Giuseppe Costantino

Pain in end-stage renal disease: a frequent and neglected clinical problem

Pain is a major health problem in end-stage renal disease (ESRD) affecting half of the dialysis patients; most of them experience a moderate to severe degree of pain. Nevertheless, the impact of chronic pain and its consequences are often underestimated. Sources of pain related to the uremic environment are renal bone disease (osteitis fibrosa cystica, amyloidosis, osteomalacia), osteoarthritis, calcific uremic arteriolopathy and peripheral neuropathy. Moreover, comorbid conditions such as ischemic peripheral artery disease, diabetic neuropathy, osteopenia/ osteoporosis (due to long-standing hypertension, diabetes, or old age) result in various kinds of pain. Also the primary kidney disease (e.g. autosomal dominant polycystic kidney disease (ADPKD)) as well as performance of hemodialysis or peritoneal dialysis are important causes of pain. Potential consequences of persistent pain are disturbed sleep, weakened memory/attention, altered mood (anxiety and depressive disorder), impotence, poorer physical state, less social activities and consideration of withdrawal from dialysis. Consequently the health-related-quality of life (HRQOL) is diminished, associated with a higher morbidity and mortality. In the therapy of pain the WHO three-step analgesic ladder adapted for ESRD, was shown to be effective in dialysis patients. Of fundamental importance are various forms of non-pharmacological strategies including electrotherapy. Recently the so-called high tone external muscle stimulation (HTEMS) was very effective in the management of neuropathic pain in ESRD patients.

Thiopurine treatment in inflammatory bowel disease: Response predictors, safety, and withdrawal in follow-up

BACKGROUND AND AIMS Thiopurines represent the mainstay of immunosuppressive therapy in inflammatory bowel diseases. Since it is likely that response to therapy and adverse events depends on the genetic background of patients our study aimed to evaluate retrospectively response to therapy and safety in a mixed IBD population in Southern Europe. METHODS We evaluated demographic and clinical data of our patients treated with thiopurines. after 6 months in responders and non-responders to therapy. Moreover the likelihood to remain in thiopurine monotherapy was evaluated in responders, whereas adverse events were investigated in all patients. RESULTS Among disease- and patient-related parameters a shorter disease duration, female gender and ileal disease in Crohns patients were associated with better response. By ROC analysis, the best predictors of response were decreasing values of C-reactive protein and erythrocyte sedimentation rate. In the long-term more than half of IBD patients who responded at 6 months remained on monotherapy at 42 months. Flu-like syndrome represented the most frequent adverse event followed by abnormalities of liver function tests and myelotoxicity. Adverse events did occur at any time and were frequently impredictable. CONCLUSIONS In this retrospective study, thiopurines showed a good clinical efficacy, especially in patients with short duration of disease. Normalization of markers of systemic inflammation represents the most useful tool to assess response. Careful monitoring of patients is required during the whole duration of treatment although it may not prevent all severe complications.

Neutrophil Gelatinase-Associated Lipocalin Levels in Patients With Crohn Disease Undergoing Treatment With Infliximab

Increased levels of neutrophil gelatinase-associated lipocalin (NGAL), a small 25-kd stress protein released by several injured cells, have been reported in different pathological conditions such as kidney and chronic inflammatory bowel diseases. As NGAL is also emerging as a biomarker for monitoring the response to different types of treatment, the aims of this pilot study were to analyze urinary NGAL levels in a small cohort of patients affected by Crohn disease and to evaluate the eventual impact of the intravenous administration of infliximab on these levels. Crohn disease patients presented increased NGAL values compared with controls (210.5 ng/mL [88.3-1100.0 ng/mL] vs 7.6 [4.4] ng/mL; P = 0.001); the infusion of a single high dose of infliximab induced an impressive reduction in these levels to 80.1 ng/mL (38.6-400.2 ng/mL; P = 0.006) with a mean reduction ratio of 62.1%. These findings suggest a pivotal role of NGAL in the systemic adaptations to Crohn disease, also confirming the potential usefulness of NGAL measurement in the evaluation of early responses to therapy or in predicting different clinical outcomes.

Endothelial Dysfunction in Chronic Renal Failure

Cardiovascular disease is a very early phenomenon in the course of chronic renal failure, and increases continuously with decrease of renal function. Endothelial dysfunction seems to be a starting point in vascular changes leading to atherosclerosis and artery calcification. Endothelium, considered the largest organ in the body, has many functions. It senses mechanical and hormonal stimuli and in response the endothelial cells secrete a range of compounds which modulate vascular tone, coagulation, cell proliferation, and inflammation. The central role of endothelium in the development of vascular disease has led to identification of new relevant biomarkers and methods to estimate endothelial function and injury. Arterial stiffness, which is not an early phenomenon in endothelial dysfunction but a common complication of chronic renal failure may be evaluated through Pulse Wave Velocity and Augmentation Index obtained by pulse-wave analysis. Aortic stiffness is an independent predictor of cardiovascular morbidity and mortality in patients with hypertension. A new fascinating aspect of research in endothelial function is rising through the studies on endothelial progenitor cells. These are primitive bone marrow cells that have the ability to mature into endothelial cells and have a physiologic role in the repair of endothelial lesions.

Severe CMV-related pneumonia complicated by the hemophagocytic lymphohistiocytic (HLH) syndrome in quiescent Crohn's colitis: harmful cure?

In April 2009, a 32-year-old female was diagnosed with Crohn’s colitis; her history was positive for psoriasis and a cesarean section. The patient responded well to prednisone and a subsequent induction therapy with infliximab (5 mg/kg, three infusions); thereafter, she was set on azathioprine maintenance treatment (2.2 mg/kg/day). Eight months later, while in perfect clinical and biochemical remission, she developed high-grade fever (39.5 C) and was admitted on the third day to our unit. On admission, her temperature was 38.8 C, pulse rate 112 bpm, respiratory rate 35 breaths/min, and oxygen saturation of 82% on room air. The spleen was palpable 2 cm under the costal margin. The rest of the physical examination was unremarkable. Blood parameters showed pancytopenia (hemoglobin 8.1 g/dL; leukocytes 1260 el/lL x, platelets 53,000 el/lL), high levels of C-reactive protein, absent NK activity, hypertriglyceridemia (426 mg/ dL), and high values of serum ferritin (1260 lg/L). A chest film revealed bilateral infiltrates (Fig. 1A) and an ultrasound evaluation of the abdomen was negative except for a slightly enlarged spleen. Blood and urine cultures as well as serology for a number of viral and bacterial pathogens was performed and a combined broad spectrum antibiotic and antifungal treatment and methylprednisolone (20 mg/day) was started. On the second day she was transferred to the ICU because of increasing respiratory distress. Blood and urine culture were negative for bacteria and fungi. Serological studies for leishmaniasis, parvovirus B19, and human immunodeficiency virus (HIV) were negative. Polymerase chain reaction on peripheral blood was positive for CMV (2670 gEq/100,000 cells), while it was negative for human herpes virus (HHV)-6, HHV-8, and Epstein– Barr virus (EBV). Adding ganciclovir (5 mg/kg b.i.d. i.v.) to therapy the clinical picture improved within 20 days and the patient was discharged after a final control chest film (Fig. 1B) on oral valganciclovir (450 mg b.i.d.) until repeated negative results for CMV and normalization of peripheral lymphocyte subpopulations. After 1 year the patient is still in clinical remission without any therapy. Systemic infections due to CMV are well known in patients with inflammatory bowel disease (IBD), but usually associated with acute flares of disease and additive antiviral therapy improves outcome of colitis. Screening for latent CMV infection before immunosuppressive therapy is usually not recommended. In our patient with Crohn’s colitis, CMV pneumonia developed while under thiopurine monotherapy and in deep clinical remission similar to FIGURE 1. X-ray of the chest at the moment of diagnosis of CMV pneumonia (A) showing bilateral infiltrates and after resolution (B).

Cisplatin-induced kidney injury in the rat: L-carnitine modulates the relationship between MMP-9 and TIMP-3.

Renal interstitial fibrosis is a major complication of cisplatin treatment, due to the increased accumulation of extracellular matrix (ECM) proteins whose remodeling is important for the development of normal tissues; indeed, its malfunction might play a role in the etiology of various diseases. Biopharmacological evaluations suggest that L-carnitine can prevent cardiac metabolic damage caused by doxorubicin, as well as can inhibit cisplatin-induced injury in the kidney and in the small intestine, without any interference with the drugs antitumoral properties. Since the glomerular basement membrane and the mesangial matrix constitute the ECM of the renal glomerulus, we examined the localization and expression of MMP-9 and TIMP-3 in normal rat kidney and the changes in their expression over a period of time by treatment with cisplatin, with and without L-carnitine. MMP-9 immunoreaction in cisplatin-treated rat kidney tissue suggests an involution of the basal membrane, an alteration of ECM components and low glomerular function, due to the increased thickness of the mesangium. Our results suggest that the matrix remodeling by MMP-9 and TIMP-3, in the later stages, can play an important role in the development of glomerular sclerosis and interstitial fibrosis after cisplatin treatment. It can also be postulated that L-carnitine protects from cisplatin injury, by modulating the relationship between MMP-9 and TIMP-3.

Phosphate binders for the treatment of chronic kidney disease: role of iron oxyhydroxide

Chronic kidney disease-mineral bone disorder is frequent in patients with renal failure. It is characterized by abnormalities in mineral and bone metabolism with resulting hyperphosphatemia, low serum vitamin D, secondary hyperparathyroidism, altered bone morphology and strength, higher risk of bone fractures, and development of vascular or other soft tissue calcifications. Besides the recommendation to reduce phosphorus dietary intake, many drugs are currently available for the treatment of calcium/phosphate imbalance. Among them, phosphate binders represent a milestone. Calcium-based binders (calcium carbonate, calcium acetate) are effective in lowering serum phosphate, but their use has been associated with an increased risk of hypercalcemia and calcifications. Calcium-free binders (sevelamer hydrochloride, sevelamer carbonate, and lanthanum carbonate) are equally or slightly less effective than calcium-containing compounds. They would not induce an increase in calcium levels but may have relevant side effects, including gastrointestinal symptoms for sevelamer and risk of tissue accumulation for lanthanum. Accordingly, new phosphate binders are under investigation and some of them have already been approved. A promising option is sucroferric oxyhydroxide (Velphoro®, PA21), an iron-based phosphate binder consisting of a mixture of polynuclear iron(III)-oxyhydroxide, sucrose, and starches. The present review is focused on pharmacology, mode of action, and pharmacokinetics of sucroferric oxyhydroxide, with a discussion on comparative efficacy, safety, and tolerability studies of this drug in chronic kidney disease and patient perspectives such as quality of life, satisfaction, and acceptability. Sucroferric oxyhydroxide has proven to be as effective as sevelamer in reducing phosphatemia with a similar safety profile and lower pill burden. Experimental and clinical studies have documented a minimal percentage of iron absorption without inducing toxicity. In conclusion, the overall benefit–risk balance of sucroferric oxyhydroxide is deemed to be positive, and this new drug may therefore represent a good alternative to traditional phosphate binders for the treatment of hyperphosphatemia in dialysis patients.

Metformin-related lactic acidosis: is it a myth or an underestimated reality?

Abstract Metformin, belonging to a class of drugs called biguanides, is the recommended first-line treatment for overweight patients with type 2 diabetes mellitus. It has multiple mechanisms of action, such as reduction of gluconeogenesis, increases peripheral uptake of glucose, and decreases fatty acid oxidation. However, a potential serious complication, defined metformin-associated lactic acidosis (MALA), is related to increased plasma lactate levels, linked to an elevated plasma metformin concentrations and/or a coexistent condition altering lactate production or clearance. The mortality rate for MALA approaches 50% and metformin has been contraindicated in moderate and severe renal impairment, to minimize its potential toxic levels. Nevertheless, metformin prescription or administration, despite the presence of contraindications or precipitating factors for MALA, was a common topic highlighted in all reviewed papers. Routine assessment of metformin plasma concentration is not easily available in all laboratories, but plasma metformin concentrations measured in the emergency room could ensure the correct diagnosis, eliminating metformin as the cause of lactic acidosis if low plasma levels occurred. Renal replacement therapies have been successfully employed to achieve the correction of metabolic acidosis and rapidly remove metformin and lactate, but the optimal treatment modality for MALA is still controversial.

Role of Paricalcitol in Modulating the Immune Response in Patients with Renal Disease

Introduction. The aim was to highlight the existence of a relationship between vitamin D deficiency, chronic inflammation, and proteinuria, by measuring neutrophil gelatinase associated lipocalin (NGAL) and common inflammatory markers after administration of paricalcitol, a vitamin D analog, in vivo and in vitro. Methods. 40 patients with end-stage chronic kidney disease (CKD) and secondary hyperparathyroidism and 40 healthy subjects were enrolled. Serum calcium, phosphorus, 25(OH)-vitamin D, parathyroid hormone (PTH), erythrocyte sedimentation rate, high-sensitivity C-reactive protein, interleukin- (IL-) 17, IL-6, IL-1β, interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), plasmatic and urinary NGAL, and 24 h albuminuria and proteinuria were measured before and 24 h after an intravenous bolus of paricalcitol (5 mcg). Human peripheral blood mononuclear cells were isolated and stimulated with phytohaemagglutinin. NGAL, IL-1β, IL-17, IL-6, TNF-α, and IFN-γ were measured in the culture medium and in the 24 h urine collection. Results. 25(OH)-vitamin D was lower in CKD than in controls (p < 0.0001), while inflammatory markers were higher in CKD group (p < 0.0001). In vivo and in vitro studies showed a downregulation of NGAL, IL-17, IL-6, IL-1β, TNF-α, and IFN-γ after paricalcitol administration (p < 0.0001). Conclusions. 25(OH)-vitamin D regulates immune and inflammatory processes. Further studies are needed to confirm these data in order to improve the treatment of CKD patients.

Subcutaneous Low Doses of Recombinant Human Erythropoietin in Predialysis Patients Do Not Interfere with the Progression of Renal Failure

This paper reports a study on the treatment of predialysis patients with recombinant human erythropoietin (r-HuEPO). The haematocrit, haemoglobin, reticulocyte and platelet values as well as creatinine and creatinine clearance evaluated by standard and radio-isotopic methods before, during and after r-HuEPO treatment were determined. The slope of the inverse creatinine versus time curves was studied too. The authors did not observe any variation of the renal function parameters during and after study and suggest their protocol of r-HuEPO administration for predialysis patients.