3 Tesla-Diffusion Tensor Imaging in Autosomal Dominant Polycystic Kidney Disease: The Nephrologist's Point of View.

BACKGROUND/AIMS: CT, MRI and ultrasound are currently used for screening and follow-up of individuals affected by autosomal dominant polycystic kidney disease (ADPKD). Dynamic contrast-enhanced MRI studies renal perfusion after gadolinium administration, with possible side effects, such as nephrogenic systemic fibrosis. The aim of our study was to evaluate the clinical application of 3 Tesla (3T)-diffusion tensor image (DTI) in ADPKD patients, correlating its parameters, such as fractional anisotropy (FA), and apparent diffusion coefficient (ADC) with kidney function tests. METHODS: Eight ADPKD patients and 6 healthy volunteers (HS) were enrolled. FA and ADC mean values were calculated. And correlations between DTI-parameters, creatinine and estimated glomerular filtration rate (eGFR) were evaluated. RESULTS: Parenchymal FA was significantly lower in ADPKD than HS (FA: 0.17 ± 0.03 vs. 0.22 ± 0.01; p = 0.02), whereas parenchymal ADC was higher in patients than controls (2.48 (×10-3) ± 0.16 vs. 2.28 (×10-3) ± 0.09), but a statistically significant difference was not achieved (p = 0.27). Direct correlations were revealed between eGFR and FA (r = 0.82; p = 0.0003), whereas an inverse correlation was found with creatinine (r = -0.77; p = 0.001). Similarly, ADC closely correlated with creatinine (r = 0.79; p = 0.0006) and eGFR (r = -0.620; p = 0.01). CONCLUSION: 3T-DTI is a promising radiological tool that could be used by nephrologists to evaluate ADPKD patients, highlighting early micro-structure alterations, without side effects and contrast agent administration.

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-1ß, 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-1ß, 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-1ß, 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.

Nephro-oncology: a link in evolution.

A multidisciplinary approach represents the best method to interact with patients. Neoplastic and renal diseases are closely related to each other because of an increased risk of cancer among individuals with end-stage renal disease and because of the high prevalence of renal failure in cancer patients. Physicians should be able to know how to prevent and treat the possible complications which may appear during the course of neoplastic disease that may lead to kidney damage such as the Acute Tumor Lysis Syndrome, disorders of hydroelectrolitic balance, metabolic alterations in the calcium-phosphorus, anemia, interstitial and glomerular impairment due to chemotherapy. It is very important to know patients' renal function and directly monitor it, before and during treatment, using formulas for estimating glomerular filtration rate (GFR) and above all, specific biomarkers are more early and sensitive than the increase of creatinine, like neutrophil gelatinase-associated lipocalin. Additionally, physician should consider that alteration of GFR or substitutive renal treatments severely influence dosage of tumor markers and it could lead to wrong diagnosis of cancer. The aim of this article is to provide a review of problems related to cancer relevant in the development of renal failure and try to define the best therapeutic strategies to cope with possible kidney imbalances induced by cancer or its treatment.

Unexpected hypercalcemia in a diabetic patient with kidney disease.

We report a case of a diabetic patient with progressive chronic kidney disease and unexplained hypercalcemia. This unusual presentation and the investigation of all possible causes led us to perform a renal biopsy. The systemic sarcoidosis diagnosis was confirmed by the presence of interstitial multiple granulomas composed of epithelioid and multinucleated giant cells delimited by a thin fibrous reaction, and by pulmonary computed tomography finding of numerous lumps with ground-glass appearance. Sarcoidosis most commonly involves lungs, lymph nodes, skin and eyes, whilst kidney is less frequently involved. When it affects males it is characterized by hypercalcemia, hypercalciuria, and progressive loss of renal function. Early treatment with steroids allows for a gradual improvement in renal function and normalization of calcium serum values. Otherwise, the patient would quickly progress to end stage renal disease. Finding of hypercalcemia in a patient with renal failure must alert physicians because it may be a sign of several pathological entities.

[Lupus Nephritis and Enteritis, a dual simultaneous involvement with Arteriolar Thrombosis]. / Nefrite ed Enterite Lupica, un doppio coinvolgimento simultaneo con trombosi arteriolare.

Arteriolar thrombosis is a complication that may occur during systemic lupus erithematosus. The pathophysiology could be related to abnormal endothelial function secondary to immune dysregulation. In particular renal and intestinal vessels may be target of thrombosis. We report a simultaneous appearance of lupus nephritis and enteritis in a young female who presented with renal failure and proteinuria. The presence of renal arteriolar thrombosis together with intestinal ischemia lead us to speculate a possible common pathways.

From water to aquaretics: a legendary route.

Man is water. When life appeared on earth, the primordial cell had a simple structure and could immediately ascertain from the surrounding aquatic environment the substances for nutrition and oxygen, without any need for structural complexity. As part of evolution, during the transition from aquatic to terrestrial life, vertebrates had to fight against dehydration as well as fish in the sea. In this complex mechanism of osmoregulation, the structure and function of some osmoregulatory hormones have been maintained during the evolution of species, from fish to man. Within the homeostatic mechanism, the renin-angiotensin-aldosterone system (RAAS) is crucial in the regulation of renal reasorption of water and sodium. It is also involved in the regulation of renal plasma flux, blood volume and blood pressure. Vasopressin plays a hormonal function in the mechanisms of water homeostasis acting through Aquaporins (AQP), channel-proteins that allow bi-directional water transport across cell membranes.

Proteinuric effect of transcranial magnetic stimulation in healthy subjects and diabetic patients with stage 3-4 CKD.

BACKGROUND: Many authors have investigated the numerous connections between the nervous system and kidneys, and recent literature has indicated that these similar systems are interconnected. Recent scientific works have shown that there is similarity between the cerebral cortex 'viscera representation' and the 'motor omunculus'. We studied the connection between the brain and kidney in vivo using repetitive transcranial magnetic stimulation (rTMS). Proteinuria and albuminuria were used as markers of renal response in patients with diabetes (DP) and in a group of healthy subjects (HSs) who received rTMS for 5 consecutive days. METHODS: The study population consists of the following four groups: Group A (HS stimulated), Group B (HS sham), Group C (DP stimulated) and Group D (DP sham). All subjects in Groups A and C underwent rTMS delivered at a frequency corresponding to 90% of the threshold at rest for 5 consecutive days. All subjects in Groups B and D underwent rTMS delivered with the coil placed on the scalp without delivering electromagnetic stimuli, while another coil at a distance of ∼2 m emitted stimuli at a very low intensity. This strategy ensured that brain stimulation would not occur, so that the subjects felt the vibrations produced by the click of the TMS coil. The proteinuria and albuminuria of 24 h and creatinine clearance were measured at time 0 (T0), after the first session (T1), at the end of the treatment (T5) and 24 h after the last stimulation (Post 24 h). RESULTS: In Group A, there was a statistically significant increase in albuminuria (5.65 ± 0.52 versus 12 ± 0.55 mg/24 h, P = 0.0001) and proteinuria (6.05 ± 0.48 versus 13.1 ± 0.60 mg/24 h, P = 0.0001) at the end of the treatment (T5) compared with the baseline values (T0). In Group C, the albuminuria was statistically higher at T5 than the baseline T0 (416.22 ± 181 versus 677.25 ± 280 mg/24 h, P = 0.04), as was proteinuria (561.37 ± 86 versus 865.125 ± 104 mg/24 h, P = 0.0001); in Group C, the increase in albuminuria (T0 versus post 24 h, P = 0.02) and proteinuria (T0 versus 24 h post, P = 0.0002) persisted at 24 h post. In Groups B and D, statistically significant changes were not found in proteinuria (Group B T0 versus T5, P = 0.61; Group D: T0 versus T5, P = 0.66) and albuminuria (Group B T0 versus T5, P = 0.15; Group D T0 versus T5, P = 0.44) measured at the same times. CONCLUSIONS: Consecutive rTMS is able to induce a statistically significant increase in albuminuria and proteinuria in HS and DP. A functional link between the brain and kidney is possible. For the first time, the results have indicated an increase of proteinuria in subjects undergoing transcranial stimulation.

Relaxin: new pathophysiological aspects and pharmacological perspectives for an old protein.

Human relaxin-2 (hereafter simply defined as "relaxin") is a 6-kDa peptidic hormone best known for the physiological role played during pregnancy in the growth and differentiation of the reproductive tract and in the renal and systemic hemodynamic changes. This factor can also be involved in the pathophysiology of arterial hypertension and heart failure, in the molecular pathways of fibrosis and cancer, and in angiogenesis and bone remodeling. It belongs to the relaxin peptide family, whose members comprehensively exert numerous effects through interaction with different types of receptors, classified as relaxin family peptide (RXFP) receptors (RXFP1, RXFP2, RXFP3, RXFP4). Research looks toward the in-depth examination and complete understanding of relaxin in its various pleiotropic actions. The intent is to evaluate the likelihood of employing this substance for therapeutic purposes, for instance in diseases where a deficit could be part of the underlying pathophysiological mechanisms, also avoiding any adverse effect. Relaxin is already being considered as a promising drug, especially in acute heart failure. A careful study of the different RXFPs and their receptors and the comprehension of all biological activities of these hormones will probably provide new drugs with a potential wide range of therapeutic applications in the near future.

Apelin and copeptin: two opposite biomarkers associated with kidney function decline and cyst growth in autosomal dominant polycystic kidney disease.

Vasopressin (AVP) plays a detrimental role in autosomal dominant polycystic kidney disease (ADPKD). Copeptin represents a measurable substitute for circulating AVP whereas apelin counteracts AVP signaling. The aim of this study was to investigate the predictive value of apelin and copeptin for the progression of ADPKD disease. 52 ADPKD patients were enrolled and followed until the end of the observation period or the primary study endpoint was reached, defined by the combined outcome of decrease of glomerular filtration rate associated with a total renal volume increase. Receiver operating characteristics (ROC) analysis was employed for identifying the progression of renal disease and Kaplan-Meier curves assessed the renal survival. Adjusted risk estimates for progression endpoint and incident renal replacement therapy (RRT) were calculated using Cox proportional hazard regression analysis. ADPKD patients were characterized by lower apelin levels and higher copeptin levels when compared with healthy subjects. These biomarkers were strictly correlated with osmolality and markers of renal function. At ROC analysis, apelin and copeptin showed a very good diagnostic profile in identifying ADPKD progression. After the follow up of 24 months, 33 patients reached the endpoint. Cox proportional hazard regression analysis showed that apelin predicted renal disease progression and incident RRT independently of other potential confounders. Apelin is associated with kidney function decline in ADPKD, suggesting that it may be a new marker to predict kidney outcome.

Neutrophil gelatinase-associated lipocalin in peritoneal dialysis reflects status of peritoneum.

BACKGROUND: Ultrafiltration failure and peritonitis are the most important limitations of peritoneal dialysis (PD). The aim of our study was to evaluate peritoneum damage through neutrophil gelatinase-associated lipocalin (NGAL), white blood cell (WBC) count and cancer antigen 125 (CA125). PATIENTS AND METHODS: Thirty patients with peritonitis and 30 patients undergoing continuous ambulatory peritoneal dialysis (CAPD) were studied for 12 months. In the peritonitis group, blood samples and peritoneal fluid (lp) were collected before the onset of peritonitis, at the onset of peritonitis (T1) and every day until its resolution. CAPD patients were divided into 3 groups according to the treatment received. Long-dwell effluents were collected for NGAL, WBC count and Ca125 assessment. RESULTS: In the peritonitis group, at time T1, NGAL levels were higher compared with baseline values. lpNGAL levels decreased at least 24 hours earlier than peritoneal WBC (lpWBC). At ROC analysis, lpNGAL was characterized by a very good diagnostic profile identifying treatment failure. In CAPD patients, the highest NGAL values were observed in the icodextrin group. An inverse correlation between lpNGAL, pKt/V and peritoneal ultrafiltration volume was also found. CONCLUSION: Mesothelial cells have an active role in the structural and functional alteration of the peritoneum during PD, and NGAL represents a valid biomarker for peritoneum evaluation.

Can neutrophil gelatinase-associated lipocalin help depict early contrast material-induced nephropathy?

PURPOSE: To evaluate the utility of serum and urinary neutrophil gelatinase-associated lipocalin (NGAL) in depicting an event of contrast material-induced nephropathy (CIN) in patients who received iodinated contrast media, gadoterate meglumine, or radiopharmaceutical technetium-99m ((99m)Tc) and to evaluate the protective effect exerted by isotonic saline infusion, sodium bicarbonate administration, or N-acetylcysteine administration. MATERIALS AND METHODS: Institutional ethics committee approval was given, and informed consent was obtained. One hundred twenty patients were enrolled in a prospective study and divided into three groups: iomeprol group, magnetic resonance (MR) imaging group (gadoterate meglumine), and renal scintigraphy group ((99m)Tc). They randomly received N-acetylcysteine, physiologic saline, or sodium bicarbonate. Receiver operating characteristic (ROC) analysis, Kaplan-Meier curves, and Cox proportional hazard regression analysis were used. RESULTS: In the MR imaging and renal scintigraphy groups, there were significant changes in serum creatinine and NGAL levels, and there were no cases of CIN. In the iomeprol group, an early rise in NGAL was found, while serum creatinine level changes occurred 24 hours after contrast material administration. At ROC analysis, NGAL showed high sensitivity and specificity (serum NGAL: area under the curve, 0.995; 95% confidence interval [CI]: 0.868, 0.992; urinary NGAL: area under the curve, 0.992; 95% CI: 0.925, 1.000) in identifying CIN 8 hours after iomeprol administration. Regression analysis showed that NGAL independently predicted CIN. Administration of N-acetylcysteine, sodium bicarbonate, or physiologic saline did not influence NGAL level. CONCLUSION: NGAL depicted CIN in patients who received iodinated contrast material within 8 hours of contrast material administration. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120578/-/DC1.

Apelin, plasmatic osmolality and hypotension in dialyzed patients.

BACKGROUND/AIMS: To evaluate the balance between arginine-vasopressin (AVP) and apelin during hemodialysis and its role in hypotension onset and in the inflammation status. METHODS: We enrolled 50 patients chronically treated with hemodialysis. We assessed plasmatic osmolality, AVP, apelin, mean blood pressure (BP), high-sensitivity C-reactive protein (hsCRP) and ß(2)-microglobulin. RESULTS: Apelin rises during dialytic treatment (from 0.68 ± 0.34 to 1.89 ± 0.56 pg/ml, p < 0.0001), while plasmatic osmolality (from 325 ± 4.54 to 311 ± 1.20 mosm/kg H(2)O, p < 0.0001), AVP (from 4.28 ± 1.12 to 2.48 ± 0.50 pg/ml, p < 0.0001) and mean BP (from 124 ± 6 to 110 ± 7 mm Hg, p < 0.0001) decrease. At multivariate regression with respect to apelin, only mean BP remains (r = -0.95, p < 0.0001). We also correlated the AVP/apelin ratio with BP. Moreover, apelin is inversely related to hsCRP (r = -0.79, p < 0.0001). CONCLUSIONS: The AVP/apelin balance changes with plasmatic osmolality variations induced by hemodialytic sessions and could represent a physiopathological marker of arterial hypo- and hypertension. Finally, apelin appears inversely related to inflammation markers.

Hydrocarbons and kidney damage: potential use of neutrophil gelatinase-associated lipocalin and sister chromatide exchange.

BACKGROUND: Millions of workers are exposed to polycyclic aromatic hydrocarbons (PAHs) and it is known that the kidney is a target for toxic chemicals. We have evaluated neutrophil gelatinase-associated lipocalin (NGAL) as a potential marker of tubular damage and have used it, with sister chromatid exchange (SCE) analysis, to evaluate carcinogenic risk in a group of workers from an oil refinery. METHODS: NGAL and SCE analysis were evaluated in 160 subjects. Exposed subjects were divided into three groups, according to levels of exposure to PAHs: 40 highly exposed workmen (WM), 40 less exposed office workers (OW), and 40 subjects (GE) living in Gela. The control group included 40 healthy subjects (HS). RESULTS: WM, OW and GE showed higher NGAL levels than HS. WM had higher levels of NGAL than the OW and GE groups; in ROC analysis, serum NGAL showed a good diagnostic profile (sensitivity 87.5%; specificity 100.0%), as did urinary NGAL (sensitivity 90.0%; specificity 92.5%). Moreover, regarding SCE analysis, WM showed higher values than HS. A direct correlation between SCE and serum NGAL was found in WM, the group most exposed to PAHs. CONCLUSION: The high values of NGAL are an expression of damage to the renal tubule determined by exposure to PAHs. Compared to the other groups studied, chromosomal aberrations - expressed as SCE - were increased in WM, the group most exposed to PAHs, indicating genotoxic damage. NGAL may also play a role in the process of carcinogenesis having a direct correlation with the number of SCEs.

[From oxygen to erythropoietin, as a protagonist of the skin-brain-kidney axis]. / Dall'ossigeno all'EPO, protagonista dell'asse cute-cervello-rene.

Erythropoietin synthesis is one of the essential adaptive responses to a hypoxic environment. In mammals, a renal oxygen sensor capable of stimulating erythropoietic hormone synthesis through a transcriptional factor called HIF (hypoxia-inducible factor) has long been identified. Recent research has demonstrated that cerebral astrocytes and skin keratocytes can also produce erythropoietin as a response to different oxygen concentrations. Therefore, it is possible to hypothesize a skin-brain-kidney link which, through erythropoietin production, modulates the oxygen contribution to tissues. Moreover, the results are not so unambiguous and further research on the pleiotropic effects of erythropoetin would be opportune.