Contributors
Ala Abudayyeh, MD
Internal Medicine
Section of Nephrology
MD Anderson Cancer Center Houston, Texas
Joseph R. Angelo, MD
Assistant Professor Renal Services
Baylor College of Medicine/Texas Childrens’ Hospital Houston, Texas
Claude Bassil, MD, FACP, FASN
Assistant Professor Nephrology;
Program Director
USF Nephrology and Hypertension
University of South Florida; Renal Coordinator Onconephrology
H. Lee Moffitt Cancer Center Tampa, Florida
Vecihi Batuman, MD Professor of Medicine
Tulane University School of Medicine; Chief, Nephrology Section SLVHCS – VA Medical Center New Orleans, Louisiana
John J. Bissler, MD Nephrology Division Chief
Pediatrics
University of Tennessee Health Science Center; Nephrology Medical Director Nephrology
St. Jude Children’s Research Hospital Memphis, Tennessee
Andrew S. Bomback, MD, MPH
Assistant Professor of Medicine Department of Medicine Division of Nephrology
Columbia University Medical Center New York, New York
Brendan T. Bowman, MD
Associate Professor Department of Medicine Division of Nephrology
University of Virginia School of Medicine Charlottesville, Virginia
Juan C. Calle, MD, FASN Glomerulonephritis Group Department of Nephrology and Hypertension
Cleveland Clinic Cleveland, Ohio
Anthony Chang, MD Professor Pathology
University of Chicago Chicago, Illinois
Sheldon Chen, MD
Associate Professor of Medicine Section of Nephrology Division of Internal Medicine
The University of Texas MD Anderson Cancer Center Houston, Texas
Eric P. Cohen, MD Professor of Medicine
University of Maryland School of Medicine Deputy Director of the Medical Service; Nephrology Section Chief Baltimore VAMC Baltimore, Maryland
Laura Cosmai, MD
Department of Internal Medicine and Therapeutics
University of Pavia; Division of Translational Oncology IRCCS Istituti Clinici Scientifici Maugeri Pavia, Italy
Vidhi Desai
Assistant Professor of Medicine Division of Hematology/Oncology
Zucker School of Medicine at Hofstra/Northwell Lake Success, New York
Marcia E. Epstein, MD Associate Chief Division of Infectious Diseases
Medicine
Northwell Manhasset, New York
Mohit Gupta
Department of Nephrology and Hypertension
New York-Presbyterian Weill Cornell Medical Center New York, New York
Kevin W. Finkel, MD, FACP, FASN, FCCM
Professor of Medicine and Director Division of Renal Diseases & Hypertension
UT Health Science Center at Houston; Professor of Medicine
Nephrology Section
University of Texas MD Anderson Cancer Center Houston, Texas
Maurizio Gallieni, MD, FASN
Director Nephrology and Dialysis Unit
San Carlo Borromeo Hospital, ASST Santi Paolo e Carlo; Researcher and Adjunct Professor of Nephrology Dipartimento di Scienze Biomediche e Cliniche “L. Sacco” University of Milano Milano, Italy
Pranisha Gautam-Goyal, MD Assistant Professor Medicine
Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Manhasset, New York
Ilya Glezerman, MD
Clinical Associate Physician Renal Service
Memorial Sloan-Kettering Cancer Center; Associate Clinical Professor Department of Medicine
Weill-Cornell Medical College New York, New York
Vijay S. Gorantla, MD, PhD
Clinical Instructor of Pediatrics Department of Pediatrics Division of Pediatric Nephrology University of Tennessee Health Science Center Memphis, Tennessee
Victoria Gutgarts, MD Onconephrology Fellow Renal Service
Memorial Sloan Kettering Cancer Center New York, New York
Uwe Heemann, Prof. Chairman Nephrology
Klinikum Rechts der Isar Munich, Germany
Leal Herlitz, MD Director of Renal Pathology
Anatomic Pathology
Cleveland Clinic Cleveland, Ohio
Sangeeta Hingorani, MD, MPH Professor Pediatrics
University of Washington/Seattle Children’s Hospital; Associate Member Clinical Research Division Fred Cancer Research Center Seattle, Washington
Jonathan J. Hogan, MD
Assistant Professor of Medicine Division of Nephrology
Pereleman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania
Jean L. Holley, AB, MD
Clinical Professor of Medicine
Medicine
University of Illinois, Urbana-Champaign; Carle Physician Group Urbana, Illinois
Susie L. Hu, MD
Associate Professor of Medicine
Medicine
Division of Kidney Disease and Hypertension
Warren Alpert Medical School of Brown University Providence, Rhode Island
Colin A. Hutchison, MBChB, PhD Consultant Nephrologist
Medical Director for the Acute and Medical Directorates Hawkes Bay DHB Hastings, HB, New Zealand
Insara Jaffer Sathick, MBBS, MRCP Assistant Attending Physician Renal Service Department of Medicine
Memorial Sloan Kettering Cancer Center New York, New York
Kenar D. Jhaveri, MD Professor of Medicine
Nephrology
Zucker School of Medicine at Hofstra/Northwell Great Neck, New York
Catherine Joseph, MD Assistant Professor
Renal Services
Baylor College of Medicine/Texas Children’s Hospital Houston, Texas
Jaya Kala, MD
Assistant Professor of Medicine
Division of Renal Diseases and Hypertension
UT Health Science Center at Houston
McGovern Medical School Houston, Texas
Sabine Karam, MD
Assistant Professor of Clinical Medicine Department of Medicine
Saint George Hospital University Medical Center Beirut, Lebanon
Stefan Kemmner Department of Nephrology Klinikum Rechts der Isar Technical University of Munich Munich, Germany
Sana F. Khan, MD
Assistant Professor Department of Medicine/Division of Nephrology University of Virginia Health System Charlottesville, Virginia
Abhijat Kitchlu, MD, MSc Clinical Associate Nephrologist Department of Medicine Division of Nephrology University of Toronto Toronto, Canada
Amit Lahoti, MD Associate Professor Section of Nephrology MD Anderson Cancer Center Houston, Texas
Benjamin L. Laskin, MD Assistant Professor Nephrology
The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania
Sheron Latcha, MD Physician Medicine
Memorial Sloan Kettering Cancer Center; Clinical Instructor Medicine
Cornell University Medical Center New York, New York
Wai L. Lau, MD Instructor of Medicine Division of Nephrology
Columbia University Medical Center New York, New York
Randy L. Luciano, MD, PhD Assistant Professor of Medicine Internal Medicine Section of Nephrology
Yale University School of Medicine New Haven, Connecticut
Niti Madan, MD
Associate Professor of Medicine Division of Nephrology Department of Internal Medicine University of California Davis Sacramento, California
Prashant Malhotra, MBBS, MD Assistant Professor Medicine
Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Manhasset, New York
Peter Mollee, MBBS, FRACP, FRCPA
Associate Professor of Medicine Clinical Haematology University of Queensland Medical School Princess Alexandra Hospital Southport, Queensland, Australia
Mark A. Perazella, MD, MS Professor of Medicine
Yale University School of Medicine Section of Nephrology Department of Internal Medicine New Haven, Connecticut
Phillip M. Pierorazio, MD Associate Professor Urology and Oncology
Brady Urological Institute and Department of Urology Johns Hopkins Baltimore, Maryland
Pierre Delanaye, MD, PhD Professor Nephrology Dialysis Transplantation CHU Sart Tilman Liege, Belgium
Camillo Porta, MD Medical Oncology
IRCCS San Matteo University Hospital Foundation Pavia, Italy
Jai Radhakrishnan, MD, MS Professor of Medicine Division of Nephrology Columbia University Medical Center New York, New York
Mandana Rastegar, MD, EdM
Assistant Clinical Professor Department of Medicine
David Geffen School of Medicine at UCLA; Division of Nephrology
Greater Los Angeles Veterans Health Administration Los Angeles, California
Robert F. Reilly Jr., MD
Clinical Professor of Medicine Nephrology
University of Alabama at Birmingham; Physician Medical Service Birmingham VA Birmingham, Alabama
Danielle L. Saly, MD
Chief Resident, Instructor of Medicine Internal Medicine
Yale University School of Medicine New Haven, Connecticut
Joshua A. Samuels, MD, MPH Pediatrics University of Texas Medical School at Houston; Associate Professor Pediatrics
University of Texas MD Anderson Cancer Center Houston, Texas
Divya Shankaranarayanan, MBBS Fellow Nephrology Department of Medicine
Weill Cornell/Memorial Sloan New York, New York
Deirdre Sawinski, MD
Assistant Professor
Renal, Electrolyte and Hypertension Division Department of Medicine
Hospital of the University of Pennsylvania Philadelphia, Pennsylvania
Umut Selamet, MD Clinical Instructor Department of Medicine, Nephrology University of California Los Angeles Los Angeles, California
Anushree C. Shirali, MD Assistant Professor of Medicine Internal Medicine
Yale University School of Medicine New Haven, Connecticut
Ramapriya Sinnakirouchenan, MD
Assistant Professor Medicine, Nephrology
Medical College of Wisconsin Milwaukee, Wisconsin
Ben Sprangers, MD, PhD, MPH, MBA Department of Microbiology and Immunology Laboratory of Molecular Immunology (Rega Institute) KU Leuven; Department of Nephrology, University Hospitals Leuven Leuven, Belgium
Jyotsana Thakkar, MD
Assistant Professor Division of Nephrology
Montefiore Medical Center/Albert Einstein College of Medicine Bronx, New York
Jeffrey Turner, MD
Associate Professor of Medicine Internal Medicine
Section of Nephrology Yale University New Haven, Connecticut
Brahm Vasudev, MD
Associate Professor Division of Nephrology Medical College of Wisconsin Milwaukee, Wisconsin
Dia R. Waguespack, MD, FASN
Assistant Professor of Medicine
UTHealth Science Center at Houston- McGovern Medical School Houston, Texas
Rimda Wanchoo, MD Associate Professor Medicine
Zucker School of Medicine at Hofstra/Northwell Great Neck, New York
Brendan M. Weiss, MD
Adjunct Assistant Professor of Medicine
Hematology Oncology Division Department of Medicine
Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania
Robert H. Weiss, MD Professor Nephrology University of California Davis Davis, California
Germaine Wong, MBBS, MMED, PhD
Associate Professor
Sydney School of Public Health University of Sydney Sydney, Australia
Gökhan Temiz, MD
Associate Professor of Nephrology
Eskisehir Osmangazi University Department of Nephrology Eskisehir/Turkey
To my beautiful daughter, Megan, for all her courage and inspiration.
–Kevin W. Finkel
To my family, friends, and colleagues who have been part of my journey through medicine and my life. In particular to my parents, Joe and Santina Perazella, who sacrificed much for me and remain ardent supporters; to my wife, Donna, who selflessly continues to support my academic efforts; to my brothers, Joe and Scott, who make life interesting; and to my boys, Mark and Andrew, who always make me most proud.
–Mark A.
Perazella
Kidney Function 1
PIERRE DELANAYE
Introduction
Kidney function in oncologic patients is an important parameter for several reasons. In some specific cases, like urologic cancers, the tumor itself can cause acute or chronic kidney dysfunction. However, the renal function parameter is more frequently followed in oncologic patients because, on one hand, they are likely to get nephrotoxic drugs, and on the other hand, some oncologic patients have chronic kidney disease (CKD) that would necessitate a dosage adaptation for potentially toxic chemotherapies.1,2 Indeed, excretory renal function plays a fundamental role both in the pharmacokinetics and pharmacodynamics of several drugs. This is particularly the case for water soluble compounds and/or their active metabolites. Even for non-renally-excreted drugs, severe CKD can modify the pharmacokinetics by several mechanisms.3–6 For this reason, it is now recommended that both pharmacokinetics and pharmacodynamics of every new drug be studied in the context of CKD.7 Dosageadjustment according to excretory renal function is required for many medications. However, there is a debate in the literature regarding the best way to estimate excretory function or glomerular filtration rate (GFR) for the purpose of pharmacotherapy.8–12
Serum Creatinine
The word “creatinine” was probably used for the first time by Justus von Liebig in 1847. This German chemist was thus describing the product obtained from heating creatine with mineral salts.13 Nowadays, serum creatinine is one of the most frequently prescribed analysis in Clinical Chemistry. Serum creatinine is the only renal plasma biomarker used in daily clinical practice to estimate GFR.14,15 However, a good interpretation of the creatinine result remains sometimes problematic, or at least not so simple. To explain these difficulties, there are both physiologic (serum creatinine is not an “ideal” renal marker) and analytical reasons. First, serum creatinine can be measured by two main methods: methods derived from the classical Jaffe reaction on one part, and enzymatic methods on the other part. The Jaffe method is based on a reaction between picrate and creatinine in alkaline milieu that gives a red-orange product.16 Some components (so-called pseudochromogens) can however also interact with picrate: acetoacetate, pyruvate, ketonic acids, proteins, glucose, and ascorbic acid. These pseudochromogens take part in 15% to 20% of the Jaffe reaction if the serum creatinine is in the normal range. This limitation of Jaffe methods remains even after different technological innovations. The second method is known as
the enzymatic and is based on successive enzymatic steps. Different types of reactions have been described, but they all share a higher specificity to measure serum creatinine, compared to Jaffe assays. Enzymatic methods are thus considered as more accurate and precise than Jaffe methods. These methods are recommended even if they are more expensive and not fully free from some interferences.17 There are two methods to measure creatinine but for each method, there are also several different assays (according to the manufacturers). Until recently, a great heterogeneity was observed between the assays, because of differences in calibration.15,18–20 Nowadays, several improvements have been done in a quest to standardization, and it is recommended to measure serum creatinine with a standardized, calibrated, and so-called isotope dilution mass spectrometry (IDMS)-traceable method. This traceability is of the highest importance in the context of creatinine-based equations.15,18–20
Beyond analytical issues, there are also physiologic limitations to serum creatinine. The molecular weight of creatinine is 113 Daltons. Creatinine is the anhydric catabolite of creatine and phosphocreatine. Creatinine is a catabolite final product and has no physiologic role. The vast majority of creatine (98%) will be found in muscles where creatine is phosphorylated in phosphocreatine by creatine kinase. Each day, 1% to 2% of the muscle creatine is converted into creatinine.14 21 It is thus obvious that serum creatinine concentration is highly dependent on muscle mass. If the global creatine concentration is constant in healthy subjects, this concentration will strongly vary notably in muscular pathologies or, from a larger point of view, in all diseases with anorexia and muscle mass decreasing, as it is frequently observed in oncologic diseases. In these situations, serum creatinine will decrease, or will not increase when GFR is decreasing.14,22,23 The second important limitation is the tubular secretion of creatinine, which explains that creatinine clearance overestimated measured GFR (mGFR). Moreover, even if creatinine clearance, calculated on a 24-hour urine collection, is a relatively simple way to assess GFR, such a clearance also lacks precision, especially because of large errors in urine collection.24 Therefore creatinine clearance is not recommended for GFR estimation. 25 A last point needs to be underlined: the relationship between serum creatinine and GFR is not linear but hyperbolic (Fig. 1.1).21,26 To keep this point in mind is fundamental for a good interpretation of a creatinine result. Actually, this hyperbolic relation implies that a little creatinine change will have great consequences in terms of GFR in low creatinine levels, although the same creatinine variation in higher ranges will be negligible in terms of GFR.14,15,20
The Creatinine-Based Equations in Oncology
Serum creatinine concentration is dependent on muscular and thus on gender, age, and ethnicity. Moreover, the relationship between serum creatinine and GFR is hyperbolic (see Fig. 1.1). These observations lead authors to propose creatinine-based equations that include simple variables like age, gender, ethnicity and, for some of them, weight.27–31 Because of the hyperbolic association, a negative exponent is applied to serum creatinine value in these equations, making the association between estimated GFR (eGFR) and mGFR by a reference method, simple and linear. Several equations have been proposed since the 1950s. Before 2000, the Cockcroft and Gault (CG) equation was the most popular and has been used by generations of doctors to estimate GFR.27 This equation has, however, several limitations, notably a lack of precision caused by the variable weight included in the formula.32 Today, new equations based on serum creatinine and including only age and gender are recommended and their results can be automatically given by laboratories.33 These equations are applicable only with IDMS-traceable assays. Among these equations, we can cite the most used, that is, the modification of diet in renal disease (MDRD) equation (most valuable in CKD patients)28,34 and chronic kidney disease epidemiology (CKD-EPI) equations (also valuable in healthy populations).29 Recently, some authors have challenged the superiority of these equations both in the general and CKD populations, and proposed new algorithms, known as the revised Lund-Malmö equation31 or the full age spectrum equations30 (Table 1.1). Globally, both in the general or CKD population, one can expect an accuracy around 85% or 90% for creatinine-based equations. This means
that results of eGFR equations will be within 630% of the results of mGFR by a reference method in 85% to 90% of subjects/patients.35,36 Beyond the experts’ discussion to know which equation performs the best, we have to keep in mind that the most important variable in all these equations remains the serum creatinine. Therefore there is no reason to believe that eGFR, by any estimating equations, would be accurate in specific patients or specific populations for who the serum creatinine, in itself, is particularly inadequate.37 In the context of oncology, it will be particularly relevant in patients with anorexia, loss of weight, and cachexia.21,38 In these patients, serum creatinine concentration is inaccurate, and can decrease in patients with stable function or remain stable in patients with worsening GFR. Because serum creatinine is inaccurate, eGFR based on serum creatinine will be unable to correctly assess GFR in these patients. In 21 young patients suffering from anorexia nervosa, GFR was measured by a reference method (namely, the 51Cr-Ethylenediaminetetra-acetic acid (EDTA) plasma clearance). The performance of both the CG and MDRD equations was dramatically poor, with an accuracy within 30% of only 63% and 30%, respectively. Both the MDRD and CKD-EPI equations strongly overestimate mGFR in these specific patients.22 Redal-Baigorri et al. studied the performances of creatinine-based equations in 185 patients with cancer. GFR was measured by 51Cr-EDTA plasma clearance before chemotherapy and serum creatinine was IDMS traceable. Majority of patients were suffering from pulmonary cancer (77%). The performance of MDRD and CKD-EPI was acceptable around 89% for both equations, but most of the patients were healthy from a renal point of view, with only 17% of patients with mGFR below 60 mL/min/1.73m².39 Lauritsen et al. included patients with disseminated germ cell cancer and treated by bleomycin, etoposide, and cisplatin. The GFR was measured by 51Cr-EDTA single sample plasma clearance in 390 patients, but more than 1600 measurements were obtained with data before and just after chemotherapy, and then after 1, 3 and 5 years. Patients were young with few comorbidities and thus with normal mGFR values. CG, MDRD, and CKD-EPI equations have relatively good performance in estimating GFR before and in the years following chemotherapy (around 85% and 90%). However, values after three cycles of chemotherapy were more disappointing with an accuracy within 30% at 76%, 80%, and 50%, for CG, MDRD, and CKD-EPI, respectively. Actually, mGFR significantly declined during chemotherapy ( 9 mL/min/ 1.73m²) but serum creatinine also decreased (and so eGFR equations increased).40 Funakoshi et al. also studied the performance of the CKD-EPI equation (both original and Japanese version and de-indexed for body surface area [BSA]) in 50 patients with cancer scheduled for cisplatin therapy (majority had neck and head cancer) before and after treatment. Only subjects with mGFR over 50 mL/min were considered. The accuracy of both CKD-EPI equations was acceptable with an accuracy within 30% of 92% and better than the CG equation (accuracy of 78%) before the therapy. However, a significant decline in accuracy was observed for all equations after the cisplatin cycle: 60%, 68%, and 56% for the original CKD-EPI, the Japanese version, and the CG, respectively. All equations overestimated mGFR, especially in the lower GFR ranges. Moreover, in the
Fig. 1.1 Hyperbolic association between serum creatinine and glomerular filtration rate.
Table 1.1 Creatinine- and Cystatin C-Based Equations to Estimate Glomerular Filtration Rate
Cockcroft and Gault ((140-age) 3 weight)/(72 3 SCr)
CKD-EPI SCr
women SCr # 0.7 mg/dL 144 3 (Scr/0.7)-0.329 3 0.993age 3 [1.159 if black]
men
CKD-EPI SCys
CKD-EPI SCrCys
women
Men
FAS creatinine
SCr > 0.7 mg/dL
SCr # 0.9 mg/dL
SCr > 0.9 mg/dL
144 3 (Scr/0.7)-1.209 3 0.993age 3 [1.159 if black]
1413 (Scr/0.9)-0.411 3 0.993age 3 [1.159 if black]
1413 (Scr/0.9)-1.209 3 0.993age 3 [1.159 if black]
SCys # 0.8 mg/L 133 3 (Scyst/0,8)-0.499 3 0.996age [3 0.932 if female]
SCys > 0.8 mg/L 133 3 (Scys/0,8)-1.328 3 0.996age [3 0.932 if female]
SCr # 0.7 mg/dL and SCys # 0.8 mg/dL 130 3 (SCr/0.7)-0.248 3 (SCyst/0.8)-0.375 3 0.995age 3 [1.08 if black]
SCr # 0.7 mg/dL and SCys . 0.8 mg/dL 130 3 (SCr/0.7)-0.248 3 (SCyst/0.8)-0.711 3 0.995age 3 [1.08 if black]
SCr . 0.7 mg/dL and SCys # 0.8 mg/dL 130 3 (SCr/0.7)-0.601 3 (SCyst/0.8)-0.375 3 0.995age 3 [1.08 if black]
SCr . 0.7 mg/dL and SCys $ 0.8 mg/dL 130 3 (SCr/0.7)-0.601 3 (SCyst/0.8)-0.711 3 0.995age 3 [1.08 if black]
SCr # 0.9 mg/dL and SCys # 0.8 mg/dL 135 3 (SCr/0.9)-0.207 3 (SCyst/0.8)-0.375 3 0.995age 3 [1.08 if black]
SCr # 0.9 mg/dL and SCys . 0.8 mg/dL 135 3 (SCr/0.9)-0.207 3 (SCyst/0.8)-0.711 3 0.995age 3 [1.08 if black]
SCr . 0.9 mg/dL and SCys # 0.8 mg/dL 135 3 (SCr/0.9)-0.601 3 (SCyst/0.8)-0.375 3 0.995age 3 [1.08 if black]
SCr . 0.9 mg/dL and SCys > 0.8 mg/dL 135 3 (SCr/0.7)-0.601 3 (SCyst/0.8)-0.711 3 0.995age 3 [1.08 if black]
(107.3/SCr/Qcreat) 3 (0.988(Age-40)) if age . 40 y
FAS cystatin C (107.3/Scyst/Qcyst) 3 (0.988(Age-40)) if age . 40 y
FAS combined [107.3/(0.5 3 Scyst/Qcyst10.5 3 SCr/Qcreat ] 3 (0.988(Age-40)) if age . 40 y
LM women SCr , 150 µmol/L e[2.510.0121 3 (150-SCr)]-0.0158 3 age10.438 3 Ln(age)
women SCr $ 150 µmol/L e[2.5-0.926 3 Ln(SCr/150)]-0.0158 3 age10.438 3 Ln(age)
men SCr , 180 µmol/L
men SCr $ 180 µmol/L
e[2.5610.00968 3 (180-SCr)]-0.0158 3 age10.438 3 Ln(age)
e[2.56-0.926 3 Ln(SCr/180)]-0.0158 3 age10.438 3 Ln(age)
CAPA 130 3 SCyst-1.069 3 age-0.117 -7
All equations are in mL/min/1.73m² except the Cockcroft-Gault in mL/min. CAPA, Equation Caucasian, Asian, pediatric, and adult; CKD-EPI SCr, Chronic Kidney Disease-Epidemiology Collaboration based on serum creatinine; CKD-EPI SCys, equation CKD-EPI based on cystatin C only; CKD-EPI SCrCyst, CKD-EPI equation combining both cystatin C and creatinine; FAS, equation Full Age Spectrum; LM, equation Lund-Malmö; MDRD: Modification of Diet in Renal Disease study equation; SCr, serum creatinine (in mg/dL); SCyst, cystatine C (in mg/L).
postchemotherapy period, one-quarter of patients with CKD-EPI values over 60 mL/min had actually a measured GFR below 50 mL/min.41 Lindberg et al. also included 94 patients with advanced head and neck cancer treated by radio-chemotherapy including cisplatin. The GFR was measured by 51Cr-EDTA single sample plasma clearance before the first cycle (n594), after the third cycle of chemotherapy (n578), and after the planned five cycles (n535). The nonindexed BSA result was considered for mGFR and eGFR (CG and CKD-EPI). At baseline, five patients were eventually not treated by cisplatin because mGFR was below 50 mL/min. These five patients had eGFR with CKDEPI above 50 mL/min (and three with CG). At the end of the treatment, three patients had mGFR below 50 mL/min, but this decline in mGFR was detected by both equations in only one patient. The Bland and Altman analyses showed a relatively acceptable systematic bias between mGFR and CG and a systematic overestimation of mGFR by CKD-EPI, but the precision of both equations was actually poor.42
Hingorani et al. measured GFR by iohexol plasma clearance in 50 patients who benefit from a hematopoietic cell transplant at baseline and after 100 days.43 The authors compared the performance of mGFR with CG (nonindexed for BSA), MDRD, and CKD-EPI (both indexed for BSA). At baseline, all patients were also treated by trimethoprim, which is known to block the tubular secretion of creatinine, leading to an increase in creatinine concentration independently of any change in mGFR.44 At baseline, CKD-EPI and MDRD underestimated mGFR and CG overestimated it. The accuracies were low for patients with mean normal GFR values. Indeed, accuracy within 30% at baseline was 79%, 70%, and 57% for CKD-EPI, MDRD, and CG equations, respectively. After 100 days, the accuracy observed was similar for CKD-EPI and MDRD and slightly better for CG.43 All these data in cancer patients compared mGFR by a reference method with eGFR, but the studies share methodologic limitations, notably the samples being relatively limited. However, it appears from
these analyses that the accuracy of the equations is, at best, suboptimal in cancer patients. This observation is not fully unexpected as these patients are frequently frail and have decreased muscle mass because of their pathology and/or chemotherapy. In the same vein, the inaccuracy of these equations seems especially important during or after the chemotherapy cycles, which is, once again, not fully unexpected.
The Choice of the Equation in Oncology for Drug Dosage Adaptation
Indexing or not GFR by BSA will impact the GFR results particularly in patients or subjects with extreme height and weight values. 45,46 In the context of drug dosage adaptation, it is fully logical to consider nonindexed GFR. This recommendation is supported by the Food and Drug Administration and the European Medicines Agency (EMA). Indeed, the goal of BSA indexation is to make GFR results from subjects with different body size comparable. However, in the context of drug dosage adaptation, the GFR is considered as the capacity of a given subject to excrete drugs or drugs catabolites. As an example, for an elderly fragile woman with a weight of 45 kg, a height of 160 cm, and a BSA of 1.4 m² who is requiring a cisplatin therapy for ovarian cancer, the antimitotic therapy must be doseadjusted accordingly to her GFR. If her measured (by a reference method) GFR is 25 mL/min, demonstrating a CKD stage 4, BSA indexing will overestimate the GFR to 31 mL/ min/1.73 m², classifying the patient as stage 3 CKD. Which result should be used for dose adjustment of nephrotoxic therapy and what stage of CKD should be ascribed to the patient? It seems more correct to take into account the result of the actual patient’s GFR, not the GFR result that the patient could have if her BSA was 1.73 m².45 If it is thus widely accepted that non-GFR indexed results must be considered for drug dosage adaptation (even if it is not always applied in clinical practice or research), there is still a huge debate in the literature to know which eGFR equation must be considered for drug dosage adaptation. Several publications have illustrated potential discrepancies in eGFR results and thus in dosage prescription if different equations are used.8,11,47–59 In the context of oncology, Shord et al. retrospectively studied the dose of carboplatin given to the patient with the Calvert formula (Calvert: Total Dose [mg] 5 [target Area Under the Curve] 3 [GFR 1 25]).59 They used the CG equation in the Calvert formula for 186 patients. If they had used MDRD, a discrepant dose of carboplatin (defined as a difference of more than 20%) would have occurred in 48% of patients. Bennis et al. considered 1364 cisplatin cycles in 309 patients and observed a requirement for dose adjustment in 9.7% if the CG was used, but 4.8% if the MDRD would have been considered.57 For drug dosage adjustment, the sharpest debate consists in choosing between the CG equation,27 frequently promoted by clinical pharmacologists and geriatricians, and the CKD-EPI equation (or MDRD if CKD patients), promoted by nephrologists.28,29 From a nephrologic point of view, the superiority of the CKD-EPI over CG equation to
estimate GFR is easy to demonstrate.29,32,37 Moreover, this equation truly estimates GFR, whereas the CG equation estimates creatinine clearance, which in itself, is only a poor estimation of true GFR.37,60 Finally, sensu stricto, the CG equation cannot be used with modern, calibrated, and IDMS-traceable serum creatinine values.19,61–63 Conversely, there are arguments to support the case for applying the CG equation.4,64–67 Indeed, the CG equation is the equation that has been used to elaborate drug dosage adjustments for the vast majority of drugs.49,65–69 Furthermore, the CG equation better predicts the risk of adverse events for several drugs, notably cardiovascular therapies. This may reflect the presence of the variable “body weight” in the CG equation, not in the CKD-EPI equation.11,65,70 Also the CG equation has been reported to give systematically lower eGFR values than those obtained with CKD-EPI, particularly in the elderly.7 71 72 This underestimation will lead to a more protective behavior in terms of drug dosage in this frail population.47,73 In a simulation study, we showed that differences between the two equations are potentially influenced by each variable included in these equations: gender, age, weight, height, and serum creatinine. Among these variables, age and weight are the most important and will systematically impact the results of the equations.7 As an extreme example, in old frail patients, CG will systematically give lower eGFR results than CKD-EPI, but in young obese subjects, CG will systematically give higher results than CKD-EPI. Because drug dosage adjustment is the quintessence of personalized medicine, one should however be careful in our interpretations of differences between eGFR that are based on population studies and focus on the characteristics of the individual.
Other Biomarkers and Measured Glomerular Filtration Rate
In the general healthy or CKD population, new biomarkers have been largely studied. The most promising biomarker was cystatin C.74–76 Compared with creatinine, cystatin C is presented as being totally, or at least more, independent to muscular mass.77,78 However, cystatin C is also influenced by other so-called GFR non-determinants, the most important being thyroid function, inflammation, and obesity.79 Because of few interactions with muscular mass, cystatin C is potentially of interest in the oncologic population. However, data with this biomarker in such a population are few, lack a reference method for measuring GFR, and/or include too few patients.77,80,81 Chew-Harris et al. compared creatinine CKD-EPI and combined CKD-EPI equations including both creatinine and cystatin C with mGFR by 99Tc-Diethylenetriaminepenta-acetic acid (DTPA) in 80 cancer patients. They showed that the CKD-EPI combined equation (but not the equation based on cystatin C only) was slightly better than the creatinine-based CKDEPI equation (accuracy within 30% of 83% vs. 78%).58 Among the studies we have discussed earlier, Hingorani et al. also considered both cystatin C-based and combined equations. At baseline, only the combined equation showed a slightly better accuracy within 30% (at 89%) compared to creatinine-based equations.43 Because cystatin C is constantly produced by all nucleated cells, there is also the
theoretical possibility that cancer cells produced cystatin C with an increase in cystatin C concentrations without any change in GFR values.26 However, too few data are available to close the debate.
In oncology, drug dosage adjustment is thus influenced by the choice of the creatinine-based equation, as discussed in the prior paragraph. However, because any eGFR is far from perfect, there is a risk that all equations are inadequate for drug adjustment. A definitive conclusion could only be given by a prospective observational randomized study, where patients would get chemotherapy dosage according to mGFR in one group, and to different eGFR equations in other groups. Efficacy, cancer recurrence, and safety of the chemotherapy could then be compared between the different groups. However, such a study is not available. We have only retrospective data where the dosage of the chemotherapy (calculated with the Calvert formula) obtained with mGFR is compared, by retrospective simulations, with dosage that would have been used if eGFR had been considered instead of mGFR. Several studies performed such an analysis in oncologic patients and all these studies suggest that eGFR (whatever the equation) can lead to significant different dosage than the dosage based on mGFR effectively given to the patient.49,50,54–56,58 Ainsworth et al. showed data obtained from 660 cancer patients treated by carboplatin. GFR was measured by 51Cr-EDTA. A significant different dose (defined as a difference larger than 20%) was observed in 22% and 32% of cases for CG and MDRD, respectively.49 In the same type of patients, Craig et al. observed in their 175 subjects that eGFR would have led to a higher dose ( . 20%) in 26%, 30%, and 36% of patients with CG, MDRD, and CKD-EPI, respectively.50 Dooley et al. measured GFR with 99Tc-DTPA in 455 patients treated by carboplatin. They showed a potential discordant dose in 36%, 33%, and 29% of cases for CG, MDRD, and CKD-EPI, respectively, with a high proportion of underdosing with eGFR.54 Shepherd et al. and Cathomas et al. both studied young patients with seminoma and treated by carboplatin. Both also used the Calvert equation for the dosage adjustment and the dose was determined with GFR measured by 51Cr-EDTA (mixed with 99Tc-DTPA in the Cathomas study).55,56 Shepherd, in his simulation including 115 patients, showed that, if an error of 20% was considered in the drug dosage, such a difference would have been observed in 33% of patients with (nonindexed) CG (only 1% of underdosing, the rest being overdosing), in 22% with indexed CG (50/50 underdosing and overdosing), 28% with CKD-EPI (6% overdosing and 22% underdosing), and 14% with de-indexed CKD-EPI (11% overdosing and 3% underdosing). If an error of 10% was considered as relevant, the same dose between mGFR and all eGFR equations would have be given in less than 50% of patients.55 In the Cathomas study, 426 patients were included. A significant overdosing was considered if the difference was over 125% and an underdosing if the difference was less than 90%. Overdosing prevalence would have been 7% and 1% in CG (nonindexed) and CKD-EPI (de-indexed), respectively. Underdosing would have reached 18% and 41%, respectively.56 Again, all these studies are simulations, but they share the similar key message: using eGFR instead of mGFR for drug dosage adjustment of cis- or carboplatin
would lead to significant different doses. Overdosing can potentially lead to more secondary effects, and thus concerns with safety and underdosing would lead to a significant higher risk of disease recurrence, which is relevant, for example, in young patients treated for seminoma. From these studies, it remains, however, difficult to definitively assert that one equation will lead to overdosing and that another will underdose, because studies are different in their methodologies (different equation considered, serum creatinine IDMS traceable or not, results indexed by BSA or not, use of actual weight or ideal weight in the CG, etc.) and in their populations. If the debate still exists between different eGFR equations for drug adaptation until now, the solution could be, at least in part, in simplified protocols that used measured GFR and reference methods. For this option, it seems that iohexol plasma clearance is certainly the best balance between feasibility and physiology.82 Of interest, the EMA is now recommending that the manufacturer performs studies with mGFR (and not eGFR) for new therapies that require a dose adjustment according to CKD staging.
Conclusions
Patients with cancer are at high risk of acute or chronic renal failure. Therefore the most exact estimation of GFR is required. Because of the frequently observed anthropometrical characteristics of oncologic patients (declining muscular mass), serum creatinine and thus creatininebased equations are frequently inaccurate, leading to over- or underdosing of drugs. There is still a debate in the literature about the best creatinine-based equation to be used for drug dosage adjustment. Having said that, there is indirect proof that all equations could be misleading, and some authors argue for using mGFR to adjust drug dosage in cancer patients. No randomized prospective study strongly supports the necessity of mGFR in oncology. However, based on the available literature, we and others would recommend considering mGFR for drug dosage adjustment at least in case of chemotherapy with a potentially nephrotoxic drug and with a narrow therapeutic index, the best example being cis- or carboplatin. In other cases, different eGFR equations can be used and the doctor can calculate the absolute and relative difference between the two equations, flagging up discordant cases (difference of . 10 mL/min or . 10%). If results are concordant, the clinician can reasonably apply drug dosage recommendations available in the literature. If discrepancies occur, it would be important to consider the characteristics of the patients and the safety profile of the drug considered. For highly effective concentrationdependent drugs, the risk of underdosage (and thus risk of cancer recurrence) could be as important as the risk of overdosage, especially if the risk of nephrotoxicity is relatively low. In such cases, it could be more efficient to consider the equation that gives the higher GFR results. Conversely, it could be better to recommend adjusting the dosage of a drug to the equation giving the lower result if the prescription concerns potentially nephrotoxic drugs.7,66
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would cheer him up so, wouldn't it? I'm sure we ought totrytomakehim happy—poor Tom! He says nobody cares for him!"
Mrs. Triggs had not paid much attentionto theconversation,butshe now turned herhead sharply round.
"Is that my Tom you be speakin' of? His mother cares for himmore'nallthe world! He was such a handsome baby—took arter his father—who werea fine,upstandin'man,butwith a taste for the beer. Tom be madearter the same pattern.An' Isays if GodandNatur' made him so, why blame the poor lad? An' henever havegiven hismother anunkindword!"
"I like Tom very much," Harebell answered hereagerly. "AndwhenAunt Dianacomesback I'll beg her with tears to let me go andseehim, and I'll find him a wife as quick as everI can!"
"A wife?" screamed the old woman. "You let my Tom be! What dohe wanta wifefor? He have a good home, and there isn't agirlinthisvillagewho'd do him aught but harm. Idle worthless hussies they be! Go on withyou! A wife, indeed!"
Harebell looked frightened. She said good-byeandslipped away. MissTriggs said ina whisper to her:
"Never you mind mother, dear. She don't mean toberude, but shedon'ttakekindly to a wife for Tom, and I can't say he ought to haveone,unlesshis heartgets changed,andhis life too!"
Harebell went back to the Rectory slowly and thoughtfully, butwhenshe found Peterand Nan had put up a swing in the orchard,andwere enjoyingthemselves upon it,she joined them gleefully. They forgot their squabble, and she wasa happy light-heartedchild again.
The return of her aunt was the next event. Mrs. Garland kept her till after the arrival, and when Harebell went home the next day, thewhole house seemedtohavealtered its ways.
There was a man's coat and hat in thehall.A strange man-servantwassittingin the pantry talking to Andy. A little cheerful bustle pervaded thehouse.There wasa smellof tobacco in the morning-room. Two orthree newspapersandpipeslay on the table.
Mrs. Keith came out of the drawing-room to greet Harebell. The childwasso startled at the difference in her aunt's face that all fearof hervanished. Putting up her slim little arms, she clasped her round the neck.
"Your ice has gone!" she exclaimed."Oh,I'm so very glad!"
And Mrs. Keith did not stare, or frown,or reproveher coldly forsuch words. Shelooked tired, but very happy, and there was alight and softness in her eyes that had never been there before. "Would you like to see your uncle? You mustbevery quiet,as he is quite an invalid at present. But I have told him about you.Comethisway."
Harebell trod on tip-toe, with eager eyes and abeating heart. Onacouchnear theopen window was a grey-haired man proppedup withpillows. Hishands looked whiteandthin; his face was lined with pain; he had ahooked nose,andthickbushy eyebrows,but when he saw Harebell, both his lips and eyes smiled.
"The little niece! Come and welcome a poorold sick soldier, whoisn't worth the trouble he gives."
"I'm so very glad you're here," said Harebell standingbeforehim with clasped hands. "Me and God have talked you over often, and God seemedto tell me Hewould send youback soon."
If Colonel Keith was surprised at sucha welcome, hedid not showit. He looked athis wife, and his eyes grew softand tender. Thenhe spoketo Harebell.
"Life deals hardly with those who quarrel withher. Don't youlet your passionsever get mastery of your love, little woman."
"I don't understand a bit what you mean."
"And there is no need that you should," said her aunt a little sharply.
Colonel Keith put his hand on his wife'sarm,asshe stoodby his couch.Her voicesoftened at once.
"Come and sit down and talk to your Uncle Herbert; I must go away for alittle.I have letters to write."
So Harebell took a chair by the couch, and when her aunt had leftthe room,her tongue began to move, and she poured into her uncle's eara flood oftalk. She told him of her home in India, of Chris, of the Rectorychildren,of Tom Triggs andhis sister andhis mother, of Fanny Crake and her mother, and thelittle cottage. But she didnottalk much of her aunt, and Colonel Keith noticed the omission.Harebell found himas good a listener as Mr. Graham. She ended up by saying impulsively:
"I do like you so much,Uncle Herbert!You quiteunderstand what Imean.I haven't to keep explaining; Andy thinks me quiteeasy and understandable, he says, but Goody is always saying I amaze her. I've always saidI likemenbetter thanIdo women."
"But you can't and must not like me better than your aunt!" expostulatedColonelKeith. "You don't know what trouble I broughtuponherby my hot temper andwicked pride! She has suffered, and yet now has no reproach uponher lips. I'm a bad lot, and she's a saint!"
Harebell did not answer for a minute; thenshe said solemnly:
"I'll try and like you both the same."
Certainly she found life much gayernow. Her auntanduncle were much together, andshe was left more than ever to her own devices; but whenshewaswith them atmeals, her busy tongue was no longer repressed. Her uncleencouraged herto talk, andliked to hear all about her lessons and play. Her aunt'svoicewasgetting softer, hersmileswere more frequent. And as for Andy, his old face wasradiantwith happiness.
"Ah! The good old times have come back," he saidto Harebell. "The days of mourning are over for this old house."
The little girl nodded.
"I haven't to hush about the house any more,I canalmost makeas muchnoise as they do at the Rectory."
It was not very long before she beggedpermissionfrom heraunt to go and see Tom Triggs again. Mrs. Keith did not actually refuseher; but shesaidshemust wait. Andthen oneday
at the Rectory, Nan informed her that Tom wasvery nearlywell, andwasgoingaway from the village altogether. Harebell was muchsurprised,and rather uneasy.
"Why is he going away? How can he leavehis mother? Oh,Imustsee him,andaskhim all about it."
It happenedto be a Saturday, and every Saturday, Harebell dined atthe Rectoryandspent her half-holiday there.
"We'll go and see him this afternoon," suggestedNan. "Peterwants tosee him, don't you, Peter? Tom is making him a box withlock andkey to keephis birds' eggs in.He's outof hospital, and living with his mother."
"That will be lovely!" exclaimed Harebell. Itwasonly when shewasactually startingwith them, that she remembered her aunthadnotgiven herpermission to doit. With a little hesitation, she told Nan and Peter that perhapsshe hadbetternotgo.
"Go home and ask your aunt," said Peter; but Nan vehemently opposed thissuggestion.
"We have no time. It's such a long way off;andif we go to thevillage,we cangoon to the woods and have some fun."
Harebell hesitated.
"I'll go," cried Peter, "on my bicycle.I'llgo, and catch youup beforeyouget to thevillage."
Peter had only lately owned a bicycle,so he liked to use it on every occasion.
Harebell brightened up.
"That will be jolly! And I don't believeAunt Dianawill say 'no'to you."
He rode off at full speed, and the little girls walked in thedirection ofthe village. They had barely reached it before he overtook them.
"Can I go?" Harebell asked him eagerly.
"Yes," he said.
She skipped for joy. Tom's future held a big placeinherthoughts,andshe wasdelighted to see him again.
"Oh, do come on," she besought theotherswhenthe village sweet shop brought them to a standstill.
"I want some bull's eyes," said Peter.
He wheeled his cycle up to the shop, leant itagainst thewall, and then disappearedinside. Nan followed him.
Harebell stamped with impatience: then determined not to wait for them, and walked on quickly to Mrs. Triggs' cottage.
She had one more check.
Colonel Keith was coming out of the postofficeandmether. Hewasrapidlygetting stronger, and now got about in a lowpony trap, which for thepresent, he hired.
"Hulloa!" he said. "Where are you going?"
"I'm with Peter and Nan. We're goingto see Tom Triggs.He's goingaway."
"Oh, that's your friend, is it? And your auntknows?"
Colonel Keith knew all about the forbidden visits; forHarebell had besought him to help her, and he had been doing his best inthatway.
"Oh yes," Harebell said with assurance; "she has given meleaveto-day."
"And is it to be a wife, or work, or a cottage?"Harebell laughed, and ranon. She was breathless when she stood at the cottagedoor.
Tom himself came to open it, and smiledallover hisface when he saw whoitwas.
"Why, I thought you and me was friends no longer!"he said.
Harebell seized hold of his hand.
"Oh, Tom, dear Tom, don't go away!Do stay and havea little cottagehere.Idon'twant you to go."
He led her into the little parlour.
"Hessie be out to-day, and mother and me be mindin' each other."
"And how's your leg?"
Tom swung it slowly to and fro.
"Near as good as ever 'twas! You see,missy, I be what youcallgoingon the tack. And I have an offer ofwork in a town firm. 'Tisa contrac'forsomebig house, tenmile orso away. 'Twill be a change and a beginning!But Iain'tgoin'so very far arterall!"
Harebell smiled.
"Did you get any message about Fanny? That's what she said—thedrinkingtobe given up first, and then the work and then thewife?"
Tom's eyes twinkled.
"That there Fanny be too forward. Her must wait tillher is axed!"
"Oh, but I asked her; I besoughted her; Ibeggedher with all my heart, to marryyoujust as you were, and very quickly too! She wasa greatdisappointment tome; Idid hopeshe would have married you directly you came out of hospital!"
Tom threw his head back, and laughed aloud. There wasa clearer look in his eyes, and he held his head higher than he had ever done before.
"I shan't sit down and cry, if her don't wantme," he said. "Ican't keepa wife justat present. The girls be too expensive in these days."
Harebell was silent. This seemed quite anew Tom;a manwho could scornawife was beyond her comprehension.
"And you're never going to a nasty public-house again?"
"Ay, well, there be no tellin'; but I ain'tvisitin' the'Black Swan' justnow."
"Tom," said Harebell looking up at himwith solemn eyes, "are you through?"
His eyes met hers rather gravely
"Through? How d'ye mean?"
"Through the Door? You know I almost think you are. And I believethat'sthe first thing of all to be done. I wonder if you did itfirst."
"I wonder," said Tom, in a low grave voice, looking over Harebell'shead as hespoke.
"I wish you'd tell me.Because we'd be onthe same side,then. I ask God every day to keep me on the right side, the insideyou know, and not tolet me runout."
"Hi! Tom! Where's my box?"
Peter's shrill voice coming up the garden-pathinterrupted them.There wasno more opportunity for serious talk. Tom tookthechildren to thebackyard wherehe wasworking, and for half an hour theystayed there chatteringand watchinghimcomplete Peter'seggbox. Then they left him, and went on to thewoods, where they had a very happy time.
Coming home, Harebell said:
"Haven't we had a jolly afternoon? Andisn't Tom Triggs nice? Quite different towhenhe was drinking!"
Peter edged up to her.
"I want to tell you a secret. Go on, Nan;it isn't for you."
Nan laughed.
"I'm not a bit curious. You never haveinteresting secrets,Peter."
She obligingly crossed the road. Peter sank his voiceto awhisper
"You needn't think your aunt gave you leaveto goandseeTom, forshedidn't. You'd better keep quiet about it, and not let herknowyou went."
"Oh, Peter, what do you mean?"
"Don't shout, you stupid! I did go to askher; but she wasout,so I couldn't!"
"But you told a lie! You said she hadgiven meleave."
"I didn't!" said Peter, a little sullenly. "You asked me if youcouldgo, and I said, 'Yes.' I didn't say anything about your aunt!"
Harebell stopped still in the road. Hedragged her on by the arm.
"There's nothing to make a fuss about! I didn't tell a lie. Youneedn't say awordabout going to Tom. Tell her you went to the woods, if sheasksyou."
"But I met Uncle Herbert, and told him Iwasgoingto Tom, and I told him aunt hadgiven me leave to go!"
"You were a little fool."
Then he changed his tone.
"Look here, Harebell, don't you get me intoa row. Don't split, will you? Youaren'ta sneak, and it would be awfully mean to tell tales. You see, your auntanduncle are coming to dinner to-night at our house, and they'd makea rowover it. I only wantedyouto have a good time. I needn't have interferedat all, anditwasn't a lie, and ofcourse they'dthink it was, they'd never understand. I'll never forgiveyou ifyousplit!"
"Oh, I won't say a word about you! You needn'tbe afraid."
Harebell's voice was scornful.
Peter got rather red in the face.
"Such a fussabout nothing!" he muttered."I don'texpect your auntwill carewhere you've been. You can tell her you had to comewithus; you couldn'thelpyourself."
Harebell did not speak. Then she saidslowly:
"I have told lies myself in India, but not sinceI'vebeeninEngland. I couldn't havedone it, as you did!"
"I didn't tell a lie."
Peter left her and joined Nan. They were rather a constrained triofor therest oftheirwalk. Nan remarked—
"You and Peter don't seem to have enjoyed the secret."
And Harebell said quickly:
"I shouldn't think so!"
When they reached the Rectory, Harebellsaid good-bye. Shekissed Nan, but turned her back on Peter.
"Remember!" he called after her threateningly.
"You needn't be afraid!" she retorted.
But she entered her aunt's house witha sinking heart.
CHAPTER IX IN DISGRACE
HAREBELL had her tea inthe schoolroomalone, asshe very oftendid.Andywaited upon her.
"There be visitors in the drawin'-room,"he said. "'Tis likeold times, gentlemena-comin' here! For years we've had nothing but ladies,andafewonthem.Sir Robert Ferguson and his lady have been to tea, and the Colonelbe quite spry. What haveyoubeen a-doin' today? Somethin' to get a scoldin' for! Mistress says to me, 'Tell Miss Harebell togo to her bedroom after she has finished her tea, and stay there tillIcome to her.'
"Then she knows," said poor Harebell with adeepsigh. "Did she look very angry, Andy?"
"Very cold and quiet," said Andy. "What haveyoubeen doin'?"
But Harebell for a wonder would not tell him.
"Mayn't I go and see Chris?" she asked.
"Best not. I've given you the message exack'ly asitweregiven me!"
Harebell's tea almost choked her. She left it unfinished andwentupstairs.
"It's no good," she said to herself asshe satdowndisconsolately in her little chair by the window, "to say I'm not frightened of Aunt Diana, because I am;andshe'll say I've disobeyed her, and so I did. And I never, on my word and honour, meantto be naughty today. God knows about me; that is onecomfort. Heknows I didn't mean to be naughty. And as for Peter, he's the wickedest, meanest boy I ever knew, and I don't think I shall everbe friends with him again!"
When she heard her aunt's step at last, she stood up with a beating heart.
To her aunt, as she came into the room, Harebelllooked the picture of guilt.
Mrs. Keith's face was very hard and stern. "I havecome,"she said, "to havesome explanation from you of your conduct thisafternoon.Younot onlydirectly disobeyed me, and went off to see that drunken man, butyou told your uncle alie, and saidthat youhad my permission to do so. Do you remember whatItoldyouwhenyoufirstcame hereabout lies?"
"Yes," said Harebell miserably. "I remember quite well, but Ihaven't told alie, Ireally haven't."
"Don't try to cover up one lie with another; that isonly makingmatters worse."
Harebell was silent. What could she say?
"Have you anything to say for yourself?"
"I don't know," faltered Harebell; "it was—wasa mistake. I Ithought you'dgiven me leave."
"How can you have the face to say sucha thing to me? Youknow Idid not."
"I didn't tell a lie," Harebell murmured.
Her aunt looked at her with an expressionof disgust. "Isuppose I wasfoolish tothink that you were a truthful child. My eyes areopen now. Ifyouhadonlyfranklyconfessed, Imight have regarded it more leniently. However, I keepmy word, I shallsend youto schoolafter
the summer holidays. Never will I havea childin my house who deceives, or tries to deceive me."
Harebell began to cry.
"Oh," she sobbed in the depths of her despair, "if youwereGod,you'dunderstand!"
"Don't add hypocrisy to lies," said her aunt sharply. "Youarenot to come downstairstonight. Go to bed, and remember thatI mighthaveforgiven your disobedience—butI will never forgive lying!"
She left the room.
Harebell flung herself on the floor
"I shall never, never be happy again!I'm nota liar, I'm noteven disobedient; it's all a muddling mistake, and it's Peter, and notme, who ought tobepunished!"
She began to feel justly angry with Peter.
"He'll go on living and people will think hima goodboy, and I shallbe thought a liar for ever and ever! And school is a prison, and—oh, Inever thoughtof it! I shall haveto leave my darling Chris! My heart will be broken. I wish I could die!"
She lay there sobbing her heart out,andGoody, enteringthe roomlater, wasmuch astonished and alarmed.
Harebell raised a white tear-stained face to her.
"I ought to be in bed," she said slowly. "Aunt DianasaidI wasto go. She thinks I'vetolda lie, and I haven't, Goody, and I'm to be sent to schoolindisgrace."
"Dearie me! What an upset! You must gethold ofthe Colonel. He'll put things right."
A gleam of hope stole into Harebell's eyes; then it died away
"He thinks I told him a lie. He won't help me. I'm what youcalldoomed, Goody."
She began to undress. She would giveno explanationto Goody, for fearof inculpating Peter.
She heard a carriage come to take heruncle and aunt todinnerat theRectory.
She wondered if her aunt would tell them allthereof her wickedness;andif so, howPeter would feel when he heard it. She beganto hope that perhaps his conscience would compel him to confess and to clear her. But she remembered that Nan said once that Peternever owned himself to be in the wrong.
Goody went away at last, and she wasleftalone in bed.
It was hours before she slept, and when she did,she dreamt that a school-mistress with flaming red curls and bony hands waspushingher down somesteepsteps into adark cellar!
When the morning came, she wondered atfirst what awful thing had happenedtoher.The birds were singing. It was a lovely sunshiny morningin June, andwhen she remembered the trouble in which she was, she feltthat somehelpwould cometoher.
"Aunt Diana won't really send me away. Peterwillbe sorry and tell."
Yet as she dressed, fear overcame hope. Sheransoftlydownstairs and madeher way to the stable. Chris neighed in delight when heheardher step, and rubbed her all over with his nose. Of course he was told all, and Harebell claspedhim passionatelyround the neck.
"If they send me away from you, I shall die,"she assured him.
Then the prayer bell rang, and she slowly wentintothe house. Her uncle did not come down to breakfast, but had it in his room.He wasstillquiteaninvalid. Mrs. Keith hardly spoke to her, but as she was leaving the breakfast-table, she said:
"Are you ready to confess the lie you told? Are you sorry?"
Harebell looked at her aunt nervously.
"I feel," she said, "if I said I had toldalie,that would be a lie."
"You will be in disgrace till you do confess," said her auntshortly.
Harebell went to the Rectory with a heavyheart.
She could hardly say "Good Morning" to Peter. Nan asked her at once whatwasthematter, and Harebell looked Peter straight inthefaceas she said:
"I'm in disgrace. Aunt Diana says I'vetold alie,when Ihaven't. I'mgoing to be sent away to school, and I shall never come back again!"
"Oh yes, you will," said Peter fast and eagerly, whilsthischeeks got hotandred. "School is awfully jolly; and you always come homein the holidays. Iwish I could get senttoschool. No such luck for me."
"School is enchanting," said Nan. "Agirlinthe next village goes to a boarding-school, and she loves it. I don't pity you, if you goto school, Harebell."
"And how can I part with Chris?"
"You'll have him in the holidays," said Peter; "andp'raps dad will keephim for youwhen you're away, and we'll exercise him foryou!"
This was too much for Harebell. Sheturned upon Peterin a blazing fury.
"I hate you! I'd like Chris to kick you off and tread on you,if youever dareto ride him. He knows all about you. I've told him. And I'vetold God, too, and I'll never play withyou again, and I won't speak to you, and ifyou leaveany of your birds' eggs about, I will smash them in bits!"
"My dear child!"
Mrs. Garland had come into the room unnoticed.
Harebell's fury was stayed. She hung herhead.
Nan was looking quite frightened; Peter redanduncomfortable.
"What has Peter done to provoke suchan outburst?" Mrs.Garlandsaid.
Harebell flung herself into her arms.
"I can't say, but I never tell lies, doI?DoI?Aunt Dianasays Ido."
"And does Peter say you do?"
Mrs. Garland looked at her small son very keenly
"No—no!" he stammered. "I never saidshedid. It isn't my fault!"
"She's going to be sent to school, and she doesn'tlikeit,"said Nan. "Her auntis angry with her."
Mrs. Garland tried to discover what had happened, but neitherPeternorHarebell would tell her, and Nan was as much in the dark asshe was.
Miss Forster interrupted them, and lessonsbegan.Harebell naturally didhersvery badly, but Miss Forster saw she was muchupset and madeallowances. When twelveo'clock came, they went into the garden to play. Harebell left theothers,andwanderedround the paths in the shrubbery, feeling very miserable.
"I'm not a bit like a child who is inside theDoor," shetold herself. "I'vebeenina temper with Peter, and I'm sure I oughtn't tobe. JesusChrist wasn't angry when Hewasilltreated, and I know He doesn't want me to be. Butit's very hardnot to callPeternames. He is the meanest—sneakiest—oh, I mustn't! But how canI lovehim when it's all his fault, and not mine at all!"
It was a hard struggle with Harebell. Her senseof justice wasgreat, and her punishment she knew was not deserved. But before sheleft theRectoryshe went up to Peter.
"I'm sorry I said I would like to smash your eggs. Iwon't. I'll try and forgiveyou.But you're making me awfully miserable, andyou know youare."
Peter walked away from her.
"You're making a fuss about nothing,"he said;"you chose tothink I meant what Ididn't mean. It was only a mistake."
He was feeling miserable too, but he would not allow it, and triedtomakeexcuses for himself.
"Such a fuss!" he repeated to himself. "It isn't worth thinking about. I'm sure Mrs.Keith won't really send her to school. She'llforgetall about it in a few days."
When Harebell went home she foundheruncle pacing the garden paths. He called her to him cheerily, and wishedher "Good morning" asusual.
Harebell looked up at him wistfully. She longed to confide inhim.
"Well," he said, "how have the lessons gone?"
"Very badly," said Harebell, shaking herhead."I'vean extra lessonto learn for not attending; but my soul was in such astate, that I couldn't work at sums,so they got jumbled up."
Her uncle sat down on the garden seatanddrew her to him.
"Tell me about it, little woman."
Harebell worked her fingers in and out of hiscoat buttonhole nervously.
"Do you think I told you a lie yesterday? Ididn't.It wasa mistake, nota lie, and Aunt Diana won't believe me."
"How was it?"
Harebell was silent.
"I can't explain myself—but I'm telling true. Andif—"
Here she got excited and waved her handsabout.
"If Aunt Diana was to burn me, or flog me, ordrownme,I couldn't say anything but thatI didn't tell a lie!"
"Try and explain," said her uncle gently. "Your aunt hassucha horrorof deceitandlying that perhaps she did not give you timeto speak."
"I can't tell her. She won't believe me.Butoh,UncleHerbert, Ican't livewithout Chris. If she sends me away from him, I shall die. I shallnever liveto come back. Please don't let her send me away to school."
"I hope thatwill not be necessary."
Mrs. Keith came up to them.
"Harebell, go into the house. Until you confess your faultyouarein disgrace."
Harebell turned disconsolately away. ColonelKeithsaidsomething to her aunt,whichshe could not hear, but she heard her aunt'sclear cold voicereply:
"It is her mother over again! I warned herwhen she came to me. Thereis no mistake. She disobeyed, told a lie, and sticks to it.I will notundertakethecharge of her any more.I shall send her to a strict school, for I will notberesponsible for her training."
With despair in her heart, Harebell crept indoors.
The following days were very unhappy ones. Shegrewvery quiet,moped aboutthehouse, lost her appetite, did not sleep at nights, and got a peaked whitelook upon her face. But as time passed, she grew accustomed to her aunt's cold displeasure, and as no more was said, began to hope that perhaps shewouldnotcarry out her threat.
The summer holidays came. The Rectory children wentaway tothe seaside with their parents.
For over a month, Harebell had not been allowedtoride out on Chris; but now, owing to her uncle's intercession, she was permitted tobegin her ridesagain.
Mrs. Keith hardly ever took any notice ofher, but at lastoneday she calledher to her.
"I have made all arrangements about school,andyouwillgo next Monday. Goody will take you. The school is at Eastbourne."
Harebell looked at her aunt with frightenedmiserable eyes.
Then her aunt said in a gentler tone:
"You have still four days before you.Ifyou willfranklyconfess, and express realsorrow for the lie you told, I may be induced to forgiveyou.Your uncle has made me promisethat I will."
Harebell's lips quivered, but she said nothing.She knew there wasno hope now. Peter was away, and was not coming home tillafterMonday. Unhappy as shewas, the thoughtnever crossed her mind that she might break her promise to Peter.
The four days gradually slipped away.
She watched Goody pack her clothes;MissTriggshadcome round to makeher some new frocks, but she, as well as Andy and Goody, consideredthat goingtoschool wasnothing so very bad after all. The only comfort that cametoher washearingfromMiss Triggsthat Tom was getting on splendidly; he hadsignedthe pledgeand waskeeping it.
"He's a first-class workman, Tom is, when he's sober, and we'veheard his master thinks no end of him."
Harebell was nearly desperate when Sunday came, and when she laid herhead on her pillow in the evening a tempting plancameintoherhead.
This was to get up very early on Monday morning,saddle Chris,andrideoffwith himout of reach of all the people who weretaking part in sending her to school.
"I shall go along and get my food in farmhouses where they makenicehotbread and have cream with their porridge. I have fiveshillingsof my own, and that will lasta longtime.I will get lost where no one can find me. Andthen Peterwillbe sorry and confesswhat he did, and aunt will be sorry too!"
The more she thought about this themoreeasy and delightful it seemed to be.
"Aunt Diana wants to get rid of me, and, ifI go away, she'll be glad!"
Then, after a good deal more thinking, shefell asleep.
CHAPTER X A LITTLERUNAWAY
IT was a lovely summer morning. Harebell wokeupa little before fiveo'clock.With a set determined face she got up and dressedherself, stepping about her roomas quietly as possible. She tied up a nightgown andbrush and comb and toothbrush in a bundle. Then she began to think that she might wantmoreclothes than that. Shetookafewthings out of her drawers, and put them into a redcotton bagwhich she tied round her waist.
Then on tip-toe, she stole downstairs, and softly unbolted the back-door. It waseasy then to find her way to the stable. Andy hadtaughther howtosaddle Chris, and in about half an hour's time she had got free of thehouse, and wascantering along thecountry lanes.
Then she remembered that she hadnot said herprayers.Her conscience began to trouble her. Was this like a child of the Kingdom?Harebell refused toletherself think. In a whisper, she gabbled over her prayers;forshe felt that she wanted God totakecare of her, though she did not mean to mention herplaninher prayersto Him.
The fresh air and the birds' singing didnotseem as enjoyableto her, as sheexpected they would be. She passed through the villageas quickly as she could, and took the road that the signpost said led to London.
"Everybody goes to London," she said."ButI willstop before I get there. I'll find a nice pretty farm, with apples in the garden,andthey'll givemesomebreakfast."
But as time passed she began to feel hungry, and no pretty farmcamein sight. The country was singularly desolate. Shecame upon two or three small cottages by the wayside, and an inn; but none of these seemedto her attractiveenoughforbreakfast. At last she turned up a leafy lane.
"I must try and lose myself thoroughly, Chris,"she said; "sothat nobodycan possibly find me and take me back. Ifeel quite frightenednow, whenI think of Aunt Dianafinding me gone. How very angry she'll be!"
Childlike, she was living entirely in thepresent. Her future never troubled her. Thelane wound about in a wonderful way, then suddenlyended. Awhitegate appeared and a high wall on either side of it.
"This must be a house," said Harebell toherself.
She found the gate open and rode up aneglected drive; nettlesand rankgrass flourished on either side of a mossyroad. Overgrownshrubs andthicktreeslinedthe way.
Her heart began to beat excitedly
"It's like the palace grounds of the Sleeping Beauty. I wishIcould havea real adventure."
The drive seemed an interminabledistanceto her, butat last,to her greatdelight, she saw a big grey house in the distance. It looked still and deserted.
When she came up to the big flight of stepsleading up to the front door she persuaded herself that it was, indeed, the Sleeping Palace. Slipping off Chris, she let himturn asideto munch at the long grass on the lawn, and then mounted thesteps with eagerexpectancy. Would the door open at her touch? Wouldshe goin andfind the remains offeasting in the great hall, and the servants all asleep attheir posts?
Alas! the door was fast shut and barred,thewindows were shuttered, and through a small peephole in a broken shutter, she saw thatthe inside ofthe housewasempty and unfurnished.
Slowly and reluctantly she turned away;then, seeing a sidepathnearthe house,sheran along it, wondering if the back of the house wouldprovemore cheerful than the front. She found a side door, and to her joy, asshe turned the handle and pushed, it yieldedto her touch. The next moment, she was inside along widepassage.It waslight, andlooking up, she saw there was a big glass dome highupinthe centre.Rather fearfully she madeher way along, till she reached the centrehall.A greatstaircase wound up to a gallery round it. She was just mounting the stairs, when she suddenlyheard a man's laugh.
Now she was frightened. Into her brain rushedstoriesof ogres,giants,burglars,and criminals. Panic seized her; she fled backalongthe passage,missedher way, got into another part of the house, and couldnot find an open door anywhere. Then she screamed. It seemed like some hideous nightmare.Shebeatandkicked against adoorwithher hands and feet. The horrible thoughtcame to her that she had been purposely locked in, and that some wicked man would come and killher.
Suddenly, from behind, a big hand laid hold ofher shoulder. She screamed louder than ever in real terror, and then she turned to confront Tom Triggs,andto hear himsay with a little gasp of bewilderment:
"Why, I'm blest ifit ain't little missy!"
She clung to him in a tempest of sobs.
"Oh, take me out! Dear Tom, save me!Wheream I?"
The next moment a doorwas openedandshe wasin the fresh air, withthesun shining and the birds singing, and Chris still calmly munchingthe grass a little distanceoff. It took some minutes to soothe and calm her, but Tom did it. Hewasin hisworking clothes,with his carpenter's apron on,and looked strangely out of placein this greatempty house.
"It's the funniest thing out that you should havecome straightto the very houseI'm workin' at. Me and my mates were havin' our breakfast in thebackyard. Wearedoin' repairs to the stables, and all on a suddenweheard a scream, and it seemed to come from inside the house, an' I come alongtofindout whether it be a ghost or a h'owl, and then I catches sight of you a-beatin'your fists against adoor. Now, do youjusttell me what has brought you here. Did you come tofindout whether good-for-nothing Tom were keeping off the drink?"
Harebell smiled through her tears, butshekept a tight clutch of Tom's hand.
"I didn't think of you. I didn't know you were here. Iwasa dreadful coward, but I felt I was lost a good deal more than I meant to be.Andgenerally whenI'm frightened,I ask God to take care of me; but I couldn't,andI feltHe wasa million miles away from me, and wouldn't dream of coming near me. And thenI knew it wasbecause I must haverun outside the Door, and wasn't safe any more!"
She spoke with feverish intensity. Tomlooked at herand then at Chris in a puzzled sortof way. Then he sat her down on the broadbalustrade atthebottom of the steps.
"Take yer time, missy. Tell me just howyou cometo be so faraway from home this morning!"
Then Harebell poured it all out, every bitofhertrouble. Shefelt that she could even tell Tom about Peter's deceit, after making himpromisethathe would not tell any one.And Tom listened and rubbed his head, and thendelivered hisverdict.
"You must go back, missy; there's nohelpforit.Youmustget youback!"
Harebell began to cry. She was tiredandhungry. She beganto wonder howshe had dared to run away in such a fashion.
"Aunt Diana will be so very, very angry."
"But she'll be in a terrible state about you now. You can'tbidealonein theworld, trampin' the roads without food and money. Itbe a stoopid thing to do—"
"I s'pose you haven't got a cottage yet? Couldn't youtakemesomewhere? I'mafraid of Aunt Diana now. She'll never forgive me!"
"You must get you back," Tom repeatedwithconviction."It bebad you're comin'off in that fashion, but every hour you stay away, itbebadder!"
Harebell looked up at him beseechingly.
"I don't know what to do. I can't go back."
"Oh yes, you can! I'll come a bit of the way withyou,andif youtrot your pony pretty fast, you'll get home not so very late for breakfast after all.Wouldyoulikea sip ofhot tea? You wait here a minute."
He disappeared, but soon came backwitha hot tin of tea, and some bread and cheese.
"'Tis mos' remarkable you comin' away ina straightline to the housewhich Ibeworkin' on! How did you do it now?"
Harebell drank the tea thirstily, then she looked at Tom gravely.
"I s'pose God brought me to you, so that youwouldtell mehow wicked I was, and send me back. I used to think when I first knew about you,Tom, that youweremuch wickeder than I was. Now it's me that is wicked, and you're trying to makeme good.It's dreadfully wicked to run away, isn't it? Almost as bad as tellinga lie."
"It's a poor thing to do—to run away," said Tom slowly;"but Idon't know that Iain'tjust done it myself! You see, I knowed how my oldpalswould be gettin' over me, soIcome away twelve mile off to make a freshstart where I couldn'tbe baited!"
"But you didn't run away from home,Tom.Your mother and sisterknewyouwerecoming."
"Bless their hearts, that they did! And Ibe gettin' along fine. And some day I hopes I'll come back and be able to look my fellow-creatures straightin the face. ForI shan'tbe feared then o' nobody. An' I do allow 'tis a happy thingto feel insidethe Kingdom's Door, missy. I humbly 'ope I've crawled through, and the Lord beholdin' my feet straight, and my mouth from even wanting the accursed stuff; and He havegot me by His hand,so I just steps behind Him, and He goes first."
Harebell smiled for the first time.
"Oh, Tom dear, I'm so very glad. I always didknow youwouldget throughsoon. Whendid you do it?"
"Well, I can't rightly say as to day an' hour—but Ihada tryin hospital,andthen agenat home—an' it seemed to me as one day I wasforgoin' in,an' thenextforcomin' out,an' I didn't get much forrarder, so at lastIgets downon my kneesandtells the LordHemust please do it all Hisself, for I were come to the Door an'He must do therest. Bless His name, He seemed to stoop right down an' getholdof me—a reg'larsafe grip—and there I be—very afeared of myself, but verysureo'Him!"
"And do you think I've been naughty and so He's put me outside?Oh,Tom,do you think you're inside now and I'm outside?"
Harebell's lips were quivering.
"I ain't no scholar, missy, but there be one chapterinthe BibleI readsover and over and over! 'Tis the one you mentioned first about the Door. Ifwe be insidethe Door, I takeit we be in the sheepfold; and if we be in the sheepfold,we be the sheep; and if we be the Lord's sheep, He has us safe, sure enough, foritsays, 'Neithershall any man pluckthem out of My hand.' You be right enough—just aslip—and you're a-goin'back now tosay you're sorry an' I'm a-comin' a bit o' theway withye!"
"I haven't said my prayers properly thismorning,"Harebell confessedwith shame. "I gabbled them through. I'll just speak to God here,if you go away and tell HimI'm sorry."
Tom moved away, rolled up his apron, thencaughtChris, and by thetime he joined Harebell again, the cloudwas off herface.
She mounted Chris, and Tom walked by herside till they reached thehigh-road.
"There!" he said. "Now 'tis a straightroadhome, and youcan't miss it. Good-bye, little missy; and just put up a prayer for good-for-nothing Tom,willyou?"
"I will," promised Harebell, "but p'r'aps You'llnever seeme again. I'm goin' to besent to school, you know."
She conquered a rising sob.
Tom looked at her thoughtfully.
"Ay, 'twas through me, you be in thistrouble! Well, p'r'apsI canhelpof 'eeout."
"It will be too late. I shall be gone," saidHarebell.
Tom rubbed his head.
The little girl added, "And you mustn't tell aboutPeter, youpromised notto; and Idon't mean to tell."
"Well, you be doin' a fine thing, a-bearin'his fault."
Harebell rode away, waving her hand toher friend.
He looked after her in perplexity. "If I were a scholar now! But I'll venture onit!"
He returned to his work with a planinhis head.
And Harebell rode on home, feeling moreandmore frightened and unhappy as shedrew nearer the village.
"It all seems as bad as itcan be, and whenI say I'veseenTom, Aunt Dianawill thinkI went to him on purpose, and it will makeher angrierstill!"
Presently she met Andy at the entrance tothevillage. Hethrew up his hands.
"Ay! You naughty child, we've all turned out tocatch ye!To think ofyour goingoff for a ride this very morning when you're to goto school."
"I'm sorry, Andy. I'm coming back!"
"Comin' back! High time,too. The missisan' the master be in aterrible way. What didyou go to do it for?"
Harebell did not answer. Even Andy, her friend, wasscolding her.
The house was reached. Andy took herpony, and whenHarebell reached thefrontdoor, her aunt met her in the hall.
"Come in here," she said. "Where haveyoubeen?Did younot knowa cab wascoming at ten o'clock to take you to the station?It isnownearlyeleven."
She drew her into the morning-room. Colonel Keith wasnot there. Harebell's heart sank within her. She looked up at her aunt. Somehow orother, Mrs. Keith wasnot looking as angry as she had expected.
"I am very sorry, Aunt Diana, but I meant torun away and never come backagain; I quite meant to. And—and—I met Tom—I didn't mean to meethim—heandmethink God managed it, and—and—he made me come home again."
There was silence.
"Where did you meet him?"
"At an old, old house far away. I found it by accident and—"here Harebell's loveof romance seized her, and she forgot shewasin disgrace—"do youknow it wasexactly like the palace of the Sleeping Beauty. It wasstillandsilent, and theweeds wereenormous; and I quite hoped to see everybodyasleep, and all that wasleftof the feast. And then I got into the house and found it empty and dark,and I wasdreadfully frightened, andI couldn't find my way out, and I thoughtI waslocked in;andthen I screamed and screamed, and Tom heard me and came to me, and he's thecarpenter who's mending the stable there!"
She paused for breath.
Her aunt was silent for a moment. She seemedtobe turning over things inher mind.
Harebell puther arm out timidly andtouched heraunt's arm.
"Do please forgive me, Aunt Diana. Iknow it waswicked ofmeto run away. I knew whenI did it that it was, and that made it worse, didn'tit!"
"What madeyou come back?" her auntasked sharply
"It was Tom. I wasn't even going to do it forhim, but whenhe told me hewasinside the Door of the Kingdom and would never drink any more,I wasso glad, itmade me—well, it made something different in my heart and IknewImustcome backif you—ifyou whipped me to death!"
She ended her sentence with desperateemphasis.
"I have never yet raised my hand against you," heraunt saidgravely.
"No, but I thought you might," Harebellrepliedquickly. "Ithoughtof such a lot ofthings you could do to me; but, you know, it wasGod and Tom whomade mecome back.I had to."
"It was exceedingly naughty of you to think of running away. Ifyouhadgoneon, you might have met with accidents. We should,of course,havefollowed youandbroughtyou back before the day was over. And nothingthenwould haveprevented my sendingyou to school to-morrow. A little girl who acts likethatwants agreat deal more disciplinethan I can give her. But as you turned back ofyour own accord, Iam goingto forgiveyou.I have received a letter from Mrs. Garland thismorning. If youhadbeen here at breakfast-time, you would have heard about it. Of course, theletterhas explained what youought to have explained to me long ago—"
Harebell's eyes were open wide.
"What?" she gasped.
"It seems that Peter has been unhappy alongtime, and confessed to hismotheryesterday that he was the cause of your disobeying me. Why did notyoutellmeso before?"
"I—he—I promised him I wouldn't tell," falteredHarebell.
"You had no right to promise such athing. Itwasnot beingfrankwith me, andled me to think what was not true—"
"I—I told you it was a mistake I made, and not a lie," saidHarebell. "Icouldn'texplain properly; I really couldn't, Aunt Diana."
Tears came into her eyes. She was relieved that she wasclearedof untruthfulness,butshe still seemed to be in disgrace.
Then Mrs. Keith spoke more gently:
"I want to be fair with you, Harebell. I am deeplythankful tofindthatyou did not tell me a lie, and to think that I can still trust your word.And for the present, Ishallnot sendyou to the school I intended for you. As I told youjustnow, if youhadnot come backof your own accord, I should still have done it. But as it is,MissForsterwill still continue to teach you. I am sorry to think that there is so little confidence between us that all this trouble has been the result. You ought to have told Peter atonce that youcouldnot withholdtruthfromme. You did not tell me an untruth, but you withheld thetruth,andbothare wrong.Do you understand me?"
"Not quite," said Harebell; "isn't it wrongtotelltales?"
"Not if it helps to deceive. Your not telling about Peterhelpedto deceiveme;andIacted wrongly because of it. I want you to rememberthis, for peoplehavemade themselves and others very miserable because of it.If shieldingone person makes anotheract unjustly, it is wrong. Now I shall say no more—you had betterhavesome breakfast."
She stooped and kissed Harebell, thenledher intothe schoolroom, where some food was awaiting her.
Harebell began to feel much happier, and whenheruncle cameinpresently, and toldher how glad he was to hear that the mystery wasall clearedup, she heaved a deep sigh and said:
"I feel as if a heavy weight has lifted out ofmy chest.And now that aunt hasforgiven me, and I'm not going to school, may I tell you aboutTom?"
CHAPTER
XI
TOM'S LAST EFFORT
THAT very same evening, Mrs. Keith received anill-written letter from Tom:
"MADAM,—This is to say aslittleMiss to my sertain nowledgehavenot toled a lie. There be anutherparty inthebisness wichif youcud discover wud be rather near home but I amplegedtosay nothing.They that lives most with her knows and ishidinge thetruth.
"Your obedientservant "TOMTRIGGS."
Mrs. Keith showed this to her husband. As Harebellwascleared,they didnot tell her anything about it, but Tom was written to and thanked for hisintervention.
And very soon the Rectory party returnedfrom theseaside. PeterandHarebell had a very solemn interview. He was made by hismother to comeup andtellMrs. Keith exactly what he had said; and then he apologisedto Harebell.
She took hisshamefaced apology verygravely. But when shebegan to relate to himher runaway ride, he brightened up and wasmostinterested.
"It's just like a story! What a pity you came back.Ishould havegone to sea!"
"I couldn't have. I couldn't have taken Chris with me. Itwashim I didn't likeleaving."
"Girls never keep things up. They always get frightened andstopinthe middle."
"What would you have felt like if I had never come back?"
Peter reflected.
"I think I should have told people it wasmy fault, and then I shouldhavefeltobliged to run away after you to find you. That would havebeengood fun! I shouldhavegone on the donkey, and you bet I should have caught you up!" Hiseyes gleamedat the idea.
"I'm very glad I didn't go on. It'shorrid ifyou feelyou're quite alone in the world. Ifelt when I was in that empty house, as if I hadlost my friendsandmy home—and the most awful thing of all—that I had lost God,anddidn't belong to Him any more."
It was Peter's turn to look grave.
"I'm glad I'm not you, without a mother. Mother isripping. She wasn't a bitangrywhen I told her, only very sorry and—well—loving. I wasrather acad, and, of course it wasa lie I told. I'm never going to tell another aslongas Ilive. If Idiefor it,Iwon't!"
Peter clenched his fists determinedly.
His sin, and the burden of it, and thenthe confession, had made him a different boy. Harebell felt he was a much nicer Peter afterwards,andother peoplefelt sotoo.
Lessons began again, and life went on withcheerful regularity, varied by picnics on halfholidays, and later on by blackberrying andnuttingexpeditions. Harebellgrew into a strong rosy girl. Her auntwas fast losinghercold indifferent mannertowards her, and Harebell now chatted to her as freelyandunconstrainedly asto any one else.Then the winter came: but Harebell enjoyed thecold,andwelcomedthe frost and snowwith delight and interest.
Christmas was a most enjoyable time, and sheand the Rectorychildren were inseparable during the holidays.
When the New Year came, there wasa good deal of sickness in thevillage,andmany of the old people died. Amongst them wasMrs. CrakeandMrs. Triggs.Tom came tohis mother's funeral, and the village hardlyknewhim. Hehadgone steadily on in the right way, and was now a respectable sober hardworking man.
Mrs. Keith no longer objected to Harebell's interest in him, and one day shewasallowed to go to tea with Tom and his sister. She walked off very proudly, and wassoonsitting up at a well-spread table in the little front parlour.
Miss Triggs was in deep mourning and wasrather sad.Harebellwastoo excited tobe so. She had never much cared for old Mrs.Triggs,who did not welcome heras avisitor, and made no secret of her dislike to children. And now she could notpretend to mourn for her.
"Do you know, Miss Harebell, I may be going away?" said MissTriggs witha sigh.
"You'll have to get somebody else tomakeyour frocksforyou.I'vehadan offer from an uncle of ours, who is a big draper in Swansea.Hewants me to go there andbe oneof the skirt hands, and Tom and me have been talking it over, and I think I'd liketo go."
"Oh, dear! This is dreadful news," saidHarebell in dismay. "Andwho will livein your cottage?"
"I'll give it up. I have only to give amonth'snotice."
"But won't Tom want it? You'll come backand livehereagain, won't you,Tom?Ido want you so much."
"Not yet awhile, missy. I'm feelin' a bit unsettled like. True, theSquire talked about wantin' an estate carpenter now his head manbe offto Canada: but that be too good a billet for me. There be a small cottage, too, for the lucky chap who getsit—"
"Oh, but what a lovely thing for you!And thenyou'dget a wife. Do say youwould, Tom. And Fanny isn't married to anybody else, and now she'sallalone,itwould bejust right, wouldn't it, Miss Triggs? She has lost her motheras well asyou."
Miss Triggs smiled, but Tom did not.He gotrather red.
"Eh, dear? But you do go on about a wife; Iain'treadyforone yet."
"I'll help you to get ready," said Harebell earnestly;"there seemalotof cottages ready for your wife. This one, and Fanny's, and theSquire's."
"Have one of these little cakes, dear," said Miss Triggs,who wished to change the conversation.
Harebell ate the cake and thought hard.At length she said:
"You see, Tom, you've given up thebeer, and you'vegot work, and now you'vegot cottages all round you, and the wife is the lastthing and thebest ofall."
"'Tis to be hoped she will be," said Tom,half tohimself.
"Well," said Miss Triggs, "I wouldn't go off and leavehim, Miss Harebell, if he'dmakehis home with me. But he won't. 'Tisn't disagreeableness; the fact is, he havekept onsendin' his money home to mother, and he hasn't enough just nowtostartahouseon his own, and he have got proud, and won't letmepay the rent and suchlike."
"You have spent too much on me all these years," muttered Tom. "Now we'll letmy affairs bide for a bit, missy. Do you think you could find room inyour home fora little chair I've been making in my odd moments? I broughtitback with me whenIcome—"
He went into the back kitchen and broughtouta beautiful little rocking-chair, which he presented to Harebell. Then he showedher someletters carved ontheback:
F.T.T.
A.B.S.
I.T.D.
Harebell screamed with delight overthechair, but puzzled over the letters.
Tom at length enlightenedher.
"I'm not a very good scholar, and my tools be notfine enoughtocarvewords, but I'veput the first letter, see?"
"From Tom Triggs A black sheep Inside the Door."
"That do describe me, by God's help."
"Oh, it's beautiful!" exclaimed Harebell. "Andso clever! Iam sure Aunt Dianawill let me have it, and I do adore a thing that rocks! Itwillbe much nicer than a rocking-horse. I used to have one of those in India."
Tom promised to bring it up that night;andHarebell wasoverwhelmingin her thanks.
At last she had to leave her friends,and shetrottedhome.It seemedto her that it was not chance that made her meet the Squire ofthe neighbourhood riding home from a hunt, with two other gentlemen with him. Itwastoo good anopportunity tobe lost.
Harebell had often seen the Squire in church, and had spoken to himonce when he had been calling upon her uncle. She nowsteppedintothe middle of the road and held up her hand authoritatively.
The Squire reined up his horse with agood-natured laugh.
"Well, little maid, are you a suffragette?Or apoliceman? Whatdoyouwant?"
Harebell was nothing if not direct.
"I want you to stop to listen to me. Tom Triggsis a very good man, and a friendof mine, and he can make beautiful rocking-chairsfit fora queen.Pleasetakehim as your carpenter and give him a cottage."
"Upon my word! Tom Triggs! Who is he? Surely notthat drunken loafer who spends his days over his beer-pot!"
"Oh, that was long, long ago; he's quite a changedman; everybody says so. At least,he's really the same, only much, much nicer."
"I know him," said one of the Squire'scompanions. "He's doing up the house I'm buying. Tom Triggs—I know the chap. He isn'ta bad workman.My foremanof works says he's the most dependable of the whole lot outthere."
The Squire looked down upon Harebell with laughingeyes.
"Now may I ask why you and he havechummed up together?An odd companionfor you, I should say."
Harebell looked up with big earnest eyes.
"I liked him when he was wicked, because I'd never seen a wicked manbefore. And then— well, you know I've been trying to get him todothings,andhe's done them all excepta cottage and a wife. I could get the wifeif you would givethecottage."
The Squire laughed heartily.
"This is most entertaining. So you can get wives for people. Could youget onefor me? I haven't one, you know."
Harebell shook her head.
"I don't know you well enough. Tomis avery greatfriendof mine. Wetalk over things, specially since we're together insidethe Door. That's thebest thing of all hehas done. He has got right through and is quite safe."
"What door?"
"It's the Door of the Kingdom. He likes tocallitthe sheepfold, but it means thesame. It tells you all about it in the Bible."
There was a minute's pause; then the Squiresaidgenially:
"I really must see this wonderful carpenter. Sendhimup tosee me—notto-day. Tomorrow morning about ten. I shall bein,andI'llhavea talkwithhim."
He nodded to her, then rode on; and Harebell dancedalong theroad for joy.
"He'll get that cottage, and then Fanny mustmarryhim!"
She told her aunt all about it when shegothome.Mrs. Keith told her she must notspeak to gentlemen whom she hardly knew when they were riding.
"It makes them think you're a most forward little girl," shesaid.
"I was so full of Tom, I didn't stop tothink," said Harebell; "andhe's made me the most beautiful rocking-chair, Aunt Diana, and he'sgoingtobringitroundto-night. You'lllet me take it, won't you? And may I tell him theSquire wants to see him to-morrow?"
Permission was given. When Tom arrived, he looked quite confused when Harebell gave him the message.
"Upon my word, missy, you don't let the grass grow under your feet! Why, youbejust wonderful with your tongue."
"And you'll tell me if you get the cottage,Tom?You'lltellmedirectly it's settled."
"There be not much chance of that, missy. TheSquirehaveknowed mein the old days."
However, Tom had his interview with theSquire, and wastaken on trial fora month, to his unbounded pride and delight. Harebellwent straightoffto see Fanny Crakewhenshe heard of it.
Unfortunately, Fanny was away from home. But Harebell wasnot easily daunted. She came home and procured a piece of paper. Inlargecopper-plate writing she wrote on it:
"Please Fanny, Tom Triggs may havethe Squire's cottage. Getready for his wife. From Harebell."
And then the next day she took thepaper andslipped it underneaththe door
But she heard nothing from Fanny. And Tom wastoo busyat workto come near her.
Lessons and games and talks with everybody who cameacrossher path nowoccupiedher time.
Mrs. Keith said to her husband one night:
"I really dread the development of that child. I don't knowwhichisbusiest—her brain or tongue. I hope she won'tgrow into a chatteringwoman. I found her havinga long dissertation to-day on the back doorstep with awandering pedlar. She knowshishistory, and all the names and ages of all hisrelations, forI heard her repeating it all to Andy in the pantry."
"Oh, she's all right!" said Colonel Keith kindly. "Sheis interested in herfellow-creatures.It is better to have one's interest circleround them thanroundoneself."
And then one day Harebell got a letter, and itwasa letter that filledher smallheart with joy and satisfaction. It was from Tom Triggs:
"MY DEAR MISSY,—I havenot yet wroteyoua letter but I doso now hoping this will find you well asitleaves me. I write tosay theSquire, he have give me the job and I thankyoudown totheground forarsking
of him to do it. I have the cottage inthe wood, and all is goingon asyou said it ought. Nex April I hopesto get it, and mother's bits will stock it fine. And Fanny Crake and me are walkingout, for onlookinground I felt as how I ought to oblige you,andthereseems no other to sootme, and Fanny says your heart be terriblesetonto it. Sowe hopesifthings go on well, to be husband andwifeinApril.Wishing youwell.
"Your obedientservant, "TOMTRIGGS."
"P.S. The best which has come to me iswhatI havenot thelearning to speak on. But I am still I humblytrust, I.T. D."
She carried this letter all day about with herand slept with it underher pillow.
Her aunt found her one evening spelling it out to herselfby the light of acandle.
"You are very fond of Tom Triggs," she said.
"He's such a good kind of friend," saidHarebell in her old-fashioned way, as shefoldedup her letter and tucked it under her pillow. "He has doneevery single thing I wantedhim to. And not many friends do that, do they?"
"Perhaps not."
"It's just five things he has done, and thewifeis thelastandbest of all."
"What things?"
"Well, first he gave up drinking, and then hegotsome work,andthen he got his cottage, and now he has got his wife."
"That is four."
"I s'pose the other thing is the reallybest thing," said Harebell, slowly and thoughtfully. "He has put it last in his letter, but I reallybelieveit came first of all."
"And what is that?"
"He came to the Door of the sheep andgotthrough it into the sheepfold."
Harebell's eyes were shining and earnestas she spoke.
Mrs. Keith stoopedand kissed her
"Yes, that is the only thing that reallymatters," she murmured.
And then when she left the room, Harebelladdedto herself:
"And in April, I mean to go to tea with them in their cottage. I said from the very firstI would do it."
She hugged her letter as she spoke, then shefellasleep.
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