The WSAVA HILL´s Excellence in Veterinary Healthcare Award
State of the Stone: Epidemiological Shifts in Feline Urolith Type
Urolithiasis is a general term referring to the causes and effects of stones anywhere in the urinary tract. Urolithiasis should not be viewed conceptually as a single disease with a single cause, but rather as a sequela of multiple interacting underlying abnormalities. Thus, the syndrome of urolithiasis may be defined as the occurrence of familial, congenital, or acquired pathophysiologic factors that, in combination, progressively increase the risk of precipitation of excretory metabolites in urine to form stones (i.e., uroliths).
Naturally occurring urolithiasis is affected by many risk factors, some of which are known and some of which are unknown. Some risk factors that influence urolith formation include breed, gender, age, anatomic and functional abnormalities of the urinary tract, abnormalities of metabolism, urinary tract infections, diet, urine pH, and body water homeostasis. Each factor may play a limited or significant role in the development or prevention of different types of uroliths. Recognition and control of lithogenic risk factors is the primary goal to prevent urolith formation and to minimize their recurrence.
The Minnesota Urolith Center has performed quantitative analysis of uroliths from cats for more than two decades. During this period we have observed substantial shifts in urolith type (Figures 1, 2, 3, 4). In 1981, struvite was the most common stone representing 78% of urolith submissions. A decade later, struvite remained the most common stone; however, its prevalence had declined to 59%. By the end of the second decade, the ever-present struvite had been supplanted by the emergence of calcium oxalate (CaOx). In 2001, uroliths were retrieved from 6185 cats and submitted for quantitative analysis; 55% were calcium oxalate and 34% were struvite. Epidemiological shifts in feline urolith type were not just confined to the United States. Increased prevalence of CaOx was also observed in Asia and Europe. Because of the short time-span in which this occurred, we hypothesized that changes in husbandry and nutrition represent significant contributing factors influencing this epidemiologic shift in urolith type.
The Rise and Decline of Struvite
In the early 1970s, the association between dry diets and feline lower urinary tract disease (LUTD) became a topic of intense discussion in England, Denmark, and the United States. Also in the early 1970s, and continuing for the next decade, several groups of investigators experimentally produced magnesium hydrogen phosphate and then magnesium ammonium phosphate (MAP) uroliths in clinically normal cats by adding various types of magnesium salts to their diets.1,2 The cats developed typical signs of LUTD, including urethral obstruction; however, they did not produce the struvite-matrix urethral plugs commonly encountered in cats with naturally occurring urethral obstruction. The general consensus of many investigators and clinicians was that consumption of dry diets with excessive magnesium was an important primary cause of lower urinary tract disease of cats.
Following development of dietary protocols to induce dissolution of naturally occurring struvite uroliths in dogs, dietary protocols to dissolve naturally occurring sterile struvite urocystoliths in cats emerged in 1983.3 Their effectiveness justified the emphasis on dietary factors in development and prevention of sterile struvite urolithiasis.
In 1985, results of studies of the effects of feeding diets containing alkalinizing and acidifying salts of magnesium to clinically normal cats were reported.4 These laboratory studies shifted the focus of attention from dietary magnesium content to alkaline urine pH as a primary factor in development of struvite crystalluria. Results of these studies had a profound effect on veterinarians and the pet food industry. Many adult feline maintenance diets eventually were modified to minimize struvite crystalluria. Because of dietary modifications, the prevalence of struvite uroliths and struvite urethral plugs began to decline in the mid-1980s. Unexpectedly, the decrease in prevalence of struvite-related urolithiasis was associated with a concomitant increase in the prevalence of calcium oxalate urolithiasis, even though struvite remained as the primary mineral component of urethral plugs.
The Emergence of Calcium Oxalate
The exact etiologic cascade of events which have lead to the increased prevalence of CaOx uroliths remains unknown. Results of epidemiologic studies support the hypothesis that diets designed to minimize MAP urolith formation may have inadvertently increased the occurrence of CaOx uroliths.5,6 Several biologic phenomena provide plausible explanations for this association. Whereas diet mediated urine acidification enhances the solubility of MAP crystals in urine, dietary acids promote CaOx crystalluria by inducing hypercalciuria. This association between aciduria, acidemia and hypercalciuria may be explained by the fact that acidemia promotes mobilization of carbonate and phosphate from bone to buffer hydrogen ions. Concomitant mobilization of bone calcium may result in hypercalciuria. In addition, metabolic acidosis in dogs, humans, and rats resulted in hypocitraturia. If consumption of dietary acids precursors is associated with hypocitraturia in cats, it may increase the risk of CaOx uroliths because citrate is a probable inhibitor of CaOx crystal formation.
The Price of Progress
Over the past 50 years, the incidence of calcium oxalate uroliths in human beings living in the United States has increased considerably.7 Global distributions of urolithiasis in human beings indicate that calcium oxalate uroliths predominate in the United States and other industrialized, technologically advanced regions of the world.8 Although originally attributed to the sedentary lifestyle of inhabitants of such countries,8 increased incidence of calcium oxalate uroliths now is believed to reflect the ability of these more affluent societies to spend disposable income for the consumption of animal protein, which leads to increased urinary excretion of calcium and oxalate.9,10 Regional environmental factors, such as water and soil quality, also may influence urolith formation. It is logical to consider that variables contributing to the increased incidence of calcium oxalate uroliths in human beings also may influence the incidence of calcium oxalate uroliths in cats. In other words, are strategies incorporating the concepts of improved nutrition or over-nutrition a risk factor for calcium oxalate urolith formation?
The Age of Nephroureterolithiasis
The increase in occurrence of CaOx uroliths in cats has been associated with a parallel increase in occurrence of CaOx uroliths found in their kidneys and ureters. In fact, there has been a 10-fold increase in the frequency of upper tract uroliths diagnosed in cats evaluated at veterinary teaching hospitals in North America during the past 20 years.11
Between 1981 and 2003, the Minnesota Urolith Center analyzed nephroureteroliths from 1599 cats. Seventy percent had uroliths composed of CaOx. By contrast, only 8% were composed of MAP. While enrolling cats with renal failure into a clinical trial, we were unexpectedly surprised to recognize that 48% of cats had radiographic evidence of nephroliths or ureteroliths. This finding emphasizes the importance of CaOx prevention and control in cats to minimize potential life-threatening renal failure.
Is kidney disease a cause or consequence of urolith formation? Hyperoxaluria may be the common link between these two processes. One current hypothesis proposes that excessive oxalate damages kidney tubules.12 The damaged tubules become mineralized (Randall's Plaques--sites of interstitialmineralization at or near the renal papilla found inkidneys of CaOx-stone formers) and serve as a nidus for calcium oxalate precipitation (epitaxy). By increasing urine saturation, hyperoxaluria also promotes precipitation of calcium. In turn, CaOx uroliths of sufficient size can block the ureter promoting kidney failure.
The Epoch of Hope
During the years following 2001, the Minnesota Urolith Center has observed a consistent decline in the yearly percentage of cats with calcium oxalate uroliths (Figure 1). Although factors other than a change in the occurrence of calcium oxalate may contribute to this reduction, we have taken the optimistic perspective that increased knowledge and understanding of the risk factors associated with calcium oxalate formation have favorably altered husbandry, nutrition, and veterinary care.
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Figure 1. The yearly percent of cats with uroliths composed of calcium oxalate compared to those composed of magnesium ammonium phosphate (Minnesota Urolith Center; n= 83,601 submissions).
Figure 2. The yearly percent of cats with urethral plugs composed of calcium oxalate compared to those composed of magnesium ammonium phosphate (Minnesota Urolith Center; n = 6,310 submissions).
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