Is It Diabetic Nephropathy? (When to Biopsy?) - Dr. Gawad

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Is It DiabeticNephropathy? (When to Biopsy?) Mohammed Abdel Gawad Nephrologist – Alexandria – Egypt Founder & Chairman of NephroTube [email protected]

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IMPORTANT MESSAGE • Renaldiseases in diabetic patients are NOT ALWAYS due to diabetic nephropathy and even it may not be due to DM. Hematuria Proteinuria Rising creatinine Others

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IMPORTANT MESSAGE • Renaldiseases in diabetic patients are NOT ALWAYS due to diabetic nephropathy and even it may not be due to DM. Hematuria Proteinuria Rising creatinine Others

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Renal & UrologicalProblems that may be presented in Diabetics Papillary necrosis - Ischemic nephropathy due to microvascular disease - Renal artery stenosis Diabetic glomerulopathy (diabetic nephropathy) Autonomic neuropathy of the bladder UTI Any other glomerular disease not related to DM - Drug induced - Other ppt factors for AKI

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Renal & UrologicalProblems that may be presented in Diabetics Papillary necrosis - Ischemic nephropathy due to microvascular disease - Renal artery stenosis Diabetic glomerulopathy (diabetic nephropathy) Autonomic neuropathy of the bladder UTI Any other glomerular disease not related to DM - Drug induced - Other ppt factors for AKI

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Renal & UrologicalProblems that may be presented in Diabetics Papillary necrosis - Ischemic nephropathy due to microvascular disease - Renal artery stenosis Diabetic glomerulopathy (diabetic nephropathy) Autonomic neuropathy of the bladder UTI Any other glomerular disease not related to DM - Drug induced - Other ppt factors for AKI When to suspect other cause rather than DN? Is it DN? When to biopsy?

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Is it DiabeticNephropathy? You have to answer the following 1. What is the type of DM? 2. Is there an evidence of Diabetic retinopathy? 3. Proteinuria: a. Is the evolution of proteinuria is typical (micro then macro)? b. Is the range of proteinuria coincides with DN stage? c. What is the rate of proteinuria progression? 4. Hematuria: Is it microscopic or macroscopic? 5. Rising Cr and decreasing GFR: a. Is it related to proteinuria? b. What is the rate of renal impairment progression? 6. Hypertension: refractory or not? 7. What is the drug history? 8. Is there any ppt factor for AKI?

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Diabetic Nephropathy &Diabetic Retinopathy Type 1 DM Mogensen CE. Diabetes. 1997;56(Suppl 2):104-111.

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Diabetic Nephropathy &Diabetic Retinopathy Type 1 DM Pre (1 &2) Incipient (3) (microalbuminuria & HTN) Overt (4) (proteinuria, nephrotic syndrome and decreasing GFR) ESRD (5) At 5 years from onset of DM type 1, nephropathy coincides with retinopathy So if nephropathy is evident in absence of retinopathy in Type 1 DM Search for other cause of nephropathy rather that DM ± Renal Biopsy (especially if there is S&S of other systemic disease) Diabetic retinopathy is present in virtually all patients with type 1 diabetes and nephropathy * * Girach A, Vignati L. Diabetic microvascular complications. J Diabetes Complications. 2006;20:228-237. 5y 15y 25y

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Diabetic Nephropathy &Diabetic Retinopathy Type 1 DM Pre (1 &2) Incipient (3) (microalbuminuria & HTN) Overt (4) (proteinuria, nephrotic syndrome and decreasing GFR) ESRD (5) At 5 years from onset of DM type 1, nephropathy coincides with retinopathy So if nephropathy is evident in absence of retinopathy in Type 1 DM Search for other cause of nephropathy rather that DM ± Renal Biopsy (especially if there is S&S of other systemic disease) Diabetic retinopathy is present in virtually all patients with type 1 diabetes and nephropathy * * Girach A, Vignati L. Diabetic microvascular complications. J Diabetes Complications. 2006;20:228-237. 5y 15y 25y

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Diabetic Nephropathy &Diabetic Retinopathy Type 2 DM ± Renal Biopsy Only 50% to 60% of proteinuric patients with type 2 diabetes suffer from retinopathy. ** Consequently, the absence of retinopathy does not exclude the diagnosis of DN in patients with type 2 diabetes. * In type 2 DM the prevalence of nondiabetic renal disease could vary from 12 to 38% *** When to suspect other cause****? 1- Younger patients with DM 2- Short duration of DM 3- Atypical presentation (atypical proteinuria or hematuria, rapid rising Cr ….. etc) or other ppt factors (discussed later) When to suspect other cause? * GIUSEPPE REMUZZI et al. N Engl J Med, Vol. 346, No. 15· April 11, 2002 *** Huang F et al. Clin ephrol 2007, 67: 293-297. **** Pham TT et al. Am J Nephrol. 2007;27:322-328. ** Wolf G, Müller N, Mandecka A, Müller UA. Clin Nephrol. 2007;68:81-86.

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Is Fluorescein AngiographySafe in Diabetics with Renal Impairment? DIABETES CARE, VOLUME 32, NUMBER 3, MARCH 2009

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Is Fluorescein AngiographySafe in Diabetics with Renal Impairment? M.J. ALEMZADEH-ANSARI ET AL. Nefrologia 2011;31(5):612-3

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Diabetic Nephropathy &Proteinuria Pre (1 &2) Incipient (3) (microalbuminuria & HTN) Overt (4) (proteinuria, nephrotic syndrome and decreasing GFR) ESRD (5) If evolution of proteinuria is atypical: development of overt proteinuria without previous microalbuminuria. Search for other cause of nephropathy rather that DM ± Renal Biopsy (especially if there is S&S of other systemic disease) If the onset of proteinuria has been sudden and rapid 10-15 years Overt proteinuria in diabetes type 1 for <10 years Rate of proteinuria progression is slow 5y 15y 25y

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DN without Albuminuria IschemicNephropathy – Type 2 DM • Renal ultrasound reveals small kidneys. • Raised Serum Cr after administration of ACE-i • Without albuminuria Jamine P. Dwyer et al. DEMAND study. Cardiorenal Med, 2012;2:1-10

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HYPERperfusion/ Hyperfiltration ↑ Intraglomerular Pressure Hyperglycemia Proteinuria Angiotensin II HYPOperfusion/ Ischemia ↓ Intraglomerular Pressure Atherosclerosis

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HYPERperfusion/ Hyperfiltration ↑ Intraglomerular Pressure Hyperglycemia Proteinuria Angiotensin II HYPOperfusion/ Ischemia ↓ Intraglomerular Pressure Atherosclerosis J AmSoc Nephrol. 2003;14:3217-3232

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Jamine P. Dwyeret al. DEMAND study. Cardiorenal Med, 2012;2:1-10

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• MARK E.MOLITCH. Diabetes Care 33:1536–1543, 2010 •Also same results are reported in: •Caramori ML et al. Diabetes 52:1036-1040, 2003. •Lane PH et al. Diabetes 41:581-586, 1992 •MacIsaac RJ et al. Diabetes Care 27:195-200,2004 DN without Albuminuria - Type 1 DM

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Diabetic Nephropathy &Hematuria Is it Micro or Macroscopic? Hematuira in diabetic patient Microscopic hematuria is seen in 66% of patients with DN * Macroscopic hematuria ± active nephritic urinary sediment (acanthocytes and red cell casts) Search for other cause of nephropathy rather that DM ± Renal Biopsy (especially if there is S&S of other systemic disease) * Akimoto T, Ito C, Saito O, et al. Nephron Clin Pract. 2008; 109:c119-c126. ** Lopes de Faria et al. Clin Nephrol. 1988;30(3):117 Red blood cell casts have also been described in patients with diabetic nephropathy **

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Diabetic Nephropathy &Renal Impairment Pre (1 &2) Incipient (3) (microalbuminuria & HTN) Overt (4) (proteinuria, nephrotic syndrome and decreasing GFR) ESRD (5) Search for other cause If renal impairment is rapid Significant proteinuria without/with non coinciding renal impairment first, of course, renovascular disease must be excluded other cause of nephropathy rather that DM ± Renal Biopsy (especially if there is S&S of other systemic disease) Rate of renal impairment progression is slow 5y 15y 25y

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Diabetic Nephropathy &Refractory HTN Refractory hypertension (and fluid retention) in diabetic patients is highly suggestive for renovascular disease

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Diabetic Nephropathy &Drugs ACEi & ARBs > 30% reduction in GFR within 2-3 months after initiation Suspect renovascular disease

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Diabetic Nephropathy &Drugs ContrastNSAIDs Diabetics kidneys are at high risk to be affected by nephrotoxic drugs Any other nephrotoxic drug

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ppt factors forAKI in Diabetics They are the same as any high risk population 1. Dehydration (fluid loss, hyperglycemia, decrease fluid intake). 2. UTI. 3. Drugs. 4. Cardiac problem. 5. Septicemia. 6. Surgery.

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USS & RenalBiopsy • If renal ultrasound reveals small kidneys it is prudent not to perform biopsy. • Overall, renal biopsy is indicated only in a small minority of diabetic patients.

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USS & RenalBiopsy

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USS & RenalBiopsy

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USS & RenalBiopsy

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Pathology Pathology - DiffusePathology- Nodular Kimmelstiel Wilson nodules Pathognomonic for diabetes But reported in only 10% to 50% of biopsy specimens in both type 1 and type 2 diabetes.

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Pathology Pathology - DiffusePathology- Nodular Kimmelstiel Wilson nodules - MORE FREQUENT than the nodular lesion - Correlates with the clinical manifestations of worsening renal function

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Pathology Kimmelstiel Wilson nodules Pathognomonicfor diabetes But reported in only 10% to 50% of biopsy specimens in both type 1 and type 2 diabetes.

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Pathology DN Other Pathology DN + Other Pathology LM/IF/EMwhenever possible, especially if there is high suspicion of other pathology

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To Conclude

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Diabetes & KidneyScenarios Diabetic with recent discovered renal problem Due to DN Not due to DN Diabetic with known old DN & recent renal problem Due to DN Not due to DN To Conclude

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To Conclude When tosuspect other Cause(s) of Renal Disease rather than DN? (Is it DN?) !!!!!!!

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To Conclude When tosuspect other Cause(s) of Renal Disease rather than DN? (Is it DN?) – Step 1 Step 1: Renal US Evidence of chronic changes No need for biopsy No evidence of chronic changes Go to Step 2

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To Conclude When tosuspect other Cause(s) of Renal Disease rather than DN? (Is it DN?) – Step 2 Suspect other cause rather that DN if: Diabetic retinopathy - Absent in Type 1 - Absent in type 2 + 1- Short duration of DM 2- Atypical presentation or other ppt factors Proteinuria & Nephrotic syndrome (Don’t forget DN without albuminuria) - Development of overt proteinuria without previous microalbuminuria - Overt proteinuria in diabetes type 1 for <10 years - If the onset of proteinuria has been sudden and rapid - Resistant Nephrotic Syndrome Hematuria Macroscopic hematuria & active urinary sediment (Don’t forget casts are described in DN also) Rising Cr and decreasing GFR - If renal impairment is rapid - If significant proteinuria without renal impairment Hypertension Refractory HTN Drug history - ACEi & ARBs: > 30% reduction in GFR within 2-3 months after initiation - NSAIDs & Contrast - Others ppt factor for AKI Dehydration, UTI, Drugs, Cardiac problem, Septicemia, Surgery. Systemic disease S&S of other systemic disease Red and green colored indications are not listed in KDOQI Guidelines for Diabetes & CKD

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Case 1 Case 1 Isit DN?

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Clinical Diabetes. April2001 vol. 19 no. 2 74 Case 2 Is it DN? Would you biopsy?

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Case 2 cont Clinical Diabetes.April 2001 vol. 19 no. 2 74

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Case 3 Is itDN? Would you biopsy?

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Case 3 Cont

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Case 4 Is itDN? Would you biopsy?

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Case 4 Cont

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Take Home Message •Renal diseases in diabetic patients are NOT ALWAYS due to diabetic nephropathy and even it may not be due to DM. Hematuria Proteinuria Rising creatinine Others

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Thank You

Is It Diabetic Nephropathy? (When to Biopsy?) - Dr. Gawad

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