Kidney stone compositions and frequencies in a Norwegian population

Abstract

Objectives: The aim of this study was to investigate frequencies of kidney stone constituents in a Norwegian population and examine trends over time by comparing with an earlier study of this population.

Materials and methods: Upper urinary tract calculi consecutively collected from patients who underwent stone surgery at Akershus University Hospital from July 2014 to December 2017, in total 1252 calculi, were analysed by infrared spectroscopy. The results were compared with a study of 500 calculi collected from June 1975 to September 1980 at the same hospital.

Results: The male:female ratio was 1.83:1. Single-component stones constituted 39%, 35% were binary, and 25% ternary. Main stone component frequencies were oxalate 71.3%, calcium oxalate monohydrate 53.7% with higher occurrence in males, calcium oxalate dihydrate 17.6%, carbonate apatite 10.8% and struvite 5.7%, both with higher occurrence in females, uric acid 8.9% with a non-significant male predominance, brushite 1.6% and cystine about 1%. Over four decades the frequency of UA stones increased by 4.6-times, whereas struvite and pure carbonate apatite stones decreased and no change was observed for brushite stones.

Conclusion: Frequencies of kidney stone types in this Norwegian population are mainly in accordance with other studies, except a large increase in UA stones over four decades, partly caused by a particularly low frequency of UA stones in the old study, a decreased carbonate apatite frequency over four decades, and an unaltered brushite frequency. Also, in contrast to other studies, a relatively small and non-significant male UA stone predominance was found.

Keywords:

• Kidney stone
• calculi
• nephrolithiasis
• epidemiology
• stone type
• stone composition
• infrared spectroscopy
• uric acid

Introduction

Nephrolithiasis is a common disease worldwide and affects 5–13% of the population in industrialized countries [1]. The incidence and prevalence of kidney stone disease have increased over the last decades, and changes in living standard and dietary habits and improvements in clinical-diagnostic procedures are supposed to explain this increase [2–4].

Kidney stones occur more frequently in males, with male:female ratios of 1.5–2.5:1 [1]. Knoll et al. [5] found an increasing male:female ratio over three decades. However, several studies have found reductions of the male predominance, indicating that this disease has become more common among women in recent decades [6,7]. The composition of kidney stones varies across sex and age [4,5,8,9]. Calcium oxalate (CaOx) and uric acid (UA) stones are reported to occur more frequently in males, whereas calcium phosphate (CaP) and struvite stones are more prevalent in females. Oxalate stones are relatively more common among those who are 40–70 years old. The frequency of UA stones increases with age. Struvite stones are found in the lower and upper age ranges. Cystine stones and other stones of metabolic origin occur more frequently at younger ages.

In parallel with the increased occurrence of kidney stones, the frequencies of the various stone types have also changed during the last decades. The main changes reported are increased frequencies of CaOx [10], UA [4,11] and brushite [4,5,10] stones and decreased frequency of infection stones [4,5,10]. The stone type frequencies also vary between countries due to different risk factors in the populations [1,4,9]. Only two reports exist of the stone compositions in Norwegian populations [12,13], and in the study from the same hospital as our study conducted by Otnes [12] four decades ago, a remarkably low UA frequency of 2.0% was reported. The aim of the present study was to investigate frequencies of kidney stone components in patients who underwent stone surgery at our hospital and then to compare our results with the study of Otnes [12].

Materials and methods

Patient population

In the period from July 2014 to December 2017, 2391 patients were hospitalized in the Department of Urology at Akershus University Hospital (Ahus) with CT-scan verified upper urinary tract stones. Of these, 220 were treated with extracorporeal shock wave lithotripsy. A total of 1252 patients underwent stone removal by percutaneous nephrolithotomy (n = 112), ureterorenoscopy (n = 634) or ureteroscopy (n = 592) (some patients needed more than one surgical procedure). All calculi from these 1252 consecutively treated patients were retrospectively included in the study. Ahus covers urological services for nearly 10% of the Norwegian population (about 500,000 inhabitants).

The results of this study were compared with the study of Otnes from the same hospital as our study, where 500 upper urinary tract stones were consecutively collected from June 1975 to September 1980 [12].

Kidney stone analysis

All calculi were analysed at the Department of Multidisciplinary Laboratory Medicine and Medical Biochemistry at Ahus, by attenuated total reflectance (ATR) Fourier transform infrared spectroscopy (FTIR). The stone components were reported with a resolution of 10%, as suggested by Mandel et al. [14].

Statistical analysis

Frequencies were compared using the chi-square test. A p-value < 0.05 was considered significant. Age was, when relevant, expressed as mean ± standard deviation.

Results

The male:female kidney stone ratio was 1.83:1 (810 males and 442 females). The patients were 1–97 years old, with a mean age for men and women of 54.4 ± 16.2 and 52.6 ± 17.0 years, respectively. Of the stones, 1.8% were from patients younger than 18 years. In total, 15 components were identified in the 1252 stones. The frequencies of the main component in each stone are displayed in Table 1 and the occurrences of the various components in all collected stones are displayed in Table 2. The frequencies of pure stones and the different combinations of components in mixed stones are presented in Table 3. For comparison, results from Otnes [12] are included in Tables 2 and 3. As Otnes [12] included only the first stone from each patient, we have extended Tables 2 and 3 with frequencies obtained after excluding recurrent stones of struvite, brushite, UA and cystine; i.e. stones with high recurrence rates.

Table 1. Stone composition expressed as main component (≥ 50%). Gender difference analysed with chi-square test.

Main stone component (%)	Females n = 442	Males n = 810	p-value (F vs M)	Total n = 1252
CaOx	63.1	75.7	<0.001*	71.3
COM	47.1	57.3	<0.001*	53.7
COD	16.1	18.4	0.30	17.6
CA (without Str)	16.2	7.8	<0.001*	10.8
Bru	1.0	2.0		1.6
Str	10.6	3.0	<0.001*	5.7
UA	7.5	9.8	0.18	8.9
Cystine	1.4	1.2	0.86	1.3
Other^a	0.5	0.4		0.4

*Significant difference; p < 0.05.

^aIncludes four protein stones and one stone of 1-methyl-xanthine.

CaOx, calcium oxalate; COM, calcium oxalate monohydrate (Whewellite); COD, calcium oxalate dihydrate (Weddellite); CA, carbonate apatite (Dahllite); Str, struvite (magnesium ammonium phosphate hexahydrate); UA, uric acid.

Table 2. Occurrence (%) of kidney stone constituents.

Number of upper urinary calculi, nComponent present (%)	Female	Male	p-value	Total	Otnes [12]	p-value
	n = 442	n = 810	(F vs M)	n = 1252	n = 500	(Present study vs Otnes' study [12])
CaOx	77.4	87.0	<0.001*	83.6
COM	74.0	82.2	<0.001*	79.3	85.0	<0.01*
COD	40.3	42.0	0.56	41.4	66.8	<0.001*
CA	54.1	30.0	<0.001*	38.5	67.4	<0.001*
Bru	1.6	2.7	0.20	2.3
Bru†				1.8	3.0	0.11
OP	2.3	3.7	0.17	3.2	0.6
Str	10.6	3.0	<0.001*	5.7
Str†	7.7	2.2	<0.001*	4.1	6.6	0.031*
UADH	1.6	2.5	0.30	2.2	—
UA	9.3^0	12.0^0	0.14	11.0^0
UA†	8.0^0	9.8^0	0.31	9.1^0	2.0	<0.001*
AmU	1.8	1.1	0.31	1.4	0.2
Cys	1.4	1.2	0.86	1.3
Cys†				0.6	0.6
Protein	8.4	6.4	0.20	7.1	—
Miscellaneous	0.5	0.2		0.3	—

Comparison between genders and with the study of Otnes [12] using the chi-square test.

For better comparison with Otnes’ [12] study where only the first stone from each patient was included, we also report frequencies after excluding recurrent stones of brushite, struvite, UA, and cystine (marked with †).

* Significant difference; p < 0.05.

OP (other phosphates), amorphous carbonated calcium phosphate, whitlockite and octa-calcium phosphate; UA⁰, anhydrous UA; UADH, uric acid dihydrate; AmU, ammonium hydrogen urate; Cys, cystine; Miscellaneous; 1-methyl-xanthine, N-acetylsulfamethoxazole and unidentified substances. Other abbreviations, see Table 1.

Table 3. Frequencies (%) of pure and mixed stones in the present study compared with the study of Otnes [12].

		Females (n = 442)	Males (n = 810)	Total (n = 1252)	Otnes [12] (n = 500)	p-values (present study vs Otnes' study [12])
CaOx	COM	19.0	34.4	29.0	8.8	<0.001*
	COD	0.9	1.1	1.0	0.4
	COM + COD	12.4	17.5	15.7	18.8
	Pure CaOx stones	32.4	53.1	45.8	28.0	<0.001*
CaP	CA	4.1	0.6	1.9	4.8	<0.001*
	Bru	0	0.4	0.2	0.2
	Bru + CA ± OP	1.1	0.7	0.9	1.0
	CA ± OP	0.5	0.6	0.6	0.2
	Pure CaP stones	5.7	2.5	3.6	6.2	0.016*
OxP	COM + CA	12.2	3.3	6.5	8.2	0.197
	COD + CA	1.6	2.3	2.1	0.4
	COM + COD + CA	23.3	17.5	19.6	45.2	<0.001*
	COM/COD ± CA + OP	1.6	2.7	2.3	0.6
	COM/COD + Bru	0.5	0.5	0.5	1.6
	COM/COD + Bru ± CA ± OP	0	1.0	0.6	0.2
	All OxP stones	39.1	27.4	31.5	56.2	<0.001*
Str	Str	0.2	0.1	0.2	—
	Str + CA ± OP	8.1	1.7	4.0	5.6	0.119
	Str + CA + COM/COD	1.8	0.5	1.0	1.0
	Str + CA + AmU ± OP	0.5	0.6	0.6	—
	All Str stones	10.6	3.0	5.7
	Str†	7.7	2.2	4.1	6.6	0.031*
UA	UA	5.2	5.6	5.4	0.8
	UA/UADH	0.5	1.0	0.8	—
	UA, pure†			5.0	0.8
	UA/UADH + COM	2.7	4.6	3.9	1.0
	UA/UADH + COM + COD	0.5	0.4	0.4	0.2
	UA/UADH + COD	0	0.2	0.2	—
	UA/UADH + AmU	0.5	0.2	0.3	—
	All UA stones	9.3	12.0	11.0
	UA†			9.1	2.0	<0.001*
Cys		1.4	1.2	1.3
	Cys†			0.6	0.6
Other	Remaining stones	1.6	0.9	1.1	0

†denotes frequencies when only including one stone per patient.

*Significant difference; p < 0.05.

CaP, calcium phosphates; OxP, CaOx + CaP. See Tables 1 and 2 for other abbreviations.

Frequencies of stone constituents

Single-component stones accounted for 39% of all stones, 35% were binary, 25% ternary and 1% consisted of more than three different minerals. The most frequently found mineral was CaOx, which was present in 83.6% of all stones, the major component in 71.3% of the stones, and 45.8% of the stones consisted of pure CaOx. Calcium oxalate monohydrate (COM) was found in 79.3% of the stones, and was the major component in 53.7% and the only component in 29% of the stones. Similarly, calcium oxalate dihydrate (COD) was detected in 41.4%, the main component in 17.6%, and the only component in 1% of the stones. COM was significantly more common in stones from males.

Carbonate apatite (CA) was found in 38.5% of all stones and 10.8% contained CA as the main component, struvite-containing stones excluded. CA was significantly more common in stones from females and CA (devoid of struvite) was the main component in stones from females twice as often as from males. Other CaP minerals were uncommon. One of these minerals, brushite, was present in 2.3% of the stones, and 1.6% of the stones had brushite as the main component, and it occurred commonly together with CA and CaOx, while pure brushite was rare (0.2%). Only 3.6% of all stones were pure CaP stones.

Struvite was found in 5.7% of all stones, with a 3.5-times higher frequency in females. Female struvite stone-formers were older compared to the entire female stone patient group (mean age (63.8 vs 52.6 years) and all were older than 18 years. In contrast, several male struvite formers were younger than 18 years. Nearly all struvite stones also contained CA and less often also CaOx, protein and ammonium hydrogen urate (AmU).

Anhydrous UA was present in 11.0% of all stones, whereas the dihydrate form (UADH) was present in 2.2%. UA was found as the main component in 8.9% of all stones, with a non-significant male predominance. Pure UA had a frequency of 6.2% and mixed UA-COM/COD stones 4.5%.

AmU in small amounts was present in 1.4% of all stones and was commonly mixed with struvite, UA, or CaOx. Cystine stones had a frequency of 1.3%, and all were pure. Protein, mainly small amounts, was found in 7.1% of the stones, and was most often combined with struvite, oxalate, and phosphate.

Comparison with the four-decade old study of Otnes

The male:female kidney stone ratio of 1.83:1 in our study is not statistical different from the ratio of 2.0:1 in Otnes’ [12] study (p = 0.39). In the present study, 39% of the stones contained only one component, which is considerably higher than the 15.8% reported by Otnes [12]. Compared to Otnes’ [12] study, we found significantly lower frequencies of stones containing COM and COD, but higher frequencies of pure CaOx and COM stones (Tables 2 and 3). Furthermore, our study showed significantly lower frequencies of CA-containing stones and also of pure CA and CaP stones compared to the older study, whereas a non-significant lower frequency of brushite was found in the present study (Tables 2 and 3).

However, the most striking difference between Otnes’ [12] and the present study is the considerably increased frequency of UA-containing stones. Excluding recurrent UA stones in these patients, the increase is from 2.0% to 9.1%. The proportion of pure UA stones and mixed UA-COM/COD stones increased from 0.8% to 5.0% and from 1.2% to around 3.8%, respectively.

The frequency of struvite stones in our study was 5.7% for all consecutively included stones and 4.1% when recurrent struvite stones were excluded, which is a statistically significant reduction from the 6.6% reported by Otnes [12]. Cystine stones had a frequency of 1.3% in our complete consecutive stone collection and 0.6% if only one cystine stone per patient was included, which is the same as in Otnes’ [12] study. Otnes [12] did not report gender-specific frequencies of stone components.

Discussion

We found a large increase in UA-containing stones over the last four decades, from 2.0% to 9.1%. A UA stone frequency of 3.8% was reported in a Norwegian study from 1970 from the same geographical area [13], and a frequency of 4.3% was found in a Danish study from 2007 [15]. Chemolitholysis of putative UA stones is not mentioned in the two Norwegian studies, and, therefore, we must assume that UA stones indeed were rare in Norway four decades ago. The increased UA stone frequency in Norway may be explained by changes in dietary habits (e.g. increased meat consumption) and increased frequencies of obesity, metabolic syndrome, and diabetes type 2 [16,17]. In contrast to most reports, Knoll et al. [5] found a stable frequency of UA stones over several decades, although with significant regional differences. The increased frequency of mixed UA stones (UA-COM/COD) is also coherent with increased meat consumption and obesity in the Norwegian population over the last four decades [18–21].

The 8.9% UA stone frequency in our study is in accordance with other recent studies (Table 4). However, contrary to other studies [4,5,9], we found a non-significant male predominance. The reasons behind the relatively small gender difference in our population are not known, and the age of males and females with pure UA stones was similar, 59.8 ± 12.1 vs 60.9 ± 12.7 years, respectively. A greater increase in men with high body mass index (BMI) over two decades compared to women was found in a Norwegian population [22]; however, women had a greater increase in abdominal obesity (waist circumference, WC). Obesity-related health risk is found to be explained by WC and not BMI [23]. As we do not know if this greater increase in WC applies to women in our population, we can only speculate whether this may explain or contribute to the relatively high UA stone frequency in women compared to men.

Table 4. Comparison of the present study with other recently published studies.

	Present study, 2018	Mandel et al. [14], 2017	Lieske et al. [8], 2014	Daudon and Jungers [9], 2012	Knoll et al. [5], 2011
n	1,252	88,768	43,545	31,430	224,085
Country	Norway	US	US	France	Germany
Period of stone sampling	2014–2017	1980–2015 (approximately)	2010	2001–2010	1977–2006
Spontaneously passed stones included	No	Yes	Probably	Yes	Yes
Only first stone per patient included	No	No	Yes	No	No
Method(s)	FTIR	FTIR (occasionally also X-ray diffraction)	FTIR	FTIR	FTIR, X-ray diffraction, polarization microscopy
Ca-stones					(84.1/81.3)
CaOx	71.3 (75.7/63.1)	61	67.3 (74.1/58.1)	69.7 (74.9/57.9)
COM	53.7 (57.3/47.1)	42		49.7 (52.0/44.5)
COD	17.6 (18.4/16.1)	18		20.0 (22.9/13.4)
CA	10.8 (7.8/16.2)^a	15^b	16.1^a (9.6/25.0)	12.3 (7.0/24.1)
Brushite	1.6 (2.0/1.0)	3	0.9^c	2.2 (2.4/1.9)
Struvite	5.7 (3.0/10.6)^c	6	3.0 (1.8/4.6)^c	6.2 (3.6/12.0)^c	(3.8/11.0)^d^,^e
UA (incl. UADH)	8.9 (9.8/7.5)	11.6	8.3 (10.3/5.5)^c	9.9 (11.2/7.1)	11 (11.7/7.0)^e
Cystine	1.3 (1.2/1.4)	2	0.4^c	1.5 (1.2/2.1)	0.6 (0.4/0.7)^e

Frequencies (%) of stone types are classified as main stone components (≥50%) unless otherwise specified. Male/female frequencies are reported in the parentheses.

^aCA without struvite. ^bBasic calcium phosphate (includes hydroxyl apatite, carbonate apatite, whitlockite and octa-calcium phosphate). ^cAny presence of the mineral. ^dAll infection stones, including struvite, magnesium ammonium urate, newberyite and ammonium hydrogen urate. ^eStones containing 20% or more of the actual component.

Our finding of 10.8% of the stones containing CA (without struvite) as the main component is in accordance with other studies. However, we found a significantly lower frequency of pure CA stones than four decades ago (reductions from 6.2% to 3.6% (CaP) and 4.8% to 1.9% (CA), Table 3). This is in contrast to other studies, which found increasing frequencies of CaP stones [5,24]. Daudon et al. [10] also found a decrease in CA stones without struvite over a similar period, from 10.6% to 8.4%. However, their study showed no change in the frequency of CaP stones free of struvite. CA stones constitute a heterogeneous group with different etiologies, and the reasons behind the decrease in CA stones observed in our study are, therefore, far from obvious. One possible explanation is a reduction in CA stones caused by infection. The frequency of struvite stones in our study was 5.7%, which is comparable to other recent studies, although higher than in the study of Lieske et al. [8], who reported a frequency of 3.0%. However, our frequency when including only one struvite stone per patient is 4.1%, and, besides, Lieske et al. [8] found a considerably higher frequency of CA stones in women (25%) than observed in our study (16.2%).

The frequency of brushite stones in this Norwegian population is similar to other studies (Table 4), but, contrary to other studies [4,5,10], we found no increase over the last decades. The reasons behind this are unknown.

Two limitations with our study are the low number of kidney stones included and the way of including stones. Only stones from patients undergoing stone surgery were included, and some patients delivered more than one stone. Our study does, therefore, not reflect epidemiological kidney stone frequencies in the general population; in this respect as many spontaneously passed stones as possible should be included and only the first stone per patient. However, one strength with our stone collection is that it constitutes a complete clinical stone material from all patients in need of surgical treatment.

Several shortcomings and potential limitations arise when comparing our study with Otnes’ [12] and other studies. First, limitations occur because of differences in stone inclusion criteria, as mentioned above, as Otnes [12] also included spontaneously passed stones (27% of the stones in his study) and only the first stone per patient. Spontaneously passed stones mostly contain oxalates [25,26] and including these may result in a higher frequency of CaOx stones and a lower frequency of more severe and larger stones such as infection stones. Secondly, Otnes [12] reported stone components with concentrations as low as 1%, while we did not report components less than 10% (except for struvite). This lower limit of detection in Otnes’ [12] study could explain his finding of higher frequencies of stones containing COM, COD and CA (Table 2) and OxP (Table 3) compared to our study, and his finding of only 15.8% single-component stones, compared to our 39% and Mandel et al.’s [14] 41%. CaOx stones containing tiny amounts of CA representing Randall’s plaque are probably the largest group of stones with discrepant results between our and Otnes’ [12] study. Additionally, the reporting of mixed stones is not standardized. Table 4 displays, along with our study, an overview of some large investigations of kidney stone constituents, and the differences regarding stone type classification are specified. It is recommended to report the occurrences of various kidney stone components and the different combinations of components in mixed stones in addition to frequencies of the main components [9]. The type of surgery may also represent a bias. The present day endoscopic surgical procedures are faster and simpler, with low morbidity and rapid recovery, which may result in less willingness to await spontaneous stone passage compared with the practice in the era of open stone surgery (before 1980–1985). This may result in a higher CaOx frequency compared to, i.e. infection stones. In our study, all stones were removed by mini-invasive techniques, while in Otnes’ [12] study most of the stones were removed by open surgery and only 11% endoscopically. We found a higher CaOx:struvite ratio than in Otnes’ [12] study; however, other explanations, such as an increased frequency of CaOx stones and a decline in infection stones, are presumably more likely.

Conclusion

A large increase in the UA-stone frequency over time was found in this Norwegian population, partly caused by a very low frequency of this stone type four decades ago, and also the UA-stone gender difference was smaller compared to other studies. The CA-stone frequency decreased, while the brushite frequency was unaltered over four decades.

Disclosure statement

The authors report no conflicts of interest.