This Sunday, we bring to you an old article from our archives. Dr. NK Hase answers questions on the treatment options for CKD, diagnosis of tuberculosis of the kidney, usage of protein in kidney disease, and the best antiproteinuric drug for persons in remission.

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Question 1: What is the latest and best treatment for stage 3A CKD with type 2 diabetes and HTN?

CKD 3A means mild to moderately-decreased GFR. First confirm the diagnosis that kidney disease is due to diabetes and that there is no evidence of non-diabetic kidney disease. Rule out reversible cause of kidney function impairment like obstruction, UTI, severe hypertension, atherosclerotic renovascular kidney disease. Treat the reversible causes. The next aim will be to retard the progression:

1. Control of DM, target HbA1c: <7%: In type1 DM use insulin and in type 2 DM, use metformin first line. If the target is not achieved in 3 months the next drug will be SGLT 2 inhibitors, followed by GLP-1A, followed by DPP4 Inhibitors and then insulin and sulphonylurea (as per KDIGO & ADA 2020 guidelines).
2. Control of BP target (<130/80 mmHg): Use ACEI or ARB, calcium channel blocker, diuretics and alpha beta blockers.
3. Treat complications like acidosis, anaemia, hypocalcemia, and hyperphosphatemia.
4. Avoid nephrotoxic drugs.
5. Advise vaccinations: Hepatitis B, pneumococcal, and influenza.
6. Monitor, renal function and recommend regular follow up with the nephrologist.
7. To protect the heart, advise cardiac evaluation and treatment.

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Question 2: How can tuberculosis of the kidney can be diagnosed?

There are various presentations of genitourinary tract tuberculosis, such as:

• Prolonged fever (PUO)
• Recurrent or resistant urinary tract infection, sterile pyuria with or without haematuria
• Irritative voiding symptoms, i.e., frequency, urgency, and dysuria
• Renal: Hydronephrosis/pyonephrosis or epididymal mass
• Renal failure: Chronic kidney disease due to parenchymal infection and obstructive uropathy
• Infertility and pelvic inflammatory disease
• An incidental diagnosis in a known case of tuberculosis

The various other ways of presentation described are: flank pain with acute pyelonephritis, non-healing wounds, sinuses, or fistulae nephrocutaneous fistula or vesicovaginal fistula, and hemospermia, low grade fever night sweats weight loss, anorexia, backache, and abdominal pain.

Definitive diagnosis of tuberculosis involves demonstration of M. tuberculosis by microbiological, cytopathological, or histopathological methods (demonstration of classical granulomatous lesion). The usual tests used to diagnose GUTB are the demonstration of mycobacterium in urine or body fluid, and radiographic examination IVU for normal serum creatinine, or USG KUB, CT urography. Sterile pyuria is the classic finding.

Conventionally, demonstration of mycobacterium in urine has been used as the primary test for the diagnosis. Five consecutive early-morning specimens of urine should be examined. The yield of urine examination by smear and culture for detecting the tubercle bacillus is low, probably because of the intermittent shedding of the bacilli and is also observer-dependent. Direct smears are often negative (positive only in 30%) and urine cultures require 6 to 8 weeks in special culture media (Lowenstein-Jensen). Sensitivity of urine culture in conventional cultural media is between 80 and 97%. Urinary PCR and rapid culture for demonstration of AFB, is also available now.

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Question 3: How to prevent progression from AKI to AKD?

KDIGO definitions of AKI, CKD, and AKD functional and structural criteria:

1. AKI increase in serum creatinine by 50% within 7 days, or increase in serum creatinine by 0.3 mg/dl (26.5 μmol/l) within 2 days, or oliguria.
2. AKD: May be continuum of AKI or it can be sub-acute AKI (AKI occurring and persisting beyond 7 days becomes acute kidney disease. If there is structural damage and functional impairment (increase in serum creatinine or decrease in EGFR) persists beyond 3 months, it becomes CKD (chronic kidney disease) which is irreversible damage.

To prevent progression early diagnosis and prompt specific treatment is required.

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Question 4: Could you explain the usage of protein in kidney disease- the type of protein, quantity of protein and the conditions where we can liberally use proteins and where we have to restrict it?

CKD STAGE	Proteins	Energy	Phosphorus	Sodium
1 to 3	No restriction	No restriction	600-800 mg/day	<2 g/d
4	0.6-0.8 g/k/d	35 kgcal/kg/day	600-800 mg/day	<2 g/d
5	0.6 g/kg/d Or 0.2 g/kg with ketoanalogue	35 kgcal/kg/day	600-800 mg/day	<2 g/d
5 on Haemodialysis	1.2 G/kg/d	35 kgcal/kg/day	600-800 mg/day	<2 g/d
5 on CAPD	1.3 G/kg/day	35 kgcal/kg/day	600-800 mg/day	<2 g/d
Note: Majority of Indians are vegetarian and already taking low protein diet. So, 50% of proteins should be first class proteins

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Question 5: In a normal person, for ABG interpretation, what value should be taken for FiO2?

FiO2 (the fraction of inspired oxygen) is defined as the percentage or concentration of oxygen that a person inhales. The atmospheric air that we inhale on a day to day basis is made up of 21% oxygen, 78% nitrogen and 1% trace elements such as argon, carbon dioxide, neon, helium and methane. In a normal person, for interpretation of ABG, if the patient is breathing room air, the FiO2 will be 21%. If the patient is on oxygen therapy FiO2 will depend on method of oxygen delivery (nasal prong, mask, re-breathing mask or ventilator) and peak inspiratory flow rate of patient. Oxygen cylinders have 100% oxygen.

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Question 6: What is the role of bicarbonate in kidney disease? What will happen if it goes down?

One of the important functions of the kidneys is to maintain acid-base balance. The kidneys excrete the fixed acid and regenerate bicarbonate. In chronic kidney disease, the kidney is not able to excrete acids. They develop metabolic acidosis, characterised by low bicarbonate. Chronic metabolic acidosis in patients with chronic kidney disease (CKD) may produce a variety of pathophysiologic changes such as:

• Bone resorption and osteopenia
• Increased muscle protein catabolism
• Aggravation of secondary hyperparathyroidism
• Reduced respiratory reserve and exhaustion of body buffer systems, resulting in increased severity of acute intercurrent illnesses
• Reduced Na+-K+-ATPase activity in red blood cells and myocardial cells, which could impair myocardial contractility and produce heart failure
• Endocrine disorders such as resistance to growth hormone and insulin, and hypertriglyceridemia
• Systemic inflammation
• Hypotension and malaise

The 2013 Kidney Disease Improving Global Outcomes (KDIGO) guidelines state that, in patients with CKD and metabolic acidosis, alkali therapy usually with sodium bicarbonate should be used to maintain the serum bicarbonate concentration in the normal range (23 to 29 mEq/L). Studies have shown that treatment with bicarbonate retards the CKD progression, improves nutritional status and bone health.

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Question 7: Is kidney stone related to drinking hard water?

Kidney stone disease (KSD) is a common clinical problem worldwide. It is basically the formation of stone in the kidney (nephrolithiasis), ureter (ureterolithiasis), or urinary bladder (cystolithiasis) by the successive physicochemical events of supersaturation, nucleation, aggregation, and finally retention. The stone forms as a result of crystal deposition in the kidneys and the crystal is formed of components like calcium oxalate, calcium phosphate, calcium carbonate, magnesium-ammonium phosphate, uric acid, and cysteine.

Hard water is basically water with high mineral content and it is defined as the molar sum of calcium and magnesium found in water. Some studies have reported that intake of hard water increases the chance of calcium stones. However, no significant correlation was found in several studies between water hardness and the regional incidence of urinary calculus. Controversy remains as to whether water hardness impacts kidney stone formation. In conclusion, the evidence that tap water hardness influences calcium stone formation is mixed. While it is clear that hard water consumption can result in hypercalciuria, the multiple other factors at play in lithogenesis may have a greater overall impact on stone formation than hypercalciuria alone. Patient with calcium stones may benefit by soft water drinking.

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Question 8: What is the best antiproteinuric drug for persons in remission? ACE inhibitors or ARBs? Or is there any other novel drug apart from Tacro/ MMF?

If proteinuria is in remission (proteinuria is less than 300 mg/day), no other drug is required. Drug therapy depends on what is underlying disease to induce remission. Some patient may require only steroid, some may require steroid plus immunosuppressive drugs like cyclophosphamide, MMF, Tacrolimus. ACEI/ARB is symptomatic treatment for proteinuria. It can reduce proteinuria up to 30%.

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Question 9: Is there a role for SGLT 2 inhibitors in non-diabetic renal proteinuria?

SGLT 2 inhibitors can reduce proteinuria in non-diabetic renal disease. The DAPA-CKD trial showed that dapagliflozin results in salutary effects on renal function and mortality among patients with CKD, irrespective of DM status.

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Question 10: If one kidney shows low GFR due to injury and the other kidney has taken over function showing normal serum creatinine, what is the patient's prognosis?

In some people who were born with a single kidney, or had a kidney removed during childhood, there is a chance of slight loss in kidney function later in life. This usually takes 25 years or more to happen. There may also be a chance of having high blood pressure later in life. However, the loss in kidney function is usually very mild, and life span is normal. Most people with one kidney live healthy, normal lives with few problems. In other words, one healthy kidney can work as well as two.

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Question 11: How can you decrease level of serum creatinine and urea level?

Serum creatinine and urea are functional markers of kidney damage. Creatinine and urea is the waste product of protein metabolism. They are excreted by the kidney. The kidneys keep the level within normal range. When kidney function decreases, serum creatinine and urea will increase. The degree of increase will suggest how much the kidney is functioning.

Serum creatinine and urea will decrease when kidney function improves. To improve kidney function, we have to treat the underlying cause like control of BP, DM, and glomerular diseases. There are no medications which directly decrease the creatinine and urea. If the patient develops end stage kidney failure (permanent damage GFR less than 5ml/min), dialysis can be done. Dialysis will do excretory and regulatory function of kidney. Dialysis will remove the urea and creatinine, but it will not improve kidney function. Dialysis acts as an artificial kidney and sustains life.

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Question 12: The recent classification of MPGN is given as immunoglobulin mediated (classical pathway)
and non immunoglobulin mediated/c3 glomerulopathy(alternate pathway). Can u pls add a note about this?

MPGN is membrano proliferative glomerulonephritis. It is a pattern of glomerular injury seen on histopathology (kidney biopsy). Until recently, the MPGNs have been distinguished according to the histological and ultrastructural findings and were classified as MPGN type I, type II and type III. The glomerular lesions include mesangial hypercellularity, endocapillary proliferation and duplication of glomerular basement membrane (GBM) lesions.

Sub-endothelial and mesangial deposits are predominant in MPGN type I. Highly osmiophylic electron-dense intramembranous deposits are characterised as type II GN, which is also known as dense deposits disease (DDD). In type III, MPGN deposits may be found in the sub-endothelial and sub-epithelial space. According to the new classification, membranoproliferative GNs (MPGN) have been reclassified and divided into different chapters on the basis of pathophysiology. Glomerular injury is triggered by:

• Immune complexes which activate classical pathways
• Complement-mediated injury through excessive activation of alternate pathways like antibodies to C3 covertase C 3 nephritic factor.

MPGN on light microscopy

MPGN on light microcopy
Immunofluorescence Microscopy(IF)
Immune complex mediated (triggered by immune complexes	Complement mediated (complement dysregulation)

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Immunofluorescence (IF) (IgG and C3 Deposits)	IF (Dominant C3)
Infection related Autoimmune Lymphoproliferative disorder Primary idiopathic Monoclonal gammopathy No immunoglobulin deposits or C3 staining on IF: suspect: TMA (Thrombotic Microangiopathy)	C3 Glomerulopathy Dense deposit disease C3 GN

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This article was originally published on January 13, 2021.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author Dr. NK Hase is a Director clinical Nephrology & Transplant working at Jupiter Hospital, Thane and former Professor & Head of Department of Nephrology Seth GS Medical College and KEM Hospital, Mumbai.