before transplantation were incubated with culture media containing HGF (50 ng/mL). After 24 and 48 hours, the expression of c-met, (alpha2) IV collagen, transforming growth factor-beta (TGF-beta), metalloprotease (MMP) 2 and 9 and of the inhibitor of MMP-2, tissue inhibitors of metalloprotease-1 (TIMP-1), was evaluated by polymerase chain reaction (PCR). beta-actin was used as housekeeping gene. The production of collagen type IV and TGF-beta was evaluated by enzyme-linked immunosorbent assay (ELISA) and Western blotting and the activity of MMP by zymography. RESULTS: (alpha2) IV collagen, TGF-beta, and TIMP-1 mRNA levels were markedly decreased in glomeruli treated with HGF at 24 and 48 hours. The expression of c-met was up-regulated by HGF treatment. HGF reduced the production of collagen type IV and TGF-beta. MMP-2 but not MMP-9 mRNA level was increased in HGF-treated glomeruli, although the gelatinolytic activity of the supernatant was not changed. By light microscopic examination kidney biopsies neither showed glomerular hypercellularity nor mesangial expansion. CONCLUSION: HGF reduced expression and synthesis of TGF-beta and collagen type IV and increased MMP-2 mRNA level in normal human glomeruli. These results suggest an antifibrotic effect of HGF on glomerular cells and may explain its beneficial role in glomerulosclerosis.