What are the best treatments for proteinuria (excess protein in the urine)?

From the Guidelines

The most effective treatment for proteinuria involves uptitrating an ACEi or ARB to maximally tolerated or allowed daily dose as first-line therapy, as recommended by the 2021 KDIGO clinical practice guideline for the management of glomerular diseases 1. This approach is supported by recent evidence, including the 2023 KDOQI US commentary on the 2021 KDIGO clinical practice guideline, which highlights the benefits of antiproteinuric and antihypertensive therapy in managing proteinuria 1.

Key Considerations

• The use of ACEi or ARB is recommended for patients with proteinuria, with a threshold of 0.5 g/d, as indicated in the 2021 KDIGO guideline 1.
• The addition of SGLT2 inhibitors to ACEi or ARB has shown positive long-term potential for kidney outcomes, as demonstrated in studies such as DAPA-CKD and EMPA-KIDNEY 1.
• Dual ACEi and ARB therapy is not recommended due to the lack of additional benefit and potential safety concerns, such as hyperkalemia 1.

Treatment Approach

• First-line treatment: ACEi or ARB, uptitrated to maximally tolerated or allowed daily dose 1.
• Lifestyle modifications: sodium restriction, moderate protein intake, regular exercise, smoking cessation, and weight management if overweight.
• Additional therapies: diuretics, statins, and immunosuppressive medications as needed, depending on the underlying cause and severity of proteinuria.
• Regular monitoring: kidney function, proteinuria levels, and electrolytes to assess treatment effectiveness and adjust therapy accordingly.

From the FDA Drug Label

The RENAAL study was a randomized, placebo-controlled, double-blind, multicenter study conducted worldwide in 1513 patients with type 2 diabetes with nephropathy (defined as serum creatinine 1.3 to 3.0 mg/dL in females or males ≤60 kg and 1.5 to 3. 0 mg/dL in males >60 kg and proteinuria [urinary albumin to creatinine ratio ≥300 mg/g]). Treatment with losartan resulted in a 16% risk reduction in this endpoint (see Figure 4 and Table 4) Treatment with losartan also reduced the occurrence of sustained doubling of serum creatinine by 25% and ESRD by 29% as separate endpoints, but had no effect on overall mortality (see Table 4). Compared with placebo, losartan significantly reduced proteinuria by an average of 34%, an effect that was evident within 3 months of starting therapy, and significantly reduced the rate of decline in glomerular filtration rate during the study by 13%, as measured by the reciprocal of the serum creatinine concentration

Best treatments for proteinuria include:

• Losartan: a medication that has been shown to reduce proteinuria by an average of 34% and slow the progression of renal disease by 13% in patients with type 2 diabetes and nephropathy 2 Key benefits of losartan in treating proteinuria:
• Reduces risk of doubling of serum creatinine by 25%
• Reduces risk of end-stage renal disease (ESRD) by 29%
• Slows decline in glomerular filtration rate by 13%

From the Research

Treatment Options for Proteinuria

• Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are effective in reducing proteinuria in patients with chronic kidney disease (CKD) 3, 4, 5.
• The combination therapy of olmesartan and temocapril has been shown to have the highest probability of being the most effective treatment to reduce proteinuria in normotensive CKD patients 3.
• For IgA nephropathy, the combination therapy of olmesartan and temocapril also has the highest probability of being the best antiproteinuric treatment 3.
• Monotherapy with the ACEI enalapril seems to be the most efficacious intervention for reducing albuminuria in normotensive diabetic nephropathy 3.
• Dual renin-angiotensin system blockade at optimal doses can also be effective in reducing proteinuria, but the safety of this regimen needs to be addressed in future studies 4.

Renoprotective Therapies

• Sodium-glucose cotransporter 2 inhibitors have been recognized for their renoprotective properties in both diabetic and non-diabetic populations 6.
• Finerenone, a selective non-steroidal mineralocorticoid receptor antagonist, has emerged as a promising agent, offering anti-inflammatory and antifibrotic benefits with fewer side effects than traditional steroidal options 6.
• Dual inhibition of angiotensin II and endothelin-1 receptors through agents like Sparsentan presents a novel approach with significant antiproteinuric effects in IgA nephropathy and focal segmental glomerulosclerosis 6.

Important Considerations

• The routine use of combined renin–angiotensin–aldosterone inhibition for albuminuria is not supported by current evidence due to higher rates of adverse events such as hyperkalaemia and progressive renal impairment 7.
• Lifestyle modifications and specific treatments for underlying diseases should be combined with renoprotective therapies to mitigate the progression of chronic kidney disease 6.