This document discusses non-diabetic renal disease in diabetic patients. It begins by describing diabetic nephropathy and its characteristics. It then discusses the prevalence of proteinuria in type 1 and type 2 diabetes. Several case studies are presented showing patients with atypical presentations for diabetic nephropathy who were found to have non-diabetic renal diseases like lupus nephritis or focal segmental glomerulosclerosis instead. The document emphasizes that a renal biopsy can identify these non-diabetic diseases and lead to improved outcomes versus assuming diabetic nephropathy. It reviews several studies finding prevalence rates of non-diabetic renal disease in diabetics ranging from 17-85% depending on biopsy criteria

1. Non-diabetic renal disease in
diabetic patients
AMGAD EL-AGROUDY, MD, FACP, FASN, FAST
CONSULTANT NEPHROLOGIST AND TRANSPLANT PHYSICIAN, UROLOGY & NEPH ROLOGY CENTER, UNIVERSITY
OF MANSOURA
PROFESSOR AND HEAD OF INTERNAL MEDICINE DEPARTMENT, COLLEGE OF M EDICINE AND MEDICAL
SCIENCES, ARABIAN GULF UNIVERSITY, BAHRAIN
CONSULTANT NEPHROLOGIST AND TRANSPLANT PHYSICIAN, KING ABDULLA U NIVERSITY MEDICAL CENTER

3. Diabetic Nephropathy
Diabetic nephropathy is a devastating complication of diabetes mellitus and leading cause of
ESRD worldwide.
Diabetic nephropathy, is a chronic condition developing over many years, characterized by:
 Gradually increasing urinary albumin excretion
 High blood pressure
 Declining glomerular filtration rate
 Absence of other renal/renal tract disease
 Presence of diabetic retinopathy.

5. Decline in GFR in various stages of type 1 and type 2
diabetes

6. Diabetic Nephropathy
Approximately 20-30% of the patients develop microalbuminuria after 10-15 years of disease
duration and less than half develop real nephropathy.
Proteinuria develops in approximately 15-40% patients with type 1 DM, usually after 15-20 years
of DM duration.
In patients with type 2 DM, the prevalence of proteinuria varies between 5% and 20%
A maximum number of cases were found between 10 years’ and 20 years’ duration of diabetes
with a progressive decline in incidence taking place thereafter

7. Risk factors for Diabetic Nephropathy
Genetic Predisposition
Race
Age
Hyperglycemia
Hypertension
Hyperlipidemia
Obesity
Smoking

8. Pathology
Pathological changes develop in the glomeruli of patients with long-duration DM before the
appearance of microalbuminuria
The severity of glomerular damage is proportional to GFR value, DM duration, and blood glucose
regulation
The main pathogical changes in diabetic nephropathy include:
• The thickening of the glomerular basement membrane (GBM)
• Mesangial expansion
• Nodular sclerosis – Kimmelstiel-Wilson change
•Diffuse glomerular sclerosis
•Tubular interstitial fibrosis
•Arteriosclerosis and hyalinosis of kidney blood vessels

9. Case 1
A 63-year-old man presented to his GP with swelling of his feet. He had a 6-year history of
hypertension that had been initially treated with atenolol but he had neither visited a doctor nor
taken any medication for 3 years. There was no other significant medical history. He smoked 30
cigarettes per day.
On examination, his blood pressure was 176/96 mmHg. Fundoscopy revealed bilateral dot
hemorrhages, microaneurysms and hard exudates. Urinalysis showed protein 4+.
• Investigations
– Serum creatinine 176 μmol/L (60–110)
– Fasting plasma glucose 16.7 mmol/L (3.0–6.0)
– Urinary albumin:creatinine ratio 287 mg/mmol (<2.5)
– Ultrasound scan of kidneys increased echogenecity, left kidney 12.4 cm, right kidney 12.2 cm

10. Case 2
A 67-year-old man presented to his GP with a right inguinal hernia. He had a 16-year history of
hypertension that had been treated with amlodepine and atenolol. There was no other
significant medical history.
On examination, his blood pressure was 176/96 mmHg. Fundoscopy revealed bilateral dot
hemorrhages. Urinalysis showed protein 4+, blood 1+.
• Investigations
– Serum creatinine 166 μmol/L (60–110)
– Fasting plasma glucose 12.7 mmol/L (3.0–6.0)
– Urinary albumin:creatinine ratio 255 mg/mmol (<2.5)
– Ultrasound scan of kidneys increased echogenecity, left kidney 9.4 cm, right kidney 8.2 cm

11. Case 3
A 26 year old male is referred to nephrology clinic with a 4 month history of lower leg swelling.
He was diagnosed with Type 2 Diabetes in 2015. He smokes 40 cigarettes per day.
On examination, his BMI was 32 kg/m2, blood pressure was 180/100 mmHg, his heart sounds
were normal and his chest was clear. The abdomen was normal. He had edema to tibial
tuberosities. Fundoscopy was normal. Urinalysis showed protein 3+, blood 1+
Investigations:
Serum Creatinine 233 μmol/L, Albumin 37 g/L, HbA1c 10.4%
24 hour urine protein output 3.03g/24hr
Ultrasound scan of kidneys normal appearances, left kidney 9.9cm, right kidney 13.3cm

12. Case 4
A 18 year old lady is referred to outpatient clinic with a 6 month history of night sweats and joint pain
and swelling . She was diagnosed with Type 1 Diabetes at the age of 11 and had stopped her ACE
inhibitor 18 months ago in an attempt to conceive despite having documented proteinuria with an
ACR of 50mg/mmol .
On examination, there was bilateral synovial swelling of both hands and knees. She had ankle edema.
BP 125/87mmHg. Fundoscopy was normal. Urinalysis demonstrated 3+ protein and a trace of blood
Investigations:
Creatinine 167 umol/L, Hemoglobin 79 g/L
Urinary ACR 220mg/mmol
Anti ds DNA high titre and low C3 C4
Biopsy Lupus nephritis (Class III)

13. When does a Diabetic not need a biopsy?
• Is there a consistent history?
• Negative Immunology
• Bland Sediment
• Retinopathy
• Is renovascular disease contributing to deterioration?

14. Diabetic nephropathy and retinopathy
Retinopathy has easily recognizable clinical manifestations and always precedes the clinically
manifest signs of nephropathy in the same patient.
A strong association between severe retinopathy and presence of Kimmelstiel-Wilson nodules
According to the K/DOQI 2007 Guidelines, etiology of kidney disease in most patients with DM
type 1 should be ascribed to DM if pathologic proteinuria and retinopathy are present
The association between diabetic nephropathy and retinopathy is weaker in patients with type 2
DM
50% of patients without DR
40% of patients with DR had non-DN either alone or in combination with DN.

15. Biomarkers of diabetic nephropathy
TGF beta, vascular endothelial growth factor (VEGF), and CTGF are increased in the plasma and
Urine of patients with diabetic nephropathy
Albuminuria remains the only biomarker acceptable for diagnostic purposes

16. Non-diabetic renal diseases in diabetics
The reported prevalence of NDRD±DN in diabetes patients is in the range of 17–85% depends
upon given institution’s biopsy policy and geographic place.
The importance of NDRD diagnosis is appreciated by the reported better kidney survival
following appropriate therapy
The atypical clinical features of renal involvement
Short duration of diabetes which warrant renal biopsy,
The absence of diabetic retinopathy
Rapidly decreasing renal function
Briskly rising proteinuria
Acute onset of nephrotic syndrome
Active urine sediment

18. Prospectively enrolled type 2 diabetes patients with atypical diabetic renal involvement for renal
biopsy from 2008 to 2011 at two nephrology units in Tehran, Iran
The indications for biopsy were unexplained rapidly decreasing renal function or increasing
proteinuria, acute onset of nephrotic syndrome, active urine sediment (more than 5–8 red blood cells
with mostly acanthocyte shapes or RBC casts), and renal involvement in the absence of DR
Of 46 type 2 diabetic patients, 16 (35%) had a pathologic diagnosis of DN, 20 (43%) had NDRD, and 10
(22%) had NDRD superimposed on DN
Membranous nephropathy (MN) was the most common nephropathy in NDRD group (45%) followed
by focal segmental glomerulopathy (FGS; 30%).
There was a trend for higher nephrotic range proteinuria in NDRD group
Seventeen of 26 patients in group 1+3 (DN±NDRD) suffered from diabetic retinopathy, while one of
the 20 patients in group 2 (pure NDRD) had diabetic retinopathy (p<0.001).

19. In Kaplan–Meier Analysis, one-year kidney survival for
groups I (pure DN), II (pure NDRD), and III (DN+NDRD)
was, 84%, 91%, and 75%, respectively.
Three-year kidney survival for groups I, II, and III was
72%, 91%, and 50%, respectively.
Five-year kidney survival was 72%, 91%, and 25% for
groups I, II, and III, respectively
type 2 diabetes patients with pathology diagnosis of
NDRD benefit from an early diagnosis followed by an
appropriate disease specific therapy.
We strongly recommend renal biopsy for type 2
diabetes with unusual presentation and course,
particularly in the absence of DR.
By this strategy, we could improve their kidney survival
and potentially reduce the burden of CKD

20. Data of patients with type 2 DM who underwent renal biopsy from 1990 to 2008 were analyzed
retrospectively.
Patients were categorized as isolated NDRD, NDRD with DGS, and isolated DGS.
A total of 75 patients were included
Forty-eight (64%) cases had NDRD and 27 (36%) had DGS.
The commonest NDRD was MCNS (12.5%)
Acute kidney injury and nephritic syndrome were not observed in the DGS group
Kidney biopsy aided in the detection of NDRD in clinically suspected patients

21. They recorded the clinical and laboratory finding alongside with the histopathological
examination of the renal biopsies obtained from 71 type-2 DM patients
Based on the renal biopsy findings patients were classified into two groups (DN and NDRD)
In patients with DN (n: 34),
diabetic retinopathy was more common 47.1 % vs. 6 16.2 %, p =0.01]
duration of DM was longer (108.8 ± 58.8 months vs 57.8 ± 55.9 months, p <0.001)
the degree of proteinuria was more severe (6 ± 4.3 g/day vs. 4.5 ± 4.6 g/day; p =0.04)
compared to the patients with NDRD.
The prevalence of NDRD (52%) is remarkably frequent in DM patients in whom nephrologists
consider renal biopsy an appropriate measure.
Short duration of DM, degree of proteinuria and absence of retinopathy were predictors of
NDRD

22. Retrospective analytic study including T2DM patients in whom renal biopsies were performed
at our department from 1988 to 2014.
Seventy-five patients were included
Renal biopsy findings were isolated NDRD in 33 cases, NDRD superimposed on DN in 24 cases,
and isolated DN in 18 cases.
Most common NDRD found were focal segmental glomerulosclerosis (21%) and membranous
nephropathy (19%).
24 patients reached ESRD 55% in DN group, 16% in DN associated to NDRD group, and 30% in
NDRD group
The prevalence of NDRD found in our study confirmed usefulness of renal biopsy in patients with
T2DM, especially in those without hypertension, and insulin therapy

23. We examined 68 consecutive patients with type 2 diabetes during the period of 1985–1999 who
underwent renal biopsy for proteinuria >1 g/day, renal involvement (proteinuria or renal impairment)
at the absence of retinopathy, renal involvement with duration of diabetes < 5 years, or unexplained
hematuria of glomerular origin.
Three groups of patients were defined based on their renal pathology:
◦ group I consisted of 24 patients (35%) with diabetic glomerulosclerosis (DGS) alone,
◦ group II consisted of 13 patients (19%) with NDN superimposed on DGS,
◦ group III consisted of 31 patients (46%) with NDN alone without evidence of DGS.
After a mean follow-up of 123 months from the diagnosis of type 2 diabetes (74 months from the
time of renal biopsy), univariate analysis showed that risk factors for reaching ESRD(requiring
maintenance dialysis, or a serum creatinine [SCr] >700 mol/l):
Proteinuria>2 g/day
S Cr>120 µmol/l
Presence of retinopathy at the time of biopsy
Biopsy showing DGS (groups I and II)
On multivariate analysis, retinopathy was the only independent variable correlated with ESRD.

24. Classification of Non-diabetic renal diseases
in diabetics
Glomerular disease other than diabetic
nephropathy
Immunoglobulin A nephropathy
Focal and segmental glomerular sclerosis
Membranoproliferative glomerulonephritis
Memebranous GN
Post infectious GN
Pauci immune GN
Systemic lupus erythematosus
Others
Non-glomerular renal disease
Macrovascular (renovascular)
Acute kidney injury (ATN— contrast nephropathy,
sepsis, ACEI induced AIN
Chronic kidney disease (Ischemic nephropathy,
chronic pyelonephritis)
Electrolyte abnormality (Hyponatremia-
Hyperkalemia RTA)
Urinary tract infection (Cystitis - Acute
pyelonephritis- Chronic pyelonephritis - Papillary
necrosis- Bladder dysfunction)
Obstructive uropathy (Urethritis- Bladder
dysfunction -Bilateral papillary necrosis

25. RAS
In a study evaluating 5194 consecutive autopsy protocols it was found that 63% of patients with
renal artery stenosis (RAS) were diabetic.
Renal artery stenosis was present in 8.3% of all diabetic patients.
The frequency of RAS in diabetic patients with hypertension was 10.1%. Bilateral RAS was found
in 43% of patients with RAS and diabetes.
The presence of non-insulin-dependent diabetes mellitus increases the risk of RAS.
These results may be of significance with regard to the diagnostic evaluation and choice of
antihypertensive treatment in hypertensive non-insulin-dependent diabetic patients

26. Acute kidney injury
Diabetic patients have multiple co-morbidities and are prone to develop acute kidney injury
In a study a total of 4082 diabetics were followed between January 1999 and December 2008.
About 530 of 1822 patients experienced one AKI episode
157 of 530 experienced ≥ 2 AKI episodes
AKI episodes were also associated with a cumulative risk for developing advanced CKD in DM,
independent of other major risk factors of progression
(Thakar CV, et al. Clin J Am Soc Nephrol 2011)
Risk of AKI
◦ Pre renal
◦ ATN
◦ AIN

27. Chronic kidney disease
Various non-diabetic glomerular conditions
GN
Chronic pyelonephritis
Ischemic nephropathy

28. Electrolyte abnormality
Hyponatremia
The dilutional effect of water retention
Diuretics especially thiazides
Potassium abnormalities
Hypokalemia (diuretics- treatment of Ketoacidosis)
Hyperkalemia (ACEi- DKA- RTA type IV)
Various self-medication protocols as low salt diet

29. Urinary tract infection
UTI is more common and more severe in patients with DM.
The incidence of UTIs as well as asymptomatic bacteriuria was twice as high in diabetic
compared to non-diabetic women.
The risk was higher in women on insulin and with longer duration of diabetes
Poor glycemic control are independent factors associated with the upper UTI
UTI in diabetes is more aggressive commonly leading to complications, such as prostatic abscess,
emphysematous cystitis and pyelonephritis, intrarenal abscess, papillary necrosis, metastatic
abscess, and septicemia
Papillary necrosis occurs in severe UTI (unilateral or bilateral uretric obstruction)

30. Bladder dysfunction
Autonomic polyneuropathy
incomplete bladder evacuation leading to urinary stasis.
Predisposes for recurrent UTIs
Obstructive uropathy and worsening of renal function
Recent clinical and experimental evidence indicate storage problems such as urgency and urge
incontinence in DM cases

31. Obstructive uropathy
Co-morbidities in diabetes can lead to obstruction in the genitourinary tract at various levels.
Severe recurrent infections can lead to phimosis and obstructive uropathy.
Causes
◦ Urethral stricture following urethritis,
◦ bladder dysfunction of diabetes
◦ papillary necrosis

32. Conclusions
Diabetic nephropathy is not the sole renal disease in diabetic patients
Various renal conditions can be found in diabetic patients either superimposed upon this
condition or independent from this
Therapy and prognosis of DN and NDRD are quite different. Therefore, differential diagnosis of
these two entities in diabetic patients is of considerable importance
As DN does not have any specific therapy, identification of these non-diabetic renal conditions
will give an opportunity to treat reversible conditions thereby aiding in renoprotection.