Renal Flashcards
1
Q
Clinical Triad:
• A precipitating event (such as aortic or coronary angiography)
• Subacute or acute kidney injury
• Typical skin findings, such as blue toe syndrome and/or livedo reticularis
A
Iatrogenic/cholesterol emboli
2
Q
Role of ADH in Kidneys
A
Inserted aquaporin 2 channels in collecting duct in response to water deprivation leading to increased water absorption and thus more concentrated urine
3
Q
ATN Definition
A
Reversible or irreversible type of renal failure caused by ischaemic or toxic injury to the renal tubular epithelial cells. The injury results in cell death or detachment from basement membrane causing tubular dysfunction.
4
Q
Aminoglycoside Nephrotoxicity
A
- Manifests after 5-7 days of therapy
- Causes ATN, polyuria due to distal tubule damage, and decrease in most electrolytes due to PCT impairment
- Major risk factor is prolonged use (even if perfect control of plasma concentration)
5
Q
ATN Findings
A
Muddy Brown Casts
6
Q
Type of ATN in patients with rhabdo and haemolysis
-Features: red/brown urine, granular casts, oliguria/anuria
A
Acute pigment cast nephropathy
7
Q
Drug causes of AIN
A
●NSAIDs
●Penicillins and cephalosporins
●Rifampin
●Antimicrobial sulfonamides, including trimethoprim-sulfamethoxazole
●Ciprofloxacin and, perhaps to a lesser degree, other quinolones
●Diuretics, including loop diuretics such as furosemide and bumetanide, and thiazide-type diuretics
●Cimetidine (only rare cases have been described with other H-2 blockers such as ranitidine)
●Allopurinol
●PPIs such as omeprazole and lansoprazole
●Indinavir
●5-aminosalicylates (eg, mesalamine)
8
Q
Causes of Drug induced TMA
A
Quinine, Type 1 interferon, Cancer therapies, Calcineurin inhibitors
9
Q
IgA Renal Biopsy Findings
A
Pathognomonic finding is observed on immunofluorescence microscopy, which demonstrates dominant or codominant mesangial deposits of IgA, either alone, with IgG, with IgM, or with both IgG and IgM.
Poor Progonostic features:
- Subendothelial capillary wall IgA deposits
- IgG codeposition
10
Q
Synpharyngitic haematuria - IgA
A
- 40-50% present of patients
- One or recurrent episodes of gross (visible) hematuria, often accompanying an upper respiratory infection
- Most patients have only a few episodes of gross hematuria, and episodes usually recur for a few years at most
11
Q
Microcytic Haematuria - IgA
A
30-40% of patients with IgA nephropathy
Usually associated with mild proteinuria
Disease of uncertain duration for these patients
Gross hematuria will eventually occur in 20 to 25 percent
12
Q
IgA Nephrotic syndrome/RPGN
A
Less than 10% of patients
Oedema, HTN, renal insufficiency, and haematuria
May rarely present with malignant HTN
13
Q
IgA nephropathy Associations
A
o Cirrhosis/CLD o Coeliac Disease o HIV o Granulomatosis with polyangiitis o Minimal change disease and membranous nephropathy
14
Q
Mx of IgA nephropathy
A
- BP control w/ ACE/ARB
- Statin if LDL raised to lower CVD risk
- Immunosuppression in severe cases
15
Q
Indications for Immunosuppression in IgA nephropathy
A
Immunosuppressive therapy is indicated if there is haematuria plus one of the following
• Progressive decline in GFR
• Persistent proteinuria >1g/day on maximal ACE or ARB for 3-6 months
• Morphologic evidence of active disease on kidney biopsy (proliferative or necrotising glomerular changes)
usually corticosteroid +/- cyclophosphamide/azathioprine
16
Q
Clinical predictors of poor prognosis in IgA nephropathy
A
Higher serum creatinine at diagnosis
HTN - BP >140/90 at disease discovery
Protein Excretion > 1g/day - the incidence of dialysis and death was significantly higher
17
Q
3 CArdinal Features of Scleroderma Renal Crisis
A
o Abrupt onset of moderate to severe hypertension
o AKI
o Normal urinalysis
May also present with APO/CCF
18
Q
Risk Factors for SRC
A
o Diffuse Skin involvement (Most important risk factor, especially if it is rapidly progressive)
o Glucocorticoid use (>15 mg/day)
o Anti RNA Polymerase III
19
Q
Renal Bx for SRC
A
o Characteristic finding on histopathology is intimal proliferation and thickening that leads to narrowing and obliteration of the vascular lumen, with concentric “onion-skin” hypertrophy
Renal Bx does not diagnose SRC deut o similarities with TMAs
20
Q
Treatment of SRC
A
- Captopril - improves renal function and survival; second line add on CCB
21
Q
Prognosis of SRC
A
20-50% of patients will require dialysis temporarily.
Most will be able to regain renal function slowly up to 18 months after starting HDx, Thus transplantation delayed for at least 6 months post starting HDx
22
Q
Infections/AI Diseases causing AIN
A
Legionella Leptospira CMV Streptococcus Mycobacterium tuberculosis Corynebacterium diphtheriae EBV Yersinia Polyomavirus Enterococcus Escherichia coli Adenovirus Candida HIV
SLE
Sarcoidosis
Sjogrens
IgG4 Disease
23
Q
AIN Investigations
A
WCC casts - most specific
o Increased Creatinine
o Eosinophilia (25-35% of cases)
o Eosinophiluria - >1% of urinary WCCs (not specific for AIN)
o Urine sediment: WDD, RBC, white cell casts
o Variable proteinuria from non or minimal to >1gram/day
24
Q
Indications for Renal Bx for AIN
A
- Patients who have a characteristic urinalysis for AIN but are not being treated with a drug known to cause AIN.
- Patients who are being treated with a drug known to cause AIN but do not have a characteristic urinalysis.
- Patients who are being considered for treatment with glucocorticoids for AIN (usually drug induced).
- Patients with putative drug-related AIN who are not treated with glucocorticoids initially and do not have a recovery following cessation of drug therapy
- Patients who present with advanced renal failure (relatively recent onset <3 months)
- Patients with any features (such as high-grade proteinuria) that cause the diagnosis of AIN to be uncertain.
25
AIN Renal Bx findings
* Interstitial oedema and a marked interstitial infiltrate consisting primarily of T lymphocytes and monocytes
* Eosinophils, plasma cells, and neutrophils also may be found
* The classic lesion of "tubulitis" is found when inflammatory cells invade the tubular basement membrane
26
Types of GN associated with RA
Direct effect:
- FSGS
- mesangioproliferative
- membranous
- Rheumatoid Vasculitis
Drug Toxicity
Amyloidosis (AA) in longstanding poorly controlled, seropositive RA
27
Clinical Features of Amyloidosis
- vary depending on location of disease and type of amyloid
- waxy skin and easy bruising
- enlarged muscles (eg, tongue, deltoids)
- symptoms and signs of heart failure
- cardiac conduction abnormalities
- hepatomegaly
- evidence of heavy proteinuria or the nephrotic syndrome
- peripheral and/or autonomic neuropathy
- impaired coagulation
28
EPO Stimulus
• Major stimulus for EPO production is decreased oxygen delivery due to reduced red blood cell mass (anaemia) or decreased O2 saturation of red cell haemoglobin (hypoxia)
- The Epo promoter is suppressed by GATA-2 in normoxia. GATA-2 levels decrease in hypoxia
- More importantly, the Epo enhancer is activated by hypoxia-inducible transcription factors (HIFs).
- EPO targets CFU-E, proerythroblasts, and basophilic erythroblast portion of Hb production
29
HUS Definition
the simultaneous occurrence of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury
30
Causes of Atypical HUS
o Complement gene mutations
o Antibodies to complement factor H
o Diacylglycerol kinase epsilon gene mutations
o Inborn error of cobalamin C metabolism
31
Causes of typical HUS
o Infection:
STEC
Streptococcus pneumoniae
Human immunodeficiency viral infection
o Drug toxicity, particularly in patients with cancer or solid organ transplant recipients
o Rare occurrences in pregnant patients or in those with autoimmune disorders (eg, systemic lupus erythematous)
32
HSP Tetrad
o Palpable purpura in patients with neither thrombocytopenia nor coagulopathy
o Arthritis/arthralgia
o Abdominal pain
o Renal disease
33
HSP Bx Findings
characteristic finding of IgAV (HSP) is leukocytoclastic vasculitis accompanied by IgA immune complexes within affected organs
34
Myogenic reflex
* A first line defense against fluctuations in renal blood flow
* Acute changes in renal perfusion pressure evoke reflex constriction or dilatation of the afferent arteriole in response to increased or decreased pressure, respectively
* This phenomenon helps protect the glomerular capillary from sudden changes in systolic pressure
35
Tubuloglomerular Feedback (TGF)
* TGF changes the rate of filtration and tubular flow by reflex vasoconstriction dilatation of the afferent arteriole.
* TGF is mediated by specialized cells in the thick ascending limb of the loop of Henle called the macula densa that act as sensors of solute concentration and tubular fluid flow rate
* With high tubular flow rates, a proxy for an inappropriately high filtration rate, there is increased solute delivery to the macula densa that evokes vasconstriction of the afferent arteriole causing GFR to return to normal
* One component of the soluble signal from the macula densa is ATP released by the cells during increased NaCl reabsorption. ATP is metabolized in the extracellular space to generate adenosine, a potent vasoconstrictor of the afferent arteriole.
* During conditions associated with a fall in filtration rate, reduced solute delivery to the macula densa attenuates TGF, allowing afferent arteriolar dilatation and restoring GFR to normal levels. Angiotensin II and reactive oxygen species enhance, while NO blunts TGF
36
Angiotensin II effect on Renal Blood Flow
* During states of reduced renal blood flow, renin is released from granular cells within the wall of the afferent arteriole near the macula densa in a region called the juxtaglomerular apparatus.
* Renin, a proteolytic enzyme, catalyzes the conversion of angiotensin to angiotensin I, which is subsequently converted to angiotensin II by angiotensin-converting enzyme (ACE)
* Angiotensin evokes vasconstriction of the efferent arteriole, and the resulting increased glomerular hydrostatic pressure elevates GFR to normal levels
37
Drugs that elevate the Serum Creatinine
Trimethoprim, cemetidine, Dolutegravir, cobicstat, PARP inhibitors, TKIs
38
Pathophysiology of diabetic nephropathy
1. Hyperfiltration assocaited with increased renal size
2. Microalbuminuria (30-300mg/day or ACR 3.5-35)
3. Macroalbuminuria (>300 mg/day or ACR >35)
4. ESRF
39
Role of Bicarb Therapy in CKD
Metabolic acidosis in non dialysis dependent CKD associated with higher mortality and low bicarb associated with higher risk of progressive renal function loss.
- Bicarb supps slow progression of CKD by reducing acidosis and decreasing H+ reabsorption
- Bicarb also improves bone health, protein production, nutritional status, reduces lipids, and improves insulin sensitivity
40
CVS risk in CKD
An increased risk of death and cardiovascular mortality as GFR falls below 60ml/min/1.73m2 or when albumin is detected on urinalysis
Modifications:
• Smoking cessation
• Exercise
• Weight reduction to optimal targets
• Lipid modification recognising that the risk reduction associated with statin therapy in adults with CKD is relatively constant across a broad range of baseline low-density lipoprotein cholesterol (LCL-C) levels
• Optimal diabetes control HbA1c <7% (55mmol/mol)
• Optimal BP control to <140/90mmHg or 130/80 mmHg in those with CKD and depending on the degree of proteinuria **
• Aspirin is indicated for secondary prevention but not primary prevention.
41
MOA and Contraindications for EPO
MoA: Recombinant glycoproteins that bind to erythropoietin receptors on erythroid progenitor cells. Stimulate erythropoiesis, increasing reticulocyte count, haematocrit and haemoglobin concentration.
Contraindicated: uncontrolled hypertension
42
Side effects of EPO
Common (>1%):
Hypertension (esp with rapid haemoglobin rise), headache, flu-like symptoms, bone pain, myalgia, fever, rash, peripheral oedema
```
Rare (<1%):
Hypertensive encephalopathy (inc seizures), allergy (inc. angioedema and anaphylaxis), pure red cell aplasia (more likely with subcut route)
```
43
Pure red cell aplasia
Complication of EPO
- Autoantibodies in the serum of these patients neutralized both recombinant human erythropoietin and endogenous erythropoietin
- Dependent on Transfusions and need immunosuppression
44
Contraindications to PD
1) Peritoneal scarring
2) Anuria or large patient size
3) Active inflammatory process or cancer
4) Surgical ostomies
5) Large abdominal wall hernia
6) Ventriculoperitoneal shunts
45
Common Cancers in Renal Transplant
1. Skin cancers (basal cell and squamous cell carcinomas) – Human papilloma virus HPV
- BY FAR THE HIGHEST IS SCC
2. Lymphoproliferative disorders – likely due to Epstein-Barr virus
3. Kaposi’s sarcoma – Human herpes virus 8 HHV-8
46
Evidence of statins in CKD
statin therapy is associated with reduced cardiovascular risk and total mortality but with no significant effect on CKD progression
47
Hba1c target in CKD
7%, below this is associated with increased risk of hypos and possibly death
48
Metformin Dosing in CKD
CrCl > 90 (max 3g daily)
CrCl 60-90 (max 2g daily)
CrCl 60-30 (max 1g daily
CrCl <30 → contraindicated
49
Indications for RRT in AKI
AEIOU = Indications for Urgent Dialysis in Acute Kidney Injury
A Acidosis Metabolic acidosis with a pH <7.1
E Electrolytes Refractory hyperkalemia (K>6.5 mEq/L) or rapidly rising potassium levels
I Intoxications Some toxins can be removed with dialysis SLIME (salicylates, lithium, isopropanol, methanol, ethylene glycol)
O Overload Volume overload refractory to diuresis
U Uraemia Elevated BUN + signs/symptoms of uraemia pericarditis, neuropathy, uremic bleeding, uremic encephalopathy
50
FGF 23 function
FGF-23 is secreted by bone osteocytes and osteoblasts in response to Hyperphosphataemia.
- Decreases serum phosphate by reducing reabsorption in renal tubules and decreases Vit D 1a hydroxylase expression
- Klotho is co factor needed for expression
51
Pathophysiology of oedema in nephrotic syndrome
• Primary sodium retention that is directly induced by the renal disease (overfill hypothesis)
i.e. increased sodium reabsorption in the collecting tubules, which is also the site of action of atrial natriuretic peptide (ANP)
• Secondary sodium retention in which the low plasma oncotic pressure due to hypoalbuminemia promotes the movement of fluid from the vascular space into the interstitium, leading to underfilling of the vasculature and activation of the renin-angiotensin-aldosterone system (underfill hypothesis)
52
Management of oedema in nephrotic syndrome
1. Diuretic
2. Sodium restriction 2g/day
Non responders:
1. Thiazide to block sodium resorption
2. Acetazolamide
53
Reason for higher Frusemide dose in CKD
• All the commonly used diuretics are highly protein-bound. This limits the diuretic to the vascular space, thereby maximizing its rate of delivery to the kidney. The degree of protein-binding is reduced with hypoalbuminemia, resulting in a larger extravascular space of distribution and a slower rate of delivery to the kidney
54
Relationship between retinopathy and diabetic nephropathy
o RETINOPATHY is almost universal in all patients with T1DM and DN:
o Less concurrence with T2DM (50-75%)
o K/DOQI Guidelines: If retinopathy absent, should suspect other causes of CKD
o Converse is not true ie. Retinopathy can occur without DN
55
Screening Timeline for DN
T1DM - at age 9 with 2 year duration of diabetes
T2DM: at diagnosis
Then yearly for both
If microalbuminuria -confirm with 2 out of 3 abnormal tests over 2-12 weeks
If macroalbuminuria: Confirm with 24 hour protein = >0.5g/24 hours
56
Features suggesting alternative cause of CKD in diabetic patients
• Onset of proteinuria <5 years after onset of T1DM
-Same applies for T2DM but time of onset is often difficult to ascertain as Dx is often delayed
• Acute onset of kidney injury or nephrotic syndrome (diabetic nephropathy is usually slowly progressive)
• Presence of active urinary sediment containing red cells or cellular casts
• In T1DM, absence of diabetic retinopathy or neuropathy
• Signs or symptoms of another systemic disease
• Significant reduction in eGFR (<30%) after introduction of ACE or ARB
-More consistent with RAS or arteriosclerotic renal disease
57
Hb Target in CKD
100-110
- Trial iron first then EPO
- Increased mortality associated with higher Hb if using EPO
58
Target phosphate levels in CKD
* Non-dialysis patients - within normal range
| * Dialysis patients – 1.12-1.78mmol/L
59
Phosphate binders MOA and benefit in CKD
* Block absorption of phosphate from the small intestine, therefore must be taken with meals
* Non-calcium containing phosphate binders have been shown to decrease mortality in dialysis patients
60
Mx of Refractory hyperphosphatemia
• Calcimimetics, e.g., cinacalcet
- Increase sensitivity of calcium-sensing receptor in the parathyroid glands to calcium
- Reduce levels of PTH, calcium and phosphate
• Parathyroidectomy
-Effectively treats hyperparathyroidism related hypercalcaemia, hyperphosphaaemia, bone pain, pruritis and myopathy
61
Two main causes of Renal Artery stenosis
- Atherosclerotic disease
- -Usually proximal renal artery
- Fibromuscular dysplasia
- -Typically women 30-50 yo
- -USually mid to distal renal artery and characteristic string of beads on imaging
62
Affect on BP, renin, and volume state in unilateral RAS
Increased BP
Increased Renin
Normal Volume state
63
Affect on BP, renin, and volume state in bialteral RAS
Increased BP
Normal Renin
Increased volume state (due to loss of pressure natuersis)
64
Define the Pickering Syndrome
Flash APO secondary to bilateral RAS in the setting of normal LVEF
65
Testing for Renal Artery Stenosis
Gold Standard - Conventional Angiography
First test:
Doppler USS
--95% NPV (look at peak systolic velocity)
Resistive index:
-Represents amount of small vessel disease (High if >0.70)
CTA and MRA:
-Concern for contrast, but can be used
ACEi Scitinigraphy
- Administration of ACE will cause reduction in efferent tone so in the setting of a fixed lesion in the afferent vessel egfr will drop
66
Mx of RAS
BP - RAAS blockade, CCB, thiazide
CVS risk factors
Stenting for FMD only has shown benefit thus far only low quality evidence for severe atherosclerotic disease. No benefit in mild-mod atherosclerotic disease
67
Renal effects of NSAIDs
NSAIDS lead to PG#2 and PGI2 inhibition
- Leads to Sodium retention (oedema, BP, weight), hyperkalemia, and ARF
- Also inhibit dilation of afferent arteriole, so when used with ACEi (which dilate efferent arteriole) you drop egfr
68
Effect of angiotensin on the kidney
Maintains efferent arteriolar tone
Relaxation of efferent arteriole results in reduced intraglomerular pressure
So ACE and AII reduce gfr as part of their mechanism of action
69
SE of VEGF inhibitors on kidneys
GN type picture similar to MCD, podacyte effacement
70
S-FLT-1
Circulating VEGF receptor
High levels may be a marker for pre-eclampsia
71
Prevention of pre-eclampsia
150 mg aspirin in early pregnancy
72
Mx of pre-eclampsia
Delivery if >37 weeks (if severe deliver >32 weeks)
Labetalol QID
MgSO4 to prevent seizures
73
Medullary Sponge Kidney
MAlformation of the terminal collecting ducts
- Results in microscopic and macroscopic Medullary cysts
- Bialteral
- Benign but assocaited with stones and UTIs
74
Medullary Cystic Kidney
No renal cysts
Predominantly a tubulo-interstitial disorder
-Progresses to ESRD
75
Acquired Cystic disease (in renal failure/impairment)
Multiple and bilateral renal cysts
Distnguish from ADPCKD:
-No FHx, small to normal sized kidneys, smooth contour
Associated wit hRCC
76
Most common genetic cause of CKD
ADPCKD
77
Genes and their presentation in ADPCKD
PKD-1
- More rapid deteriroation in renal function, more cysts
- Median age of ESRD 54
PKD-2
- More indolent decline in renal function
- Median age of ESRD 74
PAthophysiology:
Polycystin mutation and these regulate tubular and vascular development in multiple organs
78
Tolvaptan Indication, MOA, SE, Evidence
Vasopressin receptor antagonist
Indication: ADPCKD
MOA: Suppression of vasopressin release reduces second messenger systems (cAMP) identifed as promoters of kidney cyst cell proliferation and luminal fluid secretion
Evidence: Decrease in cyst size, reduction in rate to ESRD, slows egfr decline
SE:
LFT derrangement
Polyuria/polydipsia (Avoid with diuretics and w/h when unwell)
Hyperuricemia
79
Criteria for diagnosis of AKI
-Increase in Serum Cr >26.5 micromol/l within 48 hours
OR
-Increase in Serum Cr > 1.5 times baseline within the last 7 days
OR
UO < 0.5 ml/kg/hr for 6 hours
80
Risk Factors for AKI
```
Main: Age
Proteinuria
CKD
Other Comorbidities
Nephrotoxic meds
```
81
Significance of AKI
Increased rates of mortality and CKD down the track
Worse the AKI the higher the mortality
82
Which part of the kidney is most sensitive to hypoprofusion
Distal prox tubule (outer medulla)
83
Cystatin C
Endogenous cysteine proteinase inhibitor
Good marker of GFR (completely filtered and then reabsorbed)
Urinary Cystatin C may be a good marker for tubular injury (usually none found in the urine)
84
Fluid of choice in AKI resuscitation
Haartmans/ lacted ringers/plasma lyte
- Less chloride than NaCl
- Reduced major adverse events
85
Most important strategy to prevent contrast induced AKI
Pre-hydration
Also have protective effect from statins
86
Ciclosporin
```
SE:
Nephrotoxicity
TMA/HUS
Diabetes
Hyperlipidaemia
MEtabolic: K+, urate
Neurotoxicity
Myoneuropathy
Hirsutism, gingivial hyperplasia
```
87
Tacrolimus/CsA
Calcineurin inhibitor
-T cell suppresses
```
SE:
Less HTN, Hyperlipidaemia, and hyperuricemia than CsA
-Diabetes more than CsA
-Hair loss (Hirsutism w/ CsA)
-Nephro/Neurotoxicity
-Acne
-Malignancy
-TMA
```
88
MMF
T and B cell targets
MOA: Inhibitor of inosine monophophate dehydrogenase; inhibits purine synthesis; anti proliferative effect on lymphocytes
SE:
GIT
Myelosuppression
89
Azathioprine
T and B cell targets
SE:
GIT
Myelosuppression
Macrocytic changes
90
Rapamycin (sirolimus/rapamune) and Everolimus
m-tor inhibitors
- Binds to FKBP like CNI but do not act the same way
- Inhibit T cell activation and proliferation in response to anigenic and cytokine stimulation
```
SE:
Lipids
Thrombocytopenia
Oedema
Poor wound healing
mouth ulcers
Pneumonitis (sirolimus)
Fertility issues
Proteinuria
```
91
Basiliximab/Daclizumab
```
IL2 receptor (CD25)
-On T cells
```
Induction of immunotherapy
92
ATG/ATGAM/Thymoglobulin
Polyclonal T cell depleting antibodies
For induction or rejection
93
Intrinsic kidney cell injury in IgA
Mesangial cells
94
Intrinsic kidney cell injury in Membranous nephropathy
Podacytes
95
Intrinsic kidney cell injury in ANCA GN
Endothelial cells
96
Intrinsic kidney cell injury in FSGS
Podacytes
97
Intrinsic kidney cell injury in MCD
Podacytes
98
Primary Membranous nephropathy Ab
PLA2R
| THSD7A
99
Secondary causes of membranous nephropathy
SLE
HBV/HCV/HIV
Solid organ malignancy (usually lung or colon)
Meds: NSAIDS, Gold, Penicillamine
100
Histo for Membranous Nephropathy
Subepithelial spikes
Thickened BM
IgG4 mainly
101
Natural History of membranous nephropathy
1/3 complete remission
1/3 partial remission
1/3 Persistent nephrotic syndrome
102
Tx of Membranous GN
1. Ponticelli (Cyclo and pred)
2. Rituximab or CsA
Usually wait and watch initially unless PLA2R positive and proteinuria >3.5 g/day then immunosuppress
ACE/ARB for proteinuria
Treat underlying cause if secondary
103
SE of Cyclophosphamide
Activation of viral hepatitis
Alopecia
Gonadal damage
Hemorrhagic cystitis (due to metabolisation into acrolein)
Neoplasia
Transitional cell carcinoma of the bladder
Toxic hepatitis
104
Histo for MCD
LM normal
EM: Diffuse foot process effacement
T cell dysfunction as pathophys
105
Mx of MCD
Steroids - most respond in 8 weeks
CNI or RTX second line if frequent relapses
106
Collapsing FSGS is associated with what
HIV/ viral causes
107
Effect on albumin in primary vs secondary FSGS
Primary have low albumin and secondary usually normal
108
Genetics in FSGS
AR
Podocin (NPSH2)
Nephrin(NPHS1)
109
Tx of FSGS
Steroids
CNIs if unable to wean
Poor prognosis if persistent proteinuria: >50% ESKD
110
Amyloidosis Histo
Congo red staining
| Apple green birefringence under polarised light
111
When to anticoagulate in nephrotic syndrome
Albumin <20
8 times higher risk of VTE and arterial thrombosis
USually in first 6 months
Esp with membranous GN
112
Which type of IgA is commonly the cause of GN
IgA1
| -Galactose deficient
113
Strongest risk factor for predicting poor prognosis in IgA GN
Proteinuria >1 g per day
114
Mx of IgA GN
ACE/ARB
Strict BP control <130/80
Steroids
- Can consider if >1g protein after 6 mo ACEi
- Improves proteinuria, but no benefit in egfr, significant toxicity compared to benefit
115
Differentiating MPGN from C3GN/DDD
All: Mesangia hypercellularity, endocapillary proliferation, double contour of BM
MPGN: Low C3 and C4 (classical complement pathway)
C3GN/DDD: Low C3 and normal C4 (alternative complement pathway)
116
MPGN with only C3 on IF
C3GN
117
MPGN with full house of Ig on IF
Lupus
118
MPGN with just kappa and lambda light chains
MGUS
119
Tx of C3GN
Conservative - ACEi
Known Ab: RTX or Eculizumab
Decreased Factor H function: FFP regularly
120
Histo for Post Strep GN
EM: Subepithelial Humps
121
Mx of ANCA vasculitis
Induction then maintainence
Steroids + CYC/RTX
AZA for maintainence
-RTX found to be more effective in maintainence though but cost ++
PLEX controversial - used in alveolar hemorrhage
122
Risk factors for relapse in ANCA vasculitis
PR3>MPO ANCA
Upper airway or lower airway involvement
10% risk per year
123
Anti GBM GN target
Ab against the NC1 domain of the alpha 3 chain of type 4 collagen in the kidneys and lungs
124
Histo for Anti GBM
Linear IgG on GBM of kidney biopsy
125
Prognosis for Anti GBM
Usually does not recurr - once off episode, but potential for rapid ESRD and 90% mortality if not treated
126
Tx of Anti GBM GN
CYC, Pred, and PLEX
127
Class 1 LN
Minimal mesangial LN
| -No treatment
128
Class 2 LN
Mesangial proliferative LN
| -No Treatment
129
Class 3/4 LN
Focal and diffuse proliferative LN
- Focal: <50% glomeruli is class 3
- Diffuse: >50% glomeruli is class 4
Tx:
- MMF
- Alt choices: CYC/RTX/AZA
- Tac and MMF together shown to reduce relapse
130
Class 5 LN
Membranous LN
| -Treatment controversial
131
Class 6 LN
Sclerotic LN
| -Too late for treatment
132
Causes for immune complex mediated MPGN
Hep C
Subacute bacterial endocarditis
CTDs
Paraproteinemia
133
Complement mediated MPGN
Alternative complement pathway
| Independent of antigen/antibody stimulus
134
Proliferative LN histo
```
Subendothelial immune deposits/wire loops
Hypercellularity
Leukocyte infiltration
Fibrinoid necrosis/hyaline thrombi
Deposits of IgG. C1q, C3, IgA, IgM
```
135
Poor prognostic indicators for proliferative LN
```
African american/hispanic
Male
Paeds onset
Neuropsych lupus
Proteinuria >4g/day at diagnosis
Frequent relapses
Elevated Cr at presentation
Failure to acheive remission
```
136
LN and pregnancy
Need to be in remission for at least 6 months and switched MMF to AZA for at least 6 weeks prior to conception
Alt drugs: CsA/Tac
137
Kimmelsteil Wilson lesions
DN
138
Leading cause of ESRF in the world
DN
139
Screening timelines for DN in T1DM and T2DM
T1DM - from 5 yrs
| T2DM - From diagnosis
140
DN:
| ACR levels suggesting macroalbuminaemia
ACR:
Males: >25 mg/mmol
Females: >35 mg/mmol
24Hr Albumin >300mg/24hrs
141
Mx of DN
```
ACE/ARB
--Slow progression
BP control
Glycemic control
SGLT2i (not used if egfr <30)
--Reduce progression, CVS, and CCF admission
CVS risk factors
```
142
What size of renal stones are likely to pass or not
<4 mm pass easily
5-7 mm 50% pass
>7 mm unlikely to pass without intervention
143
Macula Densa physiology
Macula densasenses flow and [NaCl]
•
Increase flow or increase [NaCl] increases afferent arteriole contraction decrease GFR
•
Decrease flow or decrease [NaCl] increases afferent arteriole dilatation, efferent constriction increase GFR
144
What is the dialysis paradox
Dialysis:
- Disadvantage with lower BP
- Advantage with obese patients
Opposite for transplant
145
Indications for EPO as per PBS
Hb <100 g/L and
| egfr <60 ml/min
146
Target Hb in EPO and complication if too high
Hb 100-120
Increased risk of vascular occlusive disease if greater, avoid in solid organ malignancy (EPO is a growth factor)
147
Develop functional iron deficiency with EPO, so what are the Tsat and ferritin aims
Tsat 20-50%
| Ferritin 300-500
148
Causes of EPO resistance
```
Absolute/functional Fe deficiency
Infection/Inflammation
Malignancy
Chronic blood loss
Hyper PTH
Malnutrition
Drugs (ACEi)
```
149
HIF PH inhibitors MOA and indication
Mimics normal adaptive response to hypoxia
- Induces endogenous EPO production by blocking HIF-PH and replicating hypoxic conditions
- Increases utilisation of dietary iron and reduces EPO resistance
Vedadustat, Daprostat, Molidustat, Roxadustat
150
MOA of renal bone disease
Decrease in renal function leads to hyperphosphatemia.
- Leads to hypocalcemia and increase in PTH
- Increase in PTH upregulates osteoclast activity
151
ESRF and MOA of vascular calcification
hyperphosphatemia leads to retained phosphate binding to calcium and causing vascular calcification
152
Target level for PO4 in ESRF
0.8-1.6
153
Target level for Ca in ESRF
2.1-2.4
154
Target Level for PTH in ESRF
2-3 times UNL
155
Mx of renal Bone disease
1. Phosphate binders
- -Sevelamer, Lanthanum, Calcium Carbonate, Sucroferric oxyhydroxide (not constipating)
2. Use calcitriol to titrate up Ca
- -Measure PTH 2-3 monthly
- -PTHectomy if autonomous (high PTH and Ca whilst off Ca/Vit D agents)
3. Calcimimetics (cinacalcet)
- -No survival benefit, off PBS now
156
Hormones that reduce phosphate
FGF23 and PTH
157
Hormones that increase Phosphate
Calcitriol via increasing intestinal absorption
158
FGF23
FGF23 is a phosphate regulator
- Released from bone
- Promotes urinary excretion of PO4 and combats reabsorption of phosphate (by inhibiting vit D production)
-PTH may become elevated with Vit D suppression
Klotho is an important co-receptor
159
How much of the blood flow to the kidney is filtered
kidneys have 20% of CO
20% of plasma flow delivered to each nephron becomes filtrate (180L/day)
160
What is the most important determinant of GFR
Capillary hydrostatic pressure
Reduced when there is an increase in afferent arteriolar tone or a decrease in efferent arteriolar tone
161
Gold standard for measuring GFR
Isotopic GFR (nuclear study)
162
Drugs causing afferent arteriole dilatation (increase GFR)
NO
| Prostacyclin
163
Drugs causing afferent arteriole constriction (decrease GFR)
Angiotensin 2 at high doses
Adenosine
NSAID
Norad
164
Drugs causing efferent arteriole dilatation (decrease GFR)
ACE/ARB
165
Signals to JGA
Arterial pressure
Venous volume
Fluid delivery to macula densa (nephron autoregulation)
166
JGA effects changes to
Renin release
| Nephron GFR
167
Main area of renal autoregulation
- Mainly through changes in afferent arteriolar tone (angiotensin 2 acts mainly through efferent arteriolar tone)
- Adenosine: Afferent arteriole constriction
- PG and NO: Afferent arteriole dilatation
168
Mechanism of renal autoregulation
1. Myogenic mechanism - afferent arteriole contraction via endothelin
2. Tubuloglomerular feedback
- Na and Cl concentration at macula densa increased, afferent tone is increased and GFR falls
169
Effects of Angiotensin 2
```
Increase SNS
Increase PT Na reabsorption
Increased Aldosterone secretion
Arteriolar vasoconstriction
Increased ADH secretion
```
170
Water reabsorption
Mostly in PT, small amount in decending thin limb, and variable in CD (regulated by ADH)
171
Sodium reabsorption
Mostly in PT, then ascending thin and thick, and little in CD
172
What is absorbed in the proximal tubule
```
Water
Sodium
Most of the bicarb
All glucose
All amino acids
Most phosphate
```
173
Proximal Tubule Transporters
Basolateral:
Na/K ATPase
HCO3, Organic, K+ (in)
```
Apical:
NA/Organic co transporter
Na/Amino acid cotransporter
Na/Phosphate cotransporter
Na/H+ exchanger (H+out)
```
174
MOA of Frusemide
Blocks NA/K/Cl co transpoter on apical portion of thick ascending limb and prevents those electrolytes from being reabsorbed
175
Where is the most dilute luminal fluid in the nephron
thick ascending loop
| Critical part of nephron for electrolyte reabsorption and regulation of body osmolality
176
Transporters in the distal tubule
Basolateral
- Na/K ATPAase
- Na/Ca counter transporter (Ca in)
Apical:
Na/Cl cotransporter (in)
Calcium channel (in)
177
MOA of thiazide
Blocks the NA/Cl cotransporter in the distal tubule
-Leads to increased Na excretion and decreased Ca excretion
178
MOA of thiazide/Indapamide/Metolazone
Blocks the Na/Cl cotransporter in the distal tubule (NKCC1)
-Leads to increased Na excretion and decreased Ca excretion
179
Collecting Duct and Late distal tubule transporters
Principal cell
Principal Cell
- Basolateral:
- -Na/K ATPase
- Apical:
- -Na EnaC channel
- -ROMK apical K channel
Principal area of aldersterone effect (increases production of Na EnaC channels)
180
MOA Spironalactone
Blocks the aldosterone cytoplasmic receptor binding in the principal cells of the CT/late distal tubule
Decreases a reabsorption and increases K and H+ retention
181
MOA Ameloride
Blocks EnaC channels on apical surface of CT/late distal tubule in the principal cells
Results in decreased Na absorption and increased K+ and H+ retention
182
Collecting Duct and Late distal tubule transporters
Intercalated cells type A
Secretes H+ and reabsorbs HCO3
183
Collecting Duct and Late distal tubule transporters
Intercalated cells type B
Secretes HCO3 and reabsorbs H+
184
Medullary collecting duct
Permeability controlled by ADH
Has permeability for urea unlike cortical CT
185
Potassium reabsorption
PT and thick ascending loop of henle
Regulated in the late distal tubule/CT under influence of aldosterone
186
Potassium regulation
High plasma aldosterone increases K+ secretion
Alkalosis leads to hypokalemia due to H+/K+ exchange
187
Calcium reabsorption and regulation
Reabsorbed in PT and ascending thick limb, and a little in CT
Regulated in thick ascending loop of henle and distal tubules via PTH
188
TMA definition
MAHA
- RBC fragmentation passing through thrombus laden small vessels
- Schistocytes
```
Thrombocytopenia
Organ injury (AKI)
```
189
Haemolytic anaemia + thrombocytopenia +Coombs positive =
Evan's syndrome
190
Haemolytic anaemia +thrombocytopenia +Coombs negative =
TMA
191
CAuses of TMA
```
TTP
aHUS
HUS
SLE/APLS
Pregnancy
Cancer
HIV
Drugs
```
192
Cause of TTP
ADAMTS13 deficienct (<5-10% activity) leading to vWF multimers
Usually due to an acquired Ab
193
Tx of TTP
PLEX to remove Ab
| FFP to correct ADAMST13 def
194
Mx of HUS
Supportive
195
Factor H and I
Regulate the complement Alternative pathway
196
Cause of aHUS
Usually loss of function mutation in regulator of alternative pathway such as factor H and I
Can be a gain of function mutation
Or Anti Factor H antibodies
Often have a trigger infection (pregnancy, infection)
197
Anti Factor H antibodies gene
CFHR1-2 deletion
198
Tx of aHUS
Eculizumab ASAP
| PLEX has no benefit
199
Clinical picture of TMA vs HUS/aHUS
TMA:
- Plt <30
- Neuro involvement
- AKI mild-mod
HUS/aHUS:
- Plt >30
- Less neuro
- Severe AKI
200
PNH mutation
PIG-A gene
- Clonal deletion of GPI anchor which binds CD55 and CD59 to cell surface (complement inhibitors)
- Without this complement destroys RBCs
201
Tx PNH
Eculizumab
202
Cut off egfr for SGLT2 use
egfr >30
203
Evidence for statin in CKD
Reduced CVS in non dialysis patients
204
SGLT2 presurgery
W/H 2 days prior to OT and resume when eating again
205
SGLT2 in CKD
Reduces progression to ESRF in patients with CKD/albuminuria
Most effective in macroalbuminuria
Reduces hyperfiltration via tubuloglomerular feedback
206
Riskfactors for progression of ADPKD
```
Age
GFR and rate of decline
Male
HT before age 35
PKD1 mutation
Total kidney volume (on MRI)
```
207
Mx of ADPCKD
Aim home BP <110/75 in age <50, egfr >60 ad no CV disease
Tolvaptan (V2 receptor antagonist)
208
The worse predictor of poor outcome on the MEST C score for IgA GN
Tubular atrophy/interstitial fibrosis (IFTA)
209
Cellular rejection Histo
T cell mediated
| Tubulitis, interstitial inflammation
210
Histo features of AMR
Peritubular capillaritis without tubulitis, vasculitis, C4d staining, Glomerulitis
211
CNI Nephrotoxicity features
Isometric vacuolation tubular epithelial cells
- Striped intersitial fibrosis
- Nodular hyalinosis (also in HTN and diabetes)
212
Hyperacute Rejection cause
High level preformed DSA or high level haemaglutinins (Anti-A and B)
PLEX can be trialled to remove DSA
213
Most important HLA matches that are tested in Renal Tx
A, B, DR
Score out of 6
214
AMR Rx
PLEX/IVIG
Repeat Bx at 2 and 4 weeks, if ongoing AMR - RTX, Rescue Splenectomy, High dose IVIG
215
Most significant long term problem with Renal Tx
Chronic AMR
216
Main finding associated with long term renal allograft failure
IFTA
217
Oncogenic Viruses: HHV-8
Kaposi's Sarcoma
218
Oncogenic Viruses: EBV
Lymphoma (PTLD)
219
Oncogenic Viruses: HBV
Hepatoma
220
BK virus Diagnosis and Mx
Decoy cells in urine
BK PCR
Bx: SV40 stains, resembles acute rejection
Tx: Reduce immunosuppression, switch to mTOR etc.
221
Site in nephron for SGLT2 action
Proximal tubule
222
Gene associated with FHHNC
Claudin 16
| PResentation: Hypomag, Hypercalciuria, Nephrocalcinosis
223
Bartter's Syndrome
```
AR
Thick ascending loop of henle
Normotensive
Hypokalemia
metabolic alkalosis
HYPERCALCURIA (Different from Gittleman's)
```
Dx: Increase in urine Prostaglandin E
Presents in neonates
224
TRPM6
Channel for Mg absorption in distal tubule that can be blocked by tacrolimus
225
TRPV5
Channel for calcium absorption in distal tubule
226
Gitelman's syndome
```
AR
Normotensive
metabolic alkalosis
Hypokalemia
HYPOCALCURIA (similar to thiazide) - Loss of function of NKCC1 channel
```
Presentation in childhood/adults
227
Gordon Syndrome (Pseudohypoaldosteronism Type 2)
```
AD
HTN 2nd/3rd decade
NAGMA
Hyperkalemia
Hypercalciuria
```
Tx: Thiazides (mirror image of thiazide use - upregulation of NKCC1)
228
Liddle Syndrome
```
AD
HTN
Hypokalemia
Metabolic alkalosis
Increased ENac channels
```
Tx: Amiloride, Triamterene
229
Diagnosis of ADPCKD
- 15-39YO > 3 unilateral or bilateral cysts *specificity and PPV 100%
- 40-59YO - > 2 cysts in each kidney
- 60YO or older - > 4 cysts in EACH KIDNEY
230
MOA Acetazolamide
Carbonic anhydrase inhibitor
In Proximal tubule
231
RTA Type 1
Impaired ability to excrete H+ in distal tubule
- Urine pH >5.5
- Stones/Hypercalcemia
- Hyperchloremic acidosis
- -Bicarb <15
Cause:
-SLE, Sjogrens, amphoterecin
232
RTA Type 2
Impaired HCO3 reabsorption in prox tubule
- Urine pH >5.5
- Hyperchloremic acidosis
- Plasma Bicarb usually >15
Cause:
-MM, Acetazolamice, Fanconi syndrome, Vit D deficiency, Hereditary hypercalciuria
MX: Bicarb
233
RTA Type 4
DEcreased secretion of aldosterone or decreased effect
- Urine pH <5.5
- Hyperchloremic acidosis
- High K+
- Bicarb >15
Cause:
-Aldosterone deficiency, NSAIDS, ACEi, ARB, Spiro
Mx: Dietary sodium restriction, frusemide
