Cystic phenotype and chronic kidney disease in autosomal dominant Alport syndrome.

BACKGROUND AND HYPOTHESIS: Autosomal Dominant Alport Syndrome (ADAS), also known as Thin Basement Membrane Disease (TBMD), is caused by pathogenic variants in COL4A3 and COL4A4 genes. A cystic phenotype has been described in some patients with TBMD, but no genetic studies were performed. We conducted a genetic and radiologic investigation in a cohort of ADAS patients to analyze the prevalence of multicystic kidney disease (MKD) and its association with Chronic Kidney Disease (CKD). METHODS: Retrospective single-center cohort study. Thirty-one patients showing pathogenic or likely pathogenic variants in COL4A3 or COL4A4 from a cohort of 79 patients with persistent microscopic hematuria were included. Mean follow-up was 9.4±9.6 years. The primary objective of the study was to determine the prevalence of MKD in the cohort of ADAS patients. Secondary objectives were to determine risk factors associated with an eGFR<45 ml/min/1.73m2 at the time of genetic and radiologic evaluation and to investigate the coexistence of other genetic abnormalities associated with familial hematuria and cystic kidney disease. RESULTS: MKD was found in 16 patients (52%). Mean number of cysts per kidney was 12.7±5.5. No genetic abnormalities were found in a panel of 101 other genes related to familial hematuria, focal segmental glomerulosclerosis and cystic kidney disease. A greater number of patients with MKD had an eGFR<45 ml/min/1.73m2 (63% vs 7%, p=0.006) and more advanced CKD than patients without MKD. The annual rate of eGFR decline was greater in patients with MKD: -1.8 vs 0.06 ml/min/1.73m2/year (p=0.009). By multivariable linear regression analysis, the main determinants of eGFR change per year were time-averaged proteinuria (p=0.002) and MKD (p=0.02). CONCLUSION: MKD is commonly found in ADAS and is associated with a worse kidney outcome. No pathogenic variants were found in genes other than COL4A3/COL4A4.

Remission of Hematuria Improves Renal Survival in IgA Nephropathy.

Hematuria is a cardinal symptom in IgA nephropathy, but its influence on the risk of disease progression has been scarcely investigated. We followed a cohort of 112 patients with IgA nephropathy for a mean±SEM period of 14±10.2 years, during which clinical and analytic risk factors (including urine sediment examination) were regularly recorded. According to the magnitude of time-averaged hematuria, we classified patients as those with persistent hematuria and those with negative or minimal hematuria. We also classified patients according to the magnitude of time-averaged proteinuria (>0.75 or ≤0.75 g/d). The proportion of patients reaching ESRD or a 50% reduction of renal function was significantly greater among patients with persistent hematuria than patients with minimal or negative hematuria (30.4% and 37.0% versus 10.6% and 15.2%, respectively; P=0.01). Multivariable analysis revealed time-averaged hematuria, time-averaged proteinuria, renal function at baseline, and the presence of tubulointerstitial fibrosis on renal biopsy as independent predictors of ESRD. After hematuria disappearance, which occurred in 46% of the patients, the rate of renal function decline changed from -6.45±14.66 to -0.18±2.56 ml/min per 1.73 m2 per year (P=0.001). Patients with time-averaged proteinuria >0.75 g/d had significantly poorer renal survival than those with time-averaged proteinuria ≤0.75 g/d. However, on further classification by time-averaged hematuria, only those patients with time-averaged proteinuria >0.75 g/d and persistent hematuria had significantly worse renal survival than those in the other three groups. In conclusion, remission of hematuria may have a significant favorable effect on IgA nephropathy outcomes.

Haematuria as a risk factor for chronic kidney disease progression in glomerular diseases: A review.

Haematuria has long been considered to be a benign condition associated with glomerular diseases. However, new evidences suggest that haematuria has a pathogenic role in promoting kidney disease progression. An increased risk for end-stage renal disease has been reported in adolescents and young adults with persistent microscopic haematuria. A persistent impairment of renal function has been also reported following macroscopic haematuria-associated acute kidney injury in immunoglobulin A nephropathy. Haematuria-induced renal damage has been related to oxidant, cytotoxic and inflammatory effects induced by haemoglobin or haem released from red blood cells. The pathophysiological origin of haematuria may be due to a more fragile and easily ruptured glomerular filtration barrier, as reported in several glomerular diseases. In this review we describe a number of the key issues associated with the epidemiology and pathogenesis of haematuria-associated diseases, provide an update of recent knowledge on the role of haematuria on renal function outcome and discuss specific therapeutic approaches in this setting. KEY SUMMARY POINTS: 1. Glomerular haematuria is a common observation in a number of renal diseases that may lead to persistent renal injury. 2. Haematuria in children differs from that in adults in specific aspects, particularly in the frequency of glomerular diseases and renal disease outcome. 3. Regular follow-up of renal function in children with isolated microhaematuria may be recommended.

Targeting complement in IgA nephropathy.

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Recent years have witnessed significant improvements in the understanding of the pathogenesis of IgAN and particularly, the pathogenic role of complement activation. The alternative complement pathway is the major complement cascade activator in IgAN, and glomerular C3 deposition has been shown to correlate with disease progression. In addition, several studies have provided insight into the pathogenic role of factor H-related proteins -1 and -5 in IgAN, as independent players in complement dysregulation. The lectin pathway has also been shown to be associated with the severity of IgAN. Glomerular deposition of C4d has been associated with increased histologic disease activity, faster decline in estimated glomerular filtration rate and higher risk of kidney failure. On the other hand, although overlooked in the Oxford classification, numerous studies have shown that the coexistence of thrombotic microangiopathy in IgAN is a significant indicator of a poorer prognosis. All the breakthroughs in the understanding of the contributing role of complement in IgAN have paved the way for the development of new complement-targeted therapies in this disease. Several ongoing trials are evaluating the efficacy of new agents against factor B (iptacopan, Ionis-FB-LRX), C3 (pegcetacoplan), factor D (vemircopan, pelecopan), C5 (ravulizumab, cemdisiran) and C5a receptor 1 (avacopan). In this study, we provide a comprehensive review of the role of complement in IgAN, including the emerging mechanisms of complement activation and the promising potential of complement inhibitors as a viable treatment option for IgAN.

Effect of Immunosuppressive Treatments on Kidney Outcomes After Gross Hematuria-Related Acute Kidney Injury in Older Patients With IgA Nephropathy.

Introduction: Macroscopic hematuria (MH) bouts, frequently accompanied by acute kidney injury (AKI-MH) are one of the most common presentations of IgA nephropathy (IgAN) in the elderly. Immunosuppressive therapies are used in clinical practice; however, no studies have analyzed their efficacy on kidney outcomes. Methods: This is a retrospective, multicenter study of a cohort of patients aged ≥50 years with biopsy-proven IgAN presenting with AKI-MH. Outcomes were complete, partial, or no recovery of kidney function at 1 year after AKI-MH, and kidney survival at 1, 2, and 5 years. Propensity score matching (PSM) analysis was applied to balance baseline differences between patients treated with immunosuppression and those not treated with immunosuppression. Results: The study group consisted of 91 patients with a mean age of 65 ± 15 years, with a mean follow-up of 59 ± 36 months. Intratubular red blood cell (RBC) casts and acute tubular necrosis were found in all kidney biopsies. The frequency of endocapillary hypercellularity and crescents were low. Immunosuppressive therapies (corticosteroids alone or combined with mycophenolate mofetil or cyclophosphamide) were prescribed in 52 (57%) patients, whereas 39 (43%) received conservative treatment. There were no significant differences in the proportion of patients with complete, partial, or no recovery of kidney function at 1 year between patients treated with immunosuppression and those not treated with immunosuppression (29% vs. 36%, 30.8% vs. 20.5% and 40.4 % vs. 43.6%, respectively). Kidney survival at 1, 3, and 5 years was similar among treated and untreated patients (85% vs. 81%, 77% vs. 76% and 72% vs. 66%, respectively). Despite the PSM analysis, no significant differences were observed in kidney survival between the two groups. Fourteen patients (27%) treated with immunosuppression had serious adverse events. Conclusions: Immunosuppressive treatments do not modify the unfavorable prognosis of patients with IgAN who are aged ≥50 years presenting with AKI-MH, and are frequently associated with severe complications.

IgA Nephropathy Is the Most Common Underlying Disease in Patients With Anticoagulant-Related Nephropathy.

Introduction: Anticoagulant-related nephropathy (ARN) is a relatively novel recognized entity characterized by hematuria-associated acute kidney injury (AKI) in the context of overanticoagulation. Preexisting or underlying kidney disease seems to be a predisposing factor; however, few studies have described histologic findings in patients with ARN. We aimed to evaluate underlying kidney pathology in patients on oral anticoagulation who presented an episode of AKI with hematuria in whom a kidney biopsy was performed. Methods: Retrospective observational multicenter case study in patients treated with oral anticoagulants who developed macroscopic or intense hematuria followed by AKI. Only patients with available kidney biopsy specimens were included. Histologic findings and clinical data throughout follow-up were analyzed. Results: A total of 26 patients were included with a median age of 75 years (62-80) and a follow-up period of 10.1 months. Of the patients, 80% were male, and most cases (92%) were on anticoagulation with vitamin K antagonists (VKAs). At admission, median serum creatinine (SCr) level was 4.2 mg/dl (2.8-8.2), median international normalized ratio (INR) 2.4 (1.5-3.4), and 11 patients (42%) required acute dialysis during hospitalization. Kidney biopsy results revealed that all patients except 1 had an underlying nephropathy: IgA nephropathy (IgAN) in 19, probable IgAN in 1, diabetic nephropathy in 3, nephrosclerosis in 1, and idiopathic nodular glomerulosclerosis in 1. At 12 weeks after discharge, only 6 subjects (24%) attained complete kidney recovery whereas 7 (28%) remained on chronic dialysis. Conclusion: IgAN was the most common underlying kidney disease in our biopsy-proven series of ARN, in which a significant percentage of patients did not achieve kidney function recovery.

IgA Nephropathy in Elderly Patients.

BACKGROUND AND OBJECTIVES: Some studies suggest that the incidence of IgA nephropathy is increasing in older adults, but there is a lack of information about the epidemiology and behavior of the disease in that age group. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this retrospective multicentric study, we analyzed the incidence, forms of presentation, clinical and histologic characteristics, treatments received, and outcomes in a cohort of 151 patients ≥65 years old with biopsy-proven IgA nephropathy diagnosed between 1990 and 2015. The main outcome was a composite end point of kidney replacement therapy or death before kidney replacement therapy. RESULTS: We found a significant increase in the diagnosis of IgA nephropathy over time from six patients in 1990-1995 to 62 in 2011-2015 (P value for trend =0.03). After asymptomatic urinary abnormalities (84 patients; 55%), AKI was the most common form of presentation (61 patients; 40%). Within the latter, 53 (86%) patients presented with hematuria-related AKI (gross hematuria and tubular necrosis associated with erythrocyte casts as the most important lesions in kidney biopsy), and eight patients presented with crescentic IgA nephropathy. Six (4%) patients presented with nephrotic syndrome. Among hematuria-related AKI, 18 (34%) patients were receiving oral anticoagulants, and this proportion rose to 42% among the 34 patients older than 72 years old who presented with hematuria-related AKI. For the whole cohort, survival rates without the composite end point were 74%, 48%, and 26% at 1, 2, and 5 years, respectively. Age, serum creatinine at presentation, and the degree of interstitial fibrosis in kidney biopsy were risk factors significantly associated with the outcome, whereas treatment with renin-angiotensin-aldosterone blockers was associated with a lower risk. Immunosuppressive treatments were not significantly associated with the outcome. CONCLUSIONS: The diagnosis of IgA nephropathy among older adults in Spain has progressively increased in recent years, and anticoagulant therapy may be partially responsible for this trend. Prognosis was poor. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_07_16_CJASNPodcast_19_08_.mp3.

Anakinra induces complete remission of nephrotic syndrome in a patient with familial mediterranean fever and amyloidosis.

Renal amyloidosis is one of the most severe complications of familial Mediterranean fever (FMF). Colchicine has reduced the incidence of this complication, which now only appears in untreated, under-treated and resistant patients, but it is usually ineffective in patients with advanced amyloidosis. Here we report a patient with FMF and biopsy-proven amyloidosis who presented with nephrotic syndrome despite colchicine treatment. Anakinra (an interleukin-1ß inhibitor) was started and a dramatic complete remission of nephrotic syndrome was observed in the following months. Anakinra can be an effective treatment for FMF patients with severe secondary amyloidosis.

Malignant hypertension: a type of IgA nephropathy manifestation with poor prognosis.

INTRODUCTION:  Malignant hypertension (MHT) is an uncommon clinical manifestation of IgA Nephropathy (IgAN). Its prevalence, pathogenesis and evolution are not well known.  MATERIAL AND METHODS:  We performed a descriptive and retrospective study to report the clinical characteristics and evolution of thirteen patients diagnosed as having IgA nephropathy by renal biopsy in our hospital who developed MHT (IgAN-MHT).  RESULTS:  The prevalence of MHT in our IgAN patients was 7% (13/186). The mean age was 37±12 years and 84% were males. Mean systolic/diastolic blood pressure at presentation were 219±32/132±18mmHg, respectively. Renal function impairment was detected at admission in all the patients, with a mean serum creatinine of 4.73±3.12mg/dL. No patient showed analytical data that suggested thrombotic microangiopathy. Renal biopsies showed mild chronicity lesions and only four patients presented features of thrombotic microangiopathy. All patients were treated with renin-angiotensin-aldosterone blockers and two received steroids. They all showed a progressive loss of renal function. At the end of follow up one patient had died, ten were on chronic dialysis and two presented chronic kidney disease stage 3b. Renal survival was 69% and 35% at 3 and 6 years, respectively. Six patients received a kidney transplant: IgAN relapsed in four patients. One of them presented a new episode of MHT associated with a HELLP syndrome.  CONCLUSIONS:  Malignant hypertension is a form of IgAN clinical presentation having a remarkably worse renal outcome and without specific effective treatment.

Multiple kidney cysts in thin basement membrane disease with proteinuria and kidney function impairment.

BACKGROUND: Some patients with thin basement membrane disease (TBMD) develop proteinuria, hypertension and different degrees of CKD, besides the persistent microhaematuria characteristic of the disease. Little is known about factors associated with this unfavourable outcome. METHODS: We reviewed clinical, pathological and radiological features of 32 patients with biopsy-proven TBMD. Patients were divided in two groups: those with persistent normal kidney function and negative or minimal proteinuria (n = 16) and those with persistent proteinuria >0.5 g/day (n = 16). RESULTS: Patients with proteinuria had a worse kidney function at baseline than those with negative proteinuria. Global or segmental glomerulosclerosis, together with interstitial fibrosis, was found in 37% of patients with proteinuria. All proteinuric patients were treated with renin-angiotensin system blockers. At the end of follow-up (198 months in proteinuric patients and 210 months in patients with negative proteinuria) the prevalence of hypertension was 68% in proteinuric patients (12% at baseline), compared with 12 and 6%, respectively, in non-proteinuric patients. A slow decline of renal function was observed in proteinuric patients, although no patient developed end-stage kidney disease. Ultrasound studies showed bilateral kidney cysts in nine patients (56%) with proteinuria. Cysts were bilateral and countless in six patients, and bilateral but with a limited number of cysts in the three remaining patients. No cysts were found in patients with negative proteinuria. CONCLUSIONS: Some patients with TBMD develop hypertension, proteinuria and CKD. Multiple bilateral kidney cysts were found in a majority (56%) of these patients. Further studies are needed to investigate the pathogenesis and the influence on long-term outcome of this TBMD-associated multiple kidney cysts.

Two cases of glomerulonephritis in one patient infected with the hepatitis C virus.

Membranoproliferative glomerulonephritis (GN) may be pathogenically associated with infection due to the hepatitis C virus (HCV) as many clinical cases have shown. The potential relationship between the HCV and IgA GN, by contrast, has been suggested only in isolated cases. IgA nephropathy recurs in up to 50% of cases after renal transplantation, but it is uncommon for it to appear as a de novo GN. We report the case of a patient with chronic infection due to the HCV and liver disease, who developed two different glomerular diseases during its progression: membranoproliferative GN in his native kidneys, a process that caused terminal renal failure and de novo IgA GN in the transplanted kidney. The potential pathogenic relationship of both glomerular processes with infection due to the HCV is discussed.

Anakinra induce la remisión completa del síndrome nefrótico en un paciente con fiebre mediterránea familiar y amiloidosis / Anakinra induces complete remission of nephrotic syndrome in a patient with familial mediterranean fever and amyloidosis

La amiloidosis renal es una de las complicaciones más graves de la fiebre mediterránea familiar (FMF). La colchicina ha reducido la incidencia de esta complicación, que ahora solo aparece en pacientes no tratados, tratados de manera insuficiente o resistentes al fármaco. No obstante, la colchicina se ha mostrado poco eficaz en pacientes que inician el tratamiento cuando la amiloidosis ya está presente. En este trabajo presentamos el caso de un enfermo con FMF y amiloidosis renal secundaria diagnosticada mediante biopsia renal que desarrolló un síndrome nefrótico completo a pesar del tratamiento con colchicina. Por la mala evolución del cuadro se decidió iniciar tratamiento con anakinra (un inhibidor de la interleucina 1Beta). En los meses posteriores a la instauración del fármaco el enfermo presentó una mejoría progresiva del síndrome nefrótico, hasta alcanzar la remisión completa. La función renal permaneció estable. Los inhibidores de la interleucina 1Beta pueden ser un tratamiento efectivo de la FMF en pacientes con amiloidosis renal secundaria (AU)

Renal amyloidosis is one of the most severe complications of familial Mediterranean fever (FMF). Colchicine has reduced the incidence of this complication, which now only appears in untreated, under-treated and resistant patients, but it is usually ineffective in patients with advanced amyloidosis. Here we report a patient with FMF and biopsy-proven amyloidosis who presented with nephrotic syndrome despite colchicine treatment. Anakinra (an interleukin-1Beta inhibitor) was started and a dramatic complete remission of nephrotic syndrome was observed in the following months. Anakinra can be an effective treatment for FMF patients with severe secondary amyloidosis (AU)

Hipertensión arterial maligna: una forma de presentación de la nefropatía IgA con mal pronóstico / Malignant hypertension: a type of IgA nephropathy manifestation with poor prognosis

Introducción: La hipertensión arterial maligna (HTAM) es una manifestación clínica poco frecuente de la nefropatía IgA (NIgA). Su prevalencia, patogenia y evolución son escasamente conocidas. Material y métodos: Estudio retrospectivo que muestra las características al diagnóstico y la evolución de 13 enfermos con NIgA demostrada por biopsia e HTAM (NIgA-HTAM) diagnosticados en nuestro centro. Resultados: La prevalencia de HTAM en nuestros pacientes con NIgA fue del 7 % (13/186). La edad media de los enfermos fue de 37 ± 12 años. El 84 % eran varones. La presión arterial media al debut del cuadro fue de 219 ± 32/132 ± 18 mmHg. Todos presentaban insuficiencia renal, con una creatinina sérica (Crs) media de 4,73 ± 3,12 mg/dl. Ningún enfermo presentaba datos clínicos de anemia hemolítica microangiopática. El daño histológico fue moderado, existiendo datos de microangiopatía trombótica en cuatro pacientes. Todos los enfermos se trataron con bloqueantes del sistema renina-angiotensina y dos recibieron esteroides. Pese a ello, la función renal se deterioró progresivamente en todos los casos. Al final del seguimiento un enfermo había muerto, diez estaban en diálisis y los dos restantes presentaban una insuficiencia renal crónica estadio 3b. La probabilidad de supervivencia renal fue del 69 % y del 35 % a los 3 y 6 años de seguimiento. Seis enfermos recibieron un trasplante renal: la NIgA recidivó en cuatro de ellos y uno presentó un nuevo episodio de HTAM asociado a síndrome HELLP. Conclusiones: La HTAM es una forma de presentación de la NIgA con un pronóstico renal muy desfavorable y para la que no disponemos de tratamientos eficaces en la actualidad (AU)

Introduction: Malignant hypertension (MHT) is an uncommon clinical manifestation of IgA Nephropathy (IgAN). Its prevalence, pathogenesis and evolution are not well known. Material and methods: We performed a descriptive and retrospective study to report the clinical characteristics and evolution of thirteen patients diagnosed as having IgA nephropathy by renal biopsy in our hospital who developed MHT (IgAN-MHT). Results: The prevalence of MHT in our IgAN patients was 7% (13/186). The mean age was 37±12 years and 84% were males. Mean systolic/diastolic blood pressure at presentation were 219±32/132±18mmHg, respectively. Renal function impairment was detected at admission in all the patients, with a mean serum creatinine of 4.73±3.12mg/dL. No patient showed analytical data that suggested thrombotic microangiopathy. Renal biopsies showed mild chronicity lesions and only four patients presented features of thrombotic microangiopathy. All patients were treated with renin-angiotensin-aldosterone blockers and two received steroids. They all showed a progressive loss of renal function. At the end of follow up one patient had died, ten were on chronic dialysis and two presented chronic kidney disease stage 3b. Renal survival was 69% and 35% at 3 and 6 years, respectively. Six patients received a kidney transplant: IgAN relapsed in four patients. One of them presented a new episode of MHT associated with a HELLP syndrome. Conclusions: Malignant hypertension is a form of IgAN clinical presentation having a remarkably worse renal outcome and without specific effective treatment

Microangiopatía trombótica como recidiva de síndrome antifosfolípido en trasplante renal / Primary antiphospholipid syndrome presented as thrombotic microangiopathy in renal transplantation

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Dos glomerulonefritis en un mismo paciente con infección por virus de la hepatitis C / Two cases of glomerulonephritis in one patient infected with the hepatitis C virus

La glomerulonefritis (GN) membranoproliferativa puede asociarse patogénicamente con la infección por el virus de la hepatitis C (VHC), como numerosos casos clínicos han mostrado. La posible relación entre VHC y GN IgA, por el contrario, ha sido sugerida solamente en casos aislados. La nefropatía IgA recurre hasta en un 50 % de los casos tras el trasplante renal, pero es poco frecuente que aparezca como una GN de novo. Presentamos el caso de un paciente con infección crónica por VHC y hepatopatía, que desarrolla dos patologías glomerulares diferentes a lo largo de su evolución: GN membranoproliferativa en sus riñones nativos, proceso que causó una insuficiencia renal terminal, y GN IgA de novo en el riñón trasplantado. Se discute la posible relación patogénica de ambos procesos glomerulares con la infección por VHC (AU)

Membranoproliferative glomerulonephritis (GN) may be pathogenically associated with infection due to the hepatitis C virus (HCV) as many clinical cases have shown. The potential relationship between the HCV and IgA GN, by contrast, has been suggested only in isolated cases. IgA nephropathy recurs in up to 50% of cases after renal transplantation, but it is uncommon for it to appear as a de novo GN. We report the case of a patient with chronic infection due to the HCV and liver disease, who developed two different glomerular diseases during its progression: membranoproliferative GN in his native kidneys, a process that caused terminal renal failure and de novo IgA GN in the transplanted kidney. The potential pathogenic relationship of both glomerular processes with infection due to the HCV is discussed (AU)