SOMETHING NEW, SOMETHING OLD

SOMETHING BORROWED, SOMETHING BLUE

Robert Quigley D.O.

NOMA Winter Conference

Outline

• Common office presentation-eval

• Leading cause of CKD/ESRD

• Managing side effects of ACE/ARB• Newer school/ old school

• Novelty Therapy- study published 6/2019

• Questions/ wrap up

John is a 75 y/o man whom you have known for over a year. His past medical history is positive for HTN ( well controlled on single agent lisinopril) and prostate cancer treated with prostactomy who presents for routine follow up. Pt reports that he has increased swelling in his legs over the last few months. He also reports that his blood pressure is no longer controlled as well with ranges from 150-160 systolic now. Any questions?

Physical examBP 154/92 HR 78 R 16 T 98.6Well appearing, sitting up on tableNo JVP appreciated or bruitsHeart RR S1S2 no murmurs or gallopsLungs are clear to ascultation without any focal consolidationAbdomen mild distended but non tender without guardingExtremities are without color change, +1 edema to knees B/L

How should we proceed?

Causes of Edema

• Renal failure/ CKD –proteinuria

• Heart Failure

• Liver Failure

• Deep Venous thrombosis

• Lymphedema

• Diet indescretion

• Venous insufficiency

Evaluation

• CMP-NA,Creat, LFT,ALbumin

• US lower extremity (hypercoaguable state}

• Echocardiogram (LVH)

• UA, spot protein / creatinine urine (24 hr not needed)

Relevance

• Delay in diagnosis

• Difficult to get into susbspecialists

• Difficult to obtain diagnostic testing (Kidney Biopsy)(anticoagulation)

Proteinuria in Kidney Disease

Glomerular Capillary WallFenestrated EndotheliumGlomerular Basement MembraneEpithelial Cells

1 million glomeruli in each kidney

Charge/Size of protein

PLA2R

APOL1

Diabetes

• Research suggests that 1 out of 3 adults has prediabetes. Of this group, 9 out of 10 don't know they have it.

• 29.1 million people in the United States have diabetes, but 8.1 million may be undiagnosed and unaware of their condition.

• About 1.4 million new cases of diabetes are diagnosed in United States every year.

• More than one in every 10 adults who are 20 years or older has diabetes. For seniors (65 years and older), that figure rises to more than one in four.

• Cases of diagnosed diabetes cost the United States an estimated $250 Billion

Diabetes and the kidney

• Diabetes is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) in the United States and worldwide.

• The proportion of people with diabetes who also have CKD has remained relatively stable (approximately 25 to 30 percent) over the past 20 years.

• Currently, more than 3 million people worldwide are estimated to be receiving treatment for kidney failure, with predictions that the number will increase to more than 5 million by 2035.

Risk factors for progression

• Poor glycemic control

• Older age

• Non-white race

• Low socioeconomic status

• Obesity

• Smoking

• Blood pressure control

• Genetic factors

Cascade of Chaos

• Hyperglycemia results in production of advanced glycation end-products (AGE)

• Reactive oxygen cytokines

• Aberrant metabolic products activate intercellular signaling for proinflammatory and profibrotic gene expressions

Kimmelstiel–Wilson nodules

Good

Awful

Structure Function

Natural History of Type 1 Diabetic Nephropathy

Early Nephropathy

• Microalbuminuria

• Rising Blood Pressure 6-10mL/min/y

0 2 5 11-23 13-25 15-27

Onset of Onset of Rising ESRD

Diabetes Proteinuria Serum Creatinine

Functional Changes Structural Changes

• GFR • Glomerular Basement

• Reversible Albuminuria Membrane Thickness

• Kidney Size • Mesangial Expansion

Lewis et al

Natural History of Type 2 Diabetic Nephropathy

10-14mL/min/y

0 2 5 5-7 12-15

Onset of Onset of ESRD

Diabetes Proteinuria

Functional Changes Structural Changes

• GFR • Glomerular Basement

• Kidney Size Membrane Thickness

• 50% already albuminuric • Mesangial Expansion

• 50% hypertensive

Lewis et al

Could it be something else besides DN

•Rapid decline in GFR (in a patient that has been stable)

•Sudden onset of nephrotic syndrome <5 years from diagnosis of DM

•Active urinary sediment

•Signs of systemic disease

•>30% reduction in GFR after start of ARB/ACE

•Lack of retinopathy/neuropathy

•People who have diabetes for more than 20 years without any previous evidence

Treatment of Diabetic Kidney disease

ORIGINAL ARTICLE NEJM 1993The Effect of Angiotensin-Converting-Enzyme Inhibition on Diabetic Nephropathy

Renal function declines progressively in patients who have diabetic nephropathy, and the decline may be slowed by antihypertensive drugs. The purpose of this study was to determine whether captopril has kidney-protecting properties independent of its effect on blood pressure in diabetic nephropathy.

Captopril treatment was associated with a 50 percent reduction in the risk of the combined end points of death, dialysis, and transplantation that was independent of the small disparity in blood pressure between the groups

Results

Magic of an ACE

Diabetic nephropathy is the leading cause of end-stage renal disease. Interruption of the renin–angiotensin system slows the progression of renal disease in patients with type 1 diabetes, but similar data are not available for patients with type 2, the most common form of diabetes. We assessed the role of the angiotensin-II–receptor antagonist losartan in patients with type 2 diabetes and nephropathy

ORIGINAL ARTICLEEffects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy NEJM 2001

Results

Associations with hyperkalemia from ACE/ARB• Diabetes mellitus

• Acidemia

• Low estimated glomerular filtration rate (GFR)

• Blood Glucose

• CHF

Sodium zirconium cyclosilicate (ZS-9) is a highly selective cation exchanger that entraps potassium in the intestinal tract in exchange for sodium and hydrogen and then is eliminated

Sodium Zirconium Cyclosilicate in Hyperkalemia NEJM 1/2105

Study highlight

Patiromer is a novel, spherical, nonabsorbed polymer that binds potassium in exchange for calcium predominantly in the distal colon, where the concentration of free potassium is highest, thus increasing fecal potassium excretion and lowering serum potassium levels.

Furosemide/ HCTZ

Kidneys Viagra moment

Something Blue

Sodium–glucose cotransporter 2 inhibitors

Canagliflozin (Invokana)Dapagliflozin (Farxiga)Empagliflozin (Jardiance)

ORIGINAL ARTICLE NEJM 8/2107Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes

Canagliflozin is a sodium–glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on cardiovascular, renal, and safety outcomes.

Positive Pleiotropic Points SGL2Inhibitors

• Improved glycemic control

• Lowering of blood pressure

• Decrease in intraglomerular pressure

• Reduction in albuminuria

• Amelioration of volume overload

Canagliflozin and Renal Outcomes in Type 2 Diabetes and NephropathyNEJM 6/2019

Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes.

Results

Adverse REactions

Conclusion

• Edema usually equals diuretic, but whats underneath the water?

• Don’t throw away the ACE/ARB right away• If AKI rechallenge

• Canagliflozin can help slow progression of CKD• Not tested in stage 4

• Unclear about class effect, but probably

I love my patients I see God in their faces and their form. – A. T. Still MD, DO