Mixed stones: urinary stone composition, frequency and distribution by gender and age

Urolithiasis is a highly prevalent disease worldwide that poses a significant economic burden on healthcare systems [1‐3]. The cumulative recurrence rate of urinary stones has been reported to be about 50% at 10 years [4]. The consequences of a high recurrence rate include a deterioration in the quality of life of stone formers [5]. Nephrolithiasis may also increase the risk of developing chronic kidney disease through several putative mechanisms, which differ according to the composition and size of stones [6]. Proper stone analysis is the essential prerequisite for the classification of the patient into risk groups, further diagnostic procedures, effective therapy and recurrence prevention of urinary stone formation [7‐9].

Most previous studies on urinary stone composition have focused on the major stone component, which simplifies data analysis [10‐14]. However, the majority of urinary calculi are mixed stones consisting of two or more components [15]. Knowledge of the different combinations and proportions of urinary stone constituents in specific mixtures as a function of gender and age might provide insight into the pathophysiological processes of urinary stone formation. Moreover, it is important to identify and quantify the individual components of each stone to ensure proper treatment of stone patients. However, findings of previous studies on the composition of mixed stones were based on a rather small number of cases [15‐17].

In a study on a limited number of different mixtures of stone components, the influence of patient age was not considered [18]. Although data on the association between stone composition and age are available from a high-volume urinary stone analysis laboratory, stone composition has been determined using different methods [19]. The aim of this study was to investigate the exact composition and frequency of mixed stones and to determine the distribution by gender and age of patients in a large series of urinary stone analyses to gain insight into the characteristics and potential pathophysiological processes involved in the formation of the specific combinations.

Most previous studies on urinary stone composition have focused on the major stone component [10‐14]. The few studies that evaluated the frequency of mixed stones were based on a rather small number of cases [15‐17]. A study of 10,000 urinary calculi in patients from East Berlin, Germany, revealed that about 70% of stones were composed of more than one component [16], while in a study of 10,438 calculi conducted in France, 93.1% were classified as mixed stones [15]. According to a study in the Chinese population 66.8% of stones consisted of two or more constituents [18]. Although it is known that most stones contain more than one component, the exact composition and distribution by gender and age of the patients have not yet been analysed in large series.

In the present study of 42,519 urinary stones, 73% consisted of two or more components, accounting for the vast majority of all stones. CaOx, i.e., COM, COD, and mixed COM-COD, were the predominant stone types, comprising 49.8% of all calculi. The combination of COM-COD was the most frequent mixture, accounting for 32.4% of all stones, which is consistent with previous findings [16]. COM, the most common single-component stone, was substantially more abundant compared to COD, with a ratio of 10:1 in both genders. Moreover, in 85% of COM-COD stones, the proportion of COM was above 50%. Previous studies have already reported a higher proportion of COM compared to COD in both sexes [10, 14]. An explanation for the high proportion of COM compared to COD could be the formation process of the two crystal forms of CaOx. COM is the thermodynamically more stable hydrate form, while COD is metastable and is considered the primary phase of CaOx stone formation [21, 22]. The conversion of COD to COM in urinary calculi has been convincingly demonstrated [21‐23]. The distinction between COM and COD and the COM-to-COD ratio is of clinical interest, especially when deciding on the stone removal method, since COM is difficult to disintegrate due to its density and hardness [24]. Knowing only the major constituent of a urinary stone may not allow adequate prediction of its fragility in lithotripsy treatment [25].

Although CA was the second most common stone constituent in the present study, accounting for 36.8% of all urinary stones, 95% were mixtures of CA with various stone components, including COM, COD, struvite, protein, brushite, and ammonium urate. The vast majority of CA-containing stones were combinations with COM and/or COD, accounting for 32.0% of all stones. In both COM-COD-CA and COM-CA stones, CA was mainly present in proportions below 30%, whereas the CA content in COD-CA stones was predominantly high. While the male-to-female ratio of COM, COD and COM-COD were similar at 3.41, 3.42 and 3.45, respectively, the male-to-female ratio for mixed COM-COD-CA, COM-CA and COD-CA were only 2.12, 1.32 and 1.21, respectively. Identification of CA and various other stone components in mixed stones is of interest in the etiology and treatment of urolithiasis. The predominantly low proportion of CA in COM-COD-CA and COM-CA stones suggests that growth over sites of (Randall’s) interstitial CA plaque appeared to be the mode of CaOx stone formation in these patients [26]. Because 50% of all urinary stones consisted of COM and/or COD without detectable CA, other mechanisms of CaOx stone formation are also conceivable. Another explanation could be that the percentage of CA in COM and/or COD stones was less than 5% and thus below the detection limit of the analytical method. Causes that contribute to the formation of CA-containing stones include conditions that result in a transient or persistently high urinary pH, hyperphosphaturia and hypercalciuria, such as primary hyperparathyroidism, complete and incomplete distal renal tubular acidosis, medullary sponge kidney, renal phosphate wasting disorders, abuse of absorbable antacids and drugs inducing proximal renal tubular acidosis (carbonic anhydrase inhibitors) [27, 28]. Although urinary tract infection is not a prerequisite for the formation of CA-containing stones, infectious conditions favour CA formation [27]. Treatment of mixed stones such as COM-CA, COD-CA, and COM-COD-CA can be challenging because therapy for CaOx stone disease includes urinary alkalization, whereas urinary acidification is indicated for CA stones [9, 29].

In the present study, UA stones, consisting of UAA, UAD, and mixed UAA-UAD, were the third most common type of stone, accounting for approximately 8% of all stones. Among the various constituents admixed with UAA and/or UAD, COM and/or COD were the most common components. These findings are consistent with previous studies [16, 17, 30]. The differentiation of UAA/UAD stones from non-UA calculi and the quantification of mixed components is critical because pure UA stones can be treated with oral chemolysis via urinary alkalization rather than surgical procedures [9, 31].

Rare single-component stones and rare mixtures of different constituents accounted for 8.8% of all stones. Rare stone types include, for example, cystine, brushite, struvite, 2,8-dihydroxyadenine, protein, ammonium, sodium and potassium urate, various mixtures of these stone constituents with each other and/or with COM, COD, UAA, UAD and CA. The majority of these stones are deemed at high risk of recurrence [9]. Rare mixtures of stone components may pose an additional challenge for diagnosis, treatment and recurrence prevention. Delay in recognizing and evaluating a rare stone disease in a patient may cause chronic kidney disease that would have been preventable [32].

Age was significantly inversely associated with the number of stone components. Furthermore, the proportion of men decreased significantly with the number of stone constituents. However, the reason for these associations remains unclear. Future research is needed to evaluate the impact of other factors on the formation of mixed stones, including comorbidities such as diabetes, hypertension and gout, and to assess the potential effects of medical management in changing stone composition trends. Even though information of how a stone might have been formed is lost when it is fragmented, such as the presence of Randall’s plaque, analysis of the fragments still allows for the mineral composition to be determined [8]. To clarify the causes and mechanisms of mixed stone formation, further studies on whole stones, i.e. spontaneously passed calculi and stones fully extracted by URS or PNL, are required. Although the observation of stone morphology is of potential use, more work needs to be done before it can be added to the standard stone analysis [28]. Since the current data confirm the frequency of mixed stones reported in previous studies, it can be assumed that the present findings can be generalized to countries other than Germany. This largest series of stone analysis to date differentiating between gender- and age-specific aspects should provide clues to the formation process of a number of different mixed stones.

Urinary stones rarely consisted of a single component. The vast majority of urinary calculi contained two or more components in a wide variety of different combinations. While age was inversely related to the number of stone constituents, the proportion of women increased significantly from single-component to four-component urinary calculi. Mixed stones might present a challenge for evaluation, targeted therapy and recurrence prevention of urinary stone formation. Therefore, identification and quantification of the individual stone components in mixed stones is critical for the etiology, diagnosis, and personalized treatment of urolithiasis. Understanding the pathophysiologic processes involved in the formation of mixed stones is essential to ensure appropriate prevention of stone recurrences. A personalized approach that considers all clinically relevant stone constituents could improve the treatment outcome of urinary stone disease.