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Despite the consistency with evolutionary biology [4,5,6], the known sex disparity [3], and evidence from animal experiments [9, 10], these novel findings need to be interpreted cautiously. First, the association with CKD needs to be replicated in a larger sample with more power. Second, due to the limited number with follow-up measures of kidney function, we used baseline rather than decline in kidney function. It would be valuable to assess the role of testosterone in CKD progression, specifically the relevance to decline in kidney function, when sufficient follow-up data in the UK Biobank and suitable analytic techniques are available [52]. Third, the role of endogenous testosterone might be different from the role of testosterone supplementation or other lifestyle factors that modulate testosterone. However, the findings for hemoglobin and HDL-cholesterol in MR showed consistency with meta-analysis of RCTs [19]. Moreover, MR estimates lifetime effects rather than the effects of a short-term exposure. As such, the effect on CKD and kidney function might not be comparable to the acute renal effect of testosterone supplementation, although the use of testosterone gel lowers eGFR in RCT [14]. Finally, the underlying pathways from testosterone to kidney function remain to be clarified. The inverse association with eGFRcr might be due to or partly due to testosterone increasing muscle mass and thereby increasing serum creatinine. However, the inverse association remained for eGFRcr_cys. The similar pattern of associations for CKD and albuminuria also provides consistent evidence concerning the renal effects of testosterone. The effect size is small and might not be clinically significant; however, an MR study is more useful in determining the direction of causation than the magnitude of an effect size [53]. Moreover, a small effect size may be highly relevant at the population level [54]. Several mechanisms might underlie the renal effects of testosterone, including an effect on cellular apoptosis that may impact renal disease progression, an effect on glomerular matrix accumulation, an influence on the synthesis and activity of several cytokines and vasoactive agents, an interaction with the renin-angiotensin system [55], an increase in the generation of reactive oxygen species [55, 56], and a pro-inflammatory effect in the kidney [57]. Inflammation and immune function may underlie the pathology of CKD [58], and testosterone is known to be immunomodulatory [59]. In a clinical case report, testosterone directly modulated kidney perfusion [13], but the specific pathway is unclear. Clarifying these pathways, especially as regards any sex differences in the response to testosterone, such as immune function [59], would be valuable.

Proteinuria. Proteinuria is a general term for the presence of increased amounts of protein in the urine. Proteinuria may reflect abnormal loss of plasma proteins due to a) increased glomerular permeability to large molecular weight proteins (albuminuria or glomerular proteinuria), b) incomplete tubular reabsorption of normally filtered low-molecular-weight proteins (tubular proteinuria), or c) increased plasma concentration of low-molecular-weight proteins (overproduction proteinuria, such as immunoglobulin light chains). Proteinuria may also reflect abnormal loss of proteins derived from the kidney (renal tubular cell constituents due to tubular damage) and lower urinary tract. Albuminuria, tubular proteinuria and renal tubular cell constituents are pathognomonic of kidney damage. In addition, findings from experimental and clinical studies have suggested an important role for proteinuria in the pathogenesis of disease progression of CKD.28

For a number of reasons, clinical terminology is changing to focus on albuminuria rather than proteinuria: a) albumin is the principal component of urinary protein in most kidney diseases; recent recommendations for measurement of urine proteins emphasize quantification of albuminuria rather than total protein; b) recent epidemiologic data from studies around the world demonstrate a strong graded relationship of the quantity of urine albumin with both kidney and CVD risk; and c) later recommendations in these guidelines classify kidney disease by level of albuminuria. In this guideline, we will refer to proteinuria when discussing general concepts and will refer either to total protein, albumin or other specific proteins when discussing measurements, patterns, and interpretation of proteinuria.

Normative values for albuminuria and proteinuria are generally expressed as the urinary loss rate. The urinary loss rate of albumin and protein has commonly been referred to as AER and protein excretion rate (PER), respectively, although in the strict physiological sense they are not excreted. The terms AER and PER will be retained herein.

Summary of continuous meta-analysis (adjusted RRs) for general population cohorts with ACR. Mortality is reported for general population cohorts assessing albuminuria as urine ACR. Kidney outcomes are reported for general population cohorts assessing albuminuria as either urine ACR or reagent strip. eGFR is expressed as a continuous variable. The three lines represent urine ACR of

Summary of categorical meta-analysis (adjusted RRs) for general population cohorts with ACR. Mortality is reported for general population cohorts assessing albuminuria as urine ACR. Kidney outcomes are reported for general population cohorts assessing albuminuria as either urine ACR or reagent strip. eGFR and albuminuria are expressed as categorical variables. All results are adjusted for covariates and compared to the reference cell (Ref). Each cell represents a pooled RR from a meta-analysis; bold numbers indicate statistical significance at P

Prevalence of CKD in the USA by GFR and albuminuria. Cells show the proportion of adult population in the USA. Data from the NHANES 1999-2006, N=18,026. GFR is estimated with the CKD-EPI equation and standardized serum creatinine.19 Albuminuria is determined by one measurement of ACR and persistence is estimated as described elsewhere.59 Values in cells do not total to values in margins because of rounding. Category of very high albuminuria includes nephrotic range. Green, low risk (if no other markers of kidney disease, no CKD); Yellow, moderately increased risk; Orange, high risk; Red, very high risk. ACR, albumin-to-creatinine ratio; CKD, chronic kidney disease; CKD-EPI, CKD Epidemiology Collaboration; GFR, glomerular filtration rate; NHANES, National Health and Nutrition Examination Survey. Modified with permission from Macmillan Publishers Ltd: Kidney International. Levey AS, de Jong PE, Coresh J, et al.30 The definition, classification, and prognosis of chronic kidney disease: a KDIGO controversies conference report. Kidney Int 2011; 80: 17-28; accessed

For Recommendations 1.4.4.2 and 1.4.4.2.1 this guideline is fully applicable in pediatrics. The recommendation that clinical laboratories report ACR and PCR in untimed urine samples in addition to albumin concentration or proteinuria concentrations rather than the concentrations alone is valid and useful in the pediatric population. As per Recommendation 1.2.4, however, note should be made that age-related normal values for urinary protein losses must be considered when laboratories choose to report either ACR or PCR. 153554b96e

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