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Nephrol Dial Transplant (2017) 32: ii194ii199

doi: 10.1093/ndt/gfw440
Advance Access publication 1 March 2017

Full Review

Non-proteinuric rather than proteinuric renal diseases are the


leading cause of end-stage kidney disease

Davide Bolignano and Carmine Zoccali


Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension, CNR-IFC, Reggio Calabria, Italy

Correspondence and offprint requests to: Davide Bolignano; E-mail: davide.bolignano@gmail.com; Carmine Zoccali;
E-mail: carmine.zoccali@tin.it

|| proteinuria represent time-honored risk markers of high cardi-


ABSTRACT || orenal risk [1]. Chronic kidney disease (CKD) patients with
||
|| proteinuria or albuminuria, like those with primary or second-
Proteinuria is a distinguishing feature in primary and secondary || ary forms of glomerulonephritis, are notoriously at high risk for
forms of chronic glomerulonephritis, which contribute to no ||
|| disease progression. Reabsorption of albumin escaped from the
more than the 20% of the end-stage kidney disease (ESKD) || glomerular filter by the cubilinmegalin complex in renal tubu-
population. The contribution of non-proteinuric nephropathies ||
|| lar cells sets into motion a nephrotoxic pathway whereby the
to the global ESKD burden is still poorly focused and scarce re- || complex cubilinmegalinalbumin activates reactive oxygen
search efforts are dedicated to the elucidation of risk factors and ||
|| species (ROS) synthesis, and enhances the synthesis of nuclear
mechanistic pathways triggering ESKD in these diseases. We ab- || factor jB-controlled cytokines cascade and of endothelin-I and
stracted information on proteinuria in the main renal diseases
||
|| transforming growth factor (TGF)-b, ultimately leading to
other than glomerulonephritides that may evolve into ESKD. In ||
|| tubulo-interstitial atrophy and fibrosis, and renal function loss
type 2 diabetes, non-proteinuric diabetic kidney disease (DKD) || [2] (Figure 1, left panel). While the pathogenic role of protein-
is more frequent than proteinuric DKD, and risk factors ||
|| uria in renal diseases is unquestionable, alternative, non-
for non-proteinuric forms of DKD now receive increasing at- || albuminuric pathways conducive to renal function loss exist.
tention. Similarly, proteinuria is most often inconspicuous or ||
|| Risk factors that might trigger a progressive decline of the glom-
absent in the most frequent cause of ESKD, i.e. hypertension- ||
|| erular filtration rate (GFR) in the absence of proteinuria/albu-
related chronic kidney disease (CKD), as well as in progressive
|| minuria (Figure 1, right panel) include hypertension, obesity,
cystic diseases like autosomal dominant polycystic kidney ||
|| high serum triglycerides levels and glomerular hyperfiltration,
disease and in pyelonephritis/tubulo-interstitial diseases.
|| an alteration that is not confined to diabetes, being commonly
Maintaining a high degree of attention in the care of CKD pa- ||
|| seen also in the early stages of hypertension [4]. These mechan-
tients with proteinuria is fundamental to effectively retard pro-
|| isms are often at play in nephrosclerosis, a disease characterized
gression toward kidney failure. However, substantial research ||
|| by the absence of proteinuria and inconspicuous urine sedi-
efforts are still needed to develop treatment strategies that may
|| ment, which is by far the most common form of progressive
help the vast majority of CKD patients who eventually develop ||
|| renal disease leading to end-stage kidney disease (ESKD).
ESKD via mechanistic pathways other than proteinuria. || Glomerulonephritides are most often proteinuric diseases.
Keywords: CKD, ESKD, non-proteinuric diseases, proteinuria
|| The incidence rate of ESKD due to glomerulonephritides plat-
||
|| eaued in the 1990s and since then has declined steadily.
|| Nowadays these diseases account for only 7.5 and 10% of inci-
||
INTRODUCTION || dent dialysis patients in the USA and Europe, respectively [5, 6].
||
|| On the other hand, accumulating data suggest that the propor-
Biomarkers of renal damage are established major risk factors || tion of CKD patients without proteinuria is substantial. For ex-
||
for cardiovascular (CV) and renal morbidity even in the absence || ample, in a survey made in the framework of the Third National
of clearly impaired renal function, and albuminuria and | Health and Nutrition Examination Survey (NHANES III) as

C The Author 2017. Published by Oxford University Press


V ii194
on behalf of ERA-EDTA. All rights reserved.
Risk factors and mechanisms in non-
Nephrotoxic mechanism(s) of proteinuria
proteinuric renal diseases

++RANTES

++ROS
Hypertension Tubulo intersal inammaon
cubilin Alteraons in adipokines and
Obesity/overweight secondary pro-inammatory
Renal tubule cell albumin Endothelin
(luminal side) changes
megalin
MCP-1
High serum triglycerides levels

Insulin resistance

TGF-
Glomerular hyperltraon at single nephron level in
individuals with low nephron mass
NF-k
|
Pro-inammatory cytokines

FIGURE 1: Mechanisms whereby sustained proteinuria (left panel) and non-proteinuric pathways (right panel) may lead to chronic tubulo-
interstitial damage. Nephrotoxicity of proteinuria: albumin escaped from the glomerular lter is taken up by the cubilinmegalin complex in
tubular cells. The complex cubilinmegalinalbumin triggers local production of ROS and activates regulated on activation, normal T cell ex-
pressed and secreted (RANTES), a fundamental chemotactic cytokine. Monochemotactic protein 1 (MCP-1), another chemo-attractant of in-
ammatory cells, is also activated and these factors trigger macrophage accumulation at the tubular level and in the interstitium. Nuclear factor
jB (NF-jB) and the cytokine cascade recruited by this factor are also activated in parallel with TGF-b, a factor that stimulates the proliferation
of brocytes and collagen accumulation. The cubilinmegalinalbumin complex also activates endothelin synthesis, which eventually results in
vasoconstriction and parallel inammatory changes in the vascular endothelium. Non-proteinuric pathways that may be conducive to kidney
damage include hypertension, obesity/overweight, high serum triglycerides and hyperltration at the single nephron level. As for diabetes, these
pathways are discussed in some detail in Porrini et al. [3].

many as 37% of patients with a GFR <30 mL/min/1.73 m2 had || between the two searches. Since this issue is still poorly focused
no albuminuria [7]. This is also true for a condition like type 2 || in the current literature and since proteinuric nephropathies are
diabetes, where proteinuria was seen as an obligatory step in the
|| by far more frequently investigated than non-proteinuric ones,
||
pathway conducive to kidney failure [8]. Indeed, among pa- || we felt it was important to overview the relative contribution of
tients with type 2 diabetes with GFR <60 mL/min/1.73 m2
||
|| proteinuric and non-proteinuric nephropathies to the global
included in NHANES III, 30% were normoalbuminuric [9]. || burden of ESKD. We pragmatically approached this issue by
||
While proteinuria is an unquestionable, strong risk factor for || reviewing the literature (Figure 2) on the epidemiology of pro-
CKD progression, non-proteinuric forms of CKD might be the || teinuria in chronic nephropathies that are responsible for ESKD
||
most frequent cause of ESKD. The problem is similar to that of || in the two major renal registries, the US Renal Data System
severe and moderate hypertension. Severe hypertension is a || (USRDS) [5] and the European Renal AssociationEuropean
||
condition imposing an extremely high risk for CV death and || Dialysis and Transplantation (ERA-EDTA) Registry [6]. These
non-fatal CV events, but being a relatively rare condition its glo- || diseases include diabetes, hypertension, autosomal dominant
||
bal contribution to CV disease is by far inferior to that of mild || polycystic kidney disease (ADPKD) and cystic diseases, and py-
to moderate hypertension, which are highly prevalent condi- || elonephritis/interstitial nephritis (Table 1). We deliberately did
||
tions that per se associate to a risk excess for CV events much || not review glomerulonephritis, a proteinuric condition contri-
lower than that of severe hypertension. This is precisely the rea-
||
|| buting to the ESKD burden by about 20%.
son why in the 1990s Geofrey Rose proposed that a small shift ||
||
in the blood pressure distribution curve in the general popula- ||
tion may have a greater beneficial effect in CV prevention than || DIABETES
||
focusing only on treating high-risk patients [10]. Presently, the ||
degree of attention driven within the nephrology community by || Diabetes is a pervasive cause of ESKD in western populations
||
proteinuric diseases far exceeds that of non-proteinuric ones. A || and a major contributor to the CKD epidemic worldwide [21].
simple PubMed search limited to the last 5 years made on 8 || Advanced renal disease attributable to diabetic disease accounts
||
November 2016 with the term glomerulonephritis returned || for 44 and 30% of new ESKD individuals needing to start chronic
6767 original papers, reviews or editorials focusing on this con-
|| renal replacement therapy in the USA and Europe, respectively
||
dition, whereas the numbers of corresponding papers focusing || [5, 6]. As alluded to before, the paradigm that proteinuria is a ne-
||
on nephrosclerosis, the most common form of non-proteinuric || cessary step in the course of CKD associated with type 2 diabetes,
renal disease, or with the term non-proteinuric were just 219 || causing renal dysfunction and progression to ESKD, has been
||
and 298, respectively, notwithstanding obvious overlapping reframed. Epidemiological surveys unequivocally showed that a

ESKD in non-proteinuric renal diseases ii195


|| Overall CKD increased from 14.9% to 17.7%, whereas albumin-
|| uria tended to decrease. Observations in the same dataset ex-
|| tended up to 2014 substantially confirmed these findings [12].
||
|| On the basis of these estimates it was calculated that in 2009
|| 14, approximately 8.2 million adults with diabetes in the USA
||
|| had pathological albuminuria, reduced estimated GFR (eGFR)
||
|| or both. The prevalence of albuminuria decreased progressively
|| over time from 20.8% [95% confidence interval (CI) 16.3
||
FIGURE 2: Review criteria. || 25.3%] in 198894 to 15.9% (95% CI 12.719.0%) in 200914
|| [adjusted prevalence ratio 0.76 (95% CI 0.650.89); P < 0.001
||
reduced GFR is more common among diabetic patients than in || for trend]. In contrast, the prevalence of reduced eGFR
non-diabetic subjects, but also revealed that a large number of
|| increased from 9.2% (95% CI 6.212.2%) in 198894 to 14.1%
||
such patients will never show levels of proteinuria above the || (95% CI 11.317.0%) in 200914 [adjusted prevalence ratio
traditional definition of overt diabetic nephropathy (>500 mg/g)
|| 1.61 (95% CI 1.331.95) comparing 200914 with 198894;
||
during their life course [22]. The term diabetic kidney has been || P < 0.001 for trend], with a similar pattern for severely reduced
|| eGFR [adjusted prevalence ratio 2.86 (95% CI 1.385.91);
proposed to encompass various lesions involving all kidney ||
structures to characterize kidney disease in patients with diabetes || P 0.004 for trend].
||
[diabetic kidney disease (DKD)]. While the presence of glomeru- ||
lar damage underlies either the presence or the risk for protein- ||
||
uria and dictates the linear progression that was classically || HYPERTENSIVE/RENOVASCULAR DISEASE
described decades ago [8], proteinuria cannot be considered as a ||
|| Nearly 40% of adults in the USA have either known or undiag-
marker of diabetic nephropathy tout court. Rather, proteinuria ||
in diabetes has to be seen as an indicator of glomerular lesions in
|| nosed hypertension [24] and >20% of patients with systemic
|| hypertension have either a reduced GFR (<60 mL/min/1.73 m2)
diabetic patients with CKD. Historical trends showing improve- ||
|| or significant albuminuria/proteinuria [25]. Due to the high
ments in glycaemic control over time in large databases and the ||
|| prevalence of this condition, notwithstanding that only a tiny mi-
widespread use of antagonists of the reninangiotensin system
|| nority of hypertensive individuals progress to ESKD, hyperten-
may have contributed to a decrease in the prevalence of glomeru- ||
|| sive nephropathy ranks as the second cause of ESKD requiring
lar lesions and allowed the emergence of other types of renal le- || dialysis or renal transplantation worldwide [5, 6]. In the USA,
sions affecting the interstitium and the vasculature, i.e. lesions || hypertensive renal disease accounted for approximately 158 000
that may cause progressive renal damage without triggering pro- ||
|| patients entering the USRDS during 200612 (28% of incident
teinuria or producing just mild to moderate increases in the lev- ||
|| patients) [26]. In Europe, 21% of incident and 18% of prevalent
els of this biomarker. || dialysis patients have been attributed to hypertension [6].
Parving et al. [11], in a survey by the International Diabetes ||
|| Renal changes in hypertension are often classified as benign
Federation and the International Society of Nephrology includ- || or malignant nephrosclerosis. Benign nephrosclerosis is a slow
ing about 30 000 type 2 diabetic patients from 33 countries, ||
|| process characterized by intimal fibrosis and medial thickening
found that the overall prevalence of normo-, micro- and macro- || of medium size branches of the arterial tree in the kidney and
albuminuria was 51, 39 and 10%, respectively, with wide racial ||
|| hyaline arteriolosclerosis of small arterioles, which usually pro-
differences. As expected, the prevalence of reduced GFR || gress in the absence of proteinuria. Uncontrolled malignant
(<60 mL/min/1.73 m2) increased stepwise from normo- ||
|| nephrosclerosisa rare condition characterized by severe
(17.5%) to micro- (27.5%) and macroalbuminuria (30.7%), thus || thrombotic microangiopathy, segmental fibrinoid necrosis, oc-
confirming the nephrotoxicity of proteinuria, but also high- ||
|| clusive endothelial swelling and capillary thrombi [27]repre-
lighted that, in the absence of proteinuria, a reduced GFR is || sents a strong risk factor for ESKD, and the severity of renal
observed in about one diabetic patient out of five, a risk not dra-
||
|| damage in this nephropathy is reflected by the almost obligatory
matically different from that registered in patients with macro- || presence, to various degrees, of proteinuria.
||
albuminuria (one patient out of three). These findings, || Several observational studies have reported higher urinary al-
indicating that a substantial burden of non-proteinuric forms of || bumin excretion in individuals affected by essential hypertension
||
renal damage in diabetes were largely confirmed in the analyses || as compared with healthy matched controls, but the overall preva-
in the NHANES database, have been discussed previously [9]. || lence of pathological microalbuminuria ranged from 9.2% to 40%
||
In another epidemiologic study, comparing secular trends in || [1315, 17, 2830]. Of note, in these studies, almost all subjects
the prevalence of DKD in the USA across three time windows || with essential hypertension had preserved renal function, even in
||
(198894, 19992004 and 200508) [23], the prevalence of || the presence of increased albuminuria. Absolute urinary albumin
DKD, defined as diabetes with albuminuria (albuminuria/crea- || values and the prevalence of microalbuminuria in these studies
||
tininuria 30 mg/g), reduced GFR (<60 mL/min/1.73 m2) or || went along with hypertension severity [13], an observation in line
both, increased overtime from 2.2% (198894) to 2.8% (1999
||
|| with an analysis in the time window 19992006 in the NHANES
2004), reaching 3.3% in 200508. Importantly, this concurred ||| database in 16 567 subjects [16]. Therein the prevalence of micro-
with the prevalence of diabetes in the same population, whereas || albuminuria was dose-dependently associated with hypertension
||
the prevalence of DKD among diabetic patients did not change. severity, being 4.5% in individuals with normal blood pressure,

ii196 D. Bolignano and C. Zoccali


Table 1. Main studies providing epidemiology data on proteinuric complications in the leading conditions causing ESKD

Cause of ESKD/study Study design Study population Prevalence of proteinuria/albuminuria Notes


Diabetes
Parving et al. [11] Cross-sectional 24 151 type 2 diabetic patients Microalbuminuria 38.8% (9370 patients) Independent risk factors for pathological albumin-
Macroalbuminuria 9.8% (2367 patients) uria were HbA1c, systolic BP, ethnicity, retinopathy,
duration of diabetes, kidney function, height and
smoking
Kramer et al. [9] Cross-sectional 171 diabetic individuals from the NHANES Microalbuminuria 45% (64 patients) Retinopathy and albuminuria were both absent in
database (period 198894) with type 2 dia- Macroalbuminuria 19% (47 patients) 30% (n 51) of individuals with diabetes and im-
betes and impaired renal function (eGFR paired renal function (population approximately 0.3
<60 mL/min/1.73 m2) million)
Afkarian et al. [12] Serial analysis of 6251 diabetic individuals from the NHANES Albuminuria 20.815.9% (see text) The prevalence of albuminuria decreased progres-
cross-sectional studies database (four different time periods con- sively over time from 20.8% in 198894 to 15.9% in
sidered: 198894, 19992004, 200508 and 200914 (P < 0.001); conversely, the prevalence of
200914) reduced eGFR increased from 9.2% to 14.1%
Hypertensive/renovascular disease
Jalal et al. [13] Cross-sectional 288 patients with essential hypertension Albuminuria 37.5% (108 patients) Increasing trend in albuminuria with the severity of
hypertension

ESKD in non-proteinuric renal diseases


Cerasola et al. [14] Cross-sectional 383 hospitalized essential hypertensives Albuminuria 27% (103 patients) Presence of albuminuria signicantly correlated with
clinic and 24-h systolic and diastolic BP, LVH, cre-
atinine clearance and rethinopathy
Bigazzi et al. [15] Cross-sectional 123 patients with essential hypertension Albuminuria 40% (49 patients) No correlation found between albuminuria and
mean arterial pressure or creatinine clearance
Ogunniyi et al. [16] Retrospective 16 567 individuals in the NHANES database Albuminuria 6.325.3% (see text) The prevalence of microalbuminuria increased with
19992006 hypertension severity, being 4.5% for normal BP,
6.3% for pre-hypertension, 12.4% for stage 1 hyper-
tension, 25.3% for stage 2 hypertension; the preva-
lence was 11.3% in subjects with controlled
hypertension
Leoncini et al. [17] Cross-sectional 957 never previously treated, middle-aged Albuminuria 9.2% (88 patients) Mean creatinine clearance was 83 6 21.2 mL/min;
patients with primary hypertension prevalence of LVH and retinopathy was 13 and 49%
Cystic diseases: ADPKD
Chapman et al. [18] Cross-sectional/ 270 ADPKD patients Proteinuria 17.8% (48 patients) All proteinuric subjects were hypertensive and had
prospective Albuminuria 7% (19 patients) larger renal volumes, lower creatinine clearances and
the projection of a more aggressive course of renal
disease; individuals with albuminuria had higher BP,
larger renal volumes and increased ltration fraction
Pyelonephritis
Arze et al. [19] Cross-sectional/ 130 patients with primary chronic pyelo- Proteinuria 21% (27 patients) A further 26 patients developed proteinuria during
prospective nephritis diagnosed radiologically or by follow up; incident proteinuria was associated with
nephrectomy, of which 84 had unilateral and hypertension and bilateral disease
46 had bilateral disease, followed for 6240
months
Goodship et al. [20] Cross-sectional 255 individuals with chronic pyelonephritis Proteinuria 37% (94 patients) Proteinuria was more frequent in individuals with
from the Newcastle chronic pyelonephritis higher (>90 mmoL/L) than lower plasma creatinine
database at presentation (18% versus 60%, P < 0.001) and
associated with the presence of hypertension
ADPKD, autosomal dominant polycystic kidney disease; BP, blood pressure; LVH, left ventricular hypertrophy; NHANES, National Health and Nutrition Examination Survey; eGFR, estimated glomerular ltration rate.

ii197
6.3% in those with prehypertension, 12.4% and 25.3%, respect- || Pathological proteinuria in pure pyelonephritis is an un-
ively, in those with stages 1 and 2 hypertension, but just 11.3% || common finding and rarely exceeds 1 g/24 h [4345]; higher
among those with treated, controlled hypertension.
||
|| values may reflect the concomitant presence of vesicoureteric
Although some hypertensive subjects may develop severe || reflux, particularly if bilateral, due to transudation of tissue fluid
proteinuria during the course of the disease and even manifest
||
|| out of an infected kidney [46]. Conversely, nephrotic-range pro-
nephrotic syndrome [17], this evolution is definitely uncom- || teinuria in pyelonephritis is usually a hallmark of superimposed
||
mon in the absence of other systemic or renal diseases [31, 32]. || focal segmental glomerular sclerosis or diabetic nephropathy, or
|| hypertension [47].
||
|| In a series published in the 1980s, 130 patients with primary
CYSTIC DISEASES: ADPKD || chronic pyelonephritis diagnosed radiologically or by nephrec-
||
|| tomy, of which 84 had unilateral and 46 had bilateral disease,
ADPKD is the most common inherited kidney disease leading ||
|| were followed for 6240 months [19]. At presentation, only 27
to ESKD. The incidence rate of ESKD attributable to ADPKD is || patients (21%) had proteinuria, whereas a further 26 patients
about 12% in the USA [5] and 6% in Europe [6]. By 60 years of ||
|| developed this complication during follow-up. Incident protein-
age, approximately 50% of patients with ADPKD have usually || uria was associated with hypertension and bilateral disease. The
developed ESKD [33]. Unlike other renal diseases, in ADPKD ||
|| natural history of chronic pyelonephritis was also investigated
the relationship between the presence and the magnitude of || in 255 patients from the Newcastle chronic pyelonephritis data-
proteinuria/albuminuria and renal prognosis is debated. Only ||
|| base. Overall, the prevalence of proteinuria was approximately
two studies specifically focused on proteinuria in ADPKD and ||
|| 37%. Of note, proteinuria was more frequent in individuals with
only sparse evidence exists suggesting a negative effect of pro- ||
teinuria on renal outcomes in ADPKD patients [34, 35], and tri- || high serum creatinine (>90 mmoL/L) and was associated with
als targeting proteinuria in ADPKD failed to provide clear || the presence of hypertension [20].
||
benefits [36]. Prevalence of proteinuria ranged from 18% to ||
24% in the largest ADPKD trials testing the effects of various ||
||
interventions on disease progression, such as the TEMPO [37], || CONCLUSIONS
the HALT-PKD [38], the ALADIN [39] and the SIRENA [40]
||
|| Apart from renal diseases where proteinuria is a distinguishing
trials. However, these trials focused on specific ADPKD subpo- ||
pulations and, given the restricted inclusion criteria of the same
|| feature, like primary and secondary forms of chronic glomer-
||
trials (e.g. early CKD stage, normal blood pressure or absence of || ulonephritis, which contribute to no more than 20% of the
other renal diseases), findings in these subpopulations may not
|| ESKD population, the presence of relevant proteinuria is infre-
||
reflect the ADPKD population at large. || quent in the remaining diseases that underlie the ESKD burden
|| in the US and European registries. In type 2 diabetes, non-
Pathological albuminuria or proteinuria in ADPKD may rep- ||
resent in most cases a direct consequence of poorly controlled || proteinuric DKD prevails on the proteinuric form of the same
|| disease and risk factors for non-proteinuric DKD are being in-
blood pressure, severe renovascular damage due to isolated high ||
blood pressure peaks or, more rarely, superimposed glomerular || creasingly focused on, e.g. in Porrini et al. [3]. A relevant degree
||
diseases [41]. In ADPKD, besides the specific genetic alteration, || of proteinuria is even less frequent in hypertension-related
the most relevant risk factor for adverse renal outcomes is blood || CKD as well as in progressive cystic diseases like ADPKD and
||
pressure control [42]. Therefore, the presence of proteinuria in || pyelonephritis/tubulo-interstitial diseases. Even though thera-
these patients may identify a group of patients with more severe || peutic targeting of proteinuria remains a centrepiece in the fight
||
or poorly controlled hypertension. In an cohort study of 270 || against progressive renal diseases [48], substantial research ef-
ADPKD patients [18], the mean 24-h urinary protein excretion || forts are needed to develop treatment strategies that may help
||
was on average 259 6 22 mg/day, but only 48 (17.8%) of them || the vast majority of CKD patients who eventually develop
had proteinuria >300 mg/day. Patients with clear-cut proteinuria ||
|| ESKD via mechanistic pathways other than proteinuria.
had higher mean arterial pressure, larger renal volume and lower ||
creatinine clearance. All proteinuric patients were hypertensive, ||
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Nat Rev Nephrol 2011; 7: 1121 || Received for publication: 15.11.2016; Accepted in revised form: 15.11.2016
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ESKD in non-proteinuric renal diseases ii199