Outcomes of kidney transplantation in Alport syndrome compared with other forms of renal disease.

INTRODUCTION: Alport syndrome is an inherited renal disease characterized by hematuria, renal failure, hearing loss and a lamellated glomerular basement membrane. Patients with Alport syndrome who undergo renal transplantation have been shown to have patient and graft survival rates similar to or better than those of patients with other renal diseases. METHODS: In this national case series, based in Beaumont Hospital Dublin, we studied the cohort of patients who underwent renal transplantation over the past 33 years, recorded prospectively in the Irish Renal Transplant Registry, and categorized them according to the presence or absence of Alport syndrome. The main outcomes assessed were patient and renal allograft survival. RESULTS: Fifty-one patients diagnosed with Alport syndrome in Beaumont Hospital received 62 transplants between 1982 and 2014. The comparison group of non-Alport patients comprised 3430 patients for 3865 transplants. Twenty-year Alport patient survival rate was 70.2%, compared to 44.8% for patients with other renal diseases (p = .01). Factors associated with patient survival included younger age at transplantation as well as differences in recipient sex, donor age, cold ischemia time, and episodes of acute rejection. Twenty-year graft survival was 46.8% for patients with Alport syndrome compared to 30.2% for those with non-Alport disease (p = .11). CONCLUSIONS: Adjusting for baseline differences between the groups, patients with end-stage kidney disease (ESKD) due to Alport syndrome have similar patient and graft survival to those with other causes of ESKD. This indicates that early diagnosis and management can lead to favorable outcomes for this patient cohort.

Outcome of renal transplantation in Alport's syndrome: a single-center experience.

BACKGROUND: Anti-glomerular basement membrane (anti-GBM) nephritis post-renal transplantation (RTx) is known to cause graft loss in Alport's syndrome (AS). We evaluated the results of RTx in AS patients vis à vis patient and graft survivals, incidence of anti-GBM nephritis, and causes of graft failure. MATERIALS AND METHODS: Between 1993 and 2009 we performed 31 RTx on AS patients (28 males and three females) of overall mean age of 22 ± 7.9 years from six deceased and 27 living donors. Two patients underwent second RTx. RESULTS: Over a follow-up of 1, 3, 5, and 10 years, the mean serum creatinines (mg/dL) were 1.51 ± 0.52, 1.59 ± 0.26, 1.61 ± 0.30, and 1.63 ± 0.32, respectively. Patient survivals at 1, 5, and 10 years were 89.71%, 81.32% and 81.32% with graft survival for all periods of 81.2%. Twenty-one percent experienced biopsy-proven acute rejection episodes. Graft failures were due to anti-GBM nephritis in 12.2% (n = 4), chronic allograft nephropathy in 3.2% (n = 1), and acute rejection or cyclosporine toxicity 3.2% (n = 1 each). The mean duration to graft loss was 4.9 ± 2.4 months. CONCLUSION: Graft and patient survivals were acceptable among transplant recipients with AS despite the risk of anti-GBM nephritis.

Ccl2/Mcp-1 blockade reduces glomerular and interstitial macrophages but does not ameliorate renal pathology in collagen4A3-deficient mice with autosomal recessive Alport nephropathy.

Lack of the alpha3 or alpha4 chain of type IV collagen (COL4) causes autosomal recessive Alport nephropathy in humans and mice that is characterized by progressive glomerulosclerosis and tubulointerstitial disease. Renal pathology is associated with chemokine-mediated macrophage infiltrates but their contribution to the progression of Alport nephropathy is unclear. We found Ccl2 to be expressed in increasing amounts during the progression of nephropathy in Col4a3-deficient mice; hence, we blocked Ccl2 with anti-Ccl2 Spiegelmers, biostable L-enantiomeric RNA aptamers suitable for in vivo applications. Ccl2 blockade reduced the recruitment of ex vivo-labelled macrophages into kidneys of Col4a3-deficient mice. We therefore hypothesized that a prolonged course of Ccl2 blockade would reduce renal macrophage counts and prevent renal pathology in Col4a3-deficient mice. Groups of Col4a3-deficient mice received subcutaneous injections of either an anti-mCcl2 Spiegelmer or non-functional control Spiegelmer on alternate days, starting from day 21 or 42 of age. Glomerular and interstitial macrophage counts were found to be reduced with Ccl2 blockade by 50% and 30%, respectively. However, this was not associated with an improvement of glomerular pathology, interstitial pathology, or of overall survival of Col4a3-deficient mice. We conclude that Ccl2 mediates the recruitment of glomerular and interstitial macrophages but this mechanism does not contribute to the progression of Alport nephropathy in Col4a3-deficient mice.

Kidney transplantation in patients with alport syndrome.

INTRODUCTION: The aim of this study was to evaluate the results of kidney transplantation in patients with Alport syndrome. MATERIALS AND METHODS: A total of 15 patients with Alport syndrome underwent kidney transplantation and the result of their transplantation was compared with the results in patients without Alport Syndrome. Rejection episodes and the presence of antiglomerular basement membrane (anti-GBM) nephritis were assessed in these patients. RESULTS: Fifteen patients with Alport syndrome were compared with a control group including 212 kidney allograft recipients. One patient with Alport syndrome (6.7%) and 30 controls (14.2%) experienced delayed graft function. Renal artery thrombosis was reported in 1 patient (6.7%) with Alport syndrome and 10 (4.7%) in the control group, which led to nephrectomy in all cases. Acute rejection was confirmed in 2 patients (13.3%) by kidney biopsy and classic treatment yielded relative response. However, they lost their grafts 35 and 44 months after the transplantation. On pathologic examination, no specific finding of anti-GBM nephritis was found. In the control group, 43 cases of acute rejection (20.3%) were reported and 12 patients (5.7%) returned to dialysis. The 1-, 3-, and 5-year graft survival rates were 100%, 92%, and 84% in the patients with Alport syndrome, which was not different from those in the control group (P = .53). CONCLUSION: In spite of the risk of anti-GBM nephritis in the patients with Alport Syndrome, it seems that kidney transplantation can yield favorable results and anti-GBM nephritis is not a common etiology of rejection.

Delayed chemokine receptor 1 blockade prolongs survival in collagen 4A3-deficient mice with Alport disease.

Human Alport disease is caused by a lack of the alpha3-, 4-, or 5-chain of type IV collagen (COL4A). Affected humans and COL4A3-deficient mice develop glomerulosclerosis and progressive renal fibrosis in the presence of interstitial macrophages, but their contribution to disease progression is under debate. This question was addressed by treating COL4A3-deficient mice with BX471, an antagonist of chemokine receptor 1 (CCR1) that is known to block interstitial leukocyte recruitment. Treatment with BX471 from weeks 6 to 10 of life improved survival of COL4A3-deficient mice, associated with less interstitial macrophages, apoptotic tubular epithelial cells, tubular atrophy, interstitial fibrosis, and less globally sclerotic glomeruli. BX471 reduced total renal Cll5 mRNA expression by reducing the number of interstitial CCL5-positive cells in inflammatory cell infiltrates. Intravital microscopy of the cremaster muscle in male mice identified that BX471 or lack of CCR1 impaired leukocyte adhesion to activated vascular endothelium and transendothelial leukocyte migration, whereas leukocyte rolling and interstitial migration were not affected. Furthermore, in activated murine macrophages, BX471 completely blocked CCL3-induced CCL5 production. Thus, CCR1-mediated recruitment and local activation of macrophages contribute to disease progression in COL4A3-deficient mice. These data identify CCR1 as a potential therapeutic target for Alport disease or other progressive nephropathies associated with interstitial macrophage infiltrates.

The use of frailty models in genetic studies: application to the relationship between end-stage renal failure and mutation type in Alport syndrome. European Community Alport Syndrome Concerted Action Group (ECASCA).

BACKGROUND: Alport syndrome (AS) is a severe hereditary disease usually transmitted as an X dominant trait and involving a mutation of the COL4A5 gene. It leads to end-stage renal failure (ESRF), but this progression is heterogeneous. Mutations of the COL4A5 gene have been characterised in numerous families using molecular biology. Our objective was to evaluate the interfamilial heterogeneity of the disease and to study relationships between mutation types and progression to ESRF in the European Community Alport Syndrome Concerted Action group (ECASCA) registry database. METHODS: We used the frailty model framework. Frailty models have been developed to analyse censored data with non-independent observations. Random effects are introduced in a Cox proportional regression model to take into account the intracluster correlations. In this study, ESRF is considered a censored event and the intrafamilial correlations are taken into account in the frailty models. RESULTS: These approaches allow us to demonstrate the existence of an interfamilial heterogeneity; the role of the mutation type explains the interfamilial variability. In particular, the results suggest that some mutation types are associated with a higher risk of ESRF for males. CONCLUSIONS: This study shows the importance of characterising the mutation at the molecular level in genetic studies, to understand the relationship between genotype and phenotype. The frailty models constitute an attractive approach in this context, when the phenotype is characterised by a censored end-point.

Treatment of X-linked hereditary nephritis in Samoyed dogs with angiotensin converting enzyme (ACE) inhibitor.

X-linked hereditary nephritis (HN) in Samoyed dogs is a model for human HN (Alport's syndrome). Angiotensin converting enzyme (ACE) inhibitors have been shown to slow the progression of renal disease in animal models and human patients. To determine the effect of ACE inhibitor treatment on X-linked HN in Samoyed dogs, a group of affected and a group of normal males were each randomly divided into two subgroups, which were either treated with an ACE inhibitor or left untreated. ACE inhibitor treatment caused significant increases (P < 0.05) in plasma renin activity in normal and affected dogs, confirming its effectiveness, but did not lower systemic blood pressure. Three of four affected treated dogs had improved weight gains and, overall, treated dogs survived 1.36 times longer than affected untreated dogs (P < 0.05). ACE inhibitor treatment of affected dogs significantly delayed (P < 0.05) the onset of an increase in serum creatinine concentration, tended to delay the decline of glomerular filtration rate and effective renal plasma flow (ERPF), significantly improved (P < 0.05) the ERPF at 110-154 days of age, and significantly slowed (P < 0.01) the rate of increase of proteinuria. Affected treated dogs showed a significant (P < 0.05) transient reduction in glomerular basement membrane splitting. Thus, ACE inhibitor treatment of Samoyed dogs with X-linked HN produced beneficial effects with respect to renal function, renal structure, and survival.

Outcome of renal transplantation in different primary diseases.

1. Graft survival rates increased about 3-5 percentage points for patients with all primary diseases in 1989-1990. 2. Patients with different diseases had 1-year graft survival rates that varied from 73% for noninsulin-dependent diabetes (NIDDM) to 83% for IgA nephropathy (IgAN). Five-year graft survival varied from 40% for NIDDM to 66% for IgAN. 3. Our findings in Clinical Transplants 1990 that IgAN patients have a high graft survival was confirmed and 1-year graft survival improved by 5% in the last 2 years. 4. There was a 20 percentage point increase in full-time work status of patients after transplantation; 68% of patients with polycystic kidney disease (PKD) and chronic glomerulonephritis (CGN) had full-time work status after 3 years whereas patients with diabetes mellitus (DM) and atheronephrosclerosis (NS) had about 50%. 5. Good early graft function (urine output during the first 24 hours posttransplant, no dialysis within the first-week posttransplant, and no rejection episodes before discharge), predicted good 1-year graft survival for patients with different diseases but patients with NS and DM had a poorer graft survival beyond the first year posttransplant. Patients who had poor early function had 20% lower graft survival than those who had good function. However, in patients with IgAN, no urine at day 1 still resulted in graft survival comparable to those that produced urine. 6. More patients with DM were transplanted within 1 year after going into ESRD than those with other diseases. Conversely, 46% of those with NS did not get transplanted until more than 2 years after developing ESRD. 7. Only 77% of NS patients had functioning grafts at discharge compared to DM (84%), PKD (81%), IgAN (81%), and CGN (80%). 8. Black patients had a statistically significant higher incidence of anuria on the first day compared with Whites. They also had a higher incidence of dialysis and rejection during the first hospitalization. This was true for CGN, DM, PKD, and NS patients. Following excellent early function, Black CGN and DM patients had a higher incidence of rejection than White CGN and DM patients.

The genetics of the Alport syndrome.

Analysis of the age at death of males with the Alport syndrome points out two distinct populations: one in which males die between ages 16 and 28 years, and the other in which males die between ages 33.5 and 52.2 years. Evidence suggests that these result from different genes of large effect. The segregation ratios of children of parents with Alport syndrome of either variety are generally consistent with an autosomal dominant mode of transmission, but the anomalous segregation from affected fathers remains to be explained.