The first article in this series of three summarizes the importance of filtration, the rudiments of how we measure it, and the results of research concerning how kidney stones reduce it. This article gives the details of kidney function in stone formers. It carries the key references, and supports the summary assertions of the much shorter precis. But because it does not duplicate the brief introduction to filtration per se, I advise reading the shorter first article as an introduction.
The third article tells how filtration works, and the details of its measurement in patients including the eGFR estimating equations. It illustrates how filtration affects key stone risk factors and offers a brief tour through the kidney for those who want to know where things are in it. Unlike the first and second, it is very long and complex, so perhaps only few will choose to read it.
Filtration Rates in Kidney Stone Formers
As the first article in the series mentions, physicians estimate kidney function from serum creatinine, eGFR – an index derived from serum creatinine, age, sex and race, and from clearance of creatinine CCr. This latter requires timed urine collections and we commonly calculate if from the 24 hour kidney stone evaluation urine samples when we have a corresponding paired serum creatinine measurement.
Our Population Averages
Over 45 years of practice, we have always evaluated our own stone forming patients with three 24 hour urine samples paired with three corresponding blood samples. From this trove we published mean CCr values asking of patient values lay below those from normal controls.
They do. Those with idiopathic calcium oxalate stones (CaOx in panel A and ‘ID’ in panel B) were below normal (N). All patients with stones due to primary hyperparathyroidism (HPT), bowel, or other systemic diseases, cystinuria, renal tubular acidosis (RTA) and obesity bypass surgery were obviously below normal.
Stone type also predicted CCr; apatite (Apa), struvite (Str), uric acid (UA) and especially cystine (Cys) stones associated with lower CCr values.
The magnitudes of CCr reduction were modest on average. If we take 125 ml/min as the normal mean, the most affected groups were down by an average of 20% meaning they had on average 80% of normal function. Cystinuria was lower than that, a fact noted by others before us. So although not normal, kidney function of stone formers might be spoken of as mildly impaired. This speaks to the value of prevention: Of more stones, and any injury or kidney tissue loss. Stone formers have a mild loss that calls for more than the usual precautions against further losses.
Loss Of One Kidney
Because of obstruction or surgical consequences, stone formers lose one kidney often enough we collected many such cases over our long experience. In 2003 we published CCr values over time in those with two and one kidney. Given the general reduction of filtration in stone formers one might expect loss of a kidney to have significant consequences, which is the case.
In the graph to the right, average pre-treatment CCr (mean of three measurements) is plotted against age for the two kidney patients (microdots), and those with one kidney (large circles, gray and black for men and women, respectively). Density weighted least square regression lines (solid for men and dashed for women) track the central path of the data for two kidney patients.
These regression lines make clear that CCr hardly varies between age 18 – 45, but thereafter declines in both sexes. Clearances for one kidney women lie below two kidney women, but fall at about the same rate with age. Younger men with one kidney have CCr values more or less at the two kidney level, but CCr then falls more rapidly with age. In later life, CCr of one kidney men and women lies below the lines showing two kidney averages.
This visual impression was confirmed by regression analysis in that CCr decline with age in men is higher with one kidney than with two wheres women with only one kidney lose function at the same rate as women with two kidneys.
Stone Formers vs Normals With Aging
What about stone formers with both kidneys compared to just normal people?
In that same paper we gathered data from three prior studies that had followed non stone forming people over time.
Here, to the left, kidney function is plotted as a fraction of age 20 to 25. Our data are in black triangles, men are in the panel to the left, women in the right hand panel.
Whereas CCr seems to stay constant in our stone formers until about 40 years of age and then decline (black triangles), normal people display no plateau. Kidney function fell steadily with age throughout life. As a result, at later ages all values generally overlap.
Although you might sense a conflict between these results and those showing lower kidney function in stone formers than in normals, there is no conflict. These two graphs show the changes – or loss rate – of kidney function over time, but not the absolute values as shown in the preceding graph.
Association With Chronic Kidney Disease
Our observational data come from patients at a referral center. How about population studies drawn from a broader community. Does having a history of kidney stones raise likelihood of reduced kidney function outside of a clinic population like ours?
US Population Surveys
Using the NHANES database, we asked if a history of kidney stones associated with reduced kidney function. Indeed, among overweight people, history of stones did associate with reduced kidney function. This suggested to us that loss of function might require multiple insults of which high body weight and stone disease were examples. A subsequent review of NHANES data by other investigators showed that among women but not men a history of kidney stones associated with risk of CKD and dialysis. In other words, whereas we looked only at level of eGFR or serum creatinine, this later study asked about serious kidney disease. It is more common among those who had formed stones.
Local Population Outcome Studies
In Olmsted County, where one finds Mayo Clinic, Rule and colleagues found an association between development of CKD and a history of kidney stones. This reference is to an extensive review by Rule that lists his own population work and all prior studies he could find prior to 2011. In 2012, Rule established that in Olmsted County kidney stone history associated with eventual need for dialysis. Albeit uncommon, the effect was significant. Finally in 2015, our group reviewed all of the prior evidence concerning this topic of kidney disease, blood pressure, and stones. The conclusion was, as with the work by Rule, that association is undeniable.
How Much Risk?
CKD 3 is the entry level for significant disease. In the Olmsted County study about 25% of stone formers met the criteria vs. about 18% of non stone formers.
End stage kidney disease in Olmsted County has a cumulative risk of about 0.6% in 15 years for people without kidney stones. For those with stones, the rate rises to 1.2 – 1.4% depending on the method used for verification. The hazard ratio – ratio of rates – for stone formers vs. controls without stones was about 2 – 2.4.
In the NHANES study of dialysis need, the odds ratio for dialylsis after full adjustments for confounders was 3.26 (1.48 – 7.16 95% CI). Actual age adjusted values of those needing dialysis (no other adjustments) were 1.61 and 1.52%, men and women, vs. 3.11 and 5.62% men and women with stones. The difference was significant for women not men.
I have shown you three kinds of data. The first are cross sectional CCr data comparing stone patients in a single center to normals. The second are data from a US national health survey comparing kidney function to people with and without a history of having a kidney stone. The third is a longitudinal study of a local community comparing the outcomes of CKD and dialysis in people with and stone disease. Because Mayo Clinic serves much of this population stones or not could be ascertained more directly.
That all three inquiries overlap in conclusion makes unlikely mere chance has associated stones and kidney disease. Since kidney disease has no mechanism to foster calcium stones – massively the predominant type – and stones a ready way to damage kidneys, association implies causality. Stone forming can damage kidneys and therefore prevention matters a lot.
One might imagine that increased blood pressure would be part of the process from stones to kidney disease. We found an association between stones and higher blood pressures using the NHANES database. The Rule group found it as well in the better documented Olmsted County population, even after one stone.
Taken together, one cannot easily shake the idea that stone disease can indeed lead to kidney disease of clinical consequence and also to high blood pressure. Fortunately the kidney disease only uncommonly leads to dialysis or even advanced CKD. But it does show how important prevention can be.
Last Words About Glomerular Filtration
How filtration works, and how physicians measure it, matter greatly to patients who form stones. Stone formation can lead to kidney disease, usually mild but sometimes significant. Kidney disease consists most essentially in loss of filtration. As well, stone forming may well promote hypertension.
The meaning of these results is simple and compelling. Stone forming patients need to know their eGFR values, and their physicians need to pursue any fall in eGFR with substantial efforts to locate a remediable cause such as obstruction or untreated high blood pressure. Because blood pressure itself appears to run higher among stone formers than in the general population, stone formers need to keep track of their pressures as measured in various medical settings and preferably by themselves at home using good quality OTC devices.
More fundamentally, stone prevention is always the best way to prevent kidney injury from stones. I have advocated remorselessly for early prevention and for sustained prevention. The kidney injury from stones is merely another among many reasons to pursue prevention in the service of a happier and medically sounder life.