This document provides an overview of renal involvement in systemic conditions like diabetes mellitus and systemic lupus erythematosus. It discusses the anatomy of the kidneys and nephron, stages of diabetic nephropathy, risk factors, morphological changes, and treatment focusing on glycemic and blood pressure control. It also covers lupus nephritis, defining it as renal involvement in systemic lupus erythematosus, occurring in 40-70% of patients, with features like proteinuria, hematuria, and reduced renal function. Morphological changes in diabetic nephropathy include glomerular and tubular hypertrophy, thickening of the glomerular and tubular basement membranes

1. RENAL INVOLVEMENT IN
SYSTEMIC CONDITION
Dr.Indramani Prakash
Jr3
MEDICINE DEPARTMENT

2. MODERATOR
Dr.Adesh Kumar Singh(MD)

3. Location and External Anatomy of Kidneys
• Located retroperitoneally
• Lateral to T12–L3 vertebrae
• Average kidney
• 12 cm tall, 6 cm wide, 3
cm thick
• Hilus
• On concave surface
• Vessels and nerves enter
and exit
• Renal capsule surrounds
the kidney

4. Internal Gross Anatomy of the Kidneys
• Frontal section through the
kidney
• Renal cortex
• Renal pyramids
• Renal pelvis
• Major calicies
• Minor calicies
• Gross vasculature
• Renal arteries
• Branch into segmental
arteries

5. Anatomy of the kidneys
• Superficial outer cortex and inner medulla
• The medulla consists of 6-18 renal pyramids
• The cortex is composed of roughly 1.25 million nephrons
• Major and minor calyces along with the pelvis drain urine to
the ureters

6. Nephron – The Functional Unit of Kidney
• Nephron consists of:
• Renal corpuscle
• Renal tubule:
• Proximal
convoluted tubule
(PCT)
• Loop of Henle
• Distal convoluted
tubule (DCT)
• Nephron empties
tubular fluid into a
system of collecting
ducts and papillary
ducts

7. Renal Corpuscle
• Consists of:
• Glomerulus – tuft of fenestrated capillaries
• Glomerular (Bowman’s) capsule
• Parietal layer – simple squamous epithelium
• Visceral layer – consists of podocytes
• Blood travels from efferent arteriole to peritubular capillaries
• Blood leaves the nephron via the efferent arteriole

8. Renal Corpuscle and the Filtration Membrane
Figure 23.6a

9. Glomerulus anatomy
• Podocytes cover lamina densa of
capillaries
• Project into the capsular space
• Pedicels of podocytes separated by
filtration slits

10. Two types of nephron
• Cortical nephrons
• ~85% of all
nephrons
• Located in the cortex
• Juxtamedullary
nephrons
• Closer to renal
medulla
• Loops of Henle
extend deep into
renal pyramids

11. Nephron
• Proximal convoluted
tubule (PCT)
• Actively reabsorbs
nutrients, plasma proteins
and ions from filtrate
• Released into peritubular
fluid
• Loop of Henle
• Descending limb
• Ascending limb
• Each limb has a thick and
thin section

12. Nephron
• Distal convoluted
tubule (DCT)
• Actively secretes
ions, toxins, drugs
• Reabsorbs sodium
ions from tubular
fluid

13. Figure 23.8
Collecting Tubules (Collecting ducts)
• Collecting tubules - Receive urine from
distal convoluted tubules

14. Uriniferous Tubule
Figure 23.5a

15. Types Of Capillary Beds In Nephron
• Glomerulus - Fed and
drained by afferent and
efferent arterioles
• Peritubular capillaries
• Arise from efferent
arterioles
• Low-pressure, porous
capillaries
• Absorb solutes
• Vasa recta
• Thin-walled looping
vessels
• Part of the kidney’s urine-
concentrating mechanism

16. Mechanisms of Urine Production
• Filtration - filtrate of
blood leaves kidney
capillaries
• Reabsorption – most
nutrients, water, and
essential ions reclaimed
• Secretion - active process
of removing undesirable
molecules

17. Summary of Nephron Function
• Each segment of nephron
and collecting system
contribute
• Glomerulus
• PCT
• Descending limb
• Thick ascending limb
• DCT and collecting
ducts
• Concentrated urine
produced after
considerable
modification of filtrate

18. Urine Excretion
• Leaves Collecting System
• Enters renal pelvis
• Rest of urinary system transports,
stores and eliminates
• Ureters
• Bladder
• Urethra

19. The Ureters
• Pair of muscular tubes
• Extend from renal pelvis to the bladder
• Peristaltic contractions force urine from the kidneys to the
urinary bladder
• Oblique entry into bladder prevents backflow of urine

20. Blood Flow Through the Kidney

22. Physiologic Variability of the GFR & the normal
value
• “Normal Range” ~ 90 - 150 mL/min
• Approx 170 L per day
• A larger healthy person has a higher GFR
• Can be reported as 90 - 150 mL/min/1.73m2
• Varies according to
−Age - Physical activity
−Gender - Diet
−Body size - Pharmacologic therapy
−Pregnancy

23. GFR -variables
• GFR ~ 8% higher in young men
• Declines with age ( mean rate of decline 0.75
ml/min/ year after the age of 40 yrs.)
• Pregnancy : ↑ ~ 50% in the 1st
trimester.
• Diurnal variation – 10% ↓ at midnight than
afternoon.

24. Filtration markers
Endogenous
• Urea
• Creatinine
• Cystatin C
Exogenous
• Inulin
• 125
I Iothalamate
• 99m
Tc DTPA
• 51
Cr EDTA
• Iohexol
• Iodixanol

25. SYSTEMIC INVOLVEMENT
OF KIDNEY

26. Diabetic Nephropathy: Definition
• DN is microvascular complication of DM
• Characterized by:
• Presence of Albuminuria
• Elevated blood pressure
• Declining glomerular function

27. Diabetic Nephropathy: Epidemiology
Type 1 Diabetic
• 25 - 40% will develop nephropathy
• 80 - 90% with micro-albuminuria
• progress to overt DN in 5 - 10 years
• Nearly 100% with gross proteinuria
• Will progress to ESRD in 7 - 10 yrs

28. Diabetic Nephropathy: Epidemiology
Type 2 Diabetic
• 50% have micro-albuminuria
• at the time of presentation (secondary to HTN)
• 10-20% with microalbuminuria
• Will progress to overt nephropathy

29. Diabetic Nephropathy: Risk Factors
• Age, Race, Ethnicity
• History of microalbuminuria
• Hypertension
• Poor glycaemic control
• Smoking
• Family history of nephropathy
• Genetic abnormalities of ACE gene

30. Diabetic Nephropathy: Stages
• Stage I – Hyperfiltration
• Increased blood flow in the kidney,
• Early renal hypertrophy
• Stage II - Glomerular lesions
• Without clinically evident disease
• Stage III - Incipient nephropathy with
microalbuminuria
• Alb/Cr ratio 0.03 - 0.3 or
• Albumin 20-200 mcg/min on timed
specimen

31. Diabetic Nephropathy: Stages
• Stage IV - Overt diabetic nephropathy
• With proteinuria >500 mg/24 hr
• Creatinine clearance <70 ml/min
• Stage V – End stage renal disease (ESRD)
• Creatinine clearance <15 ml/min
• Creatinine = 6mg/dl

32. Diabetic Nephropathy:
Morphological Changes
• Glomerular & tubular hypertrophy
• Thickening of GBM & TBM
• Mesangial expansion
• Nodular & Diffuse glomerulosclerosis
• Arteriosclerosis and hyalinosis of a.a & e.a
• Tubulointerstitial fibrosis

33. Diabetic Nephropathy: Treatment
• Lifestyle changes
• Lose weight
• Stop smoking
• Low salt diet for BP control
• Low protein diet?
• Glycaemic Control
• Benefit in both Type 1 and Type 2 patients
• Recommended: HbA1C <6.5 - 7.0 %

34. Diabetic Nephropathy: Treatment
• Blood Pressure control
• Current recommendations for BP <130/80-
85
• If nephropathy BP <125/75
• Several randomized controlled trials
• Indicate improved blood pressure control
• Decreases rate of progression of renal
disease
• In both type 1 & type 2 patients

35. Diabetic Nephropathy: Treatment
• ACE inhibitors & ARBs use
• Decrease microalbuminurea
• Improve diabetic nephropathy
• Mechanism of action
• ACE-inhibitors limit angiotensin II
production
• By blocking angiotensin converting enzyme
• ARB-agents block angiotensin II receptors

36. Lupus nephritis

37. Introduction
• Systemic lupus erythematosis is an
autoimmune disease in which organs and
cells undergo damage initially mediated
by tissue binding autoantibodies and
immune complexes.
• The term lupus means ‘wolf’.
• The median age of onset in Indian SLE is
24.5 years and the sex ratio (F:M) is 9:1.

38. • Some polymorphisms influence clinical
manifestations; such as single nucleotide
polymorphisms (SNPs) of STAT 4 that associate
with severe disease, anti-DNA, nephritis, and
anti-phospholipid syndrome , and an allele of
FCGRIIA encoding a receptor that binds
immune complexes poorly and predisposes to
nephritis.
• ECM components and cell surface glycoproteins
act as autoantigens in lupus nephritis.
• Lupus nephritis is rare in drug induced
lupus(DILE).

39. Diagnosis
• The Systemic Lupus International
Collaborating Clinics (SLICC)
Classification 2012 criteria were derived
for relatively simple classification rule.
Rule Sensitivity Specificity Misclassified
cases(number)
1997 ACR
criteria
267/310
(86%)
365/392 (93%) 70
SLICC
criteria
292/310
(94%)
361/392 (92%) 49

40. 1997 ACR criteria
Malar rash Fixed erythema, flat or raised, over the malar eminences
Discoid rash Erythematous circular raised patches with adherent keratotic scaling
and follicular plugging; atrophic scarring may occur
Photosensitivity Exposure to ultraviolet light causes rash
Oral ulcers Includes oral and nasopharyngeal ulcers, observed by physician
Arthritis Nonerosive arthritis of two or more peripheral joints, with tenderness,
swelling, or effusion
Serositis Pleuritis or pericarditis documented by ECG or rub or evidence of
effusion
Renal disorder Proteinuria >0.5 g/d or 3+, or cellular casts
Neurologic disorder Seizures or psychosis without other causes
Hematologic disorder Hemolytic anemia or leukopenia (<4000/L) or lymphopenia (<1500/L) or
thrombocytopenia(<100,000/L) in the absence of offending drugs
Immunologic disorder Anti-dsDNA, anti-Sm, and/or anti-phospholipid
Antinuclear antibodies An abnormal titer of ANA by immunofluorescence or an equivalent
assay at any point in time in the absence of drugs known to induce ANAs
if 4 of these criteria, well documented, are present at any time in a

41. Clinical and immunologic criteria used in the SLICC classification criteria
A. Clinical criteria
1.Acute
cutaneous lupus
Including lupus malar rash (do not count if malar discoid); bullous
lupus; toxic epidermal necrolysis variant of SLE; maculopapular lupus
rash; photosensitive lupus rash in the absence of dermatomyositis; or
subacute cutaneous lupus (nonindurated psoriaform and/or annular
polycyclic lesions that resolve without scarring, although occasionally
with postinflammatory depigmentation or telangiectasia)
2.Chronic
cutaneous lupus
Including classical discoid rash; localized (above the neck); generalized
(above and below the neck); hypertrophic (verrucous) lupus; lupus
panniculitis (profundus); mucosal lupus; lupus erythematosus tumidus;
chillblains lupus; discoid lupus/lichen planus overlap
3.Oral ulcers Palate, buccal, tongue or nasal ulcers in the absence of other causes,
such as vasculitis, Behçet’s, infection (herpes), inflammatory bowel
disease, reactive arthritis and acidic foods
4.Nonscarring
alopecia
Diffuse thinning or hair fragility with visible broken hairs in the
absence of other causes such as alopecia areata, drugs, iron deficiency
and androgenic alopecia

42. 5.Synovitis Involving two or more joints, characterized by swelling, effusion or
tenderness in two or more joints, and 30 minutes or more of morning
stiffness
6.Serositis Typical pleurisy for more than 1 day or pleural effusions or pleural rub;
typical pericardial pain (pain with recumbency improved by sitting
forward) for more than 1 day or pericardial effusion or pericardial rub
or pericarditis by electrocardiography in the absence of other causes,
such as infection, uremia and Dressler’s pericarditis
7.Renal Urine protein/creatinine (or 24-hour urine protein) representing 500 mg
of protein/24 hour or red blood cell casts
8.Neurologic Seizures; psychosis; mononeuritis multiplex in the absence of other
known causes such as primary vasculitis; myelitis; peripheral or cranial
neuropathy in the absence of other known causes such as primary
vasculitis, infection and diabetes mellitus; acute confusional state in the
absence of other causes, including toxic-metabolic, uremia, drugs
9.Hemolytic
anemia
10.Leukopeni
a
< 4,000/mm3 at least once (in the absence of other known causes such as
Felty’s, drugs and portal hypertension); or
Lymphopenia (< 1,000/mm3 at least once) in the absence of other known
causes such as corticosteroids, drugs and infection
11.Thromboc
ytopenia
Thrombocytopenia (< 100,000/mm3) at least once (in the absence of
other known causes such as drugs, portal hypertension, and TTP)

43. B. Immunologic criteria
1.ANA Above laboratory reference range
2.Anti-dsDNA Above laboratory reference range, except ELISA: twice
above laboratory reference range
3.Anti-Sm
4.Antiphospholipid antibody Any of the following lupus anticoagulant false-positive
RPR medium or high titer anticardiolipin (IgA, IgG or
IgM) anti-β2 glycoprotein I (IgA, IgG or IgM)
5.Low complement Low C3, low C4, low CH50
6.Direct Coombs test In the absence of hemolytic anemia

44. Lupus nephritis
• Renal involvement is a major cause of morbidity and
hospital admissions in SLE patients and occurs in 40% to
70% of all patients.
• Generally, renal involvement tends to occur within the first
2 years of SLE with its frequency decreasing significantly
after the first 5 years of disease.
• Almost half of patients present with asymptomatic urine
abnormalities, such as hematuria and proteinuria.
• Nephrotic or nephritic syndrome or both also may be
observed in 30% of patients.
• Rarely (<5%), patients may present with chronic renal
insufficiency, rapidly progressive glomerulonephritis, or a
pulmonary-renal vasculitis syndrome.
• Higher in men than in women.
• Survival with SLE - 95% at 5 years 92% at 10 years.
• Lupus nephritis reduces survival 88% at 10 years.

45. Features %
Proteinuria 100
Miroscopic hematuria 80
Tubular abnormalities 60-80
Reduced renal function 40-80
Nephrotic syndrome 45-65
Granular casts 30
Rapidly declining renal function 30
Hypertension 15-50
Hyperkalemia 15
Macroscopic hematuria 1-2
Acute renal failure 1-2
• Clinical features of patients with lupus.

46. International Society of Nephrology/ Renal Pathology Society (ISN/RPS) classification of
lupus nephritis (2003)
Class I Minimal mesangial lupus nephritis
Class II Mesangial proliferative lupus nephritis
Class III Focal lupus nephritis
Class IV Diffuse segmental (IV-S) or global (IV-G) lupus nephritis
Class V Membranous lupus nephritis
Class VI Advanced sclerosing lupus nephritis

47. Treatment of lupus nephritis
• Depends upon class of LN diagnosed on kidney biopsy
along with presence of extra-renal manifestations of
SLE
• Goal of treatment is to normalize kidney function,
reduce proteinuria, and prevent progressive loss of
kidney function.
• Goals of immunusuppressive treatment:
• Long-term preservation of renal function,
• Prevention of flares,
• Avoidance of treatment-related harms, and
• Improved quality of life and survival.

48. Adjunctive therapy
• All SLE patients with nephritis be treated with a
background HCQ unless there is a contraindication
Rationale:
1. Lower rates of Flares
2. Reduced renal damage
3. Less clotting events
• LN patients with proteinuria >0.5 gm per 24 hours should
have blockade of the renin–angiotensin system
Rationale:
1. Reduces proteinuria by 30%
2. Significantly delays doubling of serum creatinine
3. Delays progression to end-stage renal disease
4. Control of hypertension, with a target of <130/80 mm Hg
5. Statin therapy be introduced in patients with low-density
lipoprotein cholesterol >100 mg/dl

49. Class I and class II
• Conservative (Non-immunomodulatory) treatment is
appropriate for Class I and II LN
• RAAS Blockade with ACE/ARB delays progression of
Lupus Nephritis
• Spironolactone significantly reduces proteinuria and
lowers levels of anti ds DNA and anti ss DNA
• Class I and II LN be treated as dictated by the
extrarenal clinical manifestations of lupus

50. Class III and IV LN
• Patients with proliferative classes of lupus nephritis
need immunomodulatory treatment to turn off the
immune system.
• Induction therapy: It is initial intense treatment
given to induce remission of active disease
• Maintenance therapy: continued to keep patient in
remission and prevent relapses

51. RENAL IMPAIRMENT INRENAL IMPAIRMENT IN
MULTIPLE MYELOMAMULTIPLE MYELOMA

52. Introduction
• Multiple myeloma (MM) is a clonal B-cell disease of slowly
proliferating plasma cells, accompanied by monoclonal
protein production and lytic bone lesions.
• Common complications of MM include hypercalcemia, renal
impairment, infection, skeletal lesions, and anemia. Less
common complications include venous thromboembolism
and the hyperviscosity syndrome.
• Renal impairment affects 20-40% of new cases. Most cases
are mild and easily reversible, but it may manifest as severe
acute renal injury requiring dialysis.

53. Introduction
• Renal impairment is associated with a large tumor mass and
consequently confers a poor prognosis.
• The prognosis of MM has been improved with the introduction
of novel agents and autologous stem cell transplantation.
• These improvements appear to apply equally to patients with
renal impairment, although the risk of complications is usually
higher in this group of patients.
• In addition to improved overall survival, there is some evidence
that novel therapies have improved the renal prognosis.

54. Etiology
• Nephropathy is one of the serious adverse complications
that can be observed at the time of clinical presentation of
MM.
• The etiology of renal failure can be multifactorial.
• It is usually the result of monoclonal immunoglobulin light
chains.
• In rare occasions, monoclonal heavy chains or the entire
immunoglobulins may be involved.
• Non-monoclonal protein-related renal injury may also
occur.

55. Etiology
• The types of kidney disease can be classified by the primary
site of injury into:
• Glomerular
• Primary (AL or rarely AH) amyloidosis
• Monoclonal immunoglobulin deposition (light chain deposition
disease, heavy chain deposition disease, and light and heavy
chain deposition disease)
• Miscellaneous (monoclonal cryoglobulinemia, proliferative
glomerulonephritis due to monoclonal IgG deposition)

56. Etiology
• Types of renal disease in multiple myeloma, UpToDate 19.3
The types of kidney disease can be classified by the primary
site of injury into:
 Tubular
Light chain cast nephropathy
(myeloma kidney)
Distal tubular dysfunction
Proximal tubule dysfunction
or acquired Fanconi's syndrome
 Interstitial
Plasma cell infiltration
Interstitial nephritis

57. Etiology
• Additional factors exacerbating renal failure in myeloma
patients include:
• Volume depletion
• Use of nonsteroidal anti-inflammatory drugs for pain control
• Hyperuricemia
• Nephrotoxic chemotherapeutic agents
• Intravenous contrast for radiographic studies
• Bisphosphonate therapy
• Calcium deposition and stones in the kidney

58. Diagnosis
• While in some patients, renal failure is the only isolated sign
of MM, other patients have further simultaneous symptoms
(signs of bone destruction, hypercalcemia & cytopenia).
• Therefore, differential diagnosis of renal failure should always
include monoclonal gammopathy-associated nephropathy.
• Early diagnosis at the time when renal impairment is still
reversible is extremely important for the patient's prognosis.

59. Diagnosis
• The diagnosis must be suspected in the older patient
presenting with acute or subacute renal failure, particularly if
the urine dipstick is negative for protein, whether or not the
patient has a previously diagnosed MM or monoclonal
gammopathy.
• The diagnosis can only be made definitively with a kidney
biopsy. However, the diagnosis is often established in cases
of acute renal failure by identifying the presence of large
amounts of monoclonal free light chains in the serum and the
presence of a monoclonal protein in the urine, by protein
electrophoresis and immunofixation.

60. No Yes
Yes
No
No
NoYes
Yes
NoYes
Algorithm to approach renal
failure in MM
•Approach to acute renal failure with multiple myeloma: role of plasmapheresis. Th
Apher Dial. 2005 Oct;9(5):417-22.

61. AMYLOIDOSIS

62. DEFINATION:
• Amyloid is defined as the deposition of insoluble
protein fibrils, forming histologically a
homogeneous, extracellular eosinophilic mass.
• Congo Red +++
• Displays green birefringence under polarized light
tion

63. SYSTEMIC AMYLOIDOSIS IN
HUMANS: AMYLOID FIBRILS AND
PRECURSORS.
Amyloid protein Precursor Systemic(S) or
Localized (L)
Syndrome
AL/AH Immunoglobulin
light/heavy chain
S, L Primary, Myeloma
assosiated.
AA Serum AA protein S Sporadic, secondary,
reactive, familial
ATTR Transthyretin S, ? L Familial, Senile,
Systemic
AFib Fibrinogen A a chain S Familial

64. AApoAI, II, IV Apolipoprotein AI.
AII, AIV
S, L Familial,
sporadic(aging)
AGEL Gelsolin S Familial
ALys Lysosome S Familial
ACys Cystatin C S Familial
Ab2M B2 Microglobulin S, ? L Dialysis associated

65. GROSS PATHOLOGY
• Enlarged kidneys
• Pale, waxy appearing cut surfaces
• Increase in the weight of kidney

66. Renal amyloidosis was divided into 6 classes
Similar to the classification of SLE
A proposed histopathologic classification

67. LIGHT MICROSCOPY:
• Amyloid deposits can be found in
any of the renal compartments.
• Glomerular amyloid formations
begin in the mesangium.
• And then extends to the capillary
walls.
In H/E sections, amyloid appears as
eosinophilic, amorphous, hyaline
material.
In H/E sections, amyloid appears as
eosinophilic, amorphous, hyaline
material.

68. Continued..
Amyloid deposition in glomeruli may occur in
following patterns:
• 1) Segmental.
• 2) Diffuse mesangial.
• 3) Nodular.
• 4) Pure basement membrane pattern

71. HYPERTENSION

72. Definition
• A systolic blood pressure ( SBP) >139
mmHg and/or
• A diastolic (DBP) >89 mmHg.
• Based on the average of two or more
properly measured, seated BP
readings.
• On each of two or more office visits.

73. Types of Hypertension
• Primary HTN:
also known as
essential HTN.
accounts for 95%
cases of HTN.
no universally
established cause
known.
• Secondary HTN:
less common cause of
HTN ( 5%).
secondary to other
potentially rectifiable
causes.

75. Causes of Secondary HTN
• Common
• Intrinsic renal disease
• Renovascular disease
• Mineralocorticoid
excess
• Sleep Breathing disorder
• Uncommon
• Pheochromocytoma
• Glucocorticoid excess
• Coarctation of Aorta
• Hyper/hypothyroidism

76. Hypertensive Crises
• Hypertensive Urgencies: No progressive
target-organ dysfunction. (Accelerated
Hypertension)
• Hypertensive Emergencies: Progressive
end-organ dysfunction. (Malignant
Hypertension)

77. Hypertensive Urgencies
• Severe elevated BP in the upper range of
stage II hypertension.
• Without progressive end-organ
dysfunction.
• Examples: Highly elevated BP without
severe headache, shortness of breath or
chest pain.
• Usually due to under-controlled HTN.

78. Renal Parenchymal Disease
• Common cause of secondary HTN (2-5%)
• HTN is both cause and consequence of
renal disease
• Multifactorial cause for HTN including
disturbances in Na/water balance,
vasodepressors/ prostaglandins imbalance
• Renal disease from multiple etiologies.

79. Renovascular HTN
• Atherosclerosis 75-90% ( more common in older
patients)
• Fibromuscular dysplasia 10-25% (more common
in young patients, especially females)
• Other
• Aortic/renal dissection
• Takayasu’s arteritis
• Thrombotic/cholesterol emboli
• CVD
• Post transplantation stenosis
• Post radiation

81. • In the general population, pharmacologic treatment should be initiated
when blood pressure is 150/90 mm Hg or higher in adults 60 years and
older, or 140/90 mm Hg or higher in adults younger than 60 years.
• In patients with hypertension and diabetes, pharmacologic treatment
should be initiated when blood pressure is 140/90 mm Hg or higher,
regardless of age.
• Initial antihypertensive treatment should include a thiazide diuretic,
calcium channel blocker, ACE inhibitor, or ARB in the general nonblack
population or a thiazide diuretic or calcium channel blocker in the
general black population.
• If the target blood pressure is not reached within one month after
initiating therapy, the dosage of the initial medication should be
increased, or a second medication should be added
JNC 8 Guidelines for the Management of Hypertension in Adults