Roles of hypertension and proteinuria in chronic kidney disease (Proceedings)

By altering pre-glomerular resistance, healthy kidneys can maintain relatively stable glomerular capillary pressures despite variations in systemic blood pressure. This process is termed "renal autoregulation". Autoregulation can be reduced when renal disease results in loss of nephrons. Compromised autoregulation allows high systemic blood pressure to be transmitted to glomerular capillaries. This glomerular hypertension has been documented by micropuncture studies in dogs and cats with surgically reduced renal mass. In these models, glomerular hypertension was associated with glomerular hypertrophy and sclerosis and proteinuria. Systemic hypertension is relatively common in dogs with renal disease. In a recent study of dogs with spontaneous chronic kidney disease (CKD), 29/45 (64%) had systolic blood pressure ≥ 144 mm Hg and 14/45 (31%) had systolic blood pressure ≥ 161 mm Hg. In cats with naturally-occurring CKD, systemic hypertension has been observed in 19-65% of cases.

Glomerular proteinuria can result from immune complex disease or structural abnormalities involving the glomerular capillary wall (e.g., x-linked hereditary nephropathy). Protein-losing nephropathy caused by glomerular capillary wall lesions is often accompanied by systemic hypertension. Proteinuria can also arise as a consequence of intraglomerular glomerular hypertension. Whether caused by capillary wall lesions or intraglomerular hypertension, excessive quantities of protein in the glomerular filtrate can cause additional glomerular lesions as well as tubulointerstitial lesions leading to loss of more nephrons.

Chronic Kidney Disease

The pathophysiology of CKD can be considered at both the organ and systemic level. At the level of the kidney, the primary pathology of CKD is loss of nephrons and decreased glomerular filtration. Reduced glomerular filtration results in increased plasma concentrations of substances that are normally eliminated from the body by renal excretion. In addition to excretion of metabolic wastes and maintenance of fluid and electrolyte balance, the kidneys also function as endocrine organs and catabolize several peptide hormones. Therefore hormonal disturbances also play a role in the pathogenesis of CKD. For example, decreased production of erythropoietin contributes to the nonregenerative anemia of CKD and decreased metabolism and excretion of parathyroid hormone and gastrin contribute to osteodystrophy and gastritis, respectively. Finally, part of the pathophysiology of CKD is brought about by compensatory mechanisms like the hyperparathyroidism that develops in an attempt to maintain normal plasma calcium and phosphorus concentrations. Similarly, the individual glomerular filtration rate of intact nephrons increases in CKD in an attempt to maintain adequate renal function; however, proteinuria and glomerulosclerosis may be consequences or "trade-offs" of this hyperfiltration.

Hypertension

Systemic hypertension in animals has largely been thought to be secondary to another disease (e.g., renal disease and endocrinopathies), as opposed to idiopathic (primary or essential). This has recently been called into question. For example, in a report of 69 hypertensive cats, seen at North Carolina State University (NCSU) for ocular disease, revealed that at least 17%, and possibly as many as 50%, of cats had no identifiable cause for their systemic hypertension. Elliott and associates at the Royal Veterinary College in London have documented that approximately 20% of hypertensive cats, diagnosed in primary-care practices, were idiopathic. Another retrospective study, which used very strict criteria for the diagnosis of primary (essential, idiopathic) hypertension, revealed a prevalence of 11%.

Described and potential etiologies of secondary hypertension include acute and chronic renal disease, hyperthyroidism, hypothyroidism, hyperadrenocorticism, hyperaldosteronism, pheochromocytoma, diabetes mellitus, and obesity. Chronic kidney disease has the greatest association with hypertension and may often be causal. A recent report suggested approximately 29% of elderly cats with CKD were hypertensive, with the range reported in 4 studies being 19-65%. In dogs with CKD, approximately one-third will be normotensive, one-third will have borderline hypertension, and one-third will be hypertensive.

Systemic hypertension may contribute to progressive nephron loss by causing irreversible glomerular damage via increased intraglomerular pressures and glomerulosclerosis. By altering pre-glomerular resistance, healthy kidneys can maintain relatively static glomerular capillary pressures despite variations in systemic blood pressure via autoregulation. Inappropriate dilation of the afferent glomerular arteriole occurs in dogs and cats with CKD and diminishes the ability of the afferent arteriole to protect the glomerulus from variations in systemic blood pressure. Although the exact mechanism of the CKD-associated hypertension is not known, a combination of glomerular capillary and arteriolar scarring, decreased production of renal vasodilatory prostaglandins, increased responsiveness to normal pressor mechanisms, and activation of the renin-angiotensin system secondary to impaired sodium excretion and excessive renin secretion may be involved. The increased renin secretion leads to increased production of angiotensin II and aldosterone. In addition to its pressor effects, angiotensin II also has a direct stimulatory effect on the sympathetic nervous system, increasing vascular tone, and, in CKD vasoconstriction of the efferent arteriole which further contributes to the intraglomerular hypertension.

The consequences of systemic hypertension are usually dependent on the magnitude and duration of the blood pressure elevations. Acute ocular and central nervous system abnormalities can occur associated with hemorrhage or edema formation. Renal damage associated with hypertension tends to be more chronic and characterized by glomerular lesions (e.g., glomerulosclerosis) and proteinuria. Finally, functional/adaptive changes like ventricular hypertrophy can occur due to increased after-load in patients with hypertension. Diagnosis and treatment of hypertension in dogs and cats with CKD renal may prevent development of retinal lesions or may limit or slow progression of renal and cardiac lesions.

Proteinuria

Renal proteinuria is both a diagnostic marker of the severity of renal disease and a potential mediator of glomerular and tubular injury. Recent findings have demonstrated that proteinuria is associated with increased risk of developing end-stage CKD in dogs and cats. In addition, studies have shown that therapies that reduce the magnitude of proteinuria are often renoprotective. Proteinuric renal disease is often associated with systemic hypertension, which can conversely exacerbate renal proteinuria and therefore, it is difficult at times to separate the effects of high systemic and intraglomerular pressures and proteinuria.

Diagnosis of Hypertension and Proteinuria

Current recommendations are that blood pressure be measured in a quiet area prior to examining the patient, typically in the presence of the owner and after a 5-10 minute period of acclimation. The ACVIM Panel on Hypertension suggests discarding the first measurement, then obtaining a minimum of 3, preferably 5-7, consecutive measurements with less than 20% variability in systolic blood pressure. The animal's disposition, cuff size, measurement site, as well as all measured values should be recorded in the medical record. Many clinicians suggest that hypertension be documented on more than one occasion before accepting the diagnosis.

Diagnosis and management of proteinuria in cats and dogs with CKD should be accomplished in a step-wise fashion. The specificity of the dipstick screening test for proteinuria is poor and therefore confirmation of traditional dipstick positive proteinuria should be accomplished with a more specific follow-up test such as the sulfosalicylic acid (SSA) turbidimetric test, UP/C, or species specific albuminuria assay. The second step is assessment of proteinuria is to determine its origin. Proteinuria of renal origin can adversely affect the prognosis of dogs and cats with CKD and therefore, physiologic or benign proteinuria and pre- and post-renal proteinuria should be ruled out. Subsequently, via serial monitoring, it should be determined if the proteinuria is persistent or transient and if persistent – is the magnitude stable or increasing or decreasing over time? Persistent proteinuria is defined as at least two positive tests at two week intervals. Relatively mild proteinuria in dogs and cats with spontaneous/naturally-occurring CKD appears to be a negative predictor of survival. In dogs and cats with the remnant kidney model of CKD, proteinuria is associated with nephron hypertrophy and increased intraglomerular pressures. Persistent proteinuria of renal origin of a magnitude ≥ UP/C of 0.4 in cats and ≥ 0.5 in dogs with azotemic CKD should be treated with an ACEI and/or dietary protein reduction.

Management

Gradual reduction of dietary salt is often recommended as the first line of treatment for hypertension; however there are no studies that document the efficacy of this treatment. In many cases, vasodilators (angiotensin-converting enzyme inhibitors [ACEI] and calcium channel antagonists [CCA] may be necessary to control systemic hypertension. The CCA amlodipine is often recommended as the first choice anti-hypertensive treatment for cats, however recent information has raised concerns that treatment with a CCA alone may activate the renin-angiotensin-aldosterone system and potentially create higher intraglomerular pressures via further efferent arteriolar vasoconstriction. Initial treatment with an ACEI may be appropriate in both dogs and cats with CKD because of the beneficial effects on intraglomerular pressure and proteinuria. In those cases where systemic hypertension persists after initiation of ACEI treatment, or is initially ≥ 180 mm Hg, a CCA can be added. The overall risk of target organ damage to the eyes, brain, heart, and kidneys is thought to be minimal if systolic blood pressure is maintained at ≤ 150 mm Hg.

What Evidence Exists that Systemic Hypertension and/or Proteinuria Are Detrimental to Canine and Feline Kidneys?

1) In dogs with the page/remnant kidney model of chronic renal failure (CRF), systemic hypertension had adverse effects on renal function and morphology. Finco DR. J Vet Intern Med 2004;18:289.

2) In dogs with remnant kidneys, 40-45 mmHg increases in systolic blood pressure over baseline resulted in enhanced renal damage. Brown SA, et al. J Vet Intern Med 2000;14:351.

3) In dogs with spontaneous chronic renal failure, initial high systolic blood pressure was associated with increased risk of developing a uremic crisis and of dying. Jacob F, et al. J Am Vet Med Assoc 2003;222:322.

4) Angiotensin-converting enzyme inhibition (ACEI) treatment that lowered systolic blood pressure and decreased proteinuria was associated with improve outcome in dogs with spontaneous glomerulonephritis. Grauer GF, et al. J Vet Intern Med 2000;14:526.

5) ACEI treatment in dogs with remnant kidney CRF was effective in modulating progressive renal injury, which was associated with a reduction in glomerular and systemic hypertension. Brown SA, et al. Am J Vet Res 2003;64:321.

6. Glomerular capillary hypertension, glomerular enlargement, and proteinuria have been documented in dogs with the remnant kidney model of renal failure. Brown SA, et al. Am J Physiol 1990;258:F495.

7. In cats with the remnant kidney model of CKD, increases in single nephron GFR occur in association with glomerular hypertrophy, increasing intraglomerular pressures, hyperfiltration, mesangial matrix expansion, and proteinuria. Brown SA, et al. Am J Physiol 1995;269:R1002.

8. In dogs with naturally occurring CKD, the relative risk of uremic crises and mortality was approximately three time greater in dogs with UP/C's > 1.0 (n=25) compared with dogs with UP/C's < 1.0 (n=20). In this study the risk of an adverse outcome was approximately 1.5 times greater for every 1 unit increase in UP/C and the decline in renal function was greater in dogs with higher UP/C's. Jacob F, et al. Am J Vet Res 2005;226:393.

9. In cats with naturally occurring CKD, relatively mild proteinuria (UP/C's > 0.4) appear to be negative predictors of survival. Increasing proteinuria was associated with increasing serum creatinine concentrations and increasing systolic blood pressure (presumably related to glomerular hyperfiltration). UP/C, age, and serum creatinine concentration (but not blood pressure) were independently associated with mortality. Syme HM, et al. J Vet Intern Med 2006;20:528.

10. Proteinuria has been associated with increased risk of mortality due to all causes in cats that have normal renal function when their proteinuria is first detected. Walker D, et al. J Vet Intern Med 2004;18:417.

11. In 141 client-owned cats with naturally-occurring systemic hypertension, amlodipine treatment decreased both blood pressure and proteinuria. Proteinuria (UP/C) (before and after treatment as well as the change in UP/C were the only varibles related to survival in these cats. Jepson RE, et al. J Vet Intern Med 2007;21:402.

12. In cats with naturally-occurring CKD, shorter survival time was associated with an increased UP/C as an independent risk factor. KingJN, et al. J Vet Intern Med 2007;21:906.

13. In 61 cats with naturally-occurring CKD, treatment with benazepril decreased proteinuria (UP/C) and decreased progression of the CKD to advanced stages. Mizutani H, et al. J Vet Intern Med 2006;20:1074.