ND-CKD Causes 21st July 2021.pptx

Non-diabetic causes of Renal
Failure in Diabetic Patients
31-01-2024 Presented by: 1

“ End-stage Renal disease in T2DM is due to
Non-diabetic Renal Disease in 40 – 60% of the
cases ”
Gopaliah LR, Lakshminarayana SG, Nalumakkal SV. Nondiabetic renal disease in type 2 diabetes mellitus. J Integr Nephrol Androl 2017;4:21-5

Prevalence – Non-diabetic Kidney Disease
India
Various studies report high prevalence of
NDRD in India ranging from
46 – 50% - 64%
https://www.journal-ina.com/article.asp?issn=2394-2916;year=2017;volume=4;issue=1;spage=21;epage=25;aulast=Gopaliah
Global Data
Several studies have suggested that nondiabetic
renal disease (NDRD) is common in diabetic
patients, with the prevalence ranging from 27%
to 79% among patients undergoing renal biopsy

Definitions of Diabetic and Non-diabetic nephropathy in diabetes patients

Introduction to ND-Kidney Disease
• Diabetic nephropathy (DN) is one of the major complications of diabetes
mellitus (DM). It is estimated that 20–40% of patients with DM will develop a
diabetic renal disease.
• DN is the leading cause of chronic kidney disease and end-stage renal disease
worldwide.
• Non-diabetic renal diseases (NDRD) such as minimal change disease or
idiopathic membranous nephropathy, are either isolated or superimposed on
an underlying DN.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0064184

• Treatments for DN and NDRD are quite different.
• Many NDRD lesions can be treated with immuno-suppressants other than the
standard angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin
receptor blockers (ARBs).
• Thus, it is important to distinguish NDRD from DN early !!
• A kidney biopsy is necessary to confirm the diagnosis……….BUT …..
Introduction to ND-Kidney Disease

A kidney biopsy is INVASIVE
Nephros reluctant to perform potential risks of the
procedure such as hematuria, peri-renal hematoma, arterial
embolization, and even the necessity for a nephrectomy
Contraindications for renal biopsy such as the
solitary kidney and cortical atrophy
Many primary hospitals may be unable to
perform the renal biopsy
Therefore, nephrologists must provide a suspected
diagnosis using the clinical and laboratory data available
before a biopsy is performed.

Indications for a Kidney Biopsy
Kidney biopsy indication:
a) Nephrotic Proteinuria without retinopathy
b) kidney function involvement without retinopathy
c) Nephrotic Proteinuria and diabetes duration<5ans NDRD
d) Nephrotic Proteinuria discordant with normal clearance
e) Acute kidney injury unexplained
f) Unexplained haematuria.
g) Rapid degradation of kidney function
https://lupinepublishers.com/urology-nephrology-journal/fulltext/non-diabetic-nephropathy-when-should-we-think-about-it.ID.000126.php

The kidney biopsy is helpful in two ways;
(i) It will differentiate diabetic from non-diabetic
glomerulopathy and
(ii) Knowledge of the underlying cause of proteinuria, may play
an important role in planning the correct treatment of these
patients.

Classification of non-diabetic renal diseases in Diabetics

IgA Nephropathy in most
studies is the most
common type of NDRD
seen

Clinical Predictors that help to differentiate NDRD from DN
Absence of
Diabetic
retinopathy*
Shorter Diabetes
Mellitus
Duration
Lower HbA1C
Lower Blood
pressure
Abrupt increase
in serum
creatinine
Active urinary
sediment
Presence of
Hematuria
A higher level of
proteinuria and hematuria
with the absence of
retinopathy* strongly
predicts NDRD
superimposed on DGS
Renal biopsy should be performed
in diabetics when the clinical
scenario is atypical
* In some cases, the presence or absence of DR alone does not prove to
be significant enough in distinguishing between DN and NDRD in T2DM.

Clinical Predictors that help to differentiate NDRD from DN

Indian Studies – NDRD

A 2017 Indian Study - Nondiabetic renal disease (NDRD) in type 2 diabetes mellitus
Among patients with NDRD:
• 69% - Primary Glomerular Diseases – (IgA
Nephropathy (Most common among PGDs)
• 16% - Tubulo-interstitial diseases (Acute
Interstitial Nephritis – Most common)
• 13% - secondary Glomerular diseases
(Primary Amyloidosis most common)
• DN with associated NDRD was found in
21.13% patients

A 2017 Indian Study – Clinico-pathological study of nondiabetic renal disease in type 2
diabetic patients: A single center experience from India
https://www.sjkdt.org/article.asp?issn=1319-2442;year=2017;volume=28;issue=6;spage=1330;epage=1337;aulast=Kanodia
Key Findings from the study
NDRD prevalence in this study was 66%
Males more commonly affected than females
SCr - significantly high in combined disease than in patients with isolated NDRD and DN
Proteinuria was higher in patients with DN than those with NDRD
Strong correlation between NDRD and microscopic hematuria
Low serum complement (C3 and/or C4) levels in patients with isolated NDRD and combined
disease rather than DN alone

Types of Nephropathy in relation to duration of diabetes
(Indian Study 2015)
Longer duration of
diabetes was
associated with a
greater likelihood of DN
and lower likelihood of
NDRD
https://indianjnephrol.org/article.asp?issn=0971-
4065;year=2015;volume=25;issue=4;spage=222;epage=228;aulast=Prakash
Diabetic patients with micro-haematuria, older age and without
DR are more prone to develop NDRD
Hence, in such patients a renal biopsy should be indicated under
the minimal suspicion of non-diabetic kidney disease

Non-diabetic renal diseases in patients with diabetes mellitus clinico-pathological
correlation – 2020 Indian Study
Isolated Non-diabetic renal diseases spectrum.
ANCA = Antineutrophil cytoplasmic antibodies; GN = Glomerulonephritis; HIV = Human immune deficiency virus; IgA = Immunoglobulin A
https://www.indianjnephrol.org/article.asp?issn=0971-4065;year=2020;volume=30;issue=5;spage=295;epage=300;aulast=Arora

Various Diseases under the
spectrum of NDKD

1. Minimal Change Disease

Minimal change disease (MCD) is characterized clinically by the nephrotic syndrome (NS) and a
renal biopsy that shows no glomerular lesions on light microscopy (or only minimal mesangial
prominence), negative staining on immuno-flouorescence microscopy (or low-level staining for
C3 and IgM), and foot process effacement but no electron-dense deposits on electron
microscopy.
MCD may also be suspected clinically in the absence of a biopsy by exhibiting responsiveness to
corticosteroid treatment, and it is sometimes called steroid-sensitive NS.
The causes of NS in adults are more varied, and although some physicians may choose a trial of
corticosteroids without histologic evidence of MCD, a kidney biopsy is usually warranted to
establish the etiology.
Minimal Change Disease

Treatment of MCD with corticosteroids
The steroid group showed a rapid decrease in proteinuria and improvement in edema
within the first month of treatment compared with control.
Importantly, by 2 years, a significant number of patients in the control group had
experienced a spontaneous remission, leading ultimately to similar outcomes with
respect to proteinuria, serum albumin, and edema in the two groups
https://jasn.asnjournals.org/content/24/5/702

Corticosteroid therapy leads to complete remission in over 80% of adults
with MCD.
The time to complete remission is longer than the time observed in
children, with 50% of patients responding by 4 weeks and 10%–25% of
patients requiring 12–16 weeks of therapy.
Moreover, although alternate-day (every other day) therapy may have a
more favorable effect on growth rates in children, the advantages of this
regimen in adults have not been proven.

Alkylating agents In retrospective reports, oral cyclophosphamide (CYC) leads to remission in a significant number
of FR or SD adults with MCD. The relapse-free interval seems to be longer than with
cyclosporine.
Calcineurin
inhibitors
Tacrolimus achieved 6-month and 2-year remission rates of 79%–91% and 50%–62% in SD/SR
MCD patients and it may allow for the discontinuation of steroids. Tacrolimus has also shown
efficacy in various case studies with remission rates of 64%–100%. Moreover, as observed with
cyclosporine, relapse after tacrolimus discontinuation compared with CYC favors a slow taper
off this medication.
Mycophenolate
mofetil
In adults, mycophenolate mofetil has shown efficacy in case reports and small case series, with
remission rates of 60%–80%
Azathioprine One retrospective series described 13 patients with SR MCD, 5 of whom (on biopsy review) had
FSGS, who were treated with azathioprine (2–2.5 mg/kg per day) for 4 years. The time to
remission in the MCD patients was variable at 3–18 months, and all patients continued to be in
remission 3–15 years after discontinuation of therapy.
Treatment of frequently relapsing, steroid-dependent and steroid resistant MCD

2. IgA Nephropathy

IgA nephropathy (IgAN) is an inflammatory renal disease characterised
by the deposition of IgA in the glomerular mesangium.
Described first by Jean Berger in 1968, it is now recognised as the most
commonly reported primary glomerulonephritis worldwide
IgAN has a distinct geographical variation, being more common and
aggressive in East and South East Asia, and only 30–40% of patients
develop a progressive form of the disease, typically necessitating renal
replacement therapy within two decades of diagnosis
IgA Nephropathy

Asymptomatic urine abnormalities, microscopic hematuria with or without proteinuria, are a common presentation
and with increasing age these features are more likely to be accompanied by renal impairment and hypertension
when first seen.
The typical presentation of macroscopic hematuria following a mucosal (usually upper respiratory) infection is most
common in the second and third decades of life and is almost never the presenting symptom after the age of 40
years.
Nephrotic syndrome occurs in around 5% of cases. Acute renal failure may result from acute tubular necrosis as a
consequence of macroscopic hematuria or superimposed crescentic nephritis and is seen during the course of the
disease in o5% of cases.
Renal biopsy confirms the diagnostic feature of diffuse mesangial IgA deposition with a wide range of light
microscopic appearances, although diffuse or segmental mesangial proliferation is the most common
Clinical Presentation

Supportive management
Diet modification Low-sodium diets have been shown to be efficacious in IgAN. The benefits of sodium restriction
are thought to be related to sodium sensitivity of blood pressure, which correlates with renal
ultrastructural damage
The deleterious effects of heightened sodium sensitivity are thought to be mediated through
the renin–angiotensin system (RAS) and indeed, sodium restriction enhances the
antiproteinuric effects of RAS inhibition in IgAN
Weight
management
Body mass index (BMI) at either extreme correlates with increased morbidity and mortality in
CKD
Obesity is postulated to increase proteinuria by inducing ultrastructural changes to the
glomerular basement membrane
Smoking
cessation
There is some evidence from case–control and observational cohort studies that smoking may
be an independent and dose-dependent risk factor for progressive renal function decline in
IgAN
Fish oil
supplementation
KDIGO and Japanese guidelines both suggest use of fish oil in IgAN, with KDIGO limiting its
recommendation to patients with persistent proteinuria despite optimised supportive care
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469670/

Supportive management
The role of RAS blockade in IgAN patients is well established. Guidelines recommend RAS
antagonism with an angiotensin-converting enzyme inhibitor (ACE-I) or an angiotensin II-receptor
blocker (ARB) in patients with proteinuria greater than 1 g/day. Several RCTs have demonstrated
the benefits of RAS blockade, and a meta-analysis of 11 such trials found ACE-I/ARBs were
successful at reducing proteinuria, lowering blood pressure and slowing the rate of renal
function decline.
This finding has been corroborated by more recent studies, such as the STOP-IgAN trial, in which
the use of ACE-I /ARBs in addition to other supportive measures was as effective as combination
therapy with immunosuppressants in preventing decline in eGFR in IgAN
RAS blockade is the first-line management in IgAN

Recommended Treatments
Kidney International (2006) 69, 1934–1938. doi:10.1038/sj.ki.5000419; published online 26 April 2006

Novel therapies in the management of IgA Nephropathy

Treatment Algorithm
for Primary
membranous
nephropathy
https://cjasn.asnjournals.org/content/12/6/983

Management of NDRD in T2DM
The nature of specific therapy will depend on the nature of underlying NDRD (e.g. corticosteroid
for minimal change disease/or FSGS, combination of steroid and cytotoxic drugs for idiopathic
membranous nephropathy, intensive immunosuppressive therapy for crescentic GN).
In certain studies, remission of nephrotic syndrome was observed with prolonged (4-6 month)
course of corticosteroid therapy in patients with FSGS in Type 2 proteinuric diabetic patients
https://www.japi.org/q2647434/non-diabetic-renal-disease-ndrd-in-patients-with-type-2-diabetes-mellitus-type-2-dm

ND-CKD Causes 21st July 2021.pptx

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