60% Of CKD Patients Are Complicated With Hyperuricemia, How To Deal With It

Previous studies have shown that with the decline of renal function, the serum uric acid level of patients with chronic kidney disease (CKD) will gradually increase, and gradually develop into hyperuricemia, and related symptoms will appear. It is reported that 25% and 60% of CKD patients have symptomatic and asymptomatic hyperuricemia. Although most scholars recognize that hyperuricemia is harmful to CKD patients, there are some differences among scholars on how to manage hyperuricemia in CKD patients. For example, regarding whether CKD patients with asymptomatic hyperuricemia need to lower uric acid, what is the uric acid control target for CKD patients?

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In February 2023, the Kidney International reports network released a literature review from scholars from many countries. The literature review summarized the existing debates on CKD with hyperuricemia in detail and believed that even asymptomatic hyperuricemia is harmful to CKD patients. It may also be harmful, and uric acid-lowering treatment should be carried out.

Chronic Kidney Disease and symptomatic hyperuricemia

The main goal of treatment for symptomatic hyperuricemia is to reduce blood uric acid levels to reduce the risk of recurrent arthritis attacks and joint damage. However, in CKD patients with symptomatic hyperuricemia, it is unclear whether urate-lowering therapy is beneficial in delaying the progression of CKD and/or cardiovascular disease. It is mainly attributed to the different opinions of experts on local inflammation, cardiovascular damage, and systemic inflammation caused by hyperuricemia.

1 Local inflammation

Urate crystal deposition occurs in patients with hyperuricemia, which can lead to gouty arthritis, which is also the most common local inflammation. In fact, urate crystal deposits may also occur in the kidneys, especially in the renal tubules. Since urine concentration often occurs in the renal tubules, the renal tubules are prone to urate crystals. These crystals may adhere to the renal tubules, causing local inflammation and damage to the renal tubules. The crystals then invade the renal interstitium and further deteriorate renal function. It is worth noting that when patients with symptomatic hyperuricemia consume large amounts of purines or fructose, the possibility of causing renal urate crystal deposition is higher.

Autopsies have shown that almost all patients with gout had some degree of renal damage before urate-lowering drugs were commonly used clinically, characterized by arteriolar sclerosis, focal segmental glomerulosclerosis, and tubulointerstitial nephritis. In addition, 20% to 25% of gout patients have significantly decreased renal function. Some scholars have suggested that urate crystals are rarely found in kidney biopsies of patients with gout, so they believe that hyperuricemia has a limited impact on the kidneys. In this regard, the experts who wrote this article believe that there are two factors that can explain this phenomenon: ①The location of renal biopsy is mainly the cortex, where uric acid crystals rarely appear; ②When processing kidney tissue, most processing methods will wash away urine. Salt crystallizes unless special handling techniques such as alcohol fixation and De Galantha staining are used.

Based on the above reasons, the prevalence of urate crystals in the kidneys of CKD patients with hyperuricemia is currently unknown. However, dual-energy computed tomography (DECT) is a noninvasive, slightly more accessible test that can detect urate crystals in blood vessels. However, there is no consensus on DECT for detecting renal urate crystals, so more research is needed.

In summary, urate crystals are very likely to appear in the kidneys and cause local inflammation, thereby affecting renal function. However, the existing inspection methods are limited and cannot monitor the prevalence of urate crystals in the kidneys. Therefore, experts disagree on this. Opinion.

2 Cardiovascular damage

Existing evidence suggests that urate crystals may be directly involved in the formation of atherosclerosis, which damages the cardiovascular system of patients. Specifically, when DECT scans blood vessels of gout patients, urate crystals are commonly found in the patients' aorta and coronary arteries. Urate crystals exist in the blood vessels of 75% to 86% of gout patients, and about 30% of gout patients have urate crystals in coronary arteries. Histological examination confirmed that the areas where these crystals existed highly overlapped with the areas of atherosclerotic plaques. Some scholars believe that urate crystals, like cholesterol crystals, will increase the risk of plaque expansion and rupture. These findings may explain why hyperuricemia and gout are found to be associated with cardiovascular adverse events and death in clinical practice.

3 systemic inflammation

Hyperuricemia can cause systemic inflammation and further damage renal function and the cardiovascular. Hyperuricemia, whether acute (gout attack) or chronic, can lead to significant increases in monocyte counts and C-reactive protein (CRP) levels. Previous studies have found that allopurinol can reduce CRP levels, and interleukin-1 antibodies can reduce CRP and reduce the risk of cardiovascular events.

Collectively, symptomatic hyperuricemia can have significant renal and cardiovascular effects in CKD patients. It is recommended that all patients with symptomatic hyperuricemia, regardless of whether they have CKD, have a target serum uric acid level of<6 mg/dL.

CKD and asymptomatic hyperuricemia

Early studies have shown that asymptomatic hyperuricemia may lead to the development of CKD, and multiple clinical studies and epidemiology also support this finding. However, 2 studies recently published in NEJM showed that allopurinol did not slow the progression of kidney disease. Therefore, guidelines in Australia and New Zealand recommend that asymptomatic hyperuricemia should not be treated in patients with CKD.

Experts believe this conclusion may be premature. First, in the above two studies, many patients with normal serum uric acid levels were included, and normal uric acid levels apparently did not significantly increase the risk of CKD progression. That is, experts believe that the baseline setting of the above research is wrong.

Secondly, these two studies are intention-to-treat analyses. As the name suggests, regardless of whether patients complete the study or not, once enrolled, they will be included in the data analysis. However, approximately 17.5% and 30% of the subjects dropped out before the trial was completed. Therefore, the study did not confirm the relationship between asymptomatic hyperuricemia and CKD progression. At the same time, the results of this study combined the efficacy, compliance, side effects, and other issues of allopurinol, and comprehensively investigated the relationship between allopurinol and reducing the progression of kidney disease.

Finally, the results of the above two studies are inconsistent with many meta-analyses, which suggest that lowering serum uric acid levels is beneficial in delaying the decline in estimated glomerular filtration rate (eGFR) and helping to lower blood pressure. It is worth noting that some studies have shown that only specific urate-lowering drugs may be beneficial to eGFR and cardiovascular, such as febuxostat.

Which patients with hyperuricemia are more prone to CKD?

Since the risk of CKD progression and CVD in CKD patients with hyperuricemia is higher than that of other CKD patients, is the risk of CKD higher in patients with hyperuricemia? Experts believe that the following three hyperuricemia patients should be paid attention to.

1 Asymptomatic hyperuricemia

Urate crystals may exist in the joints, blood vessels, or kidneys of people with asymptomatic hyperuricemia, and the corresponding organs are being "silently" damaged. It should be evaluated by DECT, and hyperuricemia should be intervened before substantial damage to renal function occurs, or the occurrence of CKD can be avoided.

2 Recurrent uric acid stones

Uric acid stones can cause local inflammation and damage, and then damage the patient's kidney or urinary tract, thereby accelerating the progression of CKD. For such patients, the pH of their urine should be low, and taking alkaline drugs, such as sodium bicarbonate, can alkalize the urine and reduce the risk of recurrence of uric acid stones. In addition, some people will produce too much uric acid due to genetic variation or dietary factors, and then uric acid stones will occur. Therefore, the lifestyle and family history of such patients should be fully understood.

3 Secondary hyperuricemia

Fatty liver, polycystic kidney disease, and obstruction of intestinal uric acid excretion can lead to elevated serum uric acid levels. For example, polycystic kidney disease can lead to increased local uric acid production; obstruction of intestinal uric acid excretion will reduce uric acid excretion. Although diet control and the use of urate-lowering drugs can control the level of uric acid, the cause of treatment can benefit patients in all aspects. At the same time, the etiology of such people may be related to the kidneys, and hyperuricemia will further increase the burden on the kidneys. Hence, doctors need to pay special attention.

In general, experts believe that attention should be paid to the level of uric acid in CKD patients, and active intervention in hyperuricemia can reduce the risk of CKD and cardiovascular diseases.

References:

1. Johnson RJ, Sanchez Lozada LG, Lanaspa MA, et al. Uric Acid and Chronic Kidney Disease: Still More to Do. Kidney Int Rep. 2022 Dec 5;8(2):229-239. eCollection 2023 Feb.

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