NGAL (Lcn2) monomer is associated with tubulointerstitial damage in chronic kidney disease.

The type and the extent of tissue damage inform the prognosis of chronic kidney disease (CKD), but kidney biopsy is not a routine test. Urinary tests that correlate with specific histological findings might serve as surrogates for the kidney biopsy. We used immunoblots and ARCHITECT-NGAL assays to define the immunoreactivity of urinary neutrophil gelatinase-associated lipocalin (NGAL) in CKD, and we used mass spectroscopy to identify associated proteins. We analyzed kidney biopsies to determine whether specific pathological characteristics associated with the monomeric NGAL species. Advanced CKD urine contained the NGAL monomer as well as novel complexes of NGAL. When these species were separated, we found a significant correlation between the NGAL monomer and glomerular filtration rate (r=-0.53, P<0.001), interstitial fibrosis (mild vs. severe disease; mean 54 vs. 167 µg uNGAL/g Cr, P<0.01), and tubular atrophy (mild vs. severe disease; mean 54 vs. 164 µg uNGAL/g Cr, P<0.01). Monospecific assays of the NGAL monomer demonstrated a correlation with histology that typifies progressive, severe CKD.

Urinary NGAL marks cystic disease in HIV-associated nephropathy.

Nephrosis and a rapid decline in kidney function characterize HIV-associated nephropathy (HIVAN). Histologically, HIVAN is a collapsing focal segmental glomerulosclerosis with prominent tubular damage. We explored the expression of neutrophil gelatinase-associated lipocalin (NGAL), a marker of tubular injury, to determine whether this protein has the potential to aid in the noninvasive diagnosis of HIVAN. We found that expression of urinary NGAL was much higher in patients with biopsy-proven HIVAN than in HIV-positive and HIV-negative patients with other forms of chronic kidney disease. In the HIV-transgenic mouse model of HIVAN, NGAL mRNA was abundant in dilated, microcystic segments of the nephron. In contrast, urinary NGAL did not correlate with proteinuria in human or in mouse models. These data show that marked upregulation of NGAL accompanies HIVAN and support further study of uNGAL levels in large cohorts to aid in the noninvasive diagnosis of HIVAN and screen for HIVAN-related tubular damage.

Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens.

We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six new genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geospatial distribution of risk alleles is highly suggestive of multi-locus adaptation, and genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN.

The relationship between blood pressure and pain.

The relationship between pain and hypertension is potentially of great pathophysiological and clinical interest, but is poorly understood. The perception of acute pain initially plays an adaptive role, which results in the prevention of tissue damage. The consequence of ascending nociception is the recruitment of segmental spinal reflexes through the physiological neuronal connections. In proportion to the magnitude and duration of the stimulus, these spinal reflexes cause the activation of the sympathetic nervous system, which increases peripheral resistances, heart rate, and stroke volume. The response also involves the neuroendocrine system, and, in particular, the hypothalamic-pituitary-adrenal axis, in addition to further activation of the sympathetic system by adrenal glands. However, in proportion to an elevation in resting blood pressure, there is a contemporary and progressive reduction in sensitivity to acute pain, which could result in a tendency to restore arousal levels in the presence of painful stimuli. The pathophysiological pattern is significantly different in the setting of chronic pain, in which the adaptive relationship between blood pressure and pain sensitivity is substantially reversed. The connection between acute or chronic pain and cardiovascular changes is supported observationally, but some of this indirect evidence is confirmed by experimental models and human studies. The pain regulatory process and functional interaction between cardiovascular and pain regulatory systems are briefly reviewed. Various data obtained are described, together with their potential clinical implications.

Coexistence of different circulating anti-podocyte antibodies in membranous nephropathy.

BACKGROUND AND OBJECTIVES: The discovery of different podocyte autoantibodies in membranous nephropathy (MN) raises questions about their pathogenetic and clinical meaning. This study sought to define antibody isotypes and correlations; to compare levels in MN, other glomerulonephritides, and controls; and to determine their association with clinical outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Serum IgG(1), IgG(3), and IgG(4) against aldose reductase (AR), SOD2, and α-enolase (αENO) were measured at diagnosis in 186 consecutive MN patients, in 96 proteinuric controls (36 with FSGS, and 60 with IgA nephropathy), and in 92 healthy people recruited in four Italian nephrology units. Anti-phospholipase A2 receptor (PLA2r) and anti-neutral endopeptidase (NEP) IgG(4) were titrated in the same specimens. Association with 1-year follow-up clinical parameters was studied in 120 patients. RESULTS: IgG(4) was the most common isotype for all antibodies; IgG(1) and IgG(3) were nearly negligible. IgG(4) levels were positive in a significant proportion of MN patients (AR, 34%; SOD2, 28%; αENO, 43%). Antibody titers were higher in MN than in healthy and pathologic controls (P<0.005). Anti-NEP IgG(4) did not differ from normal controls (P=0.12). Anti-PLA2r IgG(4) was detected in 60% of patients and correlated with anti-AR, anti-SOD2, and anti-αENO IgG(4) (P<0.001). In MN patients negative for the whole antibody panel (20%), 1-year proteinuria was lower compared with patients with at least one antibody positivity (P<0.05). CONCLUSIONS: Our data suggest that IgG(4) is the prevalent isotype for antibodies against cytoplasmic antigens of podocytes (AR, SOD2, αENO). Their levels were higher than in other proteinuric glomerulonephritides and in normal controls and were correlated with anti-PLA2r. Only baseline negativity for all known antibodies predicted lower 1-year proteinuria.

Prolactinoma in a diabetic dialysis patient with erectile dysfunction: a difficult differential diagnosis.

Dialysis patients often suffer from erectile dysfunction. The prevalence of this symptom in the context of dialysis is as high as 90%. Diabetes, diffuse vascular disease and pharmacological therapy are attendant causes of this condition, severely impairing the quality of life. Due to the high frequency of erectile dysfunction in uremic patients, minimalist diagnostic approaches are often used. Nevertheless, a careful differential diagnosis is also warranted in well dialyzed patients to identify causes and corrigible patterns. The case reported here exemplifies this critical issue. A 44 year old obese diabetic patient complained about the recent onset of erectile dysfunction. On examination, the penile echo-Doppler was normal, and suggested a cause other than dia-betic vascular disease. The high dialysis efficiency (daily hemodialysis, flexible schedules, EKRc from 15 to 25 ml/min) warranted the same diagnostic work-up as would adopted for non-uremic patients. Whilst the rising prolactine level (76.1 microg/l and 129 ng/ml) was still in the range commonly found in dialysis patients, a nuclear magnetic resonance examination was carried out and led to the identification of prolactinoma. Therapy with cabergoline was found effective and sexual potency was restored. Normalization of hormonal patterns followed within 2 months. This is the first case so far reported in a daily dialysis patient. It underlines the importance of a non-minimalist approach to the problem of sexual disorders in renal replacement therapy (RRT) patients, at least when dialysis efficiency is high and onset is rapid. It also suggests considering prolactinoma as an emerging diagnosis in the general population, which can be detected by the use of sensitive imaging techniques in the differential diagnosis of this condition.

Cholesterol emboli syndrome in type 2 diabetes: the disease history of a case evaluated with renal scintigraphy.

BACKGROUND: Cholesterol crystal emboli syndrome (CCE) is an emerging disease, whose progression reflects the currently observed increase in cardiovascular diseases. Diagnostic criteria shifted from pathological to clinical criteria: creatinine increase, skin lesions, recent endovascular interventions and severe vasculopathy). Diabetes, hypertension and diffuse vascular disease are inter-linked, major risk factors. The role of imaging techniques in the diagnosis and treatment of the disease has been little investigated thus far. The AIM of this report is to describe a case exemplifying the potentials for renal scintigraphy in CCE, an emerging disease in type 2 diabetic patients. THE CASE: A 75 year-old, type 2 diabetic for over 15 years, obese, hypertensive white man was referred to the Nephrology Unit after an acute coronary syndrome. Stenosis of the left renal artery was diagnosed from the angiography. Serum creatinine (baseline: 1.9 mg/dl) increased after multiple angioplasties to 3.3 mg/dl, then slowly returned towards baseline (2.2 mg/dl), but rose, on referral, to 3.9 mg/dl, with an increase in acute phase reactants and peripheral livedo reticularis, a picture highly suggestive of CCE. The first renal scintiscan showed a reduction of the parenchymal phase, and a non-homogeneous parenchymal pattern in the right dominant kidney. The patient was started on corticosteroid therapy with a prompt decrease in creatinine; four days later (creatinine 2.5 mg/dl) a second scintiscan showed an improvement of the peak time and of the radionuclide parenchymal transit, and was further confirmed two months later (creatinine 2.2 mg/dl). No modification was detected in the left kidney, presumably mechanically "protected" from the cholesterol shedding by the stenosis. CONCLUSIONS: This is the first description of an imaging demonstration of the morpho-functional substratum to the rapid clinical response of corticosteroid therapy in a case of CCE and type 2 diabetes, underlining the potential of 99mTc-MAG3 dynamic scintiscan in this disease.