Urinary N-acetyl-ß-glucosaminidase and estimated Glomerular filtration rate may identify patients to be treated with immuno-suppression at diagnosis in idiopathic membranous nephropathy.

AIM: The clinical course of idiopathic membranous nephropathy (IMN) varies from spontaneous remission of nephrotic syndrome (NS) to end-stage renal disease (ESRD). The aim of the study was baseline identification of patients with high risk of progression for which immunosuppressive therapy is mandatory. METHODS: Eighty-six IMN subjects were followed for a median of 69 months (range 6-253). Receiver operating characteristic curve and Cox proportional hazards model were used to evaluate prognostic factors for progression, defined as ESRD or estimated glomerular filtration rate (eGFR) reduction ≥50% of baseline. RESULTS: Among all, 24 subjects had progression. Area under the ROC curve of N-acetyl-ß-glucosaminidase/creatinine ratio (NAG/C) were significantly higher than proteinuria/24 h (0.770 and 0.637 respectively, P = 0.018). In Cox proportional hazards regression analysis, NAG/C and eGFR were independent predictors of progression. Compared to lowest tertile of NAG/C (<9.4 UI/gC) or highest tertile of eGFR (≥88 mL/min per 1.73m2 ), the multivariable-adjusted hazard ratio of highest tertile of NAG/C (≥19.2) was 18.97 (95%CI, 1.70-211.86) and lowest tertile of eGFR (<59) was 11.58 (95%CI, 2.02-66.29). Subjects with high NAG/C or low eGFR (high-risk, n = 43) had greater progression rate compared to moderate to low NAG/C and high eGFR (low-risk, n = 43) with or without NS at baseline (Log-rank test P = 0.001 and 0.006, respectively). In NS subjects (n = 65), high-risk group progression rate was significantly higher (91% vs. 29%, P = 0.003) and remission rate significantly lower (0% vs. 42%, p < 0.001) in non-immunosuppressed compared to steroids and cyclophosphamide treated patients; no significant differences were observed in low-risk group. CONCLUSION: Idiopathic membranous nephropathy subjects with high NAG/C and low eGFR have greater risk of progression, and immunosuppressive treatment is suggested at diagnosis.

High (≥6.5) Spontaneous and Persistent Urinary pH Is Protective of Renal Function at Baseline and during Disease Course in Idiopathic Membranous Nephropathy.

Metabolic acidosis correction in advanced renal failure slows renal function decline attributed to tubulointerstitial damage (TID) reduction. No study evaluated if spontaneous baseline high urinary pH (UpH) is renoprotective in patients with normal renal function and without metabolic acidosis. The study tested this hypothesis in idiopathic membranous nephropathy (IMN). Eighty-five patients (follow-up 81 ± 54 months) measured UpH, serum creatinine, eGFR, protein/creatinine ratio, fractional excretion of albumin, IgG, α1-microglobulin, and urinary N-acetyl-ß-D-glucosaminidase (ß-NAG)/creatinine ratio. Twenty-eight patients (33%) had UpH ≥ 6.5 and 57 (67%) pH < 6.5; high versus low UpH patients had significantly lower values of the tubulointerstitial damage (TID) markers FE α1m and ß-NAG and significantly better baseline renal function. These differences persisted over time in a subset of 38 patients with 5 measurements along 53 ± 26 months. In 29 patients with nephrotic syndrome (NS) treated with supportive therapy (follow-up: 80 ± 52 months) renal function was stable in 10 high and significantly worse in 19 low UpH patients. Steroids + cyclophosphamide treatment in 35 NS patients masks the renoprotection of high UpH. Conclusions. In IMN high and persistent UpH is associated with reduction of the proteinuric markers of tubulointerstitial damage and baseline better renal function in all patients and in NS patients treated only with supportive therapy during disease course. The factors associated with high pH-dependent renoprotection were lower values of TID markers, eGFR ≥ 60 mL/min, BP < 140/90 mmHg, and age < 55 years.

Tubular reabsorption of high, middle and low molecular weight proteins according to the tubulo-interstitial damage marker N-acetyl-ß-D-glucosaminidase in glomerulonephritis.

BACKGROUND: Proteinuria, the hallmark of glomerular diseases, is an independent predictor of end-stage renal disease (ESRD) progression. Proteinuria is a mixture of proteins of different molecular weight (MW) dependent on alterations of glomerular filtration barrier (GFB) and reabsorption impairment by proximal tubular epithelial cells (PTECs). We aimed to evaluate the excretion of different-MW proteins according to the tubulo-interstitial damage marker N-acetyl-ß-D-glucosaminidase (NAG) in glomerulonephritides (GNs). METHODS: In 189 patients [idiopathic membranous nephropathy (IMN) n = 84, primary focal segmental glomerulosclerosis (FSGS) n = 48, crescentic IgA nephropathy (CIgAN) n = 37, minimal change disease (MCD) n = 20] several urinary proteins were measured at biopsy: α2-macroglobulin/creatinine ratio; fractional excretion of IgG, transferrin, albumin and α1-microglobulin, and the NAG/creatinine ratio divided by estimated glomerular filtration rate (eGFR) (NAG/C/eGFR), as NAG excretion is dependent on functioning nephron mass. Protein excretion was compared between 4th vs. 1st quartile of NAG/C/eGFR. RESULTS: In IMN, FSGS and CIgAN high-MW proteins excretion (α2-macroglobulin, IgG) was greater than that of middle- (transferrin, albumin) and low-MW proteins (α1-microglobulin) in 4th vs. 1st quartile of NAG/C/eGFR; the mean fold excretion increase of high-MW proteins in 3 GNs was 74.9, higher than that of middle- (34.8) and low-MW proteins (12.0). Higher excretion of high-MW proteins may be dependent on lower reabsorption by PTECs. By contrast, in MCD the difference in excretion of different-MW proteins is probably due to high GFB selectivity. CONCLUSION: High-MW protein excretion is dependent on GFB alteration and reduced reabsorption; its prognostic significance is ominous because in several glomerular diseases progression is associated with high-MW protein excretion.

Arteriolar hyalinosis and arterial hypertension as possible surrogate markers of reduced interstitial blood flow and hypoxia in glomerulonephritis.

BACKGROUND: In glomerulonephritis the final common pathway to end-stage renal disease (ESRD) is tubulo-interstitial damage (TID) whose main determinants are proteinuria and hypoxia consequent to haemodynamic and vascular alterations that reduce interstitial blood flow. Since oxygen tension is difficult to measure in human disease, arteriolar hyalinosis and arterial hypertension have been considered as possible surrogate markers of interstitial hypoxia. METHODS: The relationship between TID and arteriolar hyalinosis and arterial hypertension was evaluated in 132 IgA nephropathy (IgAN) and 79 idiopathic membranous nephropathy (IMN) patients. At biopsy tubulo-interstitial damage and arteriolar hyalinosis score were semi-quantitatively evaluated; urinary protein/creatinine ratio (P/C), fractional excretion (FE) of α1-microglobulin, urinary ß-NAG/creatinine ratio (NAG/C/eGFR) and urinary SDS-PAGE pattern were measured. RESULTS: In IgAN arteriolar hyalinosis (AH) score correlates with TID score (P < 0.0001), FE α1m (P = 0.004) and NAG/C/eGFR (P = 0.001), but not with P/C (P = 0.10). Patients with or without AH were different in terms of global glomerulosclerosis (GGS: P < 0.001), TID score (P < 0.001), FE α1m (P = 0.015), NAG/C/eGFR (P = 0.002), but not of P/C (P = 0.19). In IMN AH score correlates with TID score (P < 0.0001), FEα1m (P = 0.04), NAG/C/eGFR (P = 0.001), SDS-PAGE pattern (P = 0.018), but not with P/C (P = 0.10). Patients with or without AH were different in term of GGS% (P = 0.05), TID score (P = 0.001), FE α1m (P = 0.039), NAG/C/eGFR (P = 0.001), SDS-PAGE pattern (P = 0.02), but not of P/C (P = 0.065). Similar results for normal versus high blood pressure. CONCLUSIONS: Arteriolar hyalinosis and arterial hypertension, associated with TID and GGS, factors that reduce interstitial capillary bed and blood flow, may be considered as reliable surrogate markers of hypoxia and co-determinants of TID.

Fractional excretion of IgG in idiopathic membranous nephropathy with nephrotic syndrome: a predictive marker of risk and drug responsiveness.

BACKGROUND: Treatment of idiopathic membranous nephropathy with nephrotic syndrome is still controversial. There is currently little known about the clinical use of renal biomarkers which may explain contradictory results obtained from clinical trials. In order to assess whether IgG-uria can predict the outcome in membranous nephropathy, we examined the value of baseline EF-IgG in predicting remission and progression of nephrotic syndrome. METHODS: In a prospective cohort of 84 (34 female) idiopathic membranous nephropathy patients with nephrotic syndrome we validated the ability of the clinically available urine biomarker, IgG, to predict the risk of kidney disease progression and the beneficial effect of immunosuppression with steroids and cyclophosphamide. The fractional excretion of IgG (FE-IgG) and α1-microglobulin (FE-α1m), urine albumin/creatinine ratio, and eGFR were measured at the time of kidney biopsy. Primary outcome was progression to end stage kidney failure or kidney function (eGFR) decline ≥ 50% of baseline. Patients were followed up for 7.2 ± 4.1 years (range 1-16.8). RESULTS: High FE-IgG (≥ 0.02) predicted an increased risk of kidney failure (Hazard Ratio, (HR) 8.2, 95%CI 1.0-66.3, p=0.048) and lower chance of remission (HR 0.18, 95%CI 0.09-0.38, p<0.001). The ten-year cumulative risk of kidney failure was 51.7% for patients with high FE-IgG compared to only 6.2% for patients with low FE-IgG. During the study, only 24% of patients with high FE-IgG entered remission compared to 90% of patients with low FE-IgG. Combined treatment with steroids and cyclophosphamide decreased the progression rate (-40%) and increased the remission rate (+36%) only in patients with high FE-IgG. CONCLUSION: In idiopathic membranous nephropathy patients with nephrotic syndrome, FE-IgG could be useful for predicting kidney disease progression, remission, and response to treatment.

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.

Pregnancy and progression of IgA nephropathy: results of an Italian multicenter study.

BACKGROUND: Whether pregnancy impacts on the long-term outcome of immunoglobulin A (IgA) nephropathy is unknown. This study aims to compare the long-term outcome of kidney disease in women with IgA nephropathy and preserved kidney function who did and did not become pregnant. STUDY DESIGN: Multicenter longitudinal cohort study. SETTING & PARTICIPANTS: Women of childbearing age with biopsy-proven IgA nephropathy, serum creatinine level

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.