On 2025-11-30 16:56:07, user Cyril Burke wrote:
RESPONSE TO REVIEWER #1
June 27, 2022<br />
Re: Longitudinal changes in creatinine signal early decline in glomerular filtration rate without consideration of age, sex, ‘race’, and nationality
We greatly appreciate that the reviewers were thorough, fair, and helpful in their comments.
Comments to the Author
Reviewer #1: Burke et al submit a somewhat unusual paper, devoted to a topic of potential major clinical relevance, and as yet understudied.
General comments
1. The thesis of the authors, that using the baseline serum creatinine of a given patient would potentially improve the earlier diagnosis of kidney disease, even in the normal range, is in line with the experience of this reviewer, who always retrieves, whatever the difficulty of reaching that goal, past results of blood tests, and uses them as a way to date the onset of kidney disease, sometimes with important prognostic implications.
Your experience adds support to the literature suggesting that historical sCr levels provide a context for sCr changes. These benefits might encourage investments in digital data exchanges so that electronic health records (EHRs) can ease collection and presentation of sCr results from multiple commercial and hospital laboratories.
2. Yet, the authors do not provide data strongly supporting their thesis. For instance, when looking at case 2 [now Patient 3], should the last point (the most recent one) be omitted, there would be very little evidence supporting progressive early kidney disease.
We advocate prospective monitoring of longitudinal sCr as a proxy for glomerular filtration rate (GFR). The Cases were meant to show that charting the data and simple follow-up over several visits and months can allow general clinicians to differentiate CKD from other explanations for increased sCr. The four case histories represent patients in a non-nephrology medical practice with borderline eGFR that raised the possibility of CKD. In each of these cases, retrospective collection of sCr values suggested varied explanations for the elevated sCr, and we expect many cases will represent sCr influences other than CKD, not necessarily warranting nephrology referral. Armed with this tool, and used prospectively, Physicians, nurse practitioner, and physician assistants (PCPs) might identify and manage the 90% of patients with currently unrecognized CKD.
3. The claim that the statistics fit the data better when all points are used (page 9,11) should not come as a surprise. Using thresholds instead of the full range of values has long been known to be more powerful for statistical analysis. But fitting the data does not equal to a high positive predictive value!
We agree that this is counterintuitive, so we thought this was an important point to discuss. Research methods that get translated into clinical settings rely on assumptions that are not always familiar to healthcare workers. Whatever the merits of thresholding conventions, understanding their mathematical underpinnings can inform a more nuanced interpretation of lab results. The revision includes our initial, intuitive assessment of the data and the interpretation of the residuals – from a mathematics perspective. Lack of awareness about residuals can easily lead to improper interpretation of thresholded lab data. The use of statistics is not intended to document superiority of fit but rather to demonstrate how simplifications with practical clinical value may gloss over clinically relevant information in some cases. The inclusion of additional charts seeks to take it away from abstracted statistics and toward more intuitive clinical concerns. We favor early diagnosis of kidney injury through investigation of nonspecific changes in longitudinal sCr. This method seems usable and may be manageable by PCPs using a time frame of several visits over several months to separate false positives, which may be influenced by chance attributable to the mathematical properties of lab data.
4. A key question is whether in a real-world context, the earlier diagnosis of kidney disease would be possible, without too much background noise from intercurrent illness (functional), drugs (NSAIDS, etc.). In other words, would the specificity (or PPV) of the suspicion of early kidney disease be reasonable enough to catch the attention of clinicians
We think so. We believe longitudinal serum creatinine (sCr) will encourage dialogue between patients and clinicians, raising awareness of the importance of avoiding kidney injuries that often happen out of sight and out of mind until, for far too many, culminating in urgent dialysis. In the same way that patients now ask for their blood pressure, we anticipate patients tracking their own sCr and kidney risks. Decades after introduction of the mercury sphygmomanometer, PCPs learned how to manage blood pressure to improve health. We believe longitudinal sCr can soon be a widely used tool because the concepts are old, there is a broad literature supporting this approach, and the value can be enhanced by more frequent testing of sCr. This is what PCPs do – sort the random cough, costochondritis, or stress response from nascent pneumonia, angina, and hypertension. PCPs already worry about the kidneys. They may welcome a tool to accompany the chest radiograph, electrocardiogram, and sphygmomanometer.
Of interest, the decision analysis by den Hartog et al found markedly more false-positive diagnoses of CKD with eGFR than with serum creatinine alone.
5. Even though there has been improvement in the standardization of measurement of serum creatinine (IDMS), the comparability of results measured by different labs remains suboptimal, at least in the experience of this reviewer, and medical shopping is not uncommon, making the availability of all previous results in the same graph a logistical challenge.
We share this concern, which laboratorians have wrestled with for many years and will not be solved soon. However, we propose utilizing the maximum serum creatinine (sCr-max) to smooth the variability of these inputs (as well as the variability from patient diet and hydration). One laboratory will be the highest, and when patients use multiple laboratories, one laboratory may more often define the sCr-max. As patients learn the rationale for using the same lab, we believe most (not all) will voluntarily use one or perhaps two labs (as they mostly do when we repeating longitudinal MRI imaging studies, for example). The sCr-max reduces the effect of variability between laboratories, allowing clinical insights even without future improvements in sCr assays.
Australia, Canada, and the United Kingdom have stricter sCr analytical performance goals than the United States, which could improve its sCr comparability by matching their standards.
Specific comments
1. The authors should mention that the USPTFS decided a month ago to revisit the question of screening for kidney disease in high-risk groups (page …)
One reference stated that this initiative has not been announced publicly but is “under active consideration” by USPTFS because “…for a screening to help people live longer, healthier lives, clinicians must be able to treat the condition once it is found. The existence of effective treatments is one of many important factors that the Task Force considers.” This perspective is surprising because it ignores the potential of effective prevention by avoiding NSAIDs, hypotension, dehydration, and nephrotoxic medical treatments (e.g., aminoglycosides). We, too, look forward to updated findings from USPTFS.
2. Even though ESRD has a legal meaning in the USA, not very relevant to the topic of this paper about early kidney disease, the authors should stick to the nomenclature proposed by a recent KDIGO consensus conference (see Levey et al. Nature Reviews in Nephrology). In particular, use kidney failure instead of ESRD/ESKD. When the topic is glomerular filtration, use that wording instead of kidney function (page…)
We have adopted this terminology and would welcome any further recommendations.
3. The authors allude to the concepts of prediabetes and prehypertension. But this reviewer points to the fact that the levels used to define those entities are currently “generic”, rather than based on previous values in an individual subject. Please discuss.
We understand that the normal population ranges for serum glucose and blood pressure are narrower, with less interindividual variation, so population reference ranges work well for monitoring diabetes mellitus and hypertension. Unfortunately, this is not true for serum creatinine, though within-individual reference of longitudinal sCr appears to facilitate diagnosis of pre-CKD.
4. The authors repeatedly mention in the discussion section evidence that even small increases in serum creatinine have prognostic significance. This has indeed been known for decades but is a different topic: AKI. Admittedly, there is growing evidence that AKI and CKD are linked. But that the stability of a biological parameter is prognostically best is all except surprising: the same is true for body weight, mood, blood pressure etc.
We agree that AKI and CKD appear to be merging and this may become clearer from more frequent sampling and charting of longitudinal sCr. What has been missing is graphical representation of the data to allow quick assessment for CKD in long-term trends, and this may soon be obtainable from EHRs and IT departments, which should end the practice of deleting historical data of value to longitudinal analysis.
[See next comment for Response to Reviewer #2.]