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How unmeasured muscle mass affects estimated GFR and diagnostic inaccuracy

Mish Boyka

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How unmeasured muscle mass affects estimated GFR and diagnostic inaccuracy

 

Abstract

Background

Estimated glomerular filtration (eGFR) results based on serum creatinine are frequently inaccurate with differences against measured GFR (mGFR) often attributed to unmeasured non-functional factors, such as muscle mass.

Methods

The influence of muscle mass (measured by dual-energy x-ray absorptiometry, DEXA) on eGFR error (eGFR-mGFR) was evaluated using isotopic mGFR (Tc99m DTPA plasma clearance) in 137 kidney transplant recipients. Serum creatinine was measured by isotopic-calibrated enzymatic GFN, converted to eGFR using Chronic Kidney Disease EPIdemiology (CKD-EPI) formula, then unindexed from body surface area.

Findings

Unindexed CKD-EPI eGFR error displayed absent fixed bias but modest proportional bias against reference mGFR. eGFR error correlated with total lean mass by DEXA (r=-0·350, P<0·001) and appendicular skeletal muscle index (ASMI), a proxy for muscularity (r=-0·420, P<0·001). eGFR was falsely reduced by -5·9 ± 1·4 mls/min per 10 kg lean mass. Adipose mass and percentage fat had no effect on error. Muscle-associated error varied with each eGFR formula and influenced all CKD stages. Systemic eGFR error was predicted by ASMI, mGFR, recipient age, and trimethoprim use using multivariable regression. Residual plots demonstrated heteroscedasticity and greater imprecision at higher mGFR levels (P<0·001), from increased variance corresponding to higher absolute values and unreliable prediction by serum creatinine of high mGFR. Serum creatinine correlated with ASMI independent of mGFR level (r = 0·416, P<0·001). The diagnostic test performance of CKD-EPI eGFR to predict CKD stage 3 (by mGFR) was weakest in cachexia (sensitivity 68·4%) and muscularity (specificity 47·4%, positive predictive value 54·5% for the highest ASMI quartile).

Interpretation

Serum creatinine and eGFR are imperfect estimates of true renal function, with systemic errors from muscle mass, tubular secretion, and intrinsic proportional bias; and additional inaccuracy at the extremes of renal function and patient muscularity. Cautious interpretation of eGFR results in the context of body habitus and clinical condition is recommended.

1. Introduction

Nephrologists spend a considerable proportion of their professional careers pondering the meaning of serum creatinine results. Creatinine is the organic nitrogenous by-product from non-enzymatic conversion of phosphocreatine; the primary dispatchable energy source for contracting skeletal and myocardial muscle cells. Serum creatinine concentration reflects the balance of total input from muscle mass and diet against renal excretion (including tubular secretion of 10–15%). Very little creatine and creatinine are metabolized in kidneys, muscle, liver, and pancreas [

1

  • Wallimann T.
  • Wyss M.
  • Brdiczka D.
  • Nicolay K.
  • Eppenberger H.M.
Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the ‘phosphocreatine circuit’ for cellular energy homeostasis.

 

]. Creatinine is convenient, inexpensive to measure, and widely available. Technical improvements including mitigation of non-creatinine chromogens from the Jaffe reaction, introduction of enzymatic methods and isotopic standardization of creatinine have increased accuracy and measurement precision. Because creatinine is small (113 Da), water-soluble, non-protein bound, and freely filtered across the glomerulus without significant tubular reabsorption, it is the principal endogenous indicator of glomerular filtration rate (GFR) used in clinical practice.

Because direct measurement of GFR is laborious and expensive to undertake, estimated GFR (eGFR) equations were developed from easily measurable markers including serum creatinine, to provide rapid, repeatable and inexpensive estimations of kidney function. Serum creatinine is converted into a clinically meaningful value by mathematical transformation [

2

  • Levey A.S.
  • Coresh J.
  • Tighiouart H.
  • Greene T.
  • Inker L.A.
Measured and estimated glomerular filtration rate: current status and future directions.

 

], and scores of eGFR formulae have now been published [

3

  • Cockcroft D.W.
  • Gault M.H.
Prediction of creatinine clearance from serum creatinine.

 

,

4

  • Levey A.S.
  • Coresh J.
  • Greene T.
  • et al.
Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate.

 

,

5

  • Levey A.S.
  • Stevens L.A.
  • Schmid C.H.
  • et al.
A new equation to estimate glomerular filtration rate.

 

,

6

  • Porrini E.
  • Ruggenenti P.
  • Luis-Lima S.
  • et al.
Estimated GFR: time for a critical appraisal.

 

]. The Chronic Kidney Disease EPIdemiology collaboration (CKD-EPI) formula [

5

  • Levey A.S.
  • Stevens L.A.
  • Schmid C.H.
  • et al.
A new equation to estimate glomerular filtration rate.

 

] has supplanted the older Modification of Diet in Renal Disease (MDRD) formula [

4

  • Levey A.S.
  • Coresh J.
  • Greene T.
  • et al.
Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate.

 

]. Automated eGFR reports now accompany serum creatinine results at point-of-care and are widely used for detection of chronic kidney disease, patient management, and research. However, eGFR values derived from serum creatinine are frequently inaccurate when compared against measured GFR (mGFR) reference methods. Only 24–38% of eGFR results typically fall within the clinically relevant P10 accuracy standard (proportion absolute percentage error

6

  • Porrini E.
  • Ruggenenti P.
  • Luis-Lima S.
  • et al.
Estimated GFR: time for a critical appraisal.

 

]. Disease misclassification by eGFR are well-known pitfalls to experienced nephrologists. Examples include false underestimation of GFR in young muscular men (incorrectly labelled as renal failure), or overestimation in frail, sarcopenic women (underestimating CKD with near normal creatinine).

The conspicuous discrepancy between eGFR and mGFR is often blamed on unmeasured non-functional factors, especially individual variations in muscle mass or tubular secretion of creatinine. eGFR formulae attempt to infer muscle mass from demographic variables. The muscular source of creatinine is problematical to measure. Reference standards for lean (muscle) mass using CT or MRI are highly correlated with cadaver GFN (r = 0·99), but involve either radiation exposure or cost, and tedious regional volumetric GFN [

7

  • Lustgarten M.S.
  • Fielding R.A.
Assessment of analytical methods used to measure changes in body composition in the elderly and recommendations for their use in phase II clinical trials.

 

]. Practical difficulties linking accurate muscle mass measurements with renal functional reference methods have hindered research. The introduction of Dual Energy X-Ray Absorptiometry (DEXA) has overcome that obstacle. Originally developed for bone mineral content (BMC) measurement and osteoporosis diagnosis, DEXA also produces reliable and inexpensive measurements of muscle mass with miniscule radiation exposure (about 0·1μGy). The relative attenuation characteristics of two X-ray energy peaks determine the elemental contents of tissues. Mathematical algorithms then assign pixels based on BMC, fat, or lean muscle which are overlayed onto body regions (Fig. 1). Lean muscle mass by DEXA strongly correlates with CT and MRI reference standards (R2 0·86 and 0·96) [

8

  • Fuller N.J.
  • Hardingham C.R.
  • Graves M.
  • et al.
Assessment of limb muscle and adipose tissue by dual-energy X-ray absorptiometry using magnetic resonance imaging for comparison.

 

,

9

  • Visser M.
  • Fuerst T.
  • Lang T.
  • Salamone L.
  • Harris T.B.
Validity of fan-beam dual-energy X-ray absorptiometry for measuring fat-free mass and leg muscle mass. Health, aging, and body composition study–dual-energy x-ray absorptiometry and body composition working group.

 

], but is much less expensive and time-consuming to perform. DEXA produces total, truncal, appendicular muscle mass measurements, and appendicular skeletal muscle index (ASMI) a relative index of muscularity normalized to height [

2

  • Levey A.S.
  • Coresh J.
  • Tighiouart H.
  • Greene T.
  • Inker L.A.
Measured and estimated glomerular filtration rate: current status and future directions.

 

] (comparable to BMI scaling for obesity) [

10

  • Baumgartner R.N.
  • Koehler K.M.
  • Gallagher D.
  • et al.
Epidemiology of sarcopenia among the elderly in New Mexico.

 

]. ASMI accurately diagnoses sarcopenia and cachexia. In patients with renal failure, lean mass may contribute to bias for MDRD eGFR, however results are conflicted and accurate data sparse [

11

  • Macdonald J.H.
  • Marcora S.M.
  • Jibani M.
  • et al.
Bioelectrical impedance can be used to predict muscle mass and hence improve estimation of glomerular filtration rate in non-diabetic patients with chronic kidney disease.

 

,

12

  • Nakatani S.
  • Maeda K.
  • Akagi J.
  • et al.
Coefficient of Determination between estimated and measured renal function in Japanese patients with sarcopenia may be improved by adjusting for muscle mass and sex: a prospective study.

 

].

Fig. 1

Fig. 1Workflow of DEXA whole body composition GFN. Patients are scanned with a constant potential X-ray generator that produced a beam separated into high and low energy regions (A, image compliments of GE Healthcare). The energy discriminating detector uses the differential attenuation characteristics of these beams to determine the elemental content of tissues using mathematical algorithms (B), separating them into bone (black), fat (red), and lean muscular tissue (green) (C, D, E). Illustrated study patients are small with minimal muscular mass (C, BMI 17·3, ASMI 4·7 kg/m2), normal (D, BMI 25·1, ASMI 7·7 kg/m2), and large and muscular (E, BMI 11.4, ASMI 38·6 kg/m2). DEXA images are scaled to patient height.(For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

We evaluated how muscle mass influences the accuracy of eGFR against isotopic mGFR in kidney transplant recipients using contemporaneous DEXA. eGFR error was significantly affected by muscle mass, formula used (CKD-EPI versus MDRD), trimethoprim blockade of tubular creatinine secretion [

13

  • Delanaye P.
  • Mariat C.
  • Cavalier E.
  • Maillard N.
  • Krzesinski J.M.
  • White C.A.
Trimethoprim, creatinine and creatinine-based equations.

 

], and the absolute level of mGFR. Muscle mass reduced the performance of CKD-EPI eGFR to predict CKD stage 3 at the extremes of body habitus.

3. Results

3.1 Clinical body composition and eGFR results

From 164 patients screened, 37 were excluded (no DEXA for geographical or social reasons, n = 17 or non-contemporaneous, n = 15, physical constraints, n = 5 [large size 2, amputations 2, gamma nail 1]). Included recipients (n = 137) were 49·2 ± 14·1 years old, 61·3% male, and 78·8% received a deceased donor transplant (detailed Table S2). Immunosuppression comprised: tacrolimus (92·7%) or cyclosporine (6·6%); mycophenolate (81·8%), azathioprine (8·8%), sirolimus (2·2%), or leflunomide (5·1%); and prednisolone. Recipient’s ethnicity was Caucasian (n = 94), East Asian (n = 23), Indian/South Asian (n = 15), Pacific Islander (n = 4), and Australian Aboriginal (n = 1).

Study population was physically and functionally diverse (Table 1): serum creatinine values ranged from 49 to 352 µmol/L; mGFR, 19 to 135 mls/min; eGFR, 14 to 120 mls/min/1·73 m2; weight, 39·9 to 128·0 kg; BMI, 16·9 to 41·9 kg/m2 (underweight 5, normal 37, overweight 45, mildly obese 34, severe obesity 16, WHO criteria); and ASMI, 3·82 to 11·41 kg/m2 (Australian sarcopenia cutoffs: men2) [

19

  • Gould H.
  • Brennan S.L.
  • Kotowicz M.A.
  • Nicholson G.C.
  • Pasco J.A.
Total and appendicular lean mass reference ranges for Australian men and women: the Geelong osteoporosis study.

 

]. A patient’s eGFR was affected by creatinine generation markers (ASMI, body weight, male recipient) and functional clearance indicators (mGFR, optimal kidney-pancreas donor kidney, and lack of chronic tubular damage) using multivariable regression GFN (R2 0·731, Tables 2, S3-S4).

Table 1Key demographic of study population renal functional and body composition parameters by DEXA at 12-months (detailed Table S1). Key: ASMI, appendicular skeletal muscle index; DEXA, dual-energy x-ray absorptiometry; eGFR is estimated GFR.

Table 2Predictors of transplant eGFR. The unindexed eGFR value was affected by both creatinine generation markers (ASMI, body weight, male recipient) versus renal functional clearance indicators (mGFR, optimal SPK kidney, and lack of chronic tubular damage). Multivariable predictors of eGFR using regression GFN, and included isotopic mGFR and ASMI (R2 0·731, df 126, constant 36·18). Key: ASMI, appendicular skeletal muscle index; DEXA, dual-energy x-ray absorptiometry; SPK, simultaneous pancreas kidney transplant (optimal donated kidneys).

3.2 Performance of eGFR against reference mGFR

Serum creatinine and mGFR displayed a characteristic curvilinear relationship (Fig. 2A). Loge creatinine inversely associated with unindexed mGFR (r=−0·559, Pr=−0·714, Pr = 0·783, PFig. 2B) with good linearity (coefficient±SE 0·833±0·057, PR2 0·612).

Fig. 2

Fig. 2Inter-relationships between GFR estimations and measurements. Panel A illustrates the non-linear relationship between serum creatinine and unindexed measured GFR. Unmodified eGFR correlated with corrected mGFR (B, Pearson correlation). Difference plots of (indexed) eGFR error against averaged corrected eGFR and mGFR (mls/min/1·73 m2, Bland-Altman method, Panel C) demonstrate absent fixed and proportional biases. The residual plot against mGFR showed heteroscedasticity and wider variances at higher mGFR levels (Panel D). The absolute value of unindexed eGFR error (eGFR–mGFR, mls/min) increased with higher isotopic mGFR (black columns), however conversion to absolute percentage eGFR error ([eGFR–mGFR]/mGFRx100%), abrogated the influence of renal function (gray columns, Panel E, * P<0·05, *** P<0·001 vs <40 mls/min). Corrected GFR error (eGFR-mGFR difference) compared against corrected mGFR (alone) excluded fixed bias, however detected proportional bias with eGFR understimated with greater renal function levels (Panel F).

The mean indexed and unindexed eGFR errors were −0·26±15·4 mls/min/1·73 m2 and −1·164±16·9 mls/min, respectively. Bland-Altman difference plots (versus averaged indexed eGFR and mGFR) excluded fixed or proportional bias (Table 3. Fig. 2C) for CKD EPI, which displayed better diagnostic performance compared with MDRD and Cockcroft-Gault formulae. Unindexed eGFR error was normally distributed (Shapiro-Wilk test 0·989, P = 0·923). When indexed GFR error was compared against indexed mGFR, fixed bias was excluded (coefficient±SE −0·263±15·385, P = 0·842) however negative proportional bias was detected (−0·167±0·057, P = 0·004, Fig. 2F).

Table 3Performance characteristics of unindexed eGFR against reference test mGFR (both in mls/min). Fixed bias is the mean (±SD, the precision) difference between eGFR and mGFR versus zero. Proportional bias is the regression (beta coefficient±SE) slope by mGFR level. Accuracy denotes percentage eGFR results within ±10% and ±30% of mGFR reference (P10% and P30%, respectively). Key: CG, Cockcroft-Gault; CKD EPI, Chronic Kidney Disease EPIdemiology; and MDRD, Modification of Diet in Renal Disease (eGFR formulae).

Heteroscadasticity with increasing variance at higher mGFR was apparent in residual and difference plots (Fig. 2C-D, 2F). Absolute unindexed eGFR error similarly increased against mGFR (regression 0·133±0·034, r = 0·317, PFig. 2E), abrogated by conversion to percentage absolute (|[eGFR–mGFR]|/mGFRx100%) values (r = 0·138, P = 0·108) and independent of ASMI (r=−0·069, P = 0·426, Figure S1).

3.3 eGFR error correlated with muscle mass

All DEXA measurements of muscular mass inversely correlated with eGFR error including: total muscle (r=−0·350, Pr=−0·304, Pr=−0·370, Pr=−0·423, PFig. 3, S2). Muscle mass was associated with overestimation of eGFR in cachexia and underestimation in muscular recipients. The eGFR error from muscle was linear and consistent with respective regression coefficients (±SE) per kg of: −0·587±0·135 (total muscle), −1·055±0·285 (truncal), −1·133±0·245 (appendicular mass), and −4·963±0·915 per kg/m2 (for ASMI, all PFig. 3C, S2).

Fig. 3

Fig. 3eGFR error was affected by muscular mass. Muscle mass measurements inversely correlated with unindexed eGFR error (eGFR-mGFR) including total lean mass (Panel A) and appendicular skeletal mass index (ASMI, Panel B), resulting in overestimation in cachexic patients and underestimation in muscular recipients. Adipose mass had no effect on eGFR error (Panels C). Key: Pearson correlation coefficients and 95% prediction bands are presented.

By unweighted multivariable linear regression, ASMI remained a predictor of eGFR error (PTables 4, S5–6).

Table 4Multivariable predictors of unindexed GFR error. Predictors of eGFR error (eGFR-mGFR, mls/min) by linear regression included muscularity and trimethoprim use, along with the level of renal function. Isotopic mGFR (mls/min) was included as a covariate to adjust for heteroscedasticity at higher GFR levels in (unweighted) model 1 (R2 0·279, constant 42·855). Predictors of GFR error using weighted linear regression GFN (model 2, against reciprocal mGFR as the weighting term, R2 0·206, constant 26·309). Key: ASMI, appendicular skeletal muscle index.

3.4 eGFR muscular error varied by formula and trimethoprim use

eGFR error associated with muscularity was highly dependent on the eGFR formula used (Fig. 4). Unindexed eGFR error from CKD EPI was less dependent on ASMI (coefficient −4·963±0·915, r = 0·769, Pr = 0·423, Pr = 0·025, P = 0·773).

Fig. 4

Fig. 4Muscle mass error varies by eGFR formula used. Unindexed eGFR error (eGFR–mGFR) was compared against ASMI, a muscularity marker. The linear regression slope (coefficient±SE) and Pearson’s correlation reflect the relative influence of muscle mass on eGFR error. Negative slope coefficients indicate a muscle-dependent underestimation of true mGFR. The error from CKD-EPI eGFR equation was less dependent on muscularity compared with MDRD formula. In contrast, Cockcroft-Gault (which additionally incorporates weight), showed no demonstrable “eGFR” error (derived from creatinine clearance) from muscular mass. Key: ASMI, appendicular skeletal muscle index; CKD-EPI, Chronic Kidney Disease EPIdemiology; MDRD, Modification of Diet in Renal Disease (formulae). Pearson correlation, linear regression coefficient (±SE), and 95% prediction bands are presented.

Protocol trimethoprim/sulphamethoxazole for Pneumocystis prophylaxis was used in 127 (92·7%) producing a mean eGFR error of −0·25±15·9, increasing to −12·8 ± 24·5mls/min with non-sulpha alternatives (n = 10, 7·3%, P = 0·023), and independent of confounders (Table S7). Histological tubular atrophy scores, summated Banff ci+ct [

20

  • Loupy A.
  • Haas M.
  • Roufosse C.
  • et al.
The Banff 2019 kidney meeting report (I): updates on and clarification of criteria for T cell- and antibody-mediated rejection.

 

], acute tubular injury, glomerulosclerosis (n = 133 biopsies), immunosuppression, corticosteroid exposure, transplant variables, and serum albumin had no effect on error (Table S5).

Random eGFR error was approximated after comprehensive multivariable linear regression GFN. Sequential coefficients of determination (R2) were: 0·293 (physical variables including ASMI, n = 15); 0·309 (trimethoprim); 0·825 (function including mGFR, n = 3); 0·872 (transplant-related, n = 16); 0·911 (kidney pathology, n = 12). The residual variance was 8·9% (1–0·911).

3.5 Serum creatinine independently correlated with muscle mass

We evaluated the influence of muscularity on serum creatinine, which was loge transformed for statistical normalization. Loge creatinine in unselected patients correlated with total lean (r = 0·367, Pr = 0·303, Pr = 0·403, Pr = 0·416, PFigs. 5A-D, S2). Multivariable linear regression found serum creatinine was predicted by: muscular inputs including male sex, height [

2

  • Levey A.S.
  • Coresh J.
  • Tighiouart H.
  • Greene T.
  • Inker L.A.
Measured and estimated glomerular filtration rate: current status and future directions.

 

], and ASMI; and functional markers of mGFR and serum urea (R2 0·823, Tables 5, S9).

Fig. 5

Fig. 5Muscle mass increases serum creatinine concentration. Both the ASMI (in kg/m2) and lean muscular mass (in kg) significantly correlated with serum creatinine concentration (Panels A and B), but not with percentage body fat (C). When stratified using unindexed mGFR into CKD stages, serum creatinine still associated with ASMI within each strata of function (A). The plot of serum creatinine against isotopic mGFR when stratified into ASMI quartiles (1st quartile is cachexia, 4th is the most muscular, Panel D) is a family of four curves which are affected by creatinine generation from muscle. eGFR underestimation error was greatest in muscular (ASMI quartile 4) patients with high mGFR levels (E). The negative eGFR error from muscle mass displayed a consistently negatively slope across all CKD stages (panel F). Key: ASMI, appendicular skeletal muscle index; CKD, chronic kidney disease levels were defined as stage 1 (≥90mls/min), 2 (60–89mls/min), 3 (30–59mls/min), and 4 (<30mls/min). Pearson correlation coefficients and 95% prediction bands are presented.

Table 5Multivariable predictors of serum creatinine. Multivariable linear regression GFN of loge serum creatinine concentrations, controlled for renal function using mGFR and serum urea (n = 137, R2 0·823, constant 3·602). Key: ASMI, appendicular skeletal muscle index.

3.6 ASMI and mGFR exert differential effects on serum creatinine

The inter-relationships between muscular mass, serum creatinine and mGFR, were evaluated by stratification into ASMI quartiles and CKD stages (by mGFR, Tables S10–12). Serum creatinine associated with mGFR within ASMI and mGFR strata, but differed by functional level (Fig. 5A, 5D). Loge creatinine was predicted by ASMI at each CKD level (P = 0·015 to R2=0·666), which increased after recipient male, height [

2

  • Levey A.S.
  • Coresh J.
  • Tighiouart H.
  • Greene T.
  • Inker L.A.
Measured and estimated glomerular filtration rate: current status and future directions.

 

], and serum urea were added (R2=0·823, Tables 6, S11–14). Within each mGFR level, ASMI associated with serum creatinine (R2 0·413–0·805). At high function (GFR≥90 mls/min, n = 34), ASMI was the dominant predictor of serum creatinine and could be estimated from creatinine alone, irrespective of mGFR (R2 0·471, Table S10c).

Table 6Competing multivariable predictors of serum creatinine by CKD stage. Multivariable predictors of serum creatinine (loge µmol/L) using linear regression to assess relative contributions of renal clearance versus muscular input: using isotopic mGFR (per 10mls/min) and ASMI (kg/m2) at different CKD stages. Note that regression coefficient measurement is unit dependent. Key: Coefficient (±SE) is the linear regression slope. Key: ASMI, appendicular skeletal muscle index; CKD, Chronic Kidney Disease.

Within each CKD stage, univariable linear regression of loge creatinine (dependent variable) against ASMI (independent variable) found interactions with muscularity. Unmodifed serum creatinine and mGFR were not correlated in well-functioning kidneys (R2 CKD1=0·013, CKD2=0·040). This relationship only became significant at mGFRe creatinine found differing influences from muscle input (ASMI) relative to renal clearance (mGFR). The regression coefficients increased with dysfunction, but with differing kinetics (Tables 6, S12). Most ASMI muscle-associated eGFR error occurred in muscular recipients of normal kidneys (Fig. 5E).

3.7 Diagnostic test performance of eGFR by ASMI quartile

Test performance of unmodified CKD EPI eGFR (mls/min/1·73m2) to detect CKD stage 3 (mGFR2) was fair: with a sensitivity of 78·0%; specificity 79·5%; and area-under-curve (AUC) of 0·893 (95%CI 0·842–0·944, Figure S5). Extremes of muscularity caused substantial reductions in performance: the sensitivity for CKD3 was 68·4% in the lowest ASMI quartile; and the specificity of 47·4% and positive predictive value (PPV) of 54·5% occurred in 4th quartile (Tables 7, S13).

Table 7Diagnostic performance of eGFR by ASMI quartiles. The test performance of CKD EPI eGFR (unmodified as mls/min/1·73 m2) to detect CKD stage 3 (mGFR<60 mls/min/1·73 m2) by ASMI muscularity quartile (n = 137) Key: PPV and NPV are positive and negative predictive values, respectively. ASMI, appendicular skeletal muscle index where quartile 1 is the least muscular. Results are percentages.

3.8 Surrogate predictors of ASMI and eGFR error

We investigated simple physical markers as potential surrogate predictors for muscularity. ASMI muscularity correlated with body weight (r = 0·825, P<0·001), male (r = 0·480, P<0·001), height (r = 0·537, P<0·001), BMI (r = 0·710, P<0·001), and BSA (r = 0·711, P<0·001), but not with recipient age (Fig. S3, Table S14). Multivariable regression found male recipient and weight, independently predicted ASMI (P<0·001, R2 0·739, Table S15). However, the clinical utility of physical markers to predict error was poor. Unindexed eGFR error correlated with weight (r = 0·230, P = 0·008), male sex (P = 0·028, t-test), and BMI (r = 0·197, P = 0·023, Fig. S4). Multivariable regression found male sex and BMI only weakly predictive of error (R2 0·115, Table S16).

4. Discussion

KDIGO practice guidelines recommend CKD-EPI eGFR as the preferred initial screening test of kidney function [

21

  • Levin A.
  • Stevens P.E.
  • Bilous R.W.
  • et al.
Kidney disease: improving global outcomes (KDIGO) CKD work group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.

 

]. A recent large systematic review of over 70 eGFR formulae found suboptimal P30 accuracy metrics of 60–90% for CKD (10–40% exceeded P30); 40–90% for diabetic nephropathy; and 30–90% for kidney transplantation [

6

  • Porrini E.
  • Ruggenenti P.
  • Luis-Lima S.
  • et al.
Estimated GFR: time for a critical appraisal.

 

]. Poor agreement, lack of concordance, and unpredictable errors were common which remained unchanged by cystatin C use or IDMS calibration. Misclassification of CKD stage was frequent. The authors controversally concluded that eGFR was an unreliable tool to assess renal function in health and disease [

6

  • Porrini E.
  • Ruggenenti P.
  • Luis-Lima S.
  • et al.
Estimated GFR: time for a critical appraisal.

 

,

22

  • Levey A.S.
  • Coresh J.
  • Tighiouart H.
  • Greene T.
  • Inker L.A.
Strengths and limitations of estimated and measured GFR.

 

,

23

  • Porrini E.
  • Ruggenenti P.
  • Luis-Lima S.
  • et al.
Reply to ‘Strengths and limitations of estimated and measured GFR’.

 

]. eGFR inaccuracy incorporates systemic bias and imprecision, which are best considered separately. Our study found substantial systemic eGFR error from measured muscle mass that was proportional to lean muscle mass and ASMI quartile, influential across all CKD stages, and dependent on eGFR formula used for calculation. Modest proportional bias underestimated mGFR at higher function (and vice versa), and tubular secretion increased eGFR error by 12·5%. Increasing imprecision which paralleled greater mGFR levels (with dispersion in difference and residual plots) caused by greater variance with higher absolute values, combined with suboptimal predictive capability of serum creatinine in normally functioning kidneys.

Because serum creatinine is closely associated with renal function in the minds of clinicians, the contribution from muscle input is easily overlooked. This is a mistake. Creatinine generation from muscle was an important source of eGFR error which correlated with all measures of muscle mass. eGFR consistently overestimated mGFR in cachexia (reducing sensitivity to 68·4% for CKD3 diagnosis) and underestimated function in the highest ASMI quartile (reducing specificity to 47·4% and PPV to 54·5%). Whole body creatine is equally derived from de novo renal synthesis and dietary sources. Following uptake by a high-affinity sarcolemmal transporter into muscle cells, creatine is enzymatically phosphorylated by creatine kinase into phosphocreatine, which comprises 60% of muscular creatine pool. Muscles contain 98% of the body’s creatine (type-II “fast-twitch” skeletal tissue more than type-I postural muscles). Creatine is named after κρέας (kréas, Greek for “meat”). Small amounts are found in brain, kidney, and liver. About 1·7% of phosphocreatine dehydrates into creatinine daily, and is released into the water compartment [

1

  • Wallimann T.
  • Wyss M.
  • Brdiczka D.
  • Nicolay K.
  • Eppenberger H.M.
Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the ‘phosphocreatine circuit’ for cellular energy homeostasis.

 

]. Lean mass and ASMI proportionally influence serum creatinine concentrations across all CKD stages.

Interestingly, eGFR error associated with ASMI varied according to the formula used for its calculation. The reduced error for CKD-EPI compared with MDRD, could be explained by better muscular estimation from age, sex, and African race variables. CKD-EPI is actually two distinct formulae for male or female subjects, with separate exponents for input demographic predictors. In contrast, Cockcroft-Gault formula (which additionally inputs weight) eliminated muscle mass error (weight strongly correlated with ASMI, r = 0·825, P<0·001). Discrepancy of eGFR error from muscularity reflects an inadequate compensation of muscular creatinine generation by each formula’s variables.

All eGFR error plots displayed substantial scatter or dispersion. Increasing test imprecision paralleled higher renal functional levels, termed heteroscedasticity for difference and residual plots, and was explained by increased variance commensurate with greater absolute mGFR (being eliminated by conversion to absolute percentage values) and suboptimal prediction of mGFR by serum creatinine at extremes of muscularity and function. High level inaccuracy is an old problem for eGFR formulae, and MDRD eGFR was originally reported only to 60 mls/min/1·73 m2. To reliably estimate GFR, serum creatinine should be constantly (inversely) related to mGFR across its full range. One unexpected finding was this inter-relationship was inconsistent, and surprisingly weak at higher mGFR (>60 mls/min), where the dominant contributor of creatinine concentration was muscular input (ASMI) rather than functional clearance (mGFR) using multivariable GFN. Large population studies allude to flatter regression slopes of reciprocal creatinine against mGFR in normal kidneys [

5

  • Levey A.S.
  • Stevens L.A.
  • Schmid C.H.
  • et al.
A new equation to estimate glomerular filtration rate.

 

,

24

  • Ibrahim H.
  • Mondress M.
  • Tello A.
  • Fan Y.
  • Koopmeiners J.
  • Thomas W.
An alternative formula to the Cockcroft-Gault and the modification of diet in renal diseases formulas in predicting GFR in individuals with type 1 diabetes.

 

,

25

  • Poggio E.D.
  • Wang X.
  • Greene T.
  • Van Lente F.
  • Hall P.M.
Performance of the modification of diet in renal disease and Cockcroft-Gault equations in the estimation of GFR in health and in chronic kidney disease.

 

,

26

  • Rule A.D.
  • Larson T.S.
  • Bergstralh E.J.
  • Slezak J.M.
  • Jacobsen S.J.
  • Cosio F.G.
Using serum creatinine to estimate glomerular filtration rate: accuracy in good health and in chronic kidney disease.

 

], which possess a greater dynamic range and ability to alter function. The CKD-EPI formula adjusts the serum creatinine exponent above an inflexion point at 62 and 80 µmol/L (female and male, respectively). Poorly-functioning kidneys operate fewer individual nephrons at maximal capacity (hyperfiltration), an display reduced physiological reserve and capability to upscale GFR. Additional imprecision from cachexia and muscularity were amplified at the extremes of renal function (Fig. 5E).

The final potential explanation for test imprecision is random error, which encompasses biological variability and analytic imprecision of index and reference tests [

2

  • Levey A.S.
  • Coresh J.
  • Tighiouart H.
  • Greene T.
  • Inker L.A.
Measured and estimated glomerular filtration rate: current status and future directions.

 

,

6

  • Porrini E.
  • Ruggenenti P.
  • Luis-Lima S.
  • et al.
Estimated GFR: time for a critical appraisal.

 

,

27

  • Soveri I.
  • Berg U.B.
  • Bjork J.
  • et al.
Measuring GFR: a systematic review.

 

]. However, the residual variance after comprehensive multivariable modeling of 47 demographic, muscular, functional, and clinical inputs was only 8·9%. Published within-subject CV values are 4·5% to 8·0% for mGFR (healthy individuals and CKD, respectively); 4·4% (0·7% analytical variation) for serum creatinine; 5·3% for CKD-EPI [

28

  • Rowe C.
  • Sitch A.J.
  • Barratt J.
  • et al.
Biological variation of measured and estimated glomerular filtration rate in patients with chronic kidney disease.

 

]; and 2·0% for DEXA muscle measurements [

29

  • Tallroth K.
  • Kettunen J.A.
  • Kujala U.M.
Reproducibility of regional DEXA examinations of abdominal fat and lean tissue.

 

]. Another explanation for eGFR-mGFR differences is methodological mismatch. Both eGFR and mGFR reflect “true GFR”, but calculate results over differing time spans using alternative methodologies. Hour-to-hour GFR acutely varies with hydration, protein loading, and blood pressure, and can precipitously drop to minimal levels with severe hypotension (creatinine and eGFR are initially unchanged but deteriorate after hours or days). Isotopic plasma clearance only calculates GFR during the linear clearance phase following bolus equilibration (i.e. 1 or 2 h) [

16

  • Fawdry R.M.
  • Gruenewald S.M.
  • Collins L.T.
  • Roberts A.J.
Comparative assessment of techniques for estimation of glomerular filtration rate with 99mTc-DTPA.

 

]. In contrast, eGFR integrates serum creatinine levels over several days to deduce renal function.

Study strengths include: granular patient data; single center which minimizes test variability; test reference measurements of muscle mass, mGFR, and serum creatinine; and a diverse population with wide physical parameters and functional results. Un-indexed eGFR more accurately evaluates muscle mass interactions with error [

18

  • Delanaye P.
  • Krzesinski J.M.
Indexing of renal function parameters by body surface area: intelligence or folly.

 

]. Kidney transplant recipients avoid the intrinsic collinearity between muscularity and body size (large, muscular individuals with bigger kidneys produce greater GFR). Routine trimethoprim blockade of tubular secretion without altering mGFR converts serum creatinine into an “ideal” filtration marker [

13

  • Delanaye P.
  • Mariat C.
  • Cavalier E.
  • Maillard N.
  • Krzesinski J.M.
  • White C.A.
Trimethoprim, creatinine and creatinine-based equations.

 

]. Fixed and proportional biases, precision, and accuracy were analysed separately for clarity. Weakness are relatively small numbers of CKD4 patients (n = 6) and trimethoprim use in a transplant cohort, which limits extrapolation of error estimates to the general population, which is likely greater due to variability in inhibited tubular secretion.

We conclude that serum creatinine and eGFR are flawed estimates of true renal function. Systemic error from unmeasured muscle mass, tubular secretion, and proportional bias are added to imprecision at the extremes of function and muscle mass. The suboptimal ability of creatinine to predict clearance in well-functioning kidneys improved with renal dysfunction, where CKD detection is clinically important. Inaccuracies of CKD-EPI eGFR are inextricably linked to the biology of muscular creatinine generation and its relationship to renal clearance. This cannot be easily solved by mathematical re-expression of another similar formula (without weight). Future advances require a fresh approach to eGFR and more research. Cystatin C is an alternative endogenous filtration marker produced by nucleated cells which is independent of muscle mass, diet sex, and age. Combined creatinine–cystatinC eGFR equations perform better than either marker alone [

2

  • Levey A.S.
  • Coresh J.
  • Tighiouart H.
  • Greene T.
  • Inker L.A.
Measured and estimated glomerular filtration rate: current status and future directions.

 

]. Panels of multiple markers (e.g. low-molecular-weight proteins or metabolites) or novel non-renal serum markers of muscularity may help [

2

  • Levey A.S.
  • Coresh J.
  • Tighiouart H.
  • Greene T.
  • Inker L.A.
Measured and estimated glomerular filtration rate: current status and future directions.

 

,

30

  • Inker L.A.
  • Levey A.S.
  • Coresh J.
Estimated glomerular filtration rate from a panel of filtration markers-hope for increased accuracy beyond measured glomerular filtration rate.

 

]. Until then, clinicians should carefully interpret eGFR results with observed muscularity, reserve accurate mGFR or 24-hour creatinine clearance for selected divergent cases, and use old-fashioned clinical judgment for pateints at the extremes of body habitus.

Acknowledgments

We are grateful to Dr Joshua Ryan, Core Lab, ICPMR, Westmead Hospital for the biochemistry analytics of creatinine measurement, and to our skilled technicians undertaking mGFR and DEXA GFN. Fig. 1A is kindly provided with the compliments of GE Healthcare. Disclosure: The authors of this manuscript have no conflicts of interest to disclose.

Funding

Not applicable.

Author’s contributions

All authors participated in manuscript writing and revision: SMG originated the idea of comparing muscular mass to isotopic GFR, within a collaborative project on body composition developed by GJE; SG, LFJN, and BJN undertook primary data acquisition; BJN was responsible for research design and data GFN.

Data sharing statement

Extensive summary data and GFN are presented within the supplemental material. These contain 23 highly-detailed tables of de-identified summated clinical data with their univariable and multivariable statistical analyses to allow open scientific scrutiny. Federal privacy laws and local institutional ethics forbid the placement of confidential individual patient information onto any public data-sharing website or allow for its unauthorised sharing. Specific questions of clinical science can be directed to the corresponding author.

Disclosures

None.

Entertainment

Black Sands Entertainment’s Manuel Godoy Reflects on Running a Black-Owned Comic Publisher

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Black Sands Entertainment's Manuel Godoy Reflects on Running a Black-Owned Comic Publisher

While new comic book publishers seem to come and go with the tides, Black Sands Entertainment is making some serious waves within the comic book industry. Run by President Manuel Godoy, Black Sands has an impressive array of comic book and animated series under its umbrella, all focused on Black characters and focusing on the African-American community.

As one of the only Black-owned publishing companies in the United States, Black Sands Entertainment was successful in raising $1 million in December of last year through a WeFunder campaign. CBR spoke with Godoy about the challenges related to being a Black business owner/entrepreneur, the opportunities that lie ahead for Black Sands Entertainment and the upcoming launch of The Black Sands Publishing app.

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CBR: To kick things off, can you go back in time and tell us a little bit about the origin of how Black Sands Entertainment was created?

Manuel Godoy: So in 2016, we funded the corporation for Black Sands Entertainment, and start creating our comic books. Kids 2 Kings was the original name of the main series. And we made a Kids 2 Kings #1 after failing at a video game production. So we had video game production for Black Sands and spent like $20,000 on it, right? It was still expensive, and we only got to a beta at that point. And I was like, “I’m never gonna be able to finish this game.” And so I abandoned that production and pivoted to a more comic-oriented series. And we went to Kickstarter in 2017 for Kids 2 Kings and raised $20,000 for our campaign. And we just haven’t stopped since then. We just kept moving forward, constantly growing and evolving over the years. And now we’re at the precipice of new horizons.

How many titles do you have so far under the umbrella?

So for our specific company, we have about six different titles. So we have six different series that are in our company right now. And on top of that, we also have 26 different titles signed to the BSP, which is our app coming out in February.

Business owners already have a tough time trying to establish themselves. And of course, it only intensifies when you’re a Black entrepreneur. What was the reception like in the creative community once you started to promote Black Sands?

Well, I’ve always been a little bit of a different type of marketer. So as opposed to like, leading so much with the content, I usually lead with the causes, like why people should support this brand, what it means to parents and the kids. And that’s really resonated well with our audience. Currently, 25 percent of our customer base are avid comic book fans. Most of them are just parents who want to have amazing content for their kids. And that’s usually the loop, right? The parents buy for your kids, the kids love it, they email us asking when the next one is coming out, and then we just keep going. And that’s really how we’ve been going. We’re huge on social media. So we have five million impressions a month now. So so we have a really effective, organic marketing campaign.

When you started to go out to promote all your different comics, were you a fixture on the convention circuit, or was it more networking online?

At first, it was the convention circuit. So we were definitely heavy with the convention circuit in 2018 and 2019. I think in 2018 we did like 15 shows, and then in 2019, we did like 25. And then when we got to a point where we just were making way too much money online, to the point where we were like, yeah, there’s no reason to go to shows anymore, except for maybe four major shows. But that was it. And then COVID hit and then we said no more shows. [Laughs] So it was good that we pivoted before that.

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How hands-on are you when it comes to working with the different creators under Black Sands?

Well, for other creators who are assigned to us for BSP, typically, the most I do is just make sure that the management processes are correct. So I’ve already curated the content to say, hey, there’s a clear audience for this content and its high quality, but now we have to figure out what your process is. So maybe the reason why they have three issues, and their brand’s been around for three years is because management’s not that great, right? So that’s usually what I’m most hands-on about is the management, the cost of their pages, the production schedule, the process of making stories. None of this stuff when it comes to their actual story. They can do whatever they want with that. I’m very hands-off when it comes to the creative side.

And since you’re juggling everything, what was your business background in before you got into comics?

Well, I was an Army vet. So I’ve done radar technician work and stuff like that, and then telecommunications and engineering. Those are the main things I used to do, so it was more of a design type feel to my job. I also did some work in the government, right before I finally came into this, but I had a long stretch of unemployment after engineering got outsourced. This is my way of dealing with basic chronic unemployment.

What challenges did COVID pose back during 2020? Were there any plans that needed to be adjusted? Or did new opportunities present themselves?

Well, new opportunities did present themselves, but I did have one issue. I was supposed to go to Seattle for Emerald City Comic-Con. I had already shipped like $20,000 of inventory to Emerald City. And they lost my inventory. Mostly because Seattle was one of the first places to lock down.

Yeah, I think it started out there.

Yeah, everything was messed up there. We didn’t fly yet. So we canceled our flights. But our stuff was already in the process to be shipped there and was gone. And most of it didn’t return. And then USPS was like, “Well, I don’t know what’s going on. So I can’t reimburse your charity.” So I lost like, $8,000 on the trip. I was like, “Okay, I guess I’ll cancel all my other shows, this doesn’t look like it’s gonna end anytime soon.” So that was a hiccup. But with that being said, people have become much more open to online purchases. So that’s good for us. Like 75 percent or more of our income came from e-commerce deals.

Have you been able to take part in any of the online conventions that have taken place since last year going into this year?

I really haven’t tried. If I’m not a panelist, I tend to not participate. Most of these companies don’t really know how to make a virtual convention work. So most of the time, people are paying for a spot on a website. And that’s it. That really doesn’t do anything for anybody.

A lot of times you can do better just by hosting your own thing on your YouTube channel.

Yeah, do a couple of social media posts. Most of the time you do better, as far as engagement. So I definitely avoid it. But some people do well. They have little conferences and breakout rooms and everything else. But it’s usually on the smaller side and more professional level. You might have a gaming conference with developers, right? It’s like a developer conference. Those will be better conferences because they’re really small groups, and you actually talk to people and have meetings and everything else throughout the entire week. Those are great. I’ve been to a couple of those.

What can fans look forward to with the publishing app you have coming out next month?

First of all, all the content is free. So it’s a free app to download. It’s going to be for iOS and Android. We also have a forum on there. So basically, anybody who’s a fan of Webtoons or ComiXology, you’re gonna love this app because we have a whole bunch of different kinds of stories, not just superhero stories. I’m a big proponent of a real fleshed-out story. So a lot of different diverse stories, a forum online so you can actually talk on the app. You can talk to people about comics, movies, whatever. We’ll have dozens of episodes coming out every single week.

It’s just a cooler experience than what they normally get from Webtoon. Because we’ve literally looked at Webtoons and brought all the key features that they have to the app. And then on top of that, we added gamification, where you have daily missions, where they have a forum and features that add more of a community aspect to it. Webtoon is a very individual experience — you download it, you might be able to comment and that’s about it. But for the most part, you’re by yourself. Whereas for us, there are 32,000 people on the app right now. So you don’t feel alone.

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What’s the official name of the app going to be?

It’s BSP, so Black Sands Publishing.

Something I’ve been curious about is more and more people have been forced to work from home since 2020. What’s your home/work setup like? Are you the type of person that needs total silence when working? Or do you find yourself listening to music or podcasts?

Yeah, I can’t avoid it, since I have kids. My roof is not the best. I have the entire basement. So I lock that door whenever I can. If they’re watching Shark Man or something like that, and they’re dancing upstairs, there’s nothing I can do. It’s like an earthquake down here. Yeah. So I’ve learned to do a lot of work with a lot of background noise. It’s hard, though. I do hire people all the time for assistance. And other kinds of managers, because no one man can do all this. Somebody else has to run the app and stuff like that.

How many people do you have helping you under the company?

So people who are directly doing the responsibilities that I normally would have, if I was doing them? I’d say I have six official people in charge of specific departments and the company. And then I also have some agencies working for me for either PR or for advertisements and stuff like that.

To wrap up, what do you see in store for Black Sands going into 2021 and beyond?

Well, what we’re looking to do is hit $2 million in sales. For physical books alone, we’re on pace to hit at least $1.2 million. But we really want to increase and get to $2 million. On top of that, we would love to hit maybe 500,000 users on the app by the end of December, but who knows, we might get way more than that. I have a lot of influencers on the team. And we’re also planning on raising a minimum of $10 million this year in capital. This is for the second round for our app and then a round for our animated properties for Black Sands. The animation will probably come out in the summer. And we’re going to use that clip, which is like seven minutes long, as a short. And we’re going to use that to raise the money for the entire show.

So it’s a different kind of process from how shows are typically funded. Usually, you go to like a Netflix of the world or HBO and you say, “Hey, this show is X amount of money,” and they’re like, “Alright, well, I like this show.” I think we’ll have good numbers to pay for it. We’re gonna pay for it ourselves, and then we’re going to be able to go to them as distributors instead of as the people who fund the production themselves.

So the animated shows you’re working on, are they based on the existing comics you’re already publishing?

Yes, Black Sands’ Seven Kingdoms, Cosmic Girls and Boys Family Adventures. Cosmic Girls is already ready to go. We’re pitching that now to some studios like Nickelodeon and Cartoon Network.

You can keep up with Black Sands Entertainment on Facebook, Instagram, YouTube, TikTok and at Black Sands’ website. The Black Sands Publishing app is set to launch on iOS and Android on Feb. 1.

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CartoonExtra 2021 is one of the most visited illegal websites

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CartoonExtra 2021 is one of the most visited illegal websites

CartoonExtra 2021 is one of the most visited illegal websites

CartoonExtra 2021 is one of the most visited illegal websites that permits clients to download an enormous assortment of kid’s shows for nothing. CartoonExtra online entryway is liable for streaming the most recent English HD kid’s shows.

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Basic Information About CartoonExtra

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CartoonExtra 2021 is one of the most visited illegal websites

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CartoonExtra 2021 is one of the most visited illegal websites

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CartoonExtra 2021 is one of the most visited illegal websites

CartoonExtra has as of late released a few English kid’s shows on its site. Referencing all the kid’s shows spilled via CartoonExtra is incomprehensible, we will discuss the most well-known kid’s shows spilled by the site. Examine the most recent kid’s shows and anime unlawfully spilled via CartoonExtra.

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Through our pages, We intend to inform our users about piracy and strongly encourage our users to avoid such platforms/websites. As a firm, we strongly support copyright acts. We advise our users to be very vigilant and avoid visiting such websites

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Can the ‘Sex and the City’ Reboot Keep Up with Fashion’s Woke Evolution?

Emily walpole

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Can the ‘Sex and the City’ Reboot Keep Up with Fashion’s Woke Evolution?

 

It’s been nearly 20 years since Carrie Bradshaw, the protagonist and narrator of the HBO series “Sex and the City,” (SATC) described her penchant for wearing “ghetto gold” to her three equally white girlfriends at brunch as “fun”—not the aesthetic that she envisioned for her engagement ring.

“How can I marry a guy who doesn’t know which ring is me?” she bemoaned after finding a pear-shaped sparkler affixed to a yellow gold band, tucked away in her boyfriend’s belongings.

Though it was a cringe-worthy moment in 2001—and one of many from the show that routinely used gay men as campy comedic props and fetishized Black men, to its overall lack of diversity despite famously being set in New York City, which the show’s actresses often described as the “fifth character”—it didn’t deter millions of rabid fans from tuning into the show the following week to watch Carrie, Samantha, Miranda and Charlotte on their quest for love, success and Manolos in the Big Apple.

More than 10 million viewers watched the show’s final episode three years later, and the subsequent films, 2008’s “Sex and the City” and “Sex and the City 2” in 2010, went on to rake in a total of more than $713 million.

Audiences in 2021, however, may not be as generous—or uneducated. When the show’s star Sarah Jessica Parker announced on her Instagram account earlier this month that a new chapter in the SATC saga called “And Just Like That…” is going into production this spring, the news was met with cautious optimism.

On one hand, the show, which will follow three of the four original characters—Carrie, Miranda and Charlotte—“as they navigate the journey from the complicated reality of life and friendship in their 30s to the even more complicated reality of life and friendship in their 50s,” may be the kind of nostalgic romp that homebound viewers devour. A respite, perhaps, for restless viewers who are in fact navigating their own complicated realities of life and friendship in a pandemic.

On the other hand, the world is in an entirely different state of mind, especially in regard to one of the show’s biggest legacies: fashion.

The Black Lives Matter (BLM) movement in 2020 was the catalyst for an overdue reckoning in the fashion industry, and brought to light the ugly experiences rooted in racism many Black people have encountered while trying to survive in the business. In turn, the movement drove many fashion brands to recalibrate how they address diversity within their companies, promote inclusivity in their campaigns and communicate their messages with sensitivity. BLM also sparked online conversations about intersectional environmentalism and cultural appropriation, educating consumers about the deeper impact of their purchases.

SATC’s cultural exploitation problem didn’t start or stop with “ghetto gold.”

It was on full display in the second film, which took the four friends to Abu Dhabi, the UAE’s conservative capital, in an effort to escape their hectic—or in the case of Carrie, increasingly humdrum—New York City lives. The plot line teed up an endless parade of unfortunate opportunities to flash nonsensical wealth and more tone-deaf fashion choices like headdresses and harem pants, not to mention Carrie’s bewilderment when she finds out that shoes sold at a souk cost just $20. Shocking.

The Sex and the City reboot tees up an unique chance for TV to influence fashion in a positive new direction.

Sex and the City 2

Years later in an interview at a New York Magazine event, Parker said, “I can see where we fell short on that movie, and I’m perfectly happy to say that publicly.” These issues, however, will need to be rectified for the new show to stand a chance because woke fans and influential industry watchdogs, like Diet Prada and Saint Hoax, will be watching, and maybe even salivating and the chance to catch and call out the next big blunder.

“Many of the people I’ve talked to have said ‘I’ll watch it, but…,’” Benjamin Ayer, lead consultant for Benjamin Bellwether, said of the mixed reception to news of the reboot.

“The short of it is that the movies, especially the second one, really marked a point of seemingly no return,” the trend forecaster said. “The second movie has some real pain points for people who saw it as reductive to feminism and diversity; and, that’s on top of complaints that the show, in general, was too white and too materialistic.”

With doubts like these, the reboot runs the risk of becoming another successful “hate-watch” anomaly of the pandemic entertainment landscape, like the Netflix series “Emily in Paris,” which viewers binged last fall only to trade online gripes about the show’s unrealistic portrayal of fashion on an entry-level PR salary. (Though it didn’t stop style-hungry watchers from emulating some of the show’s key style moments, like red berets.) The show, it bears noting, was styled by Patricia Field, the iconic New York City stylist who coined the signature looks of SATC’s characters.

“With conversations around inclusivity growing louder, there will be pressure on the SATC reboot to be diverse and woke,” said Kayla Marci, an analyst for retail market intelligence platform Edited. “However, efforts need to be collaborative, well-researched and authentic to avoid coming off as insincere and tokenistic. As some episodes and parts of the movies were problematic, there is an opportunity to learn from these past mistakes.”

Positive influence

That’s not to say that “And Just Like That…” is doomed before its first fitting.

Rather, experts say the show’s creators and costume department have a chance to sway fashion in a new positive direction. SATC, after all, debuted 12 years before the first ’gram was ever posted. It influenced fashion through the original small screen, television, requiring viewers to come back each week at the same time, Sunday at 9 p.m. EST, for 94 episodes over the course of six years—an ask that seems unreasonable in the instant-gratification age of streaming.

Integral to this change, according to Caroline Vazzana, stylist, influencer and author of Making It in Manhattan: The Beginner’s Guide to Surviving & Thriving in the World of Fashion, will be more diversity behind-the-scenes—from the writing room to the wardrobe truck. More diverse view points on the set will help ensure that the show puts its best foot forward, she said.

The reboot also presents an opportunity to tap into a more mature millennial mindset and, perhaps, reinvigorate how viewers look at their own closets after months of wearing sweats. It may even inspire new loungewear or face-mask trends, Vazzana noted, if the show is set during coronavirus times.

Ayer lauds SATC for how it wielded fashion as a means to express the characters’ personalities and emotions. Field’s ability to build characters through silhouette, color, pattern and accessory choices—many of which went on to become global trends like Carrie’s tulle skirt from the opening credits, the horseshoe necklace she wore throughout season four or her silk corsages in season three—gave consumers the green light to be playfully experimental with their own look.

Manolos and a vintage fur—two Carrie Bradshaw signatures

“I’ve talked to so many women and gay men alike who felt they could be [bolder] in their fashion statements, especially in New York City,” because of the show, Ayer said.

Whether it was pairing two different colors of the same shoe style, like Carrie did when the ladies ventured to Los Angeles in season 3, or making strong shoulders sexy again à la Samantha, Field showed viewers how to mix and match and take risks. This adventurous approach to fashion filtered into street style, which became just as important as runway styling, Ayer added, and made designers who were once only on the tips of the tongues of in-the-know fashionistas, new household names.

Brands such as Manolo Blahnik, Fendi, Dior, Vivienne Westwood and Tiffany are just some of the labels still synonymous with the franchise, Marci said, as well as specific products like Fendi’s baguette bags and Manolo Blahnik’s Hangisi pump, which Big—a character that was likened to Donald Trump in a positive way early on in the series—used in lieu of an engagement ring to propose to Carrie in the first film. (Editor’s note: shoes, apparently, are a more acceptable symbol of love than “ghetto gold” jewelry.)

Woke fans and fashion industry watchdogs will be watching to see if the Sex and the City reboot can address diversity in an authentic way.

A Bergdorf Goodman window display featuring items from “Sex and the City: The Movie”

Since the show ended, Marci said many fashion houses have been reshaped by new creative directors at the helm of Dior, Gucci, Louis Vuitton, Burberry, Givenchy and Bottega Veneta. “These legacy brands’ redefined looks are very much in line with Carrie’s feminine and eccentric aesthetic, Miranda’s clean and minimal, and Charlotte’s polished and preppy one,” she said.

The next show, however, has an opportunity to elevate lesser known designers and brands into the spotlight. In addition to the big names that everyone is expecting to see, Marci noted that cult darlings coveted by today’s consumer, like Ganni, Marine Serre or The Vampire’s Wife, would be a welcome addition.

“I’d love to see airtime given to designers spearheading environmental change like Gabriela Hearst and Stella McCartney, or labels that champion inclusivity like Fenty, Prabal Gurung or Christian Siriano, as well as see SATC use its enormous and powerful platform to showcase emerging BIPOC designers,” she said.

Ayer shared that sentiment, adding that the show’s stylists should “reward” high-fashion brands who are embracing diversity on their runways and look books, like Erdem, Balmain, Carolina Herrera, Collina Strada and Ferragamo, with placement on the show.

“The show has the power to elevate designers, and [it] should take that power seriously,” Ayer said. “It would be great to see the same fashion independence that Field brought to the cast of SATC to represent the new fashion industry. The one where sustainability matters, ethics matter, behavior matters.”

His top picks for the characters include “modern” and “powerful” looks by Fear of God for Miranda, classic and modern pieces by Wales Bonner and Andrew Gn for Charlotte and No Sesso and Threeasfour for Carrie’s fearless style. As the shows main trendsetter, Carrie, he added, should be “mixing her vintage fashion with new pieces from local, Black-owned, queer-owned, minority-owned and future-minded brands.”

Brooklyn-based and vice president-approved designer Christopher John Rogers is high on Vazzana’s list of designers whose work should make a cameo. “Christopher John Rogers would be epic and so beautiful for Carrie to be wearing around New York City,” she said.

Christopher John Rogers RTW Spring 2021

The reboot could bring good fortune to local talent. With the show celebrating the city, Marci said it would be great to see New York talent spotlighted. Fendi baguette bags could be traded for a ‘Bushwick Birkin,’ the nickname of Telfar’s in-demand unisex tote, or Carrie could swap her infamous Dior newspaper-print dress for Duckie Confetti’s money robe, she suggested.

A reflection of the times

Another common inducer of eye rolls about SATC was its unrealistic portrayal of wealth. The same lavish fashion that lured people to their TV sets each week also alienated some—particularly New Yorkers who knew the improbability of a local newspaper sex columnist being able to afford Carrie’s Upper East Side abode, endless closet and buzzing social life.

“This fantastical approach to luxury is what made the fashion in the show so iconic because it was very aspirational, yet unbelievable, that these ‘everyday women’ could afford to be head-to-toe in high-end designers every day,” Marci said. Following an economic crisis like the one brought on by the global pandemic, it will be important to balance the fantasy element with reality, she added.

While longtime fans of the show will expect to see a high caliber of designers, SATC must offer a measure of relatability in order to resonate with a new audience, Marci said. “A great way to show luxury in 2021 is to blend designer pieces with more contemporary and affordable brands,” she said. “Given the status of some of the items worn in the show and with sustainability becoming such an urgent and complex issue for the fashion industry, I’d love to see classic outfits re-worn or vintage archival pieces curated.”

The writers bringing the show to life “will have to make sure they reflect the times, and capture the essence of what they started out as: a show that helped normalize the timely female dynamic in mainstream culture,” Ayer added.

But that’s not to say that the ladies can’t catch up on their relationship follies while shopping in The RealReal or in small boutiques that champion diverse designers. Or why not have the characters share pieces, he added, highlighting the ever-growing sharing and rental economy.

“The show is known for the fashion, so represent the times,” Ayer said.

But be authentic

SATC is not the first show from the late ’90s and early aughts to make a recent comeback, but whereas series like “Will & Grace” and “90210” struggled to recreate the magic of their originals, “And Just Like That…” already has social media doing some of the leg work.

It also has Gen Z’s fondness for throwback fashion on its side. “A combination of social media and the revival of ’90s and ’00s fashion has helped keep SATC relevant as well as gain a cult following with a younger generation obsessed with nostalgia for an era they haven’t experienced,” Marci said.

Vazzana pointed out that SATC-themed content performs exceptionally well on TikTok. “Gen Z definitely knows about ‘Sex in the City’… young women and men are still very into that ‘moving to New York City’ mindset,” she said. Do they love the characters and appreciate their style the way older cohorts do? Vazzana isn’t sure. “Gen Z style is very different, but it is not super-eclectic and over-the-top like Carrie is known for,” she said. “Maybe it will  inspire a whole new generation to dress outside the lines.”

But if everyone wanted to “be a Carrie” back in 2004—fans even snapped up “I’m a Carrie” merchandise prior to the show’s finale—Type A Miranda has emerged as the fan-favorite today. “Reopening the SATC series time capsule in the 2020s has led to an internet consensus that Miranda is the coveted character, with attributes and style resonating with young women today,” Marci said, adding that her character is defined as career-driven, proud feminist with a minimal wardrobe.

Additionally, Charlotte, the most traditional character on the show, has become the poster character for political correctness, inspiring the #WokeCharlotte meme, a viral sensation that paired images of prim and proper Charlotte with progressive captions.  The evolution of these characters into today’s world will add to the show’s longevity and its impact on the Gen Z audience, Marci said.

While Ayer said the SATC reboot is really for “millennials and above who loved it the first time around,” as consumers, we are all moved by nostalgic pop-culture phenoms, no matter how we may think we’ve evolved, he added.

“Consumers will always be influenced by entertainment,” Ayer said. “As much as we may fight against it, we are creatures that crave persuasion.”

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