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.

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.