In order to maintain a steady state, there should be a balance between the production and elimination of urate in the body. On daily basis, equal amounts of uric acid is produced and eliminated in the body and in the process, 2/3 of the urate pool is renewed. While much emphasis has been placed on diet, it is actually the de novo synthesis from non-purine compounds that is the major source of purines in the body. In fact, strictly adhering to a low purine diet would only reduce serum uric acid levels by a modest 0.5 – 1mg/dl. On the other hand, renal excretion accounts for 70% of the eliminated urate in the body with the remainder being handled by SI flora via the process of intestinal uricolysis. I will mention a little more about this when I discuss hyperuricemia in the setting of chronic kidney disease.In 90% of patients with sustained hyperuricemia, the dominant mechanism is the impairment in the renal excretion of urate.
Thus, it would be interesting to study, how the development of chronic kidney disease would affect how our body handles uric acid. So for the next couple of minutes, I will be Briefly reviewing how the kidneys eliminate urate in the bodyDiscuss how it changes when a patient develops hyperuricemia and chronic kidney diseaseReview the association between the two conditions and explore whether we should be treating HU in CKD in the absence of Gout
The traditional model on the renal handling of urate is the four-compartment model involving the glomerulus and proximal convoluted tubules. Since uric acid is not protein-bound, virtually all of the serum uric acid is filtered at the glomerulus, with 98-99% reabsorbed in the S1 segment of the PCT, only to be secreted back in the S2 portion. Then uric acid undergoes post secretory reabsorption before finally being eliminated in the kidneys. While most references, would state that the fractional excretion of uric acid is 10% of the filtered urate, this would suggest that urate elimination is mostly dependent of glomerular filtration. However, as we can see, uric acid is rabidly reabsorbed in the PCT. In fact, the correct statement should be that 90% of the filtered urate is reabsorbed in the proximal convoluted tubules and that the fractional excretion of uric acid is secondary to tubular secretion. This now paints a more accurate picture of what is truly responsible for the renal excretion of urate.
However, over the last decade, our understanding about the renal handling of urate is changed greatly especially with the identification and characterization of organic anion transporters (OATs) and channels mainly or exclusively restricted to urate transport. Most important of these is the URAT1 Transporter which demonstrates high affinity for urate and many organic anions. URAT1 functions mostly to reabsorb urate from the proximal convoluted tubule. Terkeltaub believes that URAT1 is the most potent regulator of serum uric acid. This has also been demonstrated to be the site of action for our uricosuric agents such as benzbromarone, sulfinpyrazone, probenecid and losartan. And as we progress in our understanding about how our kidneys handle urate more OAT have been discovered and their role as either functioning in tubular reabsorption versus secretion have at least been identified.As we said earlier, 90% of patients with sustained hyperuricemia are under excretors. But how come, when we perform 24 hour measurements of urine uric acid on many of our patients, only a few patients would actually reveal results suggestive of underexcretion? As it has been shown, patients with hyperuricemia are able capable of excreting the same amount of uric acid in their urine. However, they are only able to do so, when their serum uric acid is 2-3 mg/dl higher than normal. And it is only early in the course of hyperuricemia, when the elevation is <2-3 mg/dl that we would be able to see underexcretion.
Another interesting thing about renal hyperuricemia is that there is no single mechanism by which hyperuricemia develops. Hyperuricemia may be caused by impaired tubular secretion such as what happens in the presence of competitive anions like lactic acidosis, ketoacidosis and even simple metabolic acidosis. It may also be caused by enhanced tubular reabsorption such as what happens when patients are dehydrated or in the presence of diuretic therapy and insulin resistance. Likewise, the expression of OATs particularly URAT1 may be affected when the patient ages or experiences menopause. Estrogen actually suppresses URAT1 expression and during menopause this inhibition is removed leading to hyperuricemia. And there are still disease conditions wherein the mechanism of hyperuricemia has yet to be defined such as in hypertension, hyperparathyroidism and lead nephropathy.Now when a patient develops, chronic kidney disease or a decline in renal function, the fractional excretion of uric acid actually increases. However, since the increase is not able to compensate for the decline in renal function, patients actually develop hyperuricemia. But more than the decline in GFR – other factors also come into play and lead to hyperuricemia in chronic kidney disease. These include variable levels of local tissue hypoxia, increased cell breakdown, and changes in the renal blood flow. However, in patients with CKD, there is actually an increase in the amount urate broken down via intestinal uricolysis that’s why hyperuricemia tends to be mild and as some authors would claim gout incidence isn’t as high. So intestinal uricolysis functions as a back-up means of eliminating uric acid in cases when the kidneys are not able to fully fulfil their responsibilities.
Now to segue way to our next part, what do the Philippine Azkals and Kris Aquino have in common? Well, the Azkals have Phil and James Younghusband while Kris has Phil and James Ex-husband. Along the same lines, what do gout and its complications have in common with hypertension, cardiovascular disease and chronic kidney disease? Well, all of the have been associated with hyperuricemia. The difference is, when we talk of gout we talk of the complications from urate crystallization while in HPN, CVD and CKD we talk about the results of sustained elevated levels of the soluble urate in the body.
The relationship between hyperuricemia and these three conditions are less definite compared to what we know about hyperuricemia and gout. Is hyperuricemia the cause of these conditions? Is hyperuricemia the result of these conditions. Or is hyperuricemia collateral damage by some underlying process that also causes HPN, CVD and CKD. My task is to review the relationship between HU and CKD.
Based on experimental models, hyperuricemia induces pre-glomerular disease, renal inflammation and activation of COX2 and the RAS. Uric acid is a mitogen or stimulant for vascular smooth muscle cell proliferation. Uric acid is proinflammatory as seen in the syndrome of Gout. And this leads to COX2 activation. More so, vascular smooth muscle cells in the aorta have de novo expression of COX2 messenger RNA after being incubated with uric acid. UA mediated COX2 activation has been found to be critical in the smooth muscle cell proliferation which would eventually lead to glomerulopathy and what some authors refer to as UA induced vasculopathy which would then activate your RAS. This again contributes to glomerular hypertension which would eventually worsen these other conditions. Aside from these four, uric acid also decreases endothelial nitric oxide and level of NO synthetase which are known to affect vascular tone. With these major processes into play, it is believed that hyperuricemia induces HPN, CKD and CVD. And these processes in return would cause tissue hypoxia, increased cell death and insulin resistance which would tend to worsen hyperuricemia. And the process goes on.
To be more specific for CKD, The activation of the RAS, the renal arteriolar disease and renal vasoconstriction resulted from SM proliferation and COX2 activation, the development of oxidative stress and inflammatory cell activation are believed to be major mechanisms for the development of renal disease. And other factors also come into play that lead to hypertension which can also worsen or aggravate the development of kidney disease.
Now let’s look beyond experimental studies and see if these theories hold true in reality. Up until 2009, 12 epidemiologic studies have been done assessing the relationship of hyperuricemia and chronic kidney disease. Of these 12, 4 concluded that there was no relationship between HU and CKD. But among those showing a positive result, the following studies are of note. The largest so far, conducted by Hsu among healthy volunteers in the US Renal Data System database which followed up patients for 25 years. And they found that the highest quartile (SUA >8.5 mg%) was associated with 2x risk for developing CKD compared to those in the lowest quartile (SUA <5.0 mg%) This was also supported by the study of Iseki conducted among Japanese volunteers which followed them up for 7 years. And they found that SUA>7 mg% was associated with a three-fold increase in risk for ESRD in males while a SUA>6mg% was associated with a ten-fold increase in risk for ESRD in females. The group of Obermayr and colleagues reviewed data from the Vienna Health Screening Project and found that the higher the SUA levels, the greater the risk of developing CKD. It was 26% in those with SUA 7-9 mg% and 63% in those with SUA >9mg%. And in the Atherosclerosis Risk in the Communities (ARIC) study they were able to qualify that for every mg/dl increase in SUA, the risk for CKD rose by 7-11%. In all these studies, UA appeared as an independent risk factor for CKD in the general population, surpassed only by the presence of proteinuria and HPN. And we can that there is a gradient effect – meaning that the higher the levels, the greater the risk of developing disease. And there is some suggestion, that the risk is more pronounced among females rather than males.
Hyperuricemia is a ubiquitous finding among patients with CKD, however, the relationship between HU and progression of renal disease seem less well established compared to those done in the general population. In the study by Hsu among non-diabetic CKD patients, more patients with hyperuricemia had doubling of their serum creatinine or progressed to ESRD requiring dialysis. And the earlier study on IgA Nephropathy patients seemed to support this finding. However, following adjustment and factoring for other confounders such as the baseline renal function, age, BMI, proteinuria, HPN, and other co-morbids, the conclusions were revised and the apparent associated with disease progression no longer became significant. On the other hand, among CKD patients undergoing PD, HU was associated with a faster decline in residual renal function and was associated with an increase in markers for endothelial dysfunction. The association of HU in CKD patients with CV events was further supported by the MDRD (Modification in Diet for Renal Disease) Study, wherein each mg/dl increase in SUA was associated with 16% increase in CV deaths and a 17% increase in all-cause mortality. So we can say, the association of HU in CKD progression is less definite. However, it appears that in this sub-group of patient, HU increases the risk for CV Events.
Now, just because there are studies showing that HU is an independent risk factor for CKD and CV events, we could proceed with treating all patients with AHU. More than detecting a risk factor, we should also see in trials that modification of that risk factor would prevent development of disease. So far, only a few small, short-term, single center studies have been conducted regarding the potential role of urate lowering therapy in preventing CKD progression. I excluded one retrospective trial on the role of urate lowering therapy because the population was that of liver transplant patients with <10% having AHU. The study by Siu and Colleagues in 2006 was the subject of several articles trumpeting that treatment with Allopurinol delayed disease progression among CKD patients. The study was a prospective open-label RCT among 54 patients with CKD stage 2-4 who were randomized to receive standard treatment or standard treatment and Allopurinol 100-300 mg/d for 12 months. The end points studies were an increase in crea >40% from baseline, the initiation of dialysis or death. At the end of the study, patients who received allopurinol had a trend towards lower levels of serum crea but this did not reach statistical significance. 16% in the treatment group compared to 46% in the placebo group achieved the combined end-point of the study. There was also no significant difference between groups in terms of their blood pressures and safety parameters. Goicoechea in a more recent study gave allopurinol 100 mg daily for 24 months in 113 CKD stage 3 patients. This was also a prospective open label RCT. Compared to the one by Siu, patients who received allopurinol had improvements in their serum creatinine that was statistically significant. An interesting conclusion of the study was how Allopurinol affected CV endpoints. 12% of those who received Allopurinol suffered a CV event compared to 26% in the Placebo group. The Hazard ratio was 0.29, with a NNT of 5 to prevent a CV Event. Kao and colleagues were the only ones who conducted a randomized placebo controlled double blinded study on the use of Allopurinol in CKD patients with LVH. Unfortunately, the study end points they looked at were surrogate markers for endothelial dysfunction – particularly Left Ventricular Mass Index and Flow Mediated Dilatation of the Brachial Artery.The results appear promising however, as pointed out, these studies are small, short term and single center trials which may not adequately be powered to detect the demonstration of our desired end point – which is either renal outcomes or cardiovascular events. Furthermore, there is heterogeneity in the patients enrolled. In the trajectory of CKD, Stage 2 patients fair much better and may in fact respond more to the intervention and suffer from fewer endpoints compared to Stage 4 patients. In an article by Badve, a study population consisting of at least 620 Stage 3-4 CKD patients would be able to detect soft-end points or serve as a feasibility study while at least 7470 patients would be needed to demonstrate hard end points such as decline in GFR, ESRD or death. No such studies have been thus made.
So in summary, we have demonstrated that hyperuricemia may be a cause or a consequence of chronic kidney disease and likewise, chronic kidney disease may also be a cause or consequence of hyperuricemia based on experimental and observation studies. In the general population, hyperuricemia is an independent risk factor for development of CKD and ESRD. However, the role of hyperuricemia in disease progression among CKD patients is less well established. However, it is an independent risk factor for CV events in this patient population. Small, short term studies have shown that urate lowering therapy in CKD patients may delay decline in renal function and lessen cardiovascular endpoints.
Hyperuricemia in CKD
HYPERURICEMIA INCHRONIC KIDNEYDISEASE:DO WE TREAT OR NOT?SIDNEY ERWIN T. MANAHAN, MD, FPCP, FPRAGout Special Interest Group23 July 2011
MAINTAINING URATE HOMEOSTASIS PRODUCTION Purine Ingestion Endogenous Production Reutilization ELIMINATION Renal Excretion URATE Intestinal POOL Uricolysis M 800-1500 mg F 500-1000 mg
ObjectivesBriefly review renal urate eliminationDescribe renal handling of urate during hyperuricemia and chronic kidney diseaseReview the evidence on the impact of hyperuricemia on renal diseasePresent data from intervention studies of urate lowering in chronic kidney disease
Renal Handling of Urate in Health Uric Acid Glomerulus GLOMERULAR FILTRATION 100% S1 REABSORPTIONProximal 1-2% NetConvoluted FE UA is 10% S2 SECRETION ReabsorptionTubule of the filtered is 90% of uric acid 50% filtered urate S3 REABSORPTION 8-12%
Renal Handling of Urate in Health TRANSPORTERS Reabsorption • SLC2A9v1 • SLC2A9v2 • OAT1, 3 and 4 Secretion • MRP4 • OATv1
Renal Handling of Urate in Disease Uric Acid Inhibition of tubular secretion Glomerulus Competitive anions Enhanced tubular reabsorption 100% Dehydration, diuretics, insulin resistance S1 Modulation of OAT expressionProximal 1-2% Sex hormones, aging, diuretic therapyConvoluted S2 Mechanisms incompletelyTubule defined 50% Hypertension, hyperparathyroidism, S3 certain drugs and lead nephropathy 8-12%
Uric Acid, HPN & Kidney Disease MECHANISM FOR MECHANISM FOR RENAL DISEASE HYPERTENSIONOxidative Stress NOS InhibitionRAS Activation Induction of EndothelialRenal Arteriolar Disease DysfunctionMacrophage and T cell RAS Activation ActivationRenal Vasoconstriction and Ischemia
Observational Studies in Normal AHU Author Subjects FindingsHsu et al (2009) 177,570 Risk of chronic kidney disease is 2x in the highest Volunteers quartile of SUA vs lowest quartile of SUAIseki et al (2004) 48,177 Healthy HU increased risk of incident ESRD by 3X in males and Japanese 10x in femalesObermayr et al 21,475 Austrians Risk of incident CKD was 63% in SUA >9 mg/dl(2008) Risk of incident CKD was 26% in SUA 7-9 mg/dlDomrongkitchaiporn 3499 Adults Highest quartile of SUA associated with highest risk ofet al (2005) CKD and 2.14x risk of ESRDWeiner et al (2008) 13,338 SUA increase by 1mg/dl confers 7-11% increase in the risk for incident CKD CONCLUSION In the general population, higher levels of SUA conferred greater risks for incident CKD and ESRD. The risks appear to affect females more than males.
Observational Studies in CKD-AHU Author Subjects FindingsSiu et al (2006) 177 Patients Higher SUA associated with doubling of Crea & ESRD. No association following adjustment for baseline GFRSyrjanen et al 223 IgA HU was associated with risk for progressive CKD.(2000) Nephropathy Not statistically significant following adjustment for confounders.Tang et al (2009) 134 PD patients HU was associated with faster decline in residual renalPark et al (2009) function and increased endothelial dysfunctionMadero et al (2009) 838 CKD3-4 No association between SUA and progression of CKD. Each 1 mg/dl increase in SUA correlated with 17% increase in all cause mortality & 16% increase in CV deaths. CONCLUSION In the CKD patient, there appears to be no correlation between CKD progression/ ESRD and hyperuricemia. HU was associated with endothelial dysfunction and mortality
Intervention Studies in CKD-AHUAuthor Siu et al (2006) Goicoechea et al Kao et al (2010) (2010)Patients 54 Patients 113 Patients 53 Patients with CKD Crea >120 umol/L eGFR <60ml/min and LVH U Prot >0.5 g/24hIntervention Allop100-200 mg OD x Allop 100 mg OD x 24 Allop 300 mg OD x 9 12 months months monthsMethodology Open-Label RCT Open Label RCT Double Blind RCTOutcome 16% in Allop group vs 12% in the Allop group Improvement in 46% in the control group had a CV event vs 27% surrogate markers for reached the combined in the control group endothelial dysfunction endpoint CONCLUSION In the CKD patient, treatment with Allopurinol 100-300 mg/d was associated with less progression in CKD and fewer CV events. No impact on BP and proteinuria.
SUMMARY CAUSE / CHRONIC KIDNEYHYPERURICEMIA CONSEQUENCE DISEASE Hyperuricemia in the general population increases the risk for CKD and ESRD. Hyperuricemia in CKD patients was not associated with progression to ESRD. It was associated with increased risk for cardiovascular events. Treating Hyperuricemic CKD patients with Allopurinol 100- 300 mg/d for 9-24 months preserved renal function and reduced CV Events