Pediatr Nephrol DOI 10.1007/s00467-015-3119-1
REVIEW
Haematuria as a risk factor for chronic kidney disease progression in glomerular diseases: A review Juan Antonio Moreno 1 & Claudia Yuste 2 & Eduardo Gutiérrez 3 & Ángel M. Sevillano 3 & Alfonso Rubio-Navarro 1 & Juan Manuel Amaro-Villalobos 1 & Manuel Praga 3 & Jesús Egido 1,4
Received: 3 March 2015 / Revised: 15 April 2015 / Accepted: 20 April 2015 # IPNA 2015
Abstract 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.
* Juan Antonio Moreno [email protected] 1
Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Autonoma University, Av. Reyes Católicos 2, 28040 Madrid, Spain
2
Department of Nephrology, Gregorio Marañon Hospital, 28007 Madrid, Spain
3
Department of Nephrology, 12 de Octubre Hospital, 28041 Madrid, Spain
4
Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
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. Keywords Haematuria . Chronic kidney disease . Acute kidney injury . Red blood cells . Glomerulonephritis
Introduction Haematuria is defined by the presence of more than two red blood cells (RBCs) per high-power field in the urine on at least two to three different occasions, independent of trauma, exercise, menstruation or sexual activity [1]. The presence of haematuria can be occasional, recurrent or persistent. It is important to differentiate microhaematuria from macrohaematuria. Macrohaematuria is characterized by the massive presence of RBCs in the urine, leading to the latter acquiring a clearly discernable red-brownish colour, while microhaematuria can only be observed by dipstick or microscopic examination. Haematuria is a frequent abnormality in both glomerular and non-glomerular diseases. In this review we focus on glomerular haematuria because of its repercussion on renal outcome. Classically, haematuria has been considered to be a benign condition associated with glomerular diseases. However, recent data from clinical and experimental studies suggest a negative role of glomerular haematuria on kidney disease
Pediatr Nephrol
Prevalence of haematuria
progression. The haematuria–pathogenic effects in both paediatric and adult populations will be fully discussed in this review.
The actual prevalence of haematuria is uncertain since its presence is not usually mentioned in large epidemiological studies, possibly due to the difficulty in detecting and quantifying glomerular haematuria, as mentioned in the preceding section. Most clinical information on this issue comes from studies carried on in the 1970s and 1980s, mainly in Asian countries. These studies showed that haematuria was a common urinalysis finding in both paediatric and adult populations [1], with the prevalence of isolated microhaematuria in healthy adult screening programmes ranging from 0.18 to 16.1 % [4–8]. Several factors may explain this wide range, including age, gender and whether a positive result was confirmed with a second screening test and/or microscopic evaluation. The prevalence of haematuria in children was also found to be variable. Dipstick urine analysis screening among 870 asymptomatic school children in Lebanon showed a prevalence of haematuria of 1.5 %, whereas isolated microhaematuria was present in 1.0 % of children [9]. Screening programs in Japan (350,000 school children [10]) and China (40,000 school children [11]) reported that 0.03– 0.7 % of children had both haematuria and proteinuria [10], whereas isolated haematuria was reported in 0.4–0.52 % of children [11]. Vivante et al. reported that the prevalence of persistent isolated microhaematuria, in the absence of proteinuria, was 0.3 % in 1 million young Israelis (mean age 17.3 years) and twice as common in males than females (0.4 vs. 0.2 %, respectively) [12]. A higher presence of haematuria
Diagnosis and quantification of glomerular haematuria A number of diseases and pathological conditions may be associated with the presence of haematuria, necessitating an exhaustive microscopic evaluation of urine sediment to identify the aetiology of this finding (Fig. 1). It is possible to discriminate a glomerular origin of the haematuria based on the prevalence of dysmorphic RBCs with an irregular shape in the urine [1–3]. The quantification of haematuria is not routinely included in urine analysis for evaluation of renal function because microscopic examination of urinary sediment is a time-consuming process. This limitation has led to the determination of haematuria by dipsticks; however, these measurement devices provide false positives, do not discriminate the origin of haematuria (glomerular vs. nonglomerular) and only provide a semi-quantitative measure of the number of RBCs in urine. These pitfalls have hindered our understanding of the role of haematuria on the progression of renal disease. Therefore, studies are required which focus on how to more accurately determine haematuria.
Fig. 1 Classification of haematuric renal diseases by histopathological disorders. ANCA Antineutrophil cytoplasmic antibodies, CFHR5 complement factor H-related 5 nephropathy, CL capillary lumen, BC Bowman’s capsule, E endothelial cell, GB glomerular basement membrane, GN glomerulonephritis, IgAN immunoglobulin A nephropathy, MBP membranoproliferative, M mesangium, MYH9 myosin heavy chain 9 (MYH9)-associated kidney disease, P podocyte, RBC red blood cell, HSP Henoch– Schönlein purpura, SLE systemic lupus erythematous, TBMD thin basement membrane disease, TC tubular cell, US urinary space
Slit diaphragm disorders MYH9 disease Fabry disease
RBC CL Endothelial diseases ANCA Endocapillary
Subendothelial/ Subepithelial deposit MBP Endocapillary Crescentic SLE Cryoglobulinemia Fibronectin Disease Fibrillary Disease
P TC E
US
CL M Mesangial deposits IgAN HSP
BC
GBM disorders Alport TBMD Anti-GBM C3/CFHR5
Pediatr Nephrol
in men has also been reported in most studies, but not all, in different pathological conditions [13–15]. The prevalence of haematuria and other urinary abnormalities has been reported in a number of renal biopsy registries [16–30] (Table 1). In the Czech Registry of Renal Biopsies, 65.9 % of the 4004 biopsies that were included in the study showed microhaematuria, whereas only 9.2 % showed macrohaematuria [30]. Macrohaematuria was more frequent in children than in adults (13.0 vs. 8.3 %), whereas the opposite trend was observed for microhaematuria (60.2 vs. 67 %) [30]. Similar results have been reported in other studies, clearly showing an increased presence of macrohaematuria in renal biopsies from the pediatric population compared with those from adult patients [28].
Renal histological features associated with haematuria In the adult population, major causes of glomerular haematuria are immunoglobulin A nephropathy (IgAN), thin basement membrane disease (TBMD) and Alport syndrome (AS) [31, 32], although haematuria is also associated with other pathologies, such as crescentic glomerulonephritis, membranoproliferative glomerulonephritis or endocapillary glomerulonephritis [33–35] (Table 2). IgAN is characterized by the presence of persistent isolated microscopic haematuria, with occasional macroscopic bouts associated with upper Table 1
respiratory or gastrointestinal infections [36] (Table 2). The prevalence of haematuria in IgAN has been estimated at over 90 % in chronic kidney disease (CKD) patients and at almost 75 % in IgAN patients with conserved renal function [37, 38]. AS patients show microhaematuria early in life, with occasional bouts of macrohaematuria, principally during childhood [39]. Similar to AS, TBMD is clinically related to microhaematuria often noted during childhood. However, microhaematuria may be intermittent and not be detected until adulthood. Occasional bouts of gross haematuria are also observed in TBMD patients, frequently in association with upper respiratory infections [40]. One study in the paediatric population reported that around 70 % of children with isolated haematuria had minor glomerular abnormalities or TBMD, whereas 79 % of patients with haematuria and proteinuria were diagnosed with IgAN [40]. In another study, TBMN was also mainly reported in children with asymptomatic haematuria (53 %), followed by IgAN and membranoproliferative glomerulonephritis [41]. The study of Vivante et al. demonstrated that in adolescents with isolated microhaematuria and end-stage renal disease (ESRD) the contribution of IgAN, TBMD and AS was similar [12].
Where do RBCs come from? Glomerular haematuria results from the passage of RBCs from the glomerular capillary into the urinary space. It is widely
Prevalence of haematuria and other clinical manifestations in renal biopsy registries
First author of study (reference)
Country
Adults/ children (n)
Isolated haematuria (%)
Haematuria + proteinuria (%)
Proteinuria (%)
Nephrotic syndrome (%)
Acute renal failure (%)
Acute nephritic syndrome (%)
Bakr [16] Paripović [17] Coppo [18] Yin [19] Hussain [20] Bazina [21] Yuen [22] Covic [23] Zheng [24] Piqueras [25]a Carvalho [26] Karnib [27] Rivera [28] Simon [29] Rychlík I [30]
Egypt Serbia Italy China UK Croatia China Romania China UK Portugal Lebanon Spain France Czech Republic
ND/1096 ND/150 ND/432 ND/1579 ND/352 ND/65 ND/209 ND/635 ND/1419 ND/322 1858/358 940/108 6525/491 1742 3296/708
2.6 23.4 19.3 26.2 9.8 12.3 17 – 15.1 65 28.5 – 4.5 4.7 –
– 15.8 10.8 4.6 – – 10 3.3 24.4 35 – 46.8 21.7 19 –
– 11 31.2 38 36 30.8 6 – – – – – – 7 41.4
48 32 22.7 44.8 22.5 41.5 28 52.3 39.4 – 42 33.2 36.6 20
4.4 4 5.3 – 10.7 6.2 1 12.4 4 – 9.7 9.4 13.9 16
1.6 – 4.4 15.34 8.6 1.5 – 21.9 – – 9.3 – 4.6 –
Data are presented as the percentage of biopsies included in the study showing the clinical manifestation ND, Not determined a
Renal biopsy registry of children with hematuria
Pediatr Nephrol Table 2
Clinical manifestation and prevalence of macroscopic and microscopic haematuria in patients with glomerular diseases
Clinical manifestation
IgA nephropathy (IgAN) Alport Syndrome Thin basement membrane disease (TBMD) C3 glomerulopathy Crescentic Fibrillary Deposit disease Fibronectin Deposit Disease Mesangiocapillary Myosin heavy chain 9 kidney disease (MYH9) Endocapillary
Prevalence Macroscopic haematuria
Microscopic haematuria
Occasional and recurrent (20 % adults to 70 % children) Occasional (% unknown) Occasional (5–22 %) Occasional and recurrent (30 %) Occasional (18 %) Occasional (5 %) Occasional (% unknown) Occasional (9 %) Occasional (% unknown) Persistent (% unknown)
Persistent and recurrent (70 % adults) Persistent (100 %) Persistent (100 %) Persistent (68–82 %) Persistent and recurrent (100 %) Persistent (50 %) Persistent (53 %) Occasional (64 %) Persistent (% unknown) Occasional (% unknown)
accepted that glomerular haematuria is associated with glomerular filtration barrier dysfunction or damage [42]. Under normal conditions, endothelial fenestrations (50–100 nm) prevent the passage of RBCs (diameter 6–8 μm) through the glomerular filtration barrier. The pathogenic mechanism responsible for haematuria remains unclear, but it seems to be different in inflammatory and non-inflammatory glomerular diseases: –
–
In primary glomerulonephritis or autoimmune diseases, infiltrating leukocytes may release metalloproteinases and reactive oxygen species, leading to a glomerular basement membrane (GBM) which is more fragile and more susceptible to rupture [42]. Immune complexes produced in post-infectious glomerulonephritis may also induce a severe inflammatory response, resulting in neutrophil chemotaxis and endocapillary hypercellularity, leading to haematuria. In non-inflammatory glomerular diseases, such as TBMD and AS, the width of the GBM may be reduced to onethird of its normal width. The thinning is more often diffuse and extensive, although focal abnormalities have also been found [43]. In TBMD, type IV collagen abnormalities lead to a slightly more compact GBM, which is more fragile due to the lack of non-collagenous molecules, thereby explaining the persistent isolated haematuria observed in these individuals [42]. AS is caused by mutations in type IV collagen genes (COL4A5, in X-linked AS; COL4A3 or COL4A4 in autosomal recessive AS) that lead to persistent expression of fetal type IV collagen chains (α1/α2) [44]. Fetal type IV collagen is more susceptible to proteases, leading to a more unstable GBM.
A number of authors suggest that an exacerbated activation of the alternative complement pathway may be also
responsible for haematuria in IgAN, anti-neutrophil cytoplasmic antibodies-vasculitis, C3 glomerulonephritis and membranoproliferative glomerulonephritis [45]. These entities account for gross haematuria bouts after upper respiratory tract infections [33, 46, 47]. It has been speculated that susceptible patients may have a predisposition for complement activation [33, 48]. Under normal conditions, a number of redundant mechanisms inhibit complement, which explains why the disease does not develop in all genetically similar family members [33, 49]. However, in vulnerable patients, an additional insult, such as infection, could activate the alternative complement pathway, leading to glomerular deposition of complement factors [33]. RBCs in urinary sediments from glomerular diseases are smaller, have blebs and buds and show a star-shaped morphology and several dysmorphisms [50]. These morphological changes in RBCs are due to mechanical trauma following their passage through the injured glomerular filtration barrier membrane or to exposure to wide osmotic changes in different parts of the nephron. Electron microscopy of lupus nephritis class IV nephropathy samples have documented the presence of RBCs traversing the ruptured GBM [51]. In addition, the passage of RBCs through the thin GBM at localized gaps within the capillary endothelium has been observed in TBMD or minimal-change disease [43, 52]. It has been suggested that both increased pressure within the capillary lumina and/or GBM defects may open endothelial gaps, facilitating RBC passage to the urinary space. These defects in the GBM are thought to be temporary, as RBCs crossing the GBM are rarely seen in biopsies [52]. It is important to note that, in addition to the endothelium, other cells or structures may be important in preventing RBCs from entering the urinary space. This possibility may explain the existence of haematuria in diseases characterized with normal endothelium, such as fibrillar deposit diseases or myosin heavy chain 9 (MYH9)-associated kidney disease.
Pediatr Nephrol
Evidence supporting haematuria as a risk factor for CKD progression Haematuria has been classically considered to be a hallmark of glomerular filtration barrier dysfunction or damage, without any repercussion on progression to CKD [53]. However, novel evidences from screening programs, transplant donors, studies in glomerular diseases, among others show an adverse role of haematuria on renal outcome. 1) Screening programs Recent findings from the Israeli population-based registry (aged 16–25 years) based on 22 years of follow-up show that the presence of isolated microhaematuria increased the risk for ESRD (0.7 vs. 0.04 %, adjusted hazard ratio 18.5) [12]. Furthermore, subjects with microhaematuria were specifically at higher risk for ESRD earlier than those individuals without this condition, mainly secondary to primary glomerular diseases (58 vs. 27 %). 2) Transplant donors Glomerular haematuria in the transplant donor was found to confer a risk of progressive kidney disease to living kidney donors after heminephrectomy [54]. Otherwise stated, predonation glomerular haematuria increased the risk of kidney disease progression postdonation. The authors of this study also found that the incidence of haematuria increased after heminephrectomy and that postdonation haematuria was associated with progressive decline of renal function in donors. The results from this study show the possible risk of using potential donors with persistent glomerular haematuria and the importance of checking for the presence of haematuria in urine sediment both during donor evaluation and during the postransplant follow-up. 3) Evidence from studies in glomerular diseases 3.1 IgA nephropathy: The association between microhaematuria and progression to CKD has been best analyzed in IgAN. The general prognosis of IgAN with isolated microscopic haematuria and minimal or no proteinuria is good [55]; however, the results from studies are contradictory [56]. Nearly 20 % of IgAN patients develop ESRD within 20 years of diagnosis [38, 57–60]. In line with this, in one study mild microhaematuria increased the risk of developing ESRD after 10 years of follow-up, thereby predicting renal outcome in these patients [38]. In another study, mild haematuria was a predictor of renal deterioration in patients with an estimated glomerular filtration rate (eGFR) of >60 mL/min/1.73 m 2 , without proteinuria (50 years [67, 69–71]. In patients with TBMD, males present a worse renal outcome than females [14]. 3.4 Recently described glomerulopathies: The previously diffuse entity denoted as Bbenign familial haematuria^ (BFH) was classically applied to those causes of persistent isolated haematuria: IgAN, TBMD and AS [31, 32]. However, a better understanding of the genetic basis of the diseases has prompted a better classification of BFH into a number of rare glomerulopathies, such as MYH9associated kidney disease, giant fibronectin glomerulopathy, C3/CFHR5 glomerulonephritis, immunotactoid glomerulonephritis and fibrillary glomerulonephritis. The renal outcome of these entities is worse than was initially described for BFH [47, 72–76]. On the other hand, a recent study involving 351 children who had undergone kidney biopsy secondary to persistent asymptomatic isolated haematuria reported an increased prevalence of adverse renal events (i.e. development of proteinuria, hypertension or impaired renal function after 2–10 years of follow-up) in those children with recurrent macrohaematuria and/or proteinuria as compared with patients with asymptomatic isolated microhaematuria [31/136 (22.8 %) vs. 13/215 (6.0 %), respectively] [77]. This finding suggests that microscopic haematuria, especially when accompanied by macroscopic haematuria and proteinuria, may be associated with an adverse renal outcome. These data suggest that follow-up of children with microhaematuria may be necessary to improve clinical outcome. In line with this observation, a number of authors recommend genetic analysis in those children with family histories of haematuria and/or proteinuria or ESRD for the early detection of these progressive hereditary renal diseases [78]. 4) Macroscopic haematuria-associated acute kidney injury correlates with adverse long-term outcomes Severe gross haematuria promotes acute kidney injury (AKI), as reported in IgAN and other forms of glomerulonephritis. The estimated incidence of AKI in gross haematuria bouts in IgAN is around 40 % [79]. In this setting, macrohaematuria-associated AKI can be severe and require dialysis. Acute tubular injury is the principal mechanism responsible for AKI. Acute tubular necrosis and the presence of RBC casts in tubular lumens are the
most prominent features in biopsies of patients with glomerular haematuria and AKI, regardless of the aetiology of the haematuria [3]. In one study in IgAN patients with macrohaematuria-associated AKI, the percentage of crescents was 55 years, male sex, histological severity of acute tubular necrosis and baseline serum creatinine levels are risk factors associated with incomplete recovery of renal function by univariate analysis; however, in this study the duration of haematuria is the only factor that remained significant after multivariate analysis [80]. These results were confirmed in a subsequent study that included more subjects [3].
Clinical practice guidelines The renal clinical practice guidelines of the KDOQI (Kidney Disease Outcomes Quality Initiative) and KDIGO (Kidney Disease: Improving Global Outcome) send a contradictory message on the role of haematuria in renal disease. Although these guidelines recommend the use of dipsticks for the assessment of haematuria in CKD patients [81, 82], they do not establish a relationship between haematuria and CKD progression. Moreover, no recommendation for diagnostic testing and follow-up has been established for patients with glomerulonephritis and isolated microscopic haematuria [82]. However, these guidelines do recognize that IgAN with haematuria and minimal proteinuria is a progressive disease [83], indicating that although general renal outcome for haematuriaassociated patients is good, the lifetime risk for CKD may be elevated in these patients, depending on their specific underlying disease. Therefore, periodic clinical control may be recommended for IgAN patients with persistent isolated microscopic haematuria. Interestingly, in the Japanese population, where dipstick haematuria is a significant predictor of ESRD, the National CKD Practice Guidelines recommend that a nephrologist be consulted in patients with both dipstick proteinuria and microhaematuria (≥1+) [84, 85]. To date, there is no global consensus on urinary screening in children. In 2007, the American Academy of Pediatrics published their latest guidelines, in which urinalyses were not recommended at any age during childhood. As a consequence, no regular population-based urinary screenings have been performed in the USA or Europe. To the contrary, regular population-based urinary screenings of paediatric populations have been performed in Japan, Taiwan and Korea [86–88]. Urinalysis screening in these countries has enabled the early
Pediatr Nephrol
diagnosis and treatment of asymptomatic children with IgAN or membranoproliferative glomerulonephritis. A recent clinical practice guideline for the treatment of children with AS suggests that children should be treated with angiotensinconverting enzyme inhibitors when presenting with: (1) haematuria plus proteinuria or (2) haematuria plus microalbuminuria in those patients with COL4A5 mutations or a family history of ESRD before 30 years of age [44]. It also recommends annual determination of renal function in those children with isolated microhaematuria. A randomized prospective clinical trial study on patients with AS is recruiting patients (ClinicalTrials.gov Identifier: NCT01485978). The results will be of great interest in the context of evaluating CKD progression in patients with isolated haematuria or microalbuminuria versus those with proteinuria.
Pathophysiological mechanisms associated with haematuria Recent data from clinical and experimental studies have identified just how haematuria induces renal damage [2, 3]. The most common histological findings in AKI during macroscopic haematuria are the presence of acute tubular necrosis and the formation of RBC casts in distal convoluted tubules and collecting ducts. Haemoglobin (Hb) or its related metabolites (free haem or iron) are the key effectors of renal damage under these pathological conditions. Hb may be released by RBCs into the urinary space or may result from RBCs passing through the glomerular filtration barrier. The passage of RBCs through the glomerular filtration barrier may compromise erythrocyte integrity, causing cellular rupture and the subsequent release of Hb into the urinary space. Cell-free Hb in the tubular lumen generates reactive oxygen species and decreases nitric oxide availability [89, 90]. Hb may be taken up by tubular cells through the megalin/ cubilin system [91], promoting a number of harmful effects, such as oxidation, inflammation, fibrosis and apoptosis. Intracellular Hb dissociates into haem and globin. Free haem is very toxic, increasing lipid oxidation, protein denaturation, mitochondrial damage, intrarenal vasoconstriction and ischaemia and pro-inflammatory chemokine release via NF-kB activation and decreasing nitric oxide availability [90–92]. There are several mechanisms of defense to restrain Hbassociated toxic effects (Fig. 2). Indeed, haem oxygenase-1 (HO-1) catalyses the conversion of haem to biliverdin, iron and carbon monoxide (CO) [92]. Biliverdin is then further converted to bilirrubin by bilirubin reductase, whereas iron is stored as ferritin. HO-1, CO and bilirrubin are protective molecules with anti-oxidant and anti-inflammatory properties [91, 92]. Haptoglobin (Hp) binds to Hb and this Hp–Hb complex is taken up by CD163, a membrane receptor expressed in infiltrating macrophages [93]. In response to Hb uptake,
INJURIOUS
DEFENSIVE
Oxidative stress
Haeme oxygenase-1
Apoptosis
Carbon monoxide
Fibrosis Inflammation
HAEMATURIA
Biliverdin Bilirubin
Hypoxia
Ferritin
Vasoconstriction
Haptoglobin
Tubular obstruction
CD163
Fig. 2 Pathophysiological and defense mechanisms associated with haematuria
CD163-expressing macrophages release the antiinflammatory interleukin-10 and increase HO-1 synthesis, thereby contributing to the restoration of tissue integrity [94]. Our group has observed increased CD163 expression in kidneys from patients with haemoglobinuria, including those with paroxysmal nocturnal haemoglobinuria [95], favism-associated haemoglobinuria [96] and IgAN [97], or in excessively anti-coagulated subjects [98] with macroscopic haematuria-associated AKI. Interestingly, in the study on IgAN patients, CD163 expression and oxidative stress were significant prognostic factors for incomplete recovery of renal function in IgAN patients with macrohaematuria-associated AKI, and these factors remained significantly associated with final eGFR and proteinuria after adjustment for age, gender, duration of haematuria bouts, initial eGFR and proteinuria [97].
Therapeutic approaches for glomerular haematuria There are no specific therapies to decrease haematuriaassociated adverse effects in glomerular diseases. The only validated treatment in IgAN is the blockade of the renin–angiotensin system (RAAS), specifically when proteinuria is >1 g/day [82]. Glucocorticoids are only indicated in those IgAN patients with proteinuria of >1 g/day and a GFR of >50 mL/min after 3–6 months of treatment with RAAS inhibitors [82]. This scenario may change with the recent publication of the results of the VALIGA study (European Validation Study of the Oxford Classification of IgA Nephropathy) [99]. In this study, 46 % of patients received immunosuppressive therapy during the follow-up (98 % glucocorticoids) in the absence of specific causes to justify their use (e.g. patients had higher proteinuria, lower eGFR and/or worse histological prognosis). This therapy was significantly associated with a reduction of proteinuria and an improvement in renal function. Importantly, these benefits were even more evident in patients with a GFR of
REVIEW
Haematuria as a risk factor for chronic kidney disease progression in glomerular diseases: A review Juan Antonio Moreno 1 & Claudia Yuste 2 & Eduardo Gutiérrez 3 & Ángel M. Sevillano 3 & Alfonso Rubio-Navarro 1 & Juan Manuel Amaro-Villalobos 1 & Manuel Praga 3 & Jesús Egido 1,4
Received: 3 March 2015 / Revised: 15 April 2015 / Accepted: 20 April 2015 # IPNA 2015
Abstract 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.
* Juan Antonio Moreno [email protected] 1
Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Autonoma University, Av. Reyes Católicos 2, 28040 Madrid, Spain
2
Department of Nephrology, Gregorio Marañon Hospital, 28007 Madrid, Spain
3
Department of Nephrology, 12 de Octubre Hospital, 28041 Madrid, Spain
4
Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
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. Keywords Haematuria . Chronic kidney disease . Acute kidney injury . Red blood cells . Glomerulonephritis
Introduction Haematuria is defined by the presence of more than two red blood cells (RBCs) per high-power field in the urine on at least two to three different occasions, independent of trauma, exercise, menstruation or sexual activity [1]. The presence of haematuria can be occasional, recurrent or persistent. It is important to differentiate microhaematuria from macrohaematuria. Macrohaematuria is characterized by the massive presence of RBCs in the urine, leading to the latter acquiring a clearly discernable red-brownish colour, while microhaematuria can only be observed by dipstick or microscopic examination. Haematuria is a frequent abnormality in both glomerular and non-glomerular diseases. In this review we focus on glomerular haematuria because of its repercussion on renal outcome. Classically, haematuria has been considered to be a benign condition associated with glomerular diseases. However, recent data from clinical and experimental studies suggest a negative role of glomerular haematuria on kidney disease
Pediatr Nephrol
Prevalence of haematuria
progression. The haematuria–pathogenic effects in both paediatric and adult populations will be fully discussed in this review.
The actual prevalence of haematuria is uncertain since its presence is not usually mentioned in large epidemiological studies, possibly due to the difficulty in detecting and quantifying glomerular haematuria, as mentioned in the preceding section. Most clinical information on this issue comes from studies carried on in the 1970s and 1980s, mainly in Asian countries. These studies showed that haematuria was a common urinalysis finding in both paediatric and adult populations [1], with the prevalence of isolated microhaematuria in healthy adult screening programmes ranging from 0.18 to 16.1 % [4–8]. Several factors may explain this wide range, including age, gender and whether a positive result was confirmed with a second screening test and/or microscopic evaluation. The prevalence of haematuria in children was also found to be variable. Dipstick urine analysis screening among 870 asymptomatic school children in Lebanon showed a prevalence of haematuria of 1.5 %, whereas isolated microhaematuria was present in 1.0 % of children [9]. Screening programs in Japan (350,000 school children [10]) and China (40,000 school children [11]) reported that 0.03– 0.7 % of children had both haematuria and proteinuria [10], whereas isolated haematuria was reported in 0.4–0.52 % of children [11]. Vivante et al. reported that the prevalence of persistent isolated microhaematuria, in the absence of proteinuria, was 0.3 % in 1 million young Israelis (mean age 17.3 years) and twice as common in males than females (0.4 vs. 0.2 %, respectively) [12]. A higher presence of haematuria
Diagnosis and quantification of glomerular haematuria A number of diseases and pathological conditions may be associated with the presence of haematuria, necessitating an exhaustive microscopic evaluation of urine sediment to identify the aetiology of this finding (Fig. 1). It is possible to discriminate a glomerular origin of the haematuria based on the prevalence of dysmorphic RBCs with an irregular shape in the urine [1–3]. The quantification of haematuria is not routinely included in urine analysis for evaluation of renal function because microscopic examination of urinary sediment is a time-consuming process. This limitation has led to the determination of haematuria by dipsticks; however, these measurement devices provide false positives, do not discriminate the origin of haematuria (glomerular vs. nonglomerular) and only provide a semi-quantitative measure of the number of RBCs in urine. These pitfalls have hindered our understanding of the role of haematuria on the progression of renal disease. Therefore, studies are required which focus on how to more accurately determine haematuria.
Fig. 1 Classification of haematuric renal diseases by histopathological disorders. ANCA Antineutrophil cytoplasmic antibodies, CFHR5 complement factor H-related 5 nephropathy, CL capillary lumen, BC Bowman’s capsule, E endothelial cell, GB glomerular basement membrane, GN glomerulonephritis, IgAN immunoglobulin A nephropathy, MBP membranoproliferative, M mesangium, MYH9 myosin heavy chain 9 (MYH9)-associated kidney disease, P podocyte, RBC red blood cell, HSP Henoch– Schönlein purpura, SLE systemic lupus erythematous, TBMD thin basement membrane disease, TC tubular cell, US urinary space
Slit diaphragm disorders MYH9 disease Fabry disease
RBC CL Endothelial diseases ANCA Endocapillary
Subendothelial/ Subepithelial deposit MBP Endocapillary Crescentic SLE Cryoglobulinemia Fibronectin Disease Fibrillary Disease
P TC E
US
CL M Mesangial deposits IgAN HSP
BC
GBM disorders Alport TBMD Anti-GBM C3/CFHR5
Pediatr Nephrol
in men has also been reported in most studies, but not all, in different pathological conditions [13–15]. The prevalence of haematuria and other urinary abnormalities has been reported in a number of renal biopsy registries [16–30] (Table 1). In the Czech Registry of Renal Biopsies, 65.9 % of the 4004 biopsies that were included in the study showed microhaematuria, whereas only 9.2 % showed macrohaematuria [30]. Macrohaematuria was more frequent in children than in adults (13.0 vs. 8.3 %), whereas the opposite trend was observed for microhaematuria (60.2 vs. 67 %) [30]. Similar results have been reported in other studies, clearly showing an increased presence of macrohaematuria in renal biopsies from the pediatric population compared with those from adult patients [28].
Renal histological features associated with haematuria In the adult population, major causes of glomerular haematuria are immunoglobulin A nephropathy (IgAN), thin basement membrane disease (TBMD) and Alport syndrome (AS) [31, 32], although haematuria is also associated with other pathologies, such as crescentic glomerulonephritis, membranoproliferative glomerulonephritis or endocapillary glomerulonephritis [33–35] (Table 2). IgAN is characterized by the presence of persistent isolated microscopic haematuria, with occasional macroscopic bouts associated with upper Table 1
respiratory or gastrointestinal infections [36] (Table 2). The prevalence of haematuria in IgAN has been estimated at over 90 % in chronic kidney disease (CKD) patients and at almost 75 % in IgAN patients with conserved renal function [37, 38]. AS patients show microhaematuria early in life, with occasional bouts of macrohaematuria, principally during childhood [39]. Similar to AS, TBMD is clinically related to microhaematuria often noted during childhood. However, microhaematuria may be intermittent and not be detected until adulthood. Occasional bouts of gross haematuria are also observed in TBMD patients, frequently in association with upper respiratory infections [40]. One study in the paediatric population reported that around 70 % of children with isolated haematuria had minor glomerular abnormalities or TBMD, whereas 79 % of patients with haematuria and proteinuria were diagnosed with IgAN [40]. In another study, TBMN was also mainly reported in children with asymptomatic haematuria (53 %), followed by IgAN and membranoproliferative glomerulonephritis [41]. The study of Vivante et al. demonstrated that in adolescents with isolated microhaematuria and end-stage renal disease (ESRD) the contribution of IgAN, TBMD and AS was similar [12].
Where do RBCs come from? Glomerular haematuria results from the passage of RBCs from the glomerular capillary into the urinary space. It is widely
Prevalence of haematuria and other clinical manifestations in renal biopsy registries
First author of study (reference)
Country
Adults/ children (n)
Isolated haematuria (%)
Haematuria + proteinuria (%)
Proteinuria (%)
Nephrotic syndrome (%)
Acute renal failure (%)
Acute nephritic syndrome (%)
Bakr [16] Paripović [17] Coppo [18] Yin [19] Hussain [20] Bazina [21] Yuen [22] Covic [23] Zheng [24] Piqueras [25]a Carvalho [26] Karnib [27] Rivera [28] Simon [29] Rychlík I [30]
Egypt Serbia Italy China UK Croatia China Romania China UK Portugal Lebanon Spain France Czech Republic
ND/1096 ND/150 ND/432 ND/1579 ND/352 ND/65 ND/209 ND/635 ND/1419 ND/322 1858/358 940/108 6525/491 1742 3296/708
2.6 23.4 19.3 26.2 9.8 12.3 17 – 15.1 65 28.5 – 4.5 4.7 –
– 15.8 10.8 4.6 – – 10 3.3 24.4 35 – 46.8 21.7 19 –
– 11 31.2 38 36 30.8 6 – – – – – – 7 41.4
48 32 22.7 44.8 22.5 41.5 28 52.3 39.4 – 42 33.2 36.6 20
4.4 4 5.3 – 10.7 6.2 1 12.4 4 – 9.7 9.4 13.9 16
1.6 – 4.4 15.34 8.6 1.5 – 21.9 – – 9.3 – 4.6 –
Data are presented as the percentage of biopsies included in the study showing the clinical manifestation ND, Not determined a
Renal biopsy registry of children with hematuria
Pediatr Nephrol Table 2
Clinical manifestation and prevalence of macroscopic and microscopic haematuria in patients with glomerular diseases
Clinical manifestation
IgA nephropathy (IgAN) Alport Syndrome Thin basement membrane disease (TBMD) C3 glomerulopathy Crescentic Fibrillary Deposit disease Fibronectin Deposit Disease Mesangiocapillary Myosin heavy chain 9 kidney disease (MYH9) Endocapillary
Prevalence Macroscopic haematuria
Microscopic haematuria
Occasional and recurrent (20 % adults to 70 % children) Occasional (% unknown) Occasional (5–22 %) Occasional and recurrent (30 %) Occasional (18 %) Occasional (5 %) Occasional (% unknown) Occasional (9 %) Occasional (% unknown) Persistent (% unknown)
Persistent and recurrent (70 % adults) Persistent (100 %) Persistent (100 %) Persistent (68–82 %) Persistent and recurrent (100 %) Persistent (50 %) Persistent (53 %) Occasional (64 %) Persistent (% unknown) Occasional (% unknown)
accepted that glomerular haematuria is associated with glomerular filtration barrier dysfunction or damage [42]. Under normal conditions, endothelial fenestrations (50–100 nm) prevent the passage of RBCs (diameter 6–8 μm) through the glomerular filtration barrier. The pathogenic mechanism responsible for haematuria remains unclear, but it seems to be different in inflammatory and non-inflammatory glomerular diseases: –
–
In primary glomerulonephritis or autoimmune diseases, infiltrating leukocytes may release metalloproteinases and reactive oxygen species, leading to a glomerular basement membrane (GBM) which is more fragile and more susceptible to rupture [42]. Immune complexes produced in post-infectious glomerulonephritis may also induce a severe inflammatory response, resulting in neutrophil chemotaxis and endocapillary hypercellularity, leading to haematuria. In non-inflammatory glomerular diseases, such as TBMD and AS, the width of the GBM may be reduced to onethird of its normal width. The thinning is more often diffuse and extensive, although focal abnormalities have also been found [43]. In TBMD, type IV collagen abnormalities lead to a slightly more compact GBM, which is more fragile due to the lack of non-collagenous molecules, thereby explaining the persistent isolated haematuria observed in these individuals [42]. AS is caused by mutations in type IV collagen genes (COL4A5, in X-linked AS; COL4A3 or COL4A4 in autosomal recessive AS) that lead to persistent expression of fetal type IV collagen chains (α1/α2) [44]. Fetal type IV collagen is more susceptible to proteases, leading to a more unstable GBM.
A number of authors suggest that an exacerbated activation of the alternative complement pathway may be also
responsible for haematuria in IgAN, anti-neutrophil cytoplasmic antibodies-vasculitis, C3 glomerulonephritis and membranoproliferative glomerulonephritis [45]. These entities account for gross haematuria bouts after upper respiratory tract infections [33, 46, 47]. It has been speculated that susceptible patients may have a predisposition for complement activation [33, 48]. Under normal conditions, a number of redundant mechanisms inhibit complement, which explains why the disease does not develop in all genetically similar family members [33, 49]. However, in vulnerable patients, an additional insult, such as infection, could activate the alternative complement pathway, leading to glomerular deposition of complement factors [33]. RBCs in urinary sediments from glomerular diseases are smaller, have blebs and buds and show a star-shaped morphology and several dysmorphisms [50]. These morphological changes in RBCs are due to mechanical trauma following their passage through the injured glomerular filtration barrier membrane or to exposure to wide osmotic changes in different parts of the nephron. Electron microscopy of lupus nephritis class IV nephropathy samples have documented the presence of RBCs traversing the ruptured GBM [51]. In addition, the passage of RBCs through the thin GBM at localized gaps within the capillary endothelium has been observed in TBMD or minimal-change disease [43, 52]. It has been suggested that both increased pressure within the capillary lumina and/or GBM defects may open endothelial gaps, facilitating RBC passage to the urinary space. These defects in the GBM are thought to be temporary, as RBCs crossing the GBM are rarely seen in biopsies [52]. It is important to note that, in addition to the endothelium, other cells or structures may be important in preventing RBCs from entering the urinary space. This possibility may explain the existence of haematuria in diseases characterized with normal endothelium, such as fibrillar deposit diseases or myosin heavy chain 9 (MYH9)-associated kidney disease.
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Evidence supporting haematuria as a risk factor for CKD progression Haematuria has been classically considered to be a hallmark of glomerular filtration barrier dysfunction or damage, without any repercussion on progression to CKD [53]. However, novel evidences from screening programs, transplant donors, studies in glomerular diseases, among others show an adverse role of haematuria on renal outcome. 1) Screening programs Recent findings from the Israeli population-based registry (aged 16–25 years) based on 22 years of follow-up show that the presence of isolated microhaematuria increased the risk for ESRD (0.7 vs. 0.04 %, adjusted hazard ratio 18.5) [12]. Furthermore, subjects with microhaematuria were specifically at higher risk for ESRD earlier than those individuals without this condition, mainly secondary to primary glomerular diseases (58 vs. 27 %). 2) Transplant donors Glomerular haematuria in the transplant donor was found to confer a risk of progressive kidney disease to living kidney donors after heminephrectomy [54]. Otherwise stated, predonation glomerular haematuria increased the risk of kidney disease progression postdonation. The authors of this study also found that the incidence of haematuria increased after heminephrectomy and that postdonation haematuria was associated with progressive decline of renal function in donors. The results from this study show the possible risk of using potential donors with persistent glomerular haematuria and the importance of checking for the presence of haematuria in urine sediment both during donor evaluation and during the postransplant follow-up. 3) Evidence from studies in glomerular diseases 3.1 IgA nephropathy: The association between microhaematuria and progression to CKD has been best analyzed in IgAN. The general prognosis of IgAN with isolated microscopic haematuria and minimal or no proteinuria is good [55]; however, the results from studies are contradictory [56]. Nearly 20 % of IgAN patients develop ESRD within 20 years of diagnosis [38, 57–60]. In line with this, in one study mild microhaematuria increased the risk of developing ESRD after 10 years of follow-up, thereby predicting renal outcome in these patients [38]. In another study, mild haematuria was a predictor of renal deterioration in patients with an estimated glomerular filtration rate (eGFR) of >60 mL/min/1.73 m 2 , without proteinuria (50 years [67, 69–71]. In patients with TBMD, males present a worse renal outcome than females [14]. 3.4 Recently described glomerulopathies: The previously diffuse entity denoted as Bbenign familial haematuria^ (BFH) was classically applied to those causes of persistent isolated haematuria: IgAN, TBMD and AS [31, 32]. However, a better understanding of the genetic basis of the diseases has prompted a better classification of BFH into a number of rare glomerulopathies, such as MYH9associated kidney disease, giant fibronectin glomerulopathy, C3/CFHR5 glomerulonephritis, immunotactoid glomerulonephritis and fibrillary glomerulonephritis. The renal outcome of these entities is worse than was initially described for BFH [47, 72–76]. On the other hand, a recent study involving 351 children who had undergone kidney biopsy secondary to persistent asymptomatic isolated haematuria reported an increased prevalence of adverse renal events (i.e. development of proteinuria, hypertension or impaired renal function after 2–10 years of follow-up) in those children with recurrent macrohaematuria and/or proteinuria as compared with patients with asymptomatic isolated microhaematuria [31/136 (22.8 %) vs. 13/215 (6.0 %), respectively] [77]. This finding suggests that microscopic haematuria, especially when accompanied by macroscopic haematuria and proteinuria, may be associated with an adverse renal outcome. These data suggest that follow-up of children with microhaematuria may be necessary to improve clinical outcome. In line with this observation, a number of authors recommend genetic analysis in those children with family histories of haematuria and/or proteinuria or ESRD for the early detection of these progressive hereditary renal diseases [78]. 4) Macroscopic haematuria-associated acute kidney injury correlates with adverse long-term outcomes Severe gross haematuria promotes acute kidney injury (AKI), as reported in IgAN and other forms of glomerulonephritis. The estimated incidence of AKI in gross haematuria bouts in IgAN is around 40 % [79]. In this setting, macrohaematuria-associated AKI can be severe and require dialysis. Acute tubular injury is the principal mechanism responsible for AKI. Acute tubular necrosis and the presence of RBC casts in tubular lumens are the
most prominent features in biopsies of patients with glomerular haematuria and AKI, regardless of the aetiology of the haematuria [3]. In one study in IgAN patients with macrohaematuria-associated AKI, the percentage of crescents was 55 years, male sex, histological severity of acute tubular necrosis and baseline serum creatinine levels are risk factors associated with incomplete recovery of renal function by univariate analysis; however, in this study the duration of haematuria is the only factor that remained significant after multivariate analysis [80]. These results were confirmed in a subsequent study that included more subjects [3].
Clinical practice guidelines The renal clinical practice guidelines of the KDOQI (Kidney Disease Outcomes Quality Initiative) and KDIGO (Kidney Disease: Improving Global Outcome) send a contradictory message on the role of haematuria in renal disease. Although these guidelines recommend the use of dipsticks for the assessment of haematuria in CKD patients [81, 82], they do not establish a relationship between haematuria and CKD progression. Moreover, no recommendation for diagnostic testing and follow-up has been established for patients with glomerulonephritis and isolated microscopic haematuria [82]. However, these guidelines do recognize that IgAN with haematuria and minimal proteinuria is a progressive disease [83], indicating that although general renal outcome for haematuriaassociated patients is good, the lifetime risk for CKD may be elevated in these patients, depending on their specific underlying disease. Therefore, periodic clinical control may be recommended for IgAN patients with persistent isolated microscopic haematuria. Interestingly, in the Japanese population, where dipstick haematuria is a significant predictor of ESRD, the National CKD Practice Guidelines recommend that a nephrologist be consulted in patients with both dipstick proteinuria and microhaematuria (≥1+) [84, 85]. To date, there is no global consensus on urinary screening in children. In 2007, the American Academy of Pediatrics published their latest guidelines, in which urinalyses were not recommended at any age during childhood. As a consequence, no regular population-based urinary screenings have been performed in the USA or Europe. To the contrary, regular population-based urinary screenings of paediatric populations have been performed in Japan, Taiwan and Korea [86–88]. Urinalysis screening in these countries has enabled the early
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diagnosis and treatment of asymptomatic children with IgAN or membranoproliferative glomerulonephritis. A recent clinical practice guideline for the treatment of children with AS suggests that children should be treated with angiotensinconverting enzyme inhibitors when presenting with: (1) haematuria plus proteinuria or (2) haematuria plus microalbuminuria in those patients with COL4A5 mutations or a family history of ESRD before 30 years of age [44]. It also recommends annual determination of renal function in those children with isolated microhaematuria. A randomized prospective clinical trial study on patients with AS is recruiting patients (ClinicalTrials.gov Identifier: NCT01485978). The results will be of great interest in the context of evaluating CKD progression in patients with isolated haematuria or microalbuminuria versus those with proteinuria.
Pathophysiological mechanisms associated with haematuria Recent data from clinical and experimental studies have identified just how haematuria induces renal damage [2, 3]. The most common histological findings in AKI during macroscopic haematuria are the presence of acute tubular necrosis and the formation of RBC casts in distal convoluted tubules and collecting ducts. Haemoglobin (Hb) or its related metabolites (free haem or iron) are the key effectors of renal damage under these pathological conditions. Hb may be released by RBCs into the urinary space or may result from RBCs passing through the glomerular filtration barrier. The passage of RBCs through the glomerular filtration barrier may compromise erythrocyte integrity, causing cellular rupture and the subsequent release of Hb into the urinary space. Cell-free Hb in the tubular lumen generates reactive oxygen species and decreases nitric oxide availability [89, 90]. Hb may be taken up by tubular cells through the megalin/ cubilin system [91], promoting a number of harmful effects, such as oxidation, inflammation, fibrosis and apoptosis. Intracellular Hb dissociates into haem and globin. Free haem is very toxic, increasing lipid oxidation, protein denaturation, mitochondrial damage, intrarenal vasoconstriction and ischaemia and pro-inflammatory chemokine release via NF-kB activation and decreasing nitric oxide availability [90–92]. There are several mechanisms of defense to restrain Hbassociated toxic effects (Fig. 2). Indeed, haem oxygenase-1 (HO-1) catalyses the conversion of haem to biliverdin, iron and carbon monoxide (CO) [92]. Biliverdin is then further converted to bilirrubin by bilirubin reductase, whereas iron is stored as ferritin. HO-1, CO and bilirrubin are protective molecules with anti-oxidant and anti-inflammatory properties [91, 92]. Haptoglobin (Hp) binds to Hb and this Hp–Hb complex is taken up by CD163, a membrane receptor expressed in infiltrating macrophages [93]. In response to Hb uptake,
INJURIOUS
DEFENSIVE
Oxidative stress
Haeme oxygenase-1
Apoptosis
Carbon monoxide
Fibrosis Inflammation
HAEMATURIA
Biliverdin Bilirubin
Hypoxia
Ferritin
Vasoconstriction
Haptoglobin
Tubular obstruction
CD163
Fig. 2 Pathophysiological and defense mechanisms associated with haematuria
CD163-expressing macrophages release the antiinflammatory interleukin-10 and increase HO-1 synthesis, thereby contributing to the restoration of tissue integrity [94]. Our group has observed increased CD163 expression in kidneys from patients with haemoglobinuria, including those with paroxysmal nocturnal haemoglobinuria [95], favism-associated haemoglobinuria [96] and IgAN [97], or in excessively anti-coagulated subjects [98] with macroscopic haematuria-associated AKI. Interestingly, in the study on IgAN patients, CD163 expression and oxidative stress were significant prognostic factors for incomplete recovery of renal function in IgAN patients with macrohaematuria-associated AKI, and these factors remained significantly associated with final eGFR and proteinuria after adjustment for age, gender, duration of haematuria bouts, initial eGFR and proteinuria [97].
Therapeutic approaches for glomerular haematuria There are no specific therapies to decrease haematuriaassociated adverse effects in glomerular diseases. The only validated treatment in IgAN is the blockade of the renin–angiotensin system (RAAS), specifically when proteinuria is >1 g/day [82]. Glucocorticoids are only indicated in those IgAN patients with proteinuria of >1 g/day and a GFR of >50 mL/min after 3–6 months of treatment with RAAS inhibitors [82]. This scenario may change with the recent publication of the results of the VALIGA study (European Validation Study of the Oxford Classification of IgA Nephropathy) [99]. In this study, 46 % of patients received immunosuppressive therapy during the follow-up (98 % glucocorticoids) in the absence of specific causes to justify their use (e.g. patients had higher proteinuria, lower eGFR and/or worse histological prognosis). This therapy was significantly associated with a reduction of proteinuria and an improvement in renal function. Importantly, these benefits were even more evident in patients with a GFR of
