Mechanisms and Treatment of CKD

Abstract

As CKD continues to increase worldwide, along with the demand for related lifesaving therapies, the financial burden of CKD will place an increasing drain on health care systems. Experimental studies showed that glomerular capillary hypertension and impaired sieving function with consequent protein overload play a pathogenic role in the progression of CKD. Consistently, human studies show that proteinuria is an independent predictor of progression and that its reduction is renoprotective. At comparable BP control, inhibitors of the renin-angiotensin system (RAS), including angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), more effectively than non-RAS inhibitor therapy reduce proteinuria, slow progression to ESRD, and even improve the kidney function achieving disease regression in some cases. In participants with diabetes, RAS inhibitors delay the onset of microalbuminuria and its progression to macroalbuminuria, and ACE inhibitors may reduce the excess cardiovascular mortality associated with diabetic renal disease. In addition to RAS inhibitors, however, multimodal approaches including lifestyle modifications and multidrug therapy will be required in most cases to optimize control of the several risk factors for CKD and related cardiovascular morbidity. Whether novel medications may help further improve the cost-effectiveness of renoprotective interventions is a matter of investigation.

Current Understanding of the Pathogenesis of Progressive Chronic Kidney Disease in Cats

“…Studies investigating both ACE inhibitors (ACEi) and angiotensin receptor blockers (ARB) show improved outcome when these agents are administered for both diabetic and non-diabetic related CKD. 138 However, outcomes from these studies have not provided the degree of protection that might be anticipated and more recent studies have therefore focused on combined ACEi and ARB therapy. 138,139 Whilst dual therapy may provide further reduction in terms of proteinuria outcome measures such as requirement for dialysis, doubling of serum creatinine and mortality were not always improved when compared to monotherapy particularly for non-proteinuric patients.…”

“…138 However, outcomes from these studies have not provided the degree of protection that might be anticipated and more recent studies have therefore focused on combined ACEi and ARB therapy. 138,139 Whilst dual therapy may provide further reduction in terms of proteinuria outcome measures such as requirement for dialysis, doubling of serum creatinine and mortality were not always improved when compared to monotherapy particularly for non-proteinuric patients. 140 There continues therefore to be controversy in terms of optimal therapy for RAAS blockade and whether this should be monotherapy, combined fixed dose or individualized ACEi/ARB or combined therapy with either aldosterone antagonists or direct renin inhibitors (e.g.…”

Short-Term Gestation, Long-Term Risk: Prematurity and Chronic Kidney Disease

“…101 However, there are nonspecific therapeutic targets for CKD progression such as hypertension, 101,102 microalbuminuria, 90 and dyslipidemia. 90 In particular, inhibition of the renin-angiotensin system (RAS) has been shown to slow CKD progression in adults with proteinuria 103 and hypertensive children aged 3 to 18 104 and is standard of care in nephropathy related to diabetes. 105,106 However, these medications must be used cautiously in children because their side-effect profile is not benign, and they are a well-described cause of AKI, particularly with volume depletion or when given in combination with other medications that decrease renal blood flow.…”

Blood Pressure, Proteinuria, and Phosphate as Risk Factors for Progressive Kidney Disease: A Hypothesis

“…75 These findings are supportive of previous research in the same field, 76 recapitulated in a recent review. 77 Higher levels of proteinuria may increase the release of profibrotic, proinflammatory, and vasoactive molecules [78][79][80][81][82] with consequent oxidative stress, tubulointerstitial fibrosis, and loss of functional nephrons (Fig 1). 83 These changes cause further nephron injury, increased intraglomerular pressure, impaired filter function, and further loss of proteins in urine, with concomitant activation of the complement cascade.…”