[Left atrial appendage occlusion as replacement of coumarin anticoagulants in calciphylaxis].

Calcific uremic arteriolopathy (CUA), often referred to as calciphylaxis, is a rare condition potentially life-threatening seen in 1-4% of patients with kidney failure on chronic dialysis. Pathogenesis is not clear, but several risk factors have been identified, one of the most known among them is coumarin anticoagulants therapy (tAC). When CUA occurs, tAC is contraindicated: the left atrial appendage occlusion, in dialysed patients affected by non-valvular atrial fibrillation, could be contemplated in replacement of tAC, that should be considered by nephrologist and discussed by a multidisciplinary team including cardiologists.

COVID-19 Infection and Acute Kidney Injury: Cause or Complication?

Management of COVID-19 infection is the trend topic in the scientific community and case identification is a key step to contain the pandemic. While pneumonia and acute respiratory distress syndrome represent the typical severe manifestations of the disease, atypical presentations pose significant diagnostic and therapeutic challenges for physicians, especially when diagnostic tests are repeatedly negative. Clinical picture of COVID-19 patients is often complicated by bacterial infections or thrombotic events. Here, we present and discuss a case report identified in our center as example of a challenging diagnosis and 2 uncommon complications: severe hyponatremia and acute kidney injury requiring renal replacement therapy, caused by parenchymal damage and with a possible direct involvement of the virus.

Renal involvement in sarcoidosis: histological patterns and prognosis, an Italian survey.

BACKGROUND: Granulomatous interstitial nephritis in sarcoidosis (sGIN) is generally clinically silent, but in <1% causes acute kidney injury (AKI). METHODS: This Italian multicentric retrospective study included 39 sarcoidosis-patients with renal involvement at renal biopsy: 31 sGIN-AKI, 5 with other patterns (No-sGIN-AKI), 3 with nephrotic proteinuria. We investigate the predictive value of clinical features, laboratory, radiological parameters and histological patterns regarding steroid response. Primary endpoint: incident chronic kidney disease (CKD) beyond the 1°follow-up (FU) year; secondary endpoint: response at 1°line steroid therapy; combined endpoint: the association of initial steroid response and outcome at the end of FU. RESULTS: Complete recovery in all 5 No-sGIN-AKI-patients, only in 45% (13/29) sGIN-AKI-patients (p=0.046) (one lost in follow-up, for another not available renal function after steroids). Nobody had not response. Primary endpoint of 22 sGIN-AKI subjects: 65% (13/20) starting with normal renal function developed CKD (2/22 had basal CKD; median FU 77 months, 15-300). Combined endpoint: 29% (6/21) had complete recovery and final normal renal function (one with renal relapse), 48% (10/21) had partial recovery and final CKD (3 with renal relapse, of whom one with basal CKD) (p=0.024). Acute onset and hypercalcaemia were associated to milder AKI and better recovery than subacute onset and patients without hypercalcaemia, women had better endpoints than men. Giant cells, severe interstitial infiltrate and interstitial fibrosis seemed negative predictors in terms of endpoints. CONCLUSIONS: sGIN-AKI-patients with no complete recovery at 1°line steroid should be treated with other immunosuppressive to avoid CKD, in particular if males with subacute onset and III stage-not hypercalcaemic AKI.

High Blood Pressure Is Associated with Tubulointerstitial Damage along with Glomerular Damage in Glomerulonephritis. A large Cohort Study.

The key role of arterial hypertension in chonic kidney disease (CKD) progression is widely recognized, but its contribution to tubulointerstitial damage (TID) in glomerulonephritis (GN) remains uncertain. Hence, the objective of this study is to clarify whether TID is associated with glomerular damage, and whether the damage at the tubulointerstitial compartment is more severe in hypertensive patients. The study included retrospectively consecutive patients referred to the Nephrology Unit with diagnoses of primary glomerulonephritis, lupus nephritis (LN), and nephroangiosclerosis (NAS) at biopsy. At least six glomeruli per biopsy were analysed through light and immunofluorescence microscopy. Global glomerulosclerosis (GGS%), TID, and arteriolar hyalinosis (AH) were used as markers of CKD severity. Of the 448 patients of the cohort, 403 received a diagnosis of GN, with the remaining being diagnosed with NAS. Hypertension was found in 52% of the overall patients, with no significant differences among those with GN, and reaching 88.9% prevalence rate in NAS. The hypertensive patients with GN had more marked damage in glomerular and tubular compartments than normotensives independently of the amount of proteinuria. Moreover, hypertension and GGS% were found to be strongly associated with TID in GN. In GN patients, not only the severity of glomerular damage but also the extent of TID was associated with high blood pressure.

Clinical usefulness of autoantibodies to M-type phospholipase A2 receptor (PLA2R) for monitoring disease activity in idiopathic membranous nephropathy (IMN).

Autoantibodies to M-type phospholipase A2 receptor (PLA2R) are specific markers of idiopathic membranous nephropathy (IMN). They can differentiate IMN from other glomerular diseases and primary from secondary forms of MN. Preliminary data suggest that anti-PLA2R antibody titer correlates with disease activity but more solid evidence is needed. To evaluate the performance of anti-PLA2R antibody for monitoring nephropathy activity, 149 anti-PLA2R antibody measurements were performed during the follow-up of 42 biopsy proven IMN consecutive patients. Patients were enrolled either at time of diagnosis (33 cases, inception cohort) or after diagnosis (9 patients, non-inception cohort). Anti-PLA2R detection was performed using the highly sensitive transfected cell-based indirect immunofluorescence (IIFT). Over the follow-up there was a linear time-trend of decreasing proteinuria (P<0.001), increasing serum albumin (P<0.001) and decreasing PLA2R antibody levels (P=0.002). There was a statistically significant association between changes in PLA2R antibody levels and the clinical course of PLA2R-positive IMN. The positive PLA2R serum antibody status was linearly associated with increasing proteinuria and decreasing serum albumin over time, compared with negative antibody status. Moreover, the strong correlation between the clinical conditions and PLA2R antibody levels allowed the prediction of prevalence distribution of patients with active disease, partial and complete remission. Over the course of the follow-up, the probability of halving proteinuria increased 6.5 times after disappearance of PLA2R antibodies. Our data suggest that the serial evaluation of anti-PLA2R antibodies could help in optimal timing and duration of the immunosuppressive therapy, reducing over(under)-treatment and associated side-effects.

Urinary IgG and α2-macroglobulin are powerful predictors of outcome and responsiveness to steroids and cyclophosphamide in idiopathic focal segmental glomerulosclerosis with nephrotic syndrome.

OBJECTIVE: To assess whether high-molecular-weight proteins excretion predicts outcome and therapy-responsiveness in patients with FSGS and nephrotic syndrome. RESEARCH DESIGN AND METHODS: Thirty-eight patients measured at biopsy fractional excretion of IgG (FEIgG) and urinary α2-macroglobulin/creatinine ratio ( α m/C). Low and high risk groups were defined by cutoffs assessed by ROC analysis. In all patients first-line therapy was with steroids alone or in combination with cyclophosphamide. RESULTS: α2m/C and FEIgG were correlated with segmental sclerosis (r = 0.546; r = 0.522). Twenty-three patients (61%) entered Remission and 9 (24%) progressed to ESRD. Comparing low and high risk groups, by univariate analysis remission was predicted by FEIgG (77% versus 25%, P = 0.016) and α2m/C (81% versus 17%, P = 0.007) and ESRD at best by FEIgG (0% versus 75%, P < 0.0001) and α2m/C (4% versus 67%, P < 0.0001). By multivariate analysis FEIgG was the only independent predictor of remission and α2m/C the most powerful predictor of ESRD. Low and high risk groups of FEIgG and α2m/C in combination had very high predictive value of sustained remission and ESRD in response to therapy. CONCLUSIONS: FEIgG and α2m/C are powerful predictors of outcome and responsiveness to steroids and cyclophosphamide; their predictive value, if validated in prospective studies, may be useful in clinical practice suggesting first-line alternative treatments in high risk patients.

Validation of some pathophysiological mechanisms of the CKD progression theory and outcome prediction in IgA nephropathy.

BACKGROUND: The "remnant kidney" chronic kidney disease (CKD) progression theory based on hemodynamic, proteinuric and inflammatory mechanisms consequent to nephron loss has not been confirmed in a human disease. The aim of this study was to evaluate whether some of these mechanisms are present in IgA nephropathy (IgAN) and predict functional outcome. METHODS: In 132 IgAN patients (68 untreated, 64 angiotensin-converting enzyme inhibitor [ACEi]-treated) fractional excretion of IgG (FEIgG) and α1-microglobulin, proteinuria/day and ß-NAG excretion were divided by percentage of nonglobally sclerotic glomeruli ("surviving glomeruli" [SG]) to assess the effective glomerular loss and tubular load of proteins in surviving nephrons. Proteinuric markers were compared between 4 SG groups: group 1: ≤50%; group 2: >50% and <80%; group 3: ≥80% and <100%; and group 4: 100%. The outcome prediction (estimated glomerular filtration rate [eGFR] improvement and stability, progression) was assessed comparing low- and high-risk groups for each marker. RESULTS: Proteinuric markers showed increasing values in parallel with reduction of percentages of SG (p<0.0001). FEIgG/SG, 40-fold higher in patients with SG ≤50% vs. SG=100% (0.00040 ± 0.00039 vs. 0.00001 ± 0.00002, p<0.0001), was the most powerful outcome predictor: in ACEi-untreated patients, FEIgG/SG less or greater than 0.00010 predicted eGFR improvement and stability (88% vs. 12%, p<0.0001) and end-stage renal disease (ESRD) + eGFR reduction ≥50% (2% vs. 87.5%, p<0.0001); ACEi treatment reduced ESRD+eGFR reduction ≥50%: 36% vs. 87.5% (p=0.002). In patients with FEIgG/SG <0.00010 the eGFR increase is significantly higher in ACEi-treated for ≥70 months versus ACEi-untreated with follow up ≥70 months (+35% ± 23% vs. +13% ± 8%, p=0.004). CONCLUSIONS: In IgAN, progressive nephron loss is associated with an increase of proteinuric markers of glomerular and tubular damage. FEIgG/SG is the best outcome predictor. These data represent the first validation in a human disease of some pathophysiological mechanisms of CKD progression theory.

Renal involvement in primary antiphospholipid syndrome: retrospective analysis of 160 patients.

BACKGROUND AND OBJECTIVES: The objective of this study was to evaluate the prevalence, clinicopathologic features, and outcome of renal involvement in a large cohort of patients with primary antiphospholipid syndrome (PAPS). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We retrospectively examined medical records of 160 patients with a diagnosis of PAPS of two general hospitals of northern Italy between 1985 and 2008. RESULTS: There were 140 women and 20 men. Mean age was 35+/-12 yr. PAPS was characterized by thrombotic events in 41.2%, fetal loss in 39.4%, and both in 19.4%. Signs of renal abnormalities were present in 14 (8.7%) patients. All patients had proteinuria, in the nephrotic range in five; four patients had moderate chronic renal insufficiency, and one had end-stage kidney disease (ESKD). Two patients presented with acute renal failure and one with nephritic syndrome. Ten patients underwent a renal biopsy, which showed a membranous glomerulonephritis in four, proliferative glomerulonephritis in two, thrombotic microangiopathy in two, and vascular lesions consistent with chronic antiphospholipid antibodies nephropathy in two. Patients with renal involvement were older (41.8 versus 34.3 years; P=0.0269), more frequently lupus anticoagulant positive (92.3 versus 48.9%; P=0.0068), and had hypocomplementemia (P<0.05). CONCLUSIONS: Renal abnormalities are present in approximately 9% of patients with PAPS. In addition to APS nephropathy, the prevailing picture is membranous nephropathy. Outcome and long-term follow-up usually are good. Not all of the clinical manifestations of PAPS can be ascribed to thrombotic mechanisms. The heterogeneity of renal involvement confirms the presence of a continuum between systemic lupus erythematosus and PAPS.

Fractional urinary excretion of IgG is the most powerful predictor of renoprotection by ACE inhibitors in IgA nephropathy.

BACKGROUND: Several aspects of renoprotection by angiotensin-converting enzyme inhibitors (ACEi) in IgA nephropathy (IgAN) are poorly defined: factors affecting responsiveness, role of proteinuria components and histological lesions, and criteria to identify patients who may benefit from ACEi. METHODS: In an observational study of 140 IgAN patients (follow up 62 +/- 36 months), 73 untreated and 67 ACEitreated for 53 +/- 28 months, 9 baseline risk factors (RFs) (blood pressure, serum creatinine, proteinuria/day, fractional excretion of IgG [FEIgG] and alpha1-microglobulin, global and segmental [SS] glomerular sclerosis, tubulointerstitial damage and arteriolar hyalinosis [AH] score), each divided into 2 subgroups according to a cutoff with the highest sensitivity and specificity for progression, were evaluated for ability to predict renoprotection. Primary end point: end-stage renal disease (ESRD) and doubling of serum creatinine (sCr); secondary end point: increase >or=25% of sCr with last sCr >or=1.58 mg/dL; total progression: sum of end points. RESULTS: Patients with RFs below cutoffs did not benefit from ACEi. All clinical and proteinuric and 2 histological RFs (SS, AH score) with values above cutoffs showed significant reduction of progression in ACEitreated vs. untreated patients; FEIgG showed the highest prediction of renoprotection: ESRD/sCrx2: 20% vs. 62% (p=0.0004); total progression: 40% vs. 85% (p=0.0003). By multivariate analysis, independent predictors of progression were FEIgG, sCr and no ACEi treatment. Proteinuria reduction from -100% to -30%, spontaneous or after ACEi treatment, did not affect progression in treated vs. untreated patients (19% vs. 13%, p=0.85). Patients with proteinuria increased or reduced <30% showed a reduction of total progression if ACEi-treated (15% vs. 77%, p=0.0002). Presence of 1 clinical or proteinuric RF above the cutoff may be a criterion to identify patients who may benefit from ACEi. CONCLUSIONS: Renoprotection by ACEi is a multifactorial phenomenon: the best predictor of renoprotection is FEIgG, a marker of disruption of glomerular barrier to proteins; renoprotection depends not only on ability to reduce proteinuria, but probably also on antiinflammatory and antifibrotic activity.

In crescentic IgA nephropathy, fractional excretion of IgG in combination with nephron loss is the best predictor of progression and responsiveness to immunosuppression.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the relationship between proteinuric markers (urinary excretion of IgG, alpha2-macroglobulin, alpha1-microglobulin) and serum creatinine (sCr), histologic lesions, progression, and immunosuppression responsiveness in crescentic IgA nephropathy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Fractional excretion of IgG (FEIgG) and of alpha1-microglobulin and urinary excretion of alpha2-macroglobulin were evaluated in 37 patients, 23 treated with steroids and cyclophosphamide. For assessment of the effective tubular load of proteins in surviving nephrons, new markers that take into account not only the absolute excretion value but also nephron loss were obtained dividing proteinuric markers for percentage of nonobsolescent glomeruli (surviving glomeruli [SG]). For each parameter, low- and high-risk groups were defined according to cutoffs with the highest sensitivity and specificity for progression (ESRD/doubling sCr) assessed by receiver operating characteristic analysis; follow up was 60 +/- 40 mo. RESULTS: FEIgG/SG is the most powerful progression predictor: 5 versus 83% in all patients; in treated patients, 0 versus 89%, increased to 0 versus 100% by sCr and FEIgG/SG in combination (low risk: both markers or only one below cutoff (n = 15); high risk: both markers above cutoff (n = 8). The nonprogressors showed at last observation 65% proteinuria reduction and 10% sCr reduction. CONCLUSIONS: In crescentic IgA nephropathy, FEIgG/SG, which evaluates altered size selectivity in relation to nephron loss, is the best progression predictor. In treated patients, progression prediction was increased by FEIgG/SG and sCr in combination. Treatment may be restricted to low-risk patients.

Fractional excretion of IgG predicts renal outcome and response to therapy in primary focal segmental glomerulosclerosis: a pilot study.

BACKGROUND: Prolonged treatment with steroids and/or cyclophosphamide improves the prognosis of primary focal segmental glomerulosclerosis (FSGS). In nephrotic patients, no clinical or histological feature predicts responsiveness to therapy. METHODS: In 50 patients with FSGS, fractional excretion (FE) of immunoglobulin G (IgG), albumin, transferrin, and alpha(1)-microglobulin (alpha(1)m) was calculated. The aim of the study is to assess whether FE IgG and FE alpha(1)m: (1) correlate with histological lesions, (2) predict outcome, and (3) may be useful to guide therapy. RESULTS: The association of FE IgG with percentage of glomeruli with segmental sclerosis was at the limit of significance (P = 0.01). FE alpha(1)m was associated with extent of tubulointerstitial damage (P = 0.008). By multiple regression analysis, FE alpha(1)m was dependent on FE IgG (R(2) = 0.76; P = 0.000). The predictive value of proteinuric variables on outcome was evaluated in 29 patients with nephrotic syndrome and baseline normal renal function (serum creatinine level, 1.04 +/- 0.22 mg/dL [92 +/- 19 micromol/L]; follow-up, 50 +/- 33 months); remission rates were 91% and 0% in patients with FE IgG less than versus greater than 0.140 (P = 0.0009). By multiple logistic regression analysis, only FE IgG was associated with remission (P = 0.043). Proteinuria less than versus greater than 7.5 g/d of protein predicted end-stage renal failure (0% versus 36%; P = 0.004); the predictive value of FE IgG less than versus greater than 0.140 was higher (0% versus 71%; P = 0.0000). Patients with FE IgG less than 0.025 were responsive to steroids alone (70%) or steroids and cyclophosphamide (20%); patients with FE IgG greater than 0.025 and less than 0.140 were responsive to steroids alone (20%) or steroids and cyclophosphamide (80%); and 100% of patients with FE IgG greater than 0.140 were unresponsive to therapy (P = 0.000). CONCLUSION: In FSGS, FE IgG is at the limit of statistically significant association with segmental sclerosis, and FE alpha(1)m is associated with extent of tubulointerstitial damage. FE IgG shows the best predictive value for remission, progression, and response to therapy and may be useful to guide treatment. Am J Kidney Dis 41:328-335.

Urinary N-acetyl-beta-glucosaminidase excretion is a marker of tubular cell dysfunction and a predictor of outcome in primary glomerulonephritis.

BACKGROUND: The urinary excretion of N-acetyl-beta-glucosamynidase (NAG) is increased in subjects exposed to substances toxic for renal tubular cells. In experimental and human glomerular diseases, its increased excretion is probably due to the dysfunction of tubular epithelial cells induced by increased traffic of proteins in the tubular lumen. The first aim of this study was to evaluate whether NAG excretion is correlated not only with the amount of proteinuria but also with some proteinuric components which reflect both glomerular capillary wall damage (IgG) and an impairment of tubular reabsorption of microproteins (alpha(1) microglobulin). The second aim was to assess whether NAG excretion has a predictive value on functional outcome and response to therapy. METHODS: In 136 patients with primary glomerulonephritis [74 with idiopathic membranous nephropathy (IMN), 44 with primary focal segmental glomerulosclerosis (FSGS) and 18 with minimal change disease (MCD)] urinary NAG excretion was measured by a colorimetric method and expressed in units per gram of urinary creatinine. RESULTS: Using univariate linear regression analysis NAG excretion in all 136 patients was significantly dependent on IgG excretion, 24-h proteinuria, fractional excretion of alpha(1) microglobulin (FE alpha(1)m) and diagnosis. Using multiple linear regression analysis, NAG excretion was significantly dependent only on IgG excretion and 24-h proteinuria. Limiting the analysis to 67 patients with nephrotic syndrome (NS) and baseline normal renal function, by multiple linear regression, NAG excretion was significantly dependent on IgG excretion (P=0.0004), 24-h proteinuria (P=0.0067) and FE alpha(1)-m (P=0.0032) (R(2)=0.63). In 66 patients with NS and normal baseline renal function (MCD 10 patients; FSGS 20 patients; IMN 36 patients), according to values below or above defined cut-offs (IMN, 18 U/g urinary Cr; FSGS and MCD, 24 U/g urinary Cr), NAG excretion predicted remission in 86 vs 27% of IMN patients (P=0.0002) and 77 vs 14% of FSGS patients (P=0.005). Progression to chronic renal failure (CRF) was 0 vs 47% in IMN patients (P=0.001) and 8 vs 57% in FSGS patients (P=0.03). Using Cox model, in IMN patients only NAG excretion (P=0.01, RR 5.8), but not 24-h proteinuria, predicted progression to CRF. All MCD patients had NAG excretion values below the chosen cut-off, and 90% of them developed remission. Response to immunosuppressive therapy was significantly different in patients with NAG excretion values below or above the cut-offs. CONCLUSION: Urinary NAG excretion can be considered as a reliable marker of the tubulo-toxicity of proteinuria in the early stage of IMN, FSGS and MCD; the excretion values show a significant relationship with 24-h proteinuria, IgG excretion and FE alpha(1)m. Its determination may be a non-invasive, useful test for the early identification of patients who will subsequently develop CRF or clinical remission and responsiveness to therapy.

Circulating antibodies recognising oxidatively-modified low-density lipoproteins in patients with IgA nephropathy, membranous glomerulonephritis and focal glomerulosclerosis.

BACKGROUND: Oxidation of low-density lipoproteins (LDL) generates molecular epitopes that play a pathologic role in experimental glomerular diseases and can also elicit an immune response and the generation of anti-oxidatively-modified LDL antibodies. METHODS: We investigated, for the first time in humans, the enhanced induction of LDL oxidation in chronic glomerulonephritis, the presence of circulating antibodies against oxidatively-modified LDL in patients with IgA glomerulonephritis (IgA GN) or with nephrotic syndrome associated with focal glomerulosclerosis (FGS) and primary membranous glomerulonephritis (MGN). The antibody levels were measured by enzyme-linked immunosorbent assay (ELISA) using native and copper-, peroxidase-, hypochlorite-, and peroxynitrite-oxidized LDL. RESULTS: Compared to control subjects, the three groups of patients, particularly the IgA GN patients, had higher serum levels of antibodies recognising LDL oxidised with the four different modalities and higher concentrations of cholesterol in circulating immune complexes. None of these were significantly correlated with any demographic, histological or biochemical laboratory finding. In patients with IgAGN, we investigated the possible confounding effects of cardiovascular risk factors (hypercholesterolemia, hypertension, diabetes and overt atherosclerosis). Although the concentration of cholesterol in circulating immune complexes was significantly higher in patients with cardiovascular risk factors, no significant differences were observed in the level of anti-oxidised-LDL antibodies. This analysis, however, was impossible in FGS and MGN patients because of the high prevalence of hypercholesterolemia in these groups. CONCLUSIONS: These results suggest that IgA GN, MGN and FGS are associated with an enhanced immune response to LDL oxidised with different stimuli mimicking the pro-oxidant environment occurring in vivo, mirrored by the increased levels of specific antibodies, very likely linked to enhanced in vivo LDL oxidation which might participate in glomerular damage and progression.